levoleucovorin and Carcinoma--Squamous-Cell

Squamous cell carcinomas of the head and neck are highly responsive to induction chemotherapy. However, randomized trials have failed to demonstrate a survival advantage with the addition of induction chemotherapy to locoregional therapy consisting of surgery and/or radiation therapy. Currently, concomitant radiation and chemotherapy has emerged as a standard and has optimized locoregional control in head and neck cancer. In this setting, the addition of induction chemotherapy may further improve outcome by enhancing both locoregional and distant control. As interest in induction regimens is renewed, we elected to conduct a systematic review of trials of induction chemotherapy for locoregionally advanced head and neck cancer. The most studied combination--cisplatin plus fluorouracil (5-FU)--achieves objective response rates of about 80%. In a meta-analysis, induction with platinum/5-FU resulted in a small survival advantage over locoregional therapy alone. The introduction of a taxane into induction chemotherapy regimens has produced promising results. Induction chemotherapy should be the subject of further clinical research in head and neck cancer. Randomized clinical trials in which the control arm is concurrent chemoradiotherapy and the experimental arm is induction chemotherapy followed by concurrent chemoradiotherapy are planned. Platinum/taxane combinations are the preferred regimens for further study in the induction setting and a suitable platform with which to investigate the addition of novel targeted agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Docetaxel; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Paclitaxel; Taxoids

Patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) are often treated with induction chemotherapy or chemoradiotherapy, but to date without major impact on survival. The combination of cisplatin-5-fluorouracil (5-FU) (PF) has been used as standard induction therapy; however, poor patient survival has stimulated investigation into new agents with potential activity in SCCHN. Docetaxel has significant single-agent activity in SCCHN and has been investigated in combination with PF regimens as induction therapy. The results of six phase II studies of docetaxel-PF regimens (TPF) as induction in locally advanced SCCHN patients are reviewed and reported. Consistently, high 2-year survival rates and overall response rates were demonstrated across the phase II trials in the range 42-82 and 71-100%, respectively. The toxicity profile seen with TPF-based regimens was acceptable. The primary toxicity was neutropenia, which together with gastrointestinal complaints accounted for the majority of adverse events. Given the encouraging phase II experience with TPF-based regimens, two large-scale phase III studies comparing TPF-based regimens with standard PF regimens are underway. The results have significant potential for validating the findings of the phase II studies, demonstrating improved survival and overall response of patients treated with docetaxel-based induction chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials, Phase II as Topic; Docetaxel; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Staging; Paclitaxel; Remission Induction; Taxoids

Colon cancers arise only rarely in the course of a pregnancy. Yet colon obstruction, perforation and metastatic spread seem to occur more frequently in this setting than with the average colon cancer. Perhaps this is due to the immunotolerance which accompanies pregnancy. No case of epidermoid (squamous cell) cancer of the colon has been previously described in a pregnant woman. This conjunction has a catastrophic prognosis: the diagnosis of colon tumor is delayed since symptoms are masked by the pregnancy, and epidermoid colon cancer is a particularly aggressive lesion. A major sub-diaphragmatic surgical procedure can be performed with reasonable safety to mother and fetus. Radiotherapy is contraindicated. Neo-adjuvant chemotherapy can be administered although the risks to the fetus are not well known. During the first trimester, a therapeutic abortion can be proposed to optimise the treatment of the mother. During the second and third trimesters, treatment of the mother exposes the fetus to the risk of malformations or premature delivery; delay in maternal treatment in hopes of prolonging the pregnancy in order to obtain a viable neonate diminish the chances of maternal survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cesarean Section; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Disease Progression; Diseases in Twins; Down Syndrome; Fatal Outcome; Female; Fetal Death; Fluorouracil; Humans; Intestinal Perforation; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy, Multiple

Induction chemotherapy is appropriate for the treatment of locally advanced squamous cell carcinoma of the head and neck because it allows organ preservation without compromising survival and improves survival in unresectable disease. Radiation therapy, not surgery, should immediately follow induction chemotherapy in potentially resectable patients to prevent tumor repopulation. The results of three phase II studies of docetaxel-based regimens as induction therapy of patients with locally advanced squamous cell carcinoma of the head and neck are reviewed and reported. Overall response rates ranged from 93% to 100%, with complete response rates of 40% to 63%. The primary toxicities were neutropenia and febrile neutropenia. A North American phase III trial, randomizing patients to docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil sequentially followed by chemoradiotherapy is being performed to determine whether docetaxel improves the complete response rate, organ preservation rate, and survival of patients treated with induction chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Decision Making; Docetaxel; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Paclitaxel; Taxoids

The majority of colorectal neoplasms diagnosed are adenocarcinomas. Other histologies such as squamous, adenosquamous, carcinoid tumors, or lymphoid tumors are occasionally identified. Given the rarity of squamous-cell tumors, it is very difficult to study their natural course and response to therapy. An attempt is made to describe the frequency, anatomic location, and response to therapy with a review of the literature.. From the Cancer Registry at the University of Missouri-Columbia Ellis Fischel Cancer Center, tumors of the colon identified above the dentate line were selected for chart review. Data were extracted from cases between the years 1940 and 1996. The key terms used to identify cases were epidermoid, squamous cell, and cancer of the rectum or colon. Using this approach, forty patients were identified and each record was reviewed.. The majority of these cases were anal cancers with proximal extension into the rectum and were excluded. Of 4,561 cases of epithelial colon and rectal cancers identified, only one additional case of squamous-cell cancer could be verified. In this report we describe a patient with a primary squamous-cell carcinoma of the sigmoid colon with metastatic disease to the liver at diagnosis who responded to systemic chemotherapy. We believe this to be the first reported case of this rare tumor type in which the patient's tumor responded to systemic chemotherapy. Two cases with a thorough review of literature are presented.. Primary squamous-cell carcinoma of the colon is a rare malignancy of unknown cause and pathogenesis. Metastatic tumors to the colon should be ruled out in all cases before therapy. Early detection and surgery remain the main therapeutic options, but as presented in our case, response to chemotherapy in advanced disease is encouraging.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Colonic Neoplasms; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms

Topics: Carcinoma, Squamous Cell; Circadian Rhythm; Cisplatin; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Esophageal Neoplasms; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Interferons; Leucovorin

This review covers the clinical significance of neoadjuvant chemotherapy as initial treatment for squamous cell carcinoma of the head and neck, especially focusing on advanced but resectable disease. The rates of complete response (CR) after chemotherapy depended on the regimens and varied from 15% to 35%. Combined use with DDP/5-FU was considered as a most effective regimen. In addition of leucovorin to DDP/5-FU regimen, CR rate increased more than 50%. A randomized clinical trial has not shown any advantage for survival in advanced head and neck cancer. Recent reports have shown that distant metastases diminished in patients treated with neoadjuvant chemotherapy. When primary lesions disappeared completely after neoadjuvant chemotherapy, sequential use of radiotherapy can make the long term relapse-free in those lesions. This effort may lead to a modality of cancer treatment without surgery, so organ preservation will be possible.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Prognosis; Randomized Controlled Trials as Topic; Remission Induction

Randomized trials comparing high-dose methotrexate (HDMTX) plus leucovorin (LV) with standard-dose methotrexate (SDMTX) have not detected a therapeutic advantage for the HDMTX arm despite compelling evidence from experimental systems. We hypothesized that these negative trials might reflect modulation of the antitumor effect of methotrexate (MTX) by LV. To test this we randomized 61 patients with locally advanced and recurrent squamous cell head and neck cancer to receive SDMTX (40 mg/m2 weekly for 8 weeks) and either LV or placebo "rescue" starting 24 hours later. Of the 61 randomized patients, there were protocol violations in two cases, leaving 59 patients evaluable for response using standard criteria, and for toxicity using the Eastern Cooperative Oncology Group (ECOG) scale. Of the 29 patients randomized to MTX plus LV, there were five responders (17.2%) compared with 11 of 30 (36.7%) patients randomized to MTX plus placebo (P = .047). Response was influenced independently by age, gender, and by previous treatment. Toxicity overall was more severe in patients randomized to MTX plus placebo (P = .016). This was accounted for primarily by differences in toxicities related to bone marrow function (neutrophil and platelet counts), stomatitis, and elevations of liver function tests. MTX therapy was more often interrupted for toxicity in the placebo group (P = .007) and discontinued for progressive disease in the LV group (P = .07). These results indicate that at the doses of MTX and LV used, LV modulates the antitumor effect as well as the toxicity of MTX in patients with head and neck cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Placebos; Prospective Studies; Randomized Controlled Trials as Topic; Remission Induction

From 1975 to 1980 121 patients with advanced carcinoma of oral cavity, oropharynx and hypopharynx were treated by a primary systemic chemotherapy with vincristine/MTX-folinic acid/intrinsic factor/thymidine--bleomycin/inosine. A complete remission and partial remission of more than 50% was obtained in 81% of tumors of oral cavity, while the remission of the carcinoma of oropharynx with 73% and of hypopharynx with 50% is caused by a lower sensitivity rate of the less keratinizing tumors. The chemotherapeutic results after preceding operation and radiation underline by a lower rate of remissions the only palliative aspect and the necessity of antineoplastic chemotherapy to the first step before operation and radiation. The results of remission followed by primary antineoplastic chemotherapy bring better conditions for the operation and supplementary radiotherapy: the high number of complete remissions allows a tender operation in the field of the former carcinoma with histological security, the partial remission of more than 50% guarantees a more exact determination of the border of tumor and of the distance of security by reduction and demarcation of the tumor, its devitalisation brought by keratinisation, the stop of invasive growth and by the increase of the surrounding connective tissue. Because of the short remission of metastasis of lymph nodes a radical neck dissection and sanitation of the floor of the mouth is an oncological necessity in case of metastasis. The estimated median survival time was 21 months in advanced carcinomata of oral cavity and as for keratinizing squamous cell carcinoma of oropharynx. A lower mean survival period will be expected by the less keratinizing squamous cell carcinomata of the oro- and hypopharynx with 11 or 10 months. Fixed lymph nodes and distant metatasis bring a decrease of the estimated median survival time with a statistical significance.

Topics: Adult; Aged; Bleomycin; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Inosine; Leucovorin; Male; Methotrexate; Middle Aged; Prognosis; Thymidine; Vincristine

Topics: Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Drug Therapy, Combination; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Cyclophosphamide; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Leucovorin; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasms; Osteosarcoma; Prednisone; Rhabdomyosarcoma; Testicular Neoplasms; Thiotepa; Vinblastine; Vincristine

This paper presents an overview of studies of therapy of head and neck squamous cell carcinoma in which chemotherapy was combined with other modalities. The rationale for using chemotherapy with surgery is discussed, but ststematic studies of this combination of modalities have not been reported. Systemic chemotherapy plus radiation therapy has been studied using hydrozyurea, t-fluorouracil (5-FU), and methotrexate (MTX). Uncontrolled studies with hydroxyurea report favorable results, but a well-controlled study gave negative results. Controlled studies with 5-FU have given favorable results in certain tumor stages and sites of origin. MTX plus radiation in a small series produced slightly better survival than radiation alone. Intra-arterial chemotherapy plus radiation therapy has been the subject of exploratory studies but no firm conclusions can be drawn from these studies. Chemotherapy plus immunotherapy has been explored and merits further study. Based on the studies reported to date one can suggest the need for large-scale randomized control studies of long-term chemotherapy combined with other modalities.

Topics: Bleomycin; Carcinoma, Squamous Cell; Cyclophosphamide; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Hydroxyurea; Immunotherapy; Laryngeal Neoplasms; Leucovorin; Methotrexate; Neoplasm Metastasis; Neoplasms; Radiotherapy; Vinblastine

Topics: Bleomycin; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Therapy, Combination; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Laryngeal Neoplasms; Leucovorin; Lip Neoplasms; Lymphatic Metastasis; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Tongue Neoplasms

Topics: Adult; Animals; Carboxypeptidases; Carcinoma 256, Walker; Carcinoma, Squamous Cell; Deoxyuridine; Diet; Drug Combinations; Drug Synergism; Folic Acid Antagonists; Humans; Leucovorin; Leukemia L1210; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Mice; Rats; Tritium

The ongoing phase 2/3 PRODIGE 26/CONCORDE trial compares chemoradiation therapy with and without dose escalation in patients with locally advanced or unresectable esophageal cancer. The results of a benchmark case procedure are reported here to evaluate the protocol compliance of participating centers as part of quality assurance for radiation therapy.. Volume delineation, target coverage, and dose constraints to the organs at risk (OARs) were assessed on treatment plans of a common benchmark case performed by each participating center. The centers were classified in 3 categories: per protocol, minor acceptable deviation (MiD), or major unacceptable deviation (MaD). A plan was rejected if ≥4 MiDs or 1 MaD were found.. Thirty-5 centers submitted 43 plans. Among them, 14 (32.6%) were per protocol, 19 (44.2%) presented at least 1 MiD, 2 (4.6%) presented at least 1 MaD, and 8 (18.6%) presented both MiD and MaD. Overall, 11 (25.6%) plans were rejected. Only 1 plan was rejected because gross tumor volume was not correctly delineated. The OAR delineation was respected in all cases. Dose constraints to the OARs were respected in the majority of cases except for the heart, where one-third of the plans presented a deviation. As for the target volume, 3 plans (5.8%) had a major underdosage and 1 plan (1.9%) had a major overdosage. Overall, 58% of all treatments were planned with intensity modulated radiation therapy, whereas 42% were planned with 3-dimensional chemoradiation therapy. Significantly more plans in the intensity modulated radiation therapy group were accepted compared with the 3-dimensional chemoradiation therapy group (P = .03).. The high frequency of protocol deviations underlines the importance of a quality assurance program in clinical trials. Further work should assess the impact of quality assurance for radiation therapy on patient outcomes.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benchmarking; Cancer Care Facilities; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Fluorouracil; France; Guideline Adherence; Heart; Humans; Kidney; Leucovorin; Liver; Lung; Lymph Nodes; Lymphatic Irradiation; Male; Organoplatinum Compounds; Organs at Risk; Quality Assurance, Health Care; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Spinal Cord; Tumor Burden

A recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival.. A total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18).. Both groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil-cisplatin arm only (p = 0.047). During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil-cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020).. Analyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil-cisplatin regimen as part of definitive CRT.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Disease-Free Survival; Dose Fractionation, Radiation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; France; Humans; Leucovorin; Linear Models; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds; Prospective Studies; Quality of Life; Risk Factors; Surveys and Questionnaires; Time Factors; Treatment Outcome

The optimal perioperative treatment for resectable esophageal squamous cell carcinoma (ESCC) remains controversial. We evaluated the efficacy and safety of leucovorin and 5-fluorouracil (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) combination chemotherapies administered adjuvantly for curatively-resected, node-positive ESCC.. Patients with pathologically node-positive esophageal cancer after curative R0 resection were enrolled and randomly assigned to receive LV5FU2 or FOLFOX biweekly for up to eight cycles. The primary endpoint was disease-free survival (DFS).. Between 2011 and 2015, 62 patients were randomized into the two treatment groups (32 in the LV5FU2 arm and 30 in the FOLFOX arm). The median age was 60 years and both groups had similar pathologic characteristics in tumor, nodal status, and location. Treatment completion rates were similarly high in both groups. The DFS rate at 12 months was 67% in the LV5FU2 group and 63% in the FOLFOX group with a hazard ratio of 1.3 (95% confidence interval [CI], 0.66 to 2.62). After a median follow-up period of 27 months, the median DFS was 29.6 months (95% CI, 4.9 to 54.2) in the LV5FU2 arm and 16.8 months (95% CI, 7.5 to 26.1) in the FOLFOX arm (p=0.428), respectively, while the median overall survival was not reached in either arm. Grade 3 or 4 neutropenia was more frequent in patients in the FOLFOX arm than the LV5FU2 arm (20.0% vs. 3.1%).. The addition of oxaliplatin (FOLFOX) did not lead to better efficacy compared to LV5FU2 chemotherapy in an adjuvant setting in node-positive ESCC patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Although squamous cell anal carcinomas are relatively rare, their incidence has been increasing steadily. Because of the limited data, treatment of metastatic disease is a major therapeutic challenge. In this study, we report the safety and efficacy of epidermal growth factor receptor (EGFR) inhibitors in patients with advanced squamous cell anal carcinomas.. A retrospective analysis was conducted using the Moffitt Cancer Tumor Registry from January 2009 to January 2014. Eligible patients had diagnosis of advanced squamous cell anal carcinomas and received an EGFR inhibitor as part of their treatment.. A total of 13 patients were identified for analysis. All of them received concurrent chemoradiation as initial treatment and subsequently had recurrence. Five patients received single agent cetuximab or panitumumab, and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. The objective response rate was 30.8% including 1 complete response, and the disease control rate was 46.2%. With a median follow-up of 9.6 months, the median progression-free survival and median overall survival were 4.4 months and 11.4 months, respectively.. Our analysis suggests that EGFR inhibitors have potential efficacy and are reasonably well tolerated in patients with squamous cell anal carcinomas. These findings warrant further evaluation in a large prospective trial.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Camptothecin; Carcinoma, Squamous Cell; Cetuximab; Chemoradiotherapy; ErbB Receptors; Female; Florida; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Panitumumab; Protein Kinase Inhibitors; Retrospective Studies; Treatment Outcome

This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy.. A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients.. Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC.. We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Body Mass Index; Bone Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Models, Biological; Organoplatinum Compounds; Predictive Value of Tests; Prospective Studies; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; ROC Curve; Serum Albumin; Survival Rate; Treatment Outcome; Vinblastine; Vinorelbine

The role of preoperative chemotherapy in squamous cell esophageal carcinoma remains controversial. A prospective trial was initiated to investigate whether preoperative chemotherapy followed by surgery results in increased progression-free survival in patients with resectable thoracic esophageal carcinoma.. Patients with Stage IIb-IIIa/b resectable esophageal carcinoma were eligible for the study. They received two cycles of FLEP regimen chemotherapy (cisplatin, etoposide, leucovorine, 5-fluorouracil) followed by transthoracic extended 2- or 3-field esophagectomy. Two-year progression-free survival was the primary endpoint. To evaluate the potential benefit of the dual-modality approach we compared these results with the outcome of patients who were treated in our center in the same period of time and were non-randomly allocated to surgery alone.. From 2001 to 2008, 63 patients were included in the study (bimodality group) and 58 patients into the surgery-alone group. Median follow-up was 68 (range, 4-123) months. Squamous cell carcinoma had 93% patients. Two-year progression-free survival for all patients was 45.3 and 30.7% (hazard ratio 0.71, 95% confidence interval 0.46-1.08) and median overall survival was 26.5 months and 18.0 months (hazard ratio 0.67, 95% confidence interval 0.41-1.01) in bimodality- and surgery-alone groups, respectively. Patients who underwent R0-resection after bimodality treatment had significantly better overall survival (40.9 months) than after surgery alone (19.0 months, hazard ratio 0.51, 95% confidence interval 0.30-0.81).. Two cycles of preoperative chemotherapy did not improve progression-free survival of patients with resectable thoracic esophageal carcinoma in intent-to-treat population. However, significantly better results of bimodality approach was seen in R0-resected patients which warrants further trials with more effective chemotherapy combinations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Prospective Studies

Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial.. PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio.. This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors.. NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Dose Fractionation, Radiation; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Paclitaxel; Prospective Studies; Survival Analysis; Treatment Outcome; Young Adult

To determine the optimal chemotherapy backbone for testing in future US cooperative group studies for metastatic esophageal and gastroesophageal junction cancers. Cetuximab was added to each treatment arm based on promising preclinical data.. Patients with previously untreated metastatic esophageal or gastroesophageal junction cancer were randomly assigned at a one-to-one-to-one ratio to epirubicin, cisplatin, and continuous-infusion fluorouracil (ECF), irinotecan plus cisplatin (IC), or FOLFOX (oxaliplatin, leucovorin, and bolus and infusional fluorouracil). All treatment programs included cetuximab once per week. The primary end point was response rate. Secondary outcomes included overall survival, progression-free survival, time to treatment failure, and safety. As prespecified, primary and secondary analyses were conducted only among patients with adenocarcinoma.. This study randomly assigned 245 patients, including 222 with adenocarcinoma. Among patients with adenocarcinoma, response rate was 60.9% (95% CI, 47.9 to 72.8) for ECF plus cetuximab, 45.0% (95% CI, 33.0 to 57.0) for IC plus cetuximab, and 54.3% (95% CI, 42.0 to 66.2) for FOLFOX plus cetuximab. Median overall survival was 11.6, 8.6, and 11.8 months; median progression-free survival was 7.1, 4.9, and 6.8 months; and median time to treatment failure was 5.6, 4.3, and 6.7 months for each of these arms, respectively. FOLFOX plus cetuximab required fewer treatment modifications compared with ECF plus cetuximab and IC plus cetuximab (P = .013), and fewer patients were removed from treatment because of an adverse event or experienced treatment-related death.. In combination with cetuximab, ECF and FOLFOX had similar efficacy, but FOLFOX was better tolerated. Although differences were nonsignificant, IC plus cetuximab seemed to be the least effective and most toxic of the three regimens tested.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Squamous Cell; Cetuximab; Cisplatin; Disease Progression; Disease-Free Survival; Epirubicin; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Survival Rate; Time Factors; Treatment Failure

To evaluate the efficacy and toxicity of nedaplatin (NDP) concurrent with radiotherapy in the treatment of locally advanced esophageal carcinoma.. Sixty-eight patients with locally advanced esophageal carcinoma were randomized into either a NDP group (n = 34) or a cisplatin (DDP) group (n = 34). The NDP group received NDP 80-100 mg/m² iv on day 1 + leucovorin (CF) 100 mg/m² iv on days 1-5 + 5-fluorouracil (5-FU) 500 mg/m² iv on days 1-5. The DDP group received DDP 30 mg/m² iv on days 1-3 + CF 100 mg/m² on days 1-5 + 5-FU 500 mg/m² iv on days 1-5. The treatment was repeated every 4 wk in both groups. Concurrent radiotherapy [60-66 Gy/(30-33 f)/(6-7 wk)] was given during chemotherapy.. There was no significant difference in the short-term response rate between the NDP group and DDP group (90.9% vs 81.3%, P = 0.528). Although the 1- and 2-year survival rates were higher in the NDP group than in the DDP group (75.8% vs 68.8%, 57.6% vs 50.0%), the difference in the overall survival rate was not statistically significant between the two groups (P = 0.540). The incidences of nausea, vomiting and nephrotoxicity were significantly lower in the NDP group than in the DDP group (17.6% vs 50.0%, P = 0.031; 11.8% vs 47.1%, P = 0.016; 8.8% vs 38.2%, P = 0.039). There was no significant difference in the incidence of myelosuppression, radiation-induced esophagitis or radiation-induced pneumonia between the two groups.. NDP-based concurrent chemoradiotherapy is effective and well-tolerated in patients with locally advanced esophageal carcinoma. NDP-based regimen has comparable efficacy to DDP-based regimen but is associated with lower incidences of gastrointestinal and renal toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; China; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Radiotherapy Dosage; Radiotherapy, Conformal; Survival Rate; Time Factors; Treatment Outcome; Young Adult

Squamous cell carcinoma is the main histological subtype of esophageal cancer in the east Asia. Oxaliplatin and fluorouracil are active agents for esophageal carcinoma. The aim of this phase II study was to evaluate the efficacy and safety of oxaliplatin, fluorouracil and leucovorin in patients with metastatic esophageal squamous cell carcinoma (ESCC).. Patients with metastatic ESCC and Eastern Cooperative Oncology Group performance score of 0-2 who had not received prior systemic chemotherapy for metastatic disease were enrolled. Oxaliplatin, 100 mg/m(2), was administered as a 2-h intravenous (i.v.) infusion on day 1. Leucovorin, 400 mg/m(2) i.v., was administered as a 2-h infusion followed by fluorouracil (400 mg/m(2)) i.v. bolus immediately followed by fluorouracil (2,400 mg/m(2)) as a 46-h continuous infusion on days 1 and 2. Chemotherapy was repeated every 14 days.. Between October 2008 and September 2011, fifty-six patients, with a median age of 59 years, were enrolled in this study. The overall response rate was 23.2 % with a disease control rate of 67.9 %. The median progression-free survival (PFS) was 4.4 months, and the median overall survival (OS) was 7.7 months. Median PFS was significantly longer in patients without liver metastasis than those with liver metastasis (5.4 vs 2.4 months, P = 0.003). Partial response was associated with longer PFS (7.2 vs 2.7 months, P = 0.023) and OS (11.3 vs 7.1 months, P = 0.028). Significant difference in OS was noted between those age >65 and ≤ 65 years of age (7.9 vs 3.3 months, P = 0.033). Grade 3/4 neutropenia, leucopenia, anemia and thrombocytopenia occurred in 35.7, 28.6, 10.7 and 10.7 % of patients, respectively. The most common non-hematologic toxicities were fatigue, mucositis, nausea/vomiting and peripheral neuropathy, all of which were moderate, reversible and did not require a dose reduction.. Chemotherapy with oxaliplatin, leucovorin and fluorouracil showed moderate antitumor activity in metastatic ESCC and was well tolerated with acceptable myelosuppression, infrequent and reversible non-hematologic toxicities in patients with ESCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

The mature results of the neoadjuvant and adjuvant chemotherapy arms of the nonrandomized, phase 2 Yale University cisplatin, bleomycin, methotrexate, and 5-FU protocol are presented.. Sixty-seven patients were prospectively accrued with a median follow-up of 5.4 years, and standard parameters of toxicity and efficacy were studied. Both univariate and multivariate analyses were applied.. The 5-year disease-free survival of 78% for the 25 patients in the adjuvant group, of which 80% had high-risk features including positive margins, parametria, and lymph nodes and 28% had adenocarcinomas, was comparable to recent relevant literature. Only 64% of patients in this group received consolidation radiation therapy, which did not impact on survival. Only 12% of patients recurred distantly. Notably, those who received 4 months or more of chemotherapy had prolonged survival (P = 0.012). In the neoadjuvant group, chemotherapy response rate among 42 patients (with stages 1B-IIIB cancer) was 79% (50% partial response, 29% complete response), and no patient progressed. In the subgroup of 22 patients who underwent surgery after chemotherapy, 59% had nonsquamous histology. Forty-five percent of patients with stage IIB cancer were deemed operable after chemotherapy. Ninety-five percent received postoperative radiation therapy. There was a 9% pathologic complete response rate, with positive lymph nodes found in 27%. Notably, those who received 3 months or less of chemotherapy had improved overall survival (P = 0.030). Survival rates of these 22 patients at 3 and 5 years were 73% and 63%, respectively. Although not randomized, these survival rates were similar to those achieved with chemoradiation.. Although there are several logistical/design features of the cisplatin, bleomycin, methotrexate, and 5-FU regimen that are not in line with the current chemotherapy era, our experience with this well-tolerated regimen can serve as a proof of principle. Our data suggests that both neoadjuvant and adjuvant cisplatin-based neoadjuvant chemotherapy may have their place. It also raises the possibility that the optimal duration of chemotherapy in adjuvant cases should be longer than in neoadjuvant cases.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Maximum Tolerated Dose; Methotrexate; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Survival Rate; Treatment Outcome; Uterine Cervical Neoplasms; Young Adult

Concomitant chemoradiotherapy is the standard treatment of locally advanced, nonresectable, head-and-neck squamous cell carcinoma. However, the optimal chemotherapy regimen is still controversial. The objective of this Phase II study was to evaluate the feasibility and efficacy of a concomitant treatment using tegafur-uracil, leucovorin, carboplatin, and radiotherapy.. A total of 77 patients with head-and-neck squamous cell carcinoma Stage III and IVA were enrolled between October 2003 and July 2005. Of the 77 patients, 72 were eligible. They were treated with tegafur-uracil (300 mg/m(2)/d) and leucovorin (75 mg/d) from Days 1 to 19 and from Days 29 to 47 and carboplatin (70 mg/m(2) intravenously for 4 consecutive days), in three cycles every 21 days. Conventional radiotherapy was delivered to a total dose of 70 Gy in 35 fractions.. With a mean follow-up of 22.8 months, the 3-year locoregional control, overall survival and disease-free survival actuarial rate was 33.1%, 41.9%, and 27.2%, respectively. The compliance of the treatment was correct. The main acute toxicity was mucositis, with 62% Grade 3-4. Three patients (4.2%) died of acute toxicity. The incidence and severity of late toxicity was acceptable, with 32% Grade 3 and no Grade 4 toxicity.. The protocol of concomitant chemoradiotherapy using tegafur-uracil, leucovorin, and carboplatin for locally advanced unresectable head-and-neck squamous cell carcinoma is feasible. The compliance was correct. The incidence and severity of the acute and late toxicities were acceptable, but not improved. The efficacy of this regimen seems equivalent to the main protocols of concurrent chemoradiotherapy. It represents a possible alternative for patients without an intravenous catheter.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Combined Modality Therapy; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Follow-Up Studies; France; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Survival Analysis; Tegafur; Vitamin B Complex

We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in terms of safety and efficacy on survival. A total of 100 patients were enrolled. The TPF group received CCRT with the TPF regimen [docetaxel (50 mg/m(2): day 1), CDDP (60 mg/m(2): day 4), and continuous 5-FU infusion (600 mg/m(2)/day: days 1-5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m(2): day 4)], continuous 5-FU infusion (600 mg/m(2)/day: days 1-5), methotrexate (30 mg/m(2): day 1) and leucovorin (20 mg/m(2)/day: days 1-5)]. Both groups received 2 cycles of chemotherapy during definitive radiotherapy. The total radiation dose was between 66.6 and 70.2 Gray. The overall response rates after CCRT were 98 with 90% of a pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity. CCRT with TPF or PMFL for advanced SCCHN was tolerable and produced excellent survival rates.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Endpoint Determination; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis; Taxoids; Vitamin B Complex

Advanced esophagogastric carcinoma has a poor prognosis. Palliative chemotherapy provides a survival advantage and improved quality of life. Epirubicin, cisplatin and continuous infusional 5-fluorouracil (5-FU) (ECF) is a well-established chemotherapy regimen but a continuous chemotherapy infusion is not always feasible or acceptable.. We conducted a phase I and II trial of a modified version of ECF, utilizing 5-FU as a 24-h infusion on day 1 and day 8 of a 21-day cycle, administered with sodium folinate as a modulator of 5-FU (ECSF). In the phase I study the dose of 5-FU was increased in successive cohorts from 1250 mg/m(2) , 1500 mg/m(2) , and 1750 mg/m(2) to 2000 mg/m(2) per 24 h.. Dose limiting toxicity of febrile neutropenia was encountered at 2000 mg/m. The recommended dose for 5-FU was 1750 mg/m(2) . Overall 29 patients were treated with ECSF of whom 27 were evaluable for toxicity. The response rate was 45% on an intention-to-treat analysis with a complete response rate of 3%. The median response rate was 4.1 months and the median survival was 10.7 months. A total of 23 patients (72%) obtained clinical benefit with improvement in dysphagia or weight gain. central venous catheter (CVC) complications were observed in 12 (41%) patients.. ECSF was associated with a response rate and survival similar to that reported with standard ECF. ECSF may provide an alternative regimen to standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient. CVC complications are a limitation.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Therapy, Combination; Epirubicin; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Stomach Neoplasms; Survival Rate; Treatment Outcome; Vitamin B Complex

The aim of this study was to evaluate the activity and safety of oxaliplatin/5-fluorouracil-based chemo-radiotherapy in patients with not radically resectable locally advanced esophageal cancer.. Fifty-nine patients with adeno or squamous-cell carcinoma received oxaliplatin (60 mg/m(2)), and leucovorin (20 mg/m(2) on days 1,8,15,29,36,43,50,57) followed by continuous infusion fluorouracil (200 mg/m(2) per day on days 1-22 and 29-64) with radiotherapy (1.8 Gy daily fractions to a total dose of 45 Gy, from days 29 to 64). When feasible, surgery was scheduled 6-8 weeks after chemo-radiotherapy completion. The primary endpoint was 1-year progression-free survival.. Forty (68%) patients completed treatment without modifications. An objective clinical response was seen in 35 patients (59%). Esophagectomy was possible in 33 patients and a complete resection (R0) was achieved in 26 (79%) with 6 pathologic complete responses (pCR) and 3 near pCR. At a median follow-up of 39.7 months for the surviving patients, the median progression-free and overall survivals were 11 months (95% CI 6.5-14) and 18.5 months (95% CI 13-29). The 1-year progression-free and overall survivals were 47.5% (95% CI 34-59.5%) and 63% (95% CI 49-74%). Major toxicities were esophagitis (20% G3 and 5% G4) and diarrhea (8.5% G3 and 8.5% G4). Hematological toxicity (7% G3 and 3% G4) was less common; severe neurotoxicity (3% G3) was infrequent.. Concurrent oxaliplatin, leucovorin, fluorouracil and radiotherapy followed or not by esophagectomy has a tolerable toxicity and promising activity in locally advanced esophageal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Organoplatinum Compounds; Oxaliplatin; Radiation Dosage

In the majority of patients with oesophageal carcinoma, curative treatment proves to be impossible when diagnosis was established; therefore, most of the patients are candidates for palliative chemotherapy. The aim of this phase II study was to evaluate the efficacy and safety of 5-fluorouracil/folinic acid (AIO regimen) plus irinotecan in patients with locally advanced or metastatic carcinoma of the oesophagus. The methods used a prospective phase II trial, start: November 2002; patients: n=25; chemotherapy: irinotecan (80 mg/m2) as a 1-h infusion and 5-fluorouracil (2000 mg/m2) with sodium folinic acid (500 mg/m2) as a 24-h infusion on days 1, 8, 15, 22, 29 and 36, repeated on day 57. Last date of evaluation: 28 February 2007; n=24; adenocarcinoma: n=13, squamous cell carcinoma (SCC): n=11; UICC III/IV: 3/21; grading G1/G2/G3/G4: 0/8/12/4; median age: 58 years (range 44-75); men/women: 19/5; Eastern Cooperative Oncology Group index 0/1/2: 3/17/4; applications: 460. Higher-grade toxicity: grade 3 diarrhoea: n=2, grade 4 diarrhoea: n=1, grade 4 vomiting: n=1, grade 4 nausea: n=1, grade 3 fatigue: n=1, grade 3 hyponatraemia: n=2, grade 4 elevation of creatinine: n=1, thrombosis of the vena subclavia: n=1, ischaemic lesion of the brain stem: n=1. Three patients died after two chemotherapeutic applications because of high tumour burden. Evaluable for response: n=19. Partial response: n=8 (33%), stable disease: n=9 (38%), progressive disease: n=2 (8%), not evaluable: n=5 (21%). Time-to-progression: 6.6 months (range 1.6-24.6). Total median survival: 13.6 months (median survival of adenocarcinoma: 20.3 months, median survival of SCC: 10.0 months). Secondary resection (R0): n=3. In oesophageal carcinomas, the AIO regimen plus irinotecan is excellently manageable as an outpatient treatment and shows efficacy in adenocarcinomas and SCCs of the oesophagus.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Palliative Care; Prospective Studies; Treatment Outcome

This is a phase II clinical study conducted to evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).. Twenty-one previously untreated patients with stage III or IV SCCHN were treated with TPFL. Patients who received a complete response (CR) or partial response (PR) to three cycles of TPFL received definitive radiation therapy. The primary end points were toxicity and response to TPFL.. Fifty cycles were administered to 21 patients. The major acute toxicities to TPFL were mucositis, fatigue, and anorexia. Additional major toxicities were neutropenia, anemia, and weight loss. The overall clinical response rate to TPFL was 47.6% , with 19% CRs and 28.6% PRs. In addition, the median time to progression and overall survival time were 49.2 months and 42.7 months, respectively.. TPFL has an acceptable toxicity profile for patients with locally advanced squamous cell carcinoma of the head and neck and may hold curative potential for some patients with surgically unresectable or medical inoperable situations.. To evaluate the efficacy and safety to TPFL regimen for locally advanced squamous cell carcinoma of the head and neck.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Docetaxel; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Survival Rate; Taxoids; Tomography, X-Ray Computed

Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is not well established. We evaluated the safety and preliminary efficacy of a combination of UFT/leucovorin, carboplatin, and paclitaxel with RT in a Phase I study of patients with advanced esophageal cancer.. Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received UFT/leucovorin, carboplatin, and paclitaxel with RT (1.8 Gy daily to 45 Gy). After completion, the disease was restaged and patients were evaluated for surgery. Primary end points included determination of dose-limiting toxicities (DLTs) and a recommended Phase II dose. Secondary objectives included determination of non-DLTs, as well as preliminary radiographic and pathologic response rates.. Twelve patients were enrolled (11 men, 1 woman). All were assessable for toxicity and efficacy. One of 6 patients at Dose Level 1 (UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, area under the curve [AUC] 5, Weeks 1 and 4; paclitaxel, 175 mg/m2 Weeks 1 and 4) had a DLT (febrile neutropenia). Of these 6 patients, 4 underwent esophagectomy and none achieved a pathologic complete response. Six patients were then enrolled at Dose Level 2 (UFT/leucovorin, 300/30 mg in the morning and 200/30 mg in the evening on RT days; carboplatin, AUC 5, Weeks 1 and 4; paclitaxel, 175 mg/m2 Weeks 1 and 4). Two of 6 patients at Dose Level 2 developed DLTs (febrile neutropenia in both). Esophagectomy was performed in 3 patients, with 2 achieving a pathologic complete response.. Maximum tolerated doses in this study were UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, AUC 5, Weeks 1 and 4; and paclitaxel, 175 mg/m2 Weeks 1 and 4 when delivered with external RT. In this small study, this regimen appears active, but toxic.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Drug Combinations; Esophageal Neoplasms; Esophagogastric Junction; Female; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Paclitaxel; Radiotherapy Dosage; Tegafur; Uracil

To test the efficacy and safety of pharmacokinetic modulating chemotherapy combined with cisplatin (PMC-cisplatin) as induction chemotherapy (ICT) before definitive treatment in patients with respectable locally advanced head and neck squamous cell carcinoma (HNSCC).. Patients with stage III-IV resectable locally advanced HNSCC were enrolled. All eligible patients received PMC-cisplatin regimen as ICT containing intravenous leucovorin 250 mg/m(2) and 5-FU 600 mg/m(2) on day 1, oral tegafur-uracil (UFUR) 250 mg/m(2)/day on days 1-5, repeated every week for six courses. Cisplatin 100 mg/m(2 )was given during the first and fourth courses of PMC. For ICT responders, concurrent chemoradiotherapy (CRT) with cisplatin/tegafur-uracil/70 Gy radiotherapy was performed. Salvage surgery plus postoperative CRT was given to ICT non-responders.. The overall response rate of PMC-cisplatin as ICT was 76%, including a complete remission rate of 23%. The overall organ preservation rate of the multimodality treatment was 75%, with 97% in ICT responders. At a median follow-up of 25 months, 47% of the patients were still alive and disease-free. The superiority of disease-free survival was demonstrated in ICT responders. The 3-year overall survival rate was 67%. The toxicity of treatment was acceptable.. Application of PMC-cisplatin as the induction chemotherapy before definitive treatment provides a promising result in treatment response and survival of advanced HNSCC. This regimen is effective and safe, and further studies considering the combination of PMC with other chemotherapeutics such as taxanes to improve the clinical outcome of advanced HNSCC is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Diseases; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Radiotherapy, Adjuvant; Remission Induction; Salvage Therapy; Survival Analysis; Tegafur; Treatment Outcome; Uracil

The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), methotrexate (MTX) and leucovorin (LV) (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).. Seventy-seven patients with previously untreated stages III-IV SCCHN were included in this trial. Patients received two cycles of chemotherapy repeated every 4 weeks. The chemotherapy regimen consisted CDDP (60 mg/m2, day 4), 5-FU (600 mg/m2 given over 24 h for 5 days, days 1-5), MTX (30 mg/m2, day 1) and LV (20 mg/m2, days 1-5). Radiation was targeted to begin on the starting day of chemotherapy, day 1. The total radiation dose to the primary site and neck lymph nodes was 70.0 Gy. When grade>or=3 toxicities were observed frequently, radiotherapy and/or chemotherapy were delayed or reduced.. The main toxicities were mucositis (grade>or=3, 39%), leukocytopenia (grade>or=3, 34%) and neutropenia (grade>or=3, 30%). The overall clinical response rate and the pathological complete response (CR) were 94% (72/77) and 71% (55/77). The primary site CR and neck lymph node CR were 79% (61/77) and 85% (44/52), and 3-year survival rate was 73%.. This concurrent chemoradiotherapy with PFML was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in locally advanced SCCHN patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Leukopenia; Male; Methotrexate; Middle Aged; Mucositis; Neutropenia; Radiotherapy Dosage

Preoperative paclitaxel-based chemoradiotherapy may improve the response rates and survival in patients with localized esophageal cancer. We evaluated paclitaxel-based induction chemoradiotherapy in patients with localized esophageal cancer to determine its feasibility, clinical response, pathologic response, and overall survival.. Between 1995 and 1998, 50 patients were enrolled in this study. At study entry, patients were categorized as either resectable or unresectable according to evaluation by an experienced thoracic surgeon. All patients were treated with paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 on Day 1, 29 with radiotherapy to 3,000 cGy in 15 fractions. Resectable patients underwent esophagectomy 4 weeks later. Postoperatively, patients received two cycles of paclitaxel 175 mg/m2 on Day 1 and 5-fluorouracil 350 mg/m2 and leucovorin 300 mg on Days 1-3, given every 28 days. Patients who were deemed unsuitable for resection from the outset continued radiotherapy to a total dose of 6,000 cGy.. Of the 50 patients, all began neoadjuvant chemoradiotherapy, 40 patients underwent surgery, and 25 patients completed postoperative chemotherapy. A pathologic complete response was seen in 7 patients (17.5%). Patients with a pathologic response had a median survival of 32.4 months vs. 14.4 months for nonresponders (p < 0.001). Patients with a clinical response had a median survival of 25.2 months compared with 15.6 months for nonresponders (p = 0.002). At a median follow up of 19.8 months (range 2.4-100.8), the median survival was 20.4 months and the 3-year overall survival rate was 23.2%.. Although preoperative cisplatin/paclitaxel with 3,000 cGy was tolerable, this multimodality regimen did not appear to be superior to standard cisplatin/5-fluorouracil-containing regimens and its use is not recommended.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Esophagectomy; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Radiotherapy Dosage

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disease-Free Survival; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel

The purpose of this phase II trial was to investigate the efficacy and toxicity of oxaliplatin combined with folinic acid (FA) and 5-FU in patients with recurrent squamous cell carcinoma of the head and neck (scchn) in advanced stage of disease. Thirty-six patients with recurrent/metastatic disease with median age of 59 years were enrolled. Patients received oxaliplatin (85mg/m(2)) and FA (200mg/m(2)) followed by 5-FU (2000mg/m(2)) as 24h continuous infusion on day 1 and 15 in a 4-week cycle. On day 8 and 22 FA (200mg/m(2)) and 5-FU (2000mg/m(2)) were administered without oxaliplatin followed by two weeks without cytotoxic treatment. Toxic effects, length of survival and tumour response were assessable in 33/36 patients. The overall response was 60.6% with 7 (21.2%) complete responders (CR) and 13 (39.4%) partial responders (PR). Eight patients (24.2%) showed stable disease (SD) and 5 (15.2%) progressed. The median time to progression (TTP) was 8.1 month (range 2-14) and median overall survival was 10.8 months (range 5-16). The 1-year survival rate was 43.2%. The incidence of haematological toxicity was low but mild paraesthesias occurred in all patients received more then 3 cycles of cytotoxic therapy and dose reduction was necessary in two patients due to diarrhoea grade 3. In this small phase II study the combination of oxaliplatin, FA and 5-FU (OFF) demonstrated relative to the standard regimen of cisplatin and 5-FU a high antitumoural activity in previously treated scchn with favourable toxicity profile.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Therapy, Combination; Feasibility Studies; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Quality of Life; Recurrence; Treatment Outcome; Vitamin B Complex

Combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin is regarded as the standard regimen for advanced esophageal carcinoma. This study was to evaluate the efficacy and safety of DLF, CLF and DFM regimens, based on platinum compound plus 5-fluorouracil in the treatment of advanced esophageal carcinoma, and to further explore prognostic factors of advanced esophageal carcinoma.. From October 1999 to December 2004, 98 patients with advanced esophageal carcinoma were enrolled in the study. They were non-randomly assigned to receive a 2-hour infusion of folinic acid 200 mg/m(2), followed by a 5-FU bolus 400 mg/m(2) and 48-hour infusion of 5-FU 3,000 mg/m(2) every 3 weeks, combined with cisplatin 80 mg/m(2) (DLF, n=48) or with carboplatin AUC=5 on day 1 (CLF, n=32), or with cisplatin 80 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1-5 plus pingyangmycin 5 mg/m(2) on day 1, 3, 5 (DFM, n=18). Survival analysis and prognostic factors were evaluated by Kaplan-Meier method and Cox regression analysis.. All 98 patients were assessable for response and toxicity. There were 13 complete response, 36 partial response, 45 no changes and 4 progressive disease with a total response rate of 46.86%. The response rates of DLF, CLF and DFM regimens were 60.42%,46.86% and 27.78%, respectively (DLF vs DFM, P=0.027). The major side effects were nausea-vomiting, alopecia, bone marrow suppression and mucositis, and the others were uncommon. All side effects were tolerable and mild except for nausea-vomiting. Nausea-vomiting was mildest in CLF among the three regimens. After a median follow-up of 9 months, the overall median survival was 9 months (95% CI, 6.67 to 11.33 months), the median survival of the patients treated with DLF, CLF or DFM regimen was 10, 9 and 7 months, respectively (P=0.7402). Better prognosis was correlated with good conditions of patients before chemotherapy (KPS> or =80, P=0.000) and metastasis to lymph node, parenchyma or bone in stead of visceral organs (P=0.026). There was no correlation between the prognosis and age, sex, types of pathology and the regimen of therapy.. The DLF regimen is tolerable and more effective, thus could be recommended as a front-line standard treatment for advanced esophageal carcinoma. The CLF regimen is more suitable for feeble and older patients since it has the mildest side effects. The prognostic factors of advanced esophageal carcinoma include conditions before chemotherapy and the location of metastasis.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Leukopenia; Lymphatic Metastasis; Male; Middle Aged; Nausea; Neoplasm Staging; Proportional Hazards Models; Remission Induction; Survival Rate

We evaluated the efficacy and toxicity of cisplatin, tegafur plus uracil and leucovorin as neoadjuvant chemotherapy for locally advanced squamous cell carcinoma (SCC) of the oropharynx and hypopharynx. Forty-six patients (stage IV, 83%; N2/3, 52%) were treated with PUL (50 mg/m2 cisplatin on day 1, 300 mg/m2 tegafur plus uracil orally and 60 mg leucovorin orally on days 1-14) over a 14-day cycle. Evaluation after 3 cycles led to chemotherapy termination if primary tumor responses were less than partial responses. Otherwise, PUL was continued up to 6 cycles before locoregional therapy. Patients achieving at least good partial responses at the primary site after neoadjuvant chemotherapy received radiotherapy for organ preservation. Chemotherapy responses were analyzed by intent-to-treat. Response rates of primary sites were 71.7% (33 of 46) with 34.8% (16 of 46) showing a complete response. Thirty patients (65.2%) achieved good partial responses at the primary site. Overall response and complete response rates of neck lymph nodes were 68.6% (24 of 35) and 25.7% (nine of 35). The combined response rate of primary site and neck lymph nodes was 63% (95% confidence interval 48.5-77.5%) with a complete response rate of 15.2%. Toxicities of WHO grade 3-4 included anemia (19.6%), diarrhea (17.4%) and neutropenia (8.7%). With a median follow-up of 36 months, overall survival and disease-free survival rates were 45.7% (21 of 46) and 41.3% (19 of 46); organ preservation rate was 90% (19 of 21). We concluded that the outpatient PUL regimen was a moderately effective, less-toxic neoadjuvant chemotherapy for SCC of the oropharynx and hypopharynx. PUL should be studied further with other active agents or radiotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Hypopharyngeal Neoplasms; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oropharyngeal Neoplasms; Survival Rate; Tegafur; Uracil

Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown.. Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time.. The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001).. Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Survival Analysis

Fluorinated pyrimidines have been established as radiosensitizers in the combined modality therapy of esophageal cancer. UFT, an oral combination of a 5-fluorouracil pro-drug (uracil) and a dihydropyrimidine dehydrogenase inhibitor (ftorafur), may provide improvement in the ease of administration with equal efficacy. This Phase I study was designed to determine the maximal tolerated dose and dose-limiting toxicity of UFT, leucovorin, and cisplatin when given with radiotherapy in the neoadjuvant treatment of resectable esophageal cancer.. Chemotherapy consisted of i.v. cisplatin 80 mg/m(2) (Days 1 and 22) and UFT with leucovorin orally on Days 1-35. UFT was escalated in 50-mg/m(2) increments, starting at 200 mg/m(2)/d. Radiotherapy consisted of 4500 cGy in 25 fractions. Patients underwent resection 4-6 weeks after chemoradiotherapy.. Ten patients with resectable esophageal cancer were enrolled. Of the 7 patients entered at dose level 1, 1 developed a dose-limiting toxicity of nausea. All 3 patients entered at dose level 2 developed dose-limiting toxicity. The maximal tolerated dose for UFT was the starting level, 200 mg/m(2)/d. Of the 10 patients enrolled, 8 underwent esophagectomy and 2 developed progressive disease and did not undergo surgery. The disease of 6 of the 8 patients was downstaged at surgery.. The recommended UFT dose for Phase II studies is 200 mg/m(2)/d given orally in two divided doses when given with leucovorin, cisplatin, and radiotherapy.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Combinations; Esophageal Neoplasms; Female; Humans; Leucovorin; Male; Middle Aged; Radiation-Sensitizing Agents; Tegafur; Uracil

The aim of the study was to evaluate the efficacy and tolerability of the combination of oxaliplatin, fluorouracil and leucovorin in patients with advanced esophagus cancer.. Thirty-five patients with recurrent or metastatic esophageal adenocarcinoma or squamous cell carcinoma were enrolled. Up to one prior chemotherapy regimen was allowed. All patients had bi-dimensionally measurable disease. Patients received oxaliplatin 85 mg/m2 as a 2-h infusion on day 1. Leucovorin (500 mg/m2) followed by fluorouracil bolus (400 mg/m2) and 22-h continuous infusion fluorouracil (600 mg/m2) was administered on days 1 and 2. Granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile neutropenia or prolonged neutropenia. Treatment was repeated every 14 days.. Of the thirty-five patients enrolled, all were evaluated for toxicity and 34 were evaluated for response. The overall response rate was 40% (95% confidence interval, 24% to 57%) with complete and partial response rates of 3% and 37%, respectively. The median response duration was 4.6 months, and the median overall survival was 7.1 months. One-year survival was 31%. The major toxicity noted was cumulative neutropenia, with 29% developing grade 4 toxicity. There was one treatment-related death secondary to neutropenic sepsis. The most common non-hematologic toxicity encountered with this regimen was cumulative peripheral neuropathy, with 26% experiencing grade 2 or 3 toxicity.. The combination of oxaliplatin, leucovorin, and fluorouracil shows significant anti-tumor activity and a favorable toxicity profile in patients with metastatic carcinoma of the esophagus.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Stomach Neoplasms; Survival Rate

The primary objective of this phase II study was to access the complete response (CR) rate to a new innovative induction regimen in patients with locally advanced head and neck cancer (LA-HNC). From October 2000 until October 2003 a total of 38 eligible patients (33 men and 5 women) entered the study. The large majority of them presented with a performance status of 0-1 and with clinical stage IV disease. Treatment consisted of three cycles of induction chemotherapy (IC) with paclitaxel 175 mg/m2 in a 3-h infusion on d 1, leucovorin (LV) 200 mg/m2 over 20 min immediately followed by FU 400 mg/m2 bolus and then 600 mg/m2 as a 24-h continuous infusion on d 1 and 2 and a cisplatin 75 mg/m2 over 1-h infusion on d 2 every 3 wk. This was then followed by radiation (70 Gy) and weekly cisplatin 40 mg/m2. After the completion of IC, 6/38 (16%) patients had CR. The CR rate was increased to 66% post-concomitant chemoradiotherapy (CCRT). Neutropenia (37.5%), pain (62%), nausea/vomiting (21%), and alopecia (79%) were the most frequent side effects during IC. The most pronounced toxicities during chemoradiotherapy were stomatitis (62.5%) and xerostomia (53%). Median time to progression was 11.0 mo and median survival 16.7 mo. One- and 2-yr survival rates were 73% and 38%, respectively. In conclusion, this novel induction regimen is active, is well tolerated, and can be successfully followed by CCRT with weekly cisplatin. CCRT should remain standard treatment for patients with LA-HNC. Novel induction combinations, such as that reported in the present study, should be evaluated in combination with CCRT only in the context of clinical trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Paclitaxel; Treatment Outcome

The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin.. Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m(2). Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria.. Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia.. The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Deoxycytidine; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Outcome

To evaluate the effect and acute toxicity of late course conformal radiotherapy combined with chemotherapy for stage III and IV a nasopharyngeal carcinoma (NPC).. Ninety-six patients with stage III and IV a NPC were randomly divided into 2 groups: test group (n = 46, undergoing late course conformal radiotherapy combined with chemotherapy) and control group (n = 50, undergoing conventional radiotherapy). Both groups were treated with one-period chemotherapy, including cisplantin, 5-fluouracil, and calcium folinate, before and after the radiotherapy. The radiotherapy of the test group consisted of 2 phases: 36.0 approximately 40.0 Gy in 18 approximately 20 fractions over 3.5-4 weeks as the first phase using conventional technique was delivered with 2 lateral opposing faciocervical fields, and then 30.0-46.0 Gy in 15-23 fractions over 3-4.5 weeks as the second phase using three-dimensional conformal radiotherapy (3D-CRT).. The rates of complete remission (CR), partial remission (PR), and no change (NC) of the test group were 95.65%, 4.35%, and 0, not significantly different from those in the control group (90.00%, 10.00%, and 0, P = 0.287). The 1-year survival rate of the test group was 100%, not significantly different from that of the control group (96.00%, P = 0.170). The nasopharyngeal 1 year control rate of the test group was 97.83%, significantly higher than that of the control group (78.00%, P = 0.03). The distant metastasis rate of the test group was 8.70%, not significantly different from that of the control group (12.00%, P = 0.596). The incidence rates of radiological caries and irradiation-induced otitis media in the test group was 4.25% and 17.39% respectively, both significantly lower than those in the control group (26.00% and 42.00% respectively, P = 0.004 and P = 0.000). There was no significant difference in the incidence of nausea, vomiting, leukopenia, and severity of acute mucositis between these 2 groups.. Late course conformal radiotherapy combined with chemotherapy effectively improves the disease control, delays the distant metastasis, and alleviates radioactivity damnification.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Radiotherapy, Conformal

A randomized crossover study between 0.3 mg of ramosetron (RAM) combined with 8 mg of dexamethasone (DEX) and 0.3 mg of RAM combined with 12 mg of DEX was performed to investigate the prevention of nausea and vomiting due to chemotherapy including 60 mg/m2 or 70 mg/m2 of cisplatin (CDDP) in patients with advanced head and neck squamous cell carcinoma (HNSCC). Twenty-five patients the study consisted of who received chemotherapy with CDDP were enrolled in the present study between January 2001 and December 2002 at the Yokohama City University School of Medicine or Yokohama City University Medical Center. The antiemetic effectiveness in the group receiving 12 mg of DEX was not significantly superior to the group receiving 8 mg of DEX. It was suggested that the antiemetic therapy of RAM 0.3 mg plus DEX 8 mg was effective for the prevention of nausea and vomiting induced by CDDP in patients with advanced HNSCC.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Squamous Cell; Cisplatin; Cross-Over Studies; Dexamethasone; Drug Therapy, Combination; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nausea; Vomiting, Anticipatory

The purpose of this study was to assess the efficacy and toxicity of irinotecan and 5-fluorouracil (5-FU) in primary refractory or relapsed locally advanced or metastatic oesophagogastric (O-G) carcinoma.. Patients with documented progression on or within 3 months of chemotherapy were recruited between July 2000 and May 2002. Irinotecan (180 mg/m(2)) was given with 5-FU (400 mg/m(2) bolus) and leucovorin (folinic acid) (125 mg/m(2)) followed by 5-FU (1200 mg/m(2) infusion over 48 h) every 2 weeks. Response confirmed by computed tomography was assessed at 12 and 24 weeks.. Thirty-eight of 40 registered patients (95%) were assessable. Median follow-up was 9.3 months and median age was 59.0 years. Thirty-three patients (86.8%) had metastatic disease and 37 patients (97.4%) had previously received platinum-based chemotherapy. Overall response rate was 29% (95% confidence interval 15.4% to 45.9%) while an additional 34% had stable disease. Improvement in tumour-related symptoms included dysphagia 78.6%, reflux 60.0%, pain 54.5%, anorexia 64.3% and weight loss 72.7%. Grade 3/4 toxicities were anaemia 13.2%, neutropenia 26.4%, febrile neutropenia 5.2%, stomatitis 2.6%, nausea and vomiting 13.2% and diarrhoea 7.9%. Median failure-free survival was 3.7 months and median overall survival was 6.4 months.. 5-FU/irinotecan is a valuable regimen for second-line treatment in 5-FU/platinum-resistant O-G carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Squamous Cell; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Stomach Neoplasms; Treatment Outcome

The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors.. Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy.. Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment.. Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Quality of Life; Remission Induction; Survival Rate; Treatment Outcome

Reported is an analysis of overall survival at 10 years of 102 patients with advanced squamous cell carcinoma of the head and neck (SCCHN) who were enrolled in a prospective phase II trial of high-dose cisplatin, 5-fluorouracil (5-FU), and high-dose leucovorin (PFL) induction chemotherapy followed by surgery and/or definitive radiation therapy (RT) between 1987 and 1991. Initially, 14 patients underwent primary site (PS) and neck surgery irrespective of the clinical response to PFL. The high rate of clinical and pathologic complete response (CR) to PFL prompted a switch from PS surgery to definitive RT. Of 102 patients, 18 (17.6%) who completed PFL and local-regional treatment for SCCHN between 1988 to 1991 were alive in December 2000. Among these, 1 of 14 patients (7%) who had undergone PS resection and 17 of 85 (20%) who were treated after PFL with definitive RT but without PS surgery were alive at 10 years. Median survival time was higher in the nonsurgical group (98.9 vs. 51.9 months). Subset analysis suggested that patients with oropharyngeal PS had the longest median survival (108.6 months). The oropharyngeal patients represented the 61% (11/18) of the long-term survivors with organ preservation. An organ preservation approach for patients with advanced SCCHN who demonstrated PS CR to chemotherapy demonstrated a trend to improved overall survival.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Survival Analysis

The current study evaluated the feasibility and clinical activity of a combination of paclitaxel, cisplatin, 5-fluorouracil (5-FU), and leucovorin administered on a biweekly schedule to patients with recurrent or unresectable squamous cell carcinoma of the head and neck (HNSCC).. Patients with recurrent or unresectable HNSCC were eligible if they had received a previous regimen of neoadjuvant chemotherapy, concurrent chemoradiotherapy, or no previous systemic therapy. Patients received paclitaxel (175 mg/m2 on Day 1), cisplatin (35 mg/m2 on Days 1 and 2), leucovorin (200 mg/m2 on Day 1), and 5-FU (1000 mg/m2 per day as a 48-hour continuous intravenous infusion on Days 1 and 2) every 2 weeks. Patients received subcutaneous filgrastim (300 microg per day) on Days 3-9 of each cycle. Treatment was administered on an outpatient basis for a maximum of six cycles.. Thirty-five patients received a combined total of 194 treatment cycles. Eighteen complete responses (51%) and 12 partial responses (34%) were documented, for an overall response rate of 86% (30 of 35 patients). The median progression-free survival duration was 14 months, and the median overall survival duration was 18 months. Two toxicity-related deaths were documented (one due to neutropenic sepsis and the other due to catheter-related pulmonary embolism). Grade 4 neutropenia was observed in one patient. Other severe (Grade 3 or 4) toxic effects included mucositis (14%), anemia (6%), thrombosis (6%), thrombocytopenia (3%), and neuropathy (3%).. The current dose-dense, four-agent, taxane-containing biweekly schedule was feasible and effective in patients with recurrent or unresectable HNSCC. However, given the single-center nature of the current study and the highly selected study population, further validation of these findings is recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Filgrastim; Fluorouracil; Granulocyte Colony-Stimulating Factor; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neutropenia; Paclitaxel; Recombinant Proteins; Sepsis; Survival Analysis; Treatment Outcome

Since 1990, we have treated patients with advanced nasopharyngeal cancer with induction chemotherapy and concomitant chemoradiotherapy. We herein report the results of our experience.. From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated with induction chemotherapy followed by concomitant chemoradiotherapy. Using the American Joint Committee on Cancer's 1992 stage classification, all patients were stage III (11%) or IV (89%). By histology, 63% were poorly differentiated carcinoma and 37% squamous cell carcinoma. The median age was 42 years. Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin and interferon-alpha2b were administered, followed by concomitant chemoradiotherapy consisting of seven cycles of 5-fluorouracil, hydroxyurea and once-daily radiotherapy (FHX) on a week-on week-off schedule. The median radiotherapy dose was 70 Gy.. Clinical response to induction chemotherapy was 100%, 54.2% complete response (CR) and 45.8% partial response. Clinical and/or pathological (37% of all patients had post-treatment biopsy with or without neck dissection) CR after FHX was 100%. At a median follow-up of 52 months, three failures were observed. Two patients have died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis. At 5 years, actuarial locoregional control is 93% and actuarial distant control 92%. The overall survival at 3 and 5 years is 88% and 77%, respectively. Four patients died of unrelated illnesses and had no evidence of disease with respect to their nasopharyngeal cancer. The progression-free survival at 3 and 5 years is 92% and 86%, respectively. Thirty-three per cent of patients required a reduction in the chemotherapy dose due to acute toxicity. Chronic toxicity was not observed, with all patients able to eat orally without dietary restrictions.. Treatment of locoregionally advanced nasopharyngeal cancer with induction chemotherapy followed by concomitant chemoradiotherapy resulted in excellent overall survival with acceptable toxicity. These results are encouraging and warrant further investigation of intensified approaches.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Hydroxyurea; Interferon-alpha; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Treatment Outcome

Combination chemotherapy with docetaxel (T), cisplatin (P), fluorouracil (5-FU) and leucovorin has been reported to have major activity against squamous cell carcinoma of the head and neck (SCCHN) administered as a 4-day (TPFL4) or 5-day (TPFL5) regimen. The purpose of this study was to evaluate the efficacy and toxicity of a modified TPFL regimen (m-TPFL) for locally advanced SCCHN, consisting of a modified dosage with docetaxel, cisplatin, 5-FU and l-leucovorin (l-LV) designed for Japanese patients. Organ preservation of the primary tumor site was also assessed. Thirty-four Japanese patients with locally advanced SCCHN were eligible. Docetaxel was administered as a 1-h i.v. infusion at 48 mg/m2 on day 1; cisplatin, 24 mg/m2/day; 5-FU, 560 mg/m2/day and l-LV, 125 mg/body/day were delivered on days 1-4 by continuous i.v. infusion. This regimen was administered every 28 days. Patients who achieved a complete response (CR) after induction chemotherapy underwent radiation therapy alone. Ninety-one cycles were administered. The main hematological toxicity was neutropenia, classified as grade III or IV in 18.7% of cycles. The most common non-hematologic toxicities included anorexia, stomatitis and alopecia. The clinical overall response rate to m-TPFL was 88.2%, with 58.8% CRs and 29.4% partial responses. After definitive locoregional therapy, 25 of 34 patients were disease-free with preserved primary tumor site anatomy. Overall and progression-free survival rates at the 2-year follow-up are 92.8 and 75.3%, respectively. Our m-TPFL regimen designed for Japanese patients yielded excellent response rates with an acceptable toxicity profile in good-performance-status patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Docetaxel; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Taxoids

To evaluate the efficacy and toxicity of cisplatin, tegafur, and leucovorin as neoadjuvant chemotherapy (CT) for patients with advanced, nonmetastatic squamous cell carcinoma of the head and neck (SCCHN).. Patients with SCCHN according to World Health Organization (WHO) performance status of 2 or less and adequate organ function were enrolled. The CT regimen (PTL) was 50 mg/m(2) cisplatin (P) on Day 1, 800 mg per day oral tegafur (T), and 60 mg per day oral leucovorin (L) for 14 days. The CT was administered at outpatient clinics for 14-day cycles. PTL was initiated with the intent of organ preservation and it was continued for a maximum of six cycles before locoregional therapy. Reevaluation after three cycles led to the termination of CT when the response was less than a partial response. CT was discontinued immediately upon evidence of tumor progression or excessive toxicity.. From March 1996 through July 1999, 97 patients were enrolled consecutively. All participants were men with a median age of 56 years (range, 37-70 years). The primary tumor sites were the tongue base, 14, and the hypopharynx, 83. Sixteen percent of the tumors were Stage III, 84% were Stage IV, 62% were Stage T4, and 44% were Stage N2-3. The median number of CT cycles was six. On an intent-to-treat basis, 26 patients (27%) achieved complete responses and 32 patients (33%) achieved partial responses. The overall response rate was 60% (95% confidence interval, 50-70%). The most common toxicities of WHO Grade 3 or higher included (percent of patients): anemia, 8.3%; stomatitis, 6.3%; thrombocytopenia, 3.1%; and vomiting, 3.1%. With a median follow-up period of 3 years, the overall survival and disease-free survival rates were 40% and 38%, respectively. Organ preservation was achieved in 70% (29 of 37) of the surviving patients.. The outpatient PTL regimen was a moderately effective and minimally toxic CT for SCCHN. PTL should be studied further in combination with other active agents or radiotherapy for patients with SCCHN.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care Facilities; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Tegafur; Treatment Outcome

The authors conducted a Phase I/II study in patients with a poor prognosis who had locally advanced squamous cell carcinoma of the head and neck (SCCHN) and who were treated initially with induction chemotherapy. Patients were treated with weekly docetaxel and concurrent daily fractionated radiation therapy to determine the maximum tolerated dose (MTD) of docetaxel and the efficacy of the regimen.. Twenty-two patients were enrolled, and 21 patients were treated. Eight patients had Stage III SCCHN, and 13 patients had Stage IV SCCHN without distant metastases and were treated first with 2-3 cycles of induction chemotherapy, which consisted of cisplatin plus 5-fluorouracil with or without leucovorin. Patients with a poor prognosis were identified as those who achieved a partial response to induction treatment, achieved a complete response with a positive biopsy, or were at high risk for developing recurrent disease. Patients were treated subsequently with concurrent, escalating doses of docetaxel (given weekly x 6) and once daily 200-centigray radiation fractions.. Three patients were treated with a weekly docetaxel dose of 20 mg/m(2) without dose-limiting toxicity (DLT). Both patients who were treated at the next dose level of 30 mg/m(2) experienced DLT. A dose of 25 mg/m(2) was studied without DLT in the 16 patients who were treated, establishing this as the MTD. Sixty-seven percent of the patients are alive without disease at a median follow-up of 35 months (range, 12-59 months) after the initiation of chemoradiotherapy.. The MTD of weekly docetaxel with concurrent daily radiation therapy in the postinduction setting was 25 mg/m(2). Disease free survival data from this study were good and indicated that this regimen was effective in the treatment of patients with SCCHN who had a poor prognosis.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Paclitaxel; Taxoids

Cisplatin (CDDP) is among the most active single agents against squamous cell carcinoma of the head and neck (SCCHN), and it is still the reference drug in the induction chemotherapy setting, when used in combination with infusional 5-fluorouracil (5-FU). Raltitrexed has been shown to be devoid of clinical activity against SCCHN when used alone; however, both preclinical and early clinical data regarding the combination raltitrexed-CDDP hold promise. Thymidylate synthase is the target enzyme of both raltitrexed and 5-FU; however, the two drugs have distinct sites of action on the enzyme and the combination of the two agents may be synergistic. We have previously shown that the combination of raltitrexed, levofolinic acid (LFA) and 5-FU has clinical activity against SCCHN; in a subsequent phase I study, cisplatin was added, and the combination of CDDP plus raltitrexed on day 1, followed by LFA and 5-FU on day 2, was judged feasible and active, since a 67% response rate was shown across all dose levels, with a 100% response rate at the recommended dose for phase II.. Patients with inoperable locally advanced or metastatic SCCHN, not pretreated with chemo- or radiotherapy were randomized to receive either CDDP 60 mg/m2 and raltitrexed 2.5 mg/m2 on day 1 and LFA 250 mg/m2 and 5-FU 900 mg/m2 on day 2 (arm A) or CDDP 65 mg/m2 and methotrexate 500 mg/m2 on day 1, and LFA 250 mg/m2 and 5-FU 800 mg/m2 on day 2 (arm B). Both treatments were repeated every 2 weeks. Evaluation for tumor response was performed after four cycles. According to Simon two-stage design, with a target complete response (CR) rate (p1) of 35%, at least 7 CR among the first 31 treated patients and 16 CR among the final sample size of 52 patients were required.. An interim analysis was performed when 36 patients were evaluable in each arm. In arm A, 10 CR (28%) and 19 partial responses (PR) (53%) were observed, for an overall response rate of 81%. In arm B, 3 CR (8%) and 12 PR (34%) were observed, for an overall response rate of 42%. The difference in both CR and overall response rate between the two arms was statistically significant (p = 0.03 and <0.001, respectively). Therefore, the accrual was stopped in arm B and continued only in arm A. Overall, 13 CR (21%) and 34 PR (56%) were observed among the 61 patients who were accrued in arm A, for an overall response rate of 77% (95% confidence interval 64-87%). Neutropenia was the main side effect in both arms (grade 3-4 in 45 and 23 patients in arm A and B, respectively). Extrahematologic toxicity was mild in both arms; however, 2 patients in arm B died due to toxicity (grade 4 mucositis in one case, grade 4 renal toxicity in the other).. Although response data for our experimental treatment look encouraging, the hypothesis of a 35% activity, expressed as capability to induce a CR, cannot be accepted. The results obtained in this study are not substantially different from those of other trials of CDDP-5-FU-based regimens, and our combination is unlikely to represent a major breakthrough when used in this setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neutropenia; Quinazolines; Thiophenes; Treatment Outcome

The prognosis for advanced esophageal carcinoma is poor with a median survival of 9-12 months and 5-year-survival rate of 10-20%. Combination chemotherapy with cisplatin and 5-fluorouracil (5-FU) is considered to be the standard therapy, but has a high potential of side effects and is usually not given on an ambulatory basis. This phase I study was designed to find the maximum tolerated dose (MTD) of weekly cisplatin in combination with standard doses of gemcitabine (1,000 mg/m(2), 30 min) and 5-FU (750 mg/m(2), 24 h)/folinic acid (200 mg/m(2), 30 min). All drugs were to be given on a day 1, 8, 15 and 22 of a 6-weekly cycle in an outpatient setting. Nineteen chemonaive patients with inoperable stage IIa, III and IV squamous cell carcinoma and adenocarcinoma of the esophagus were enrolled into the study. Eight, six and five patients were enrolled at cisplatin dose levels 0 (20 mg/m(2) ), I (25 mg/m(2) ) and II (30 mg/m(2)), respectively. One hundred and eighty-one out of 187 treatments (55 cycles) were given on an outpatient basis. The dose-limiting toxicities of this schedule were leukopenia and thrombocytopenia. Other side effects were mild. Dose level II (30 mg/m(2)) was defined as the MTD for cisplatin when used in this combination and schedule. Partial responses were observed in 10 of the 19 enrolled patients. The side effect profile seen in this study in combination with the preliminary evidence of efficacy justifies further testing in a phase II setting with a cisplatin dose of 25 mg/m(2) and offers a treatment option for patients in an outpatient setting.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Deoxycytidine; Esophageal Neoplasms; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged

The purpose of this study was to establish the maximum tolerated dose (MTD) of docetaxel in an outpatient docetaxel (T), cisplatin (P), 5-fluorouracil (5-FU) (F), and leucovorin (L) (opTPFL) regimen and to obtain preliminary assessment of opTPFL efficacy. Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL. Docetaxel was escalated from 60 to 95 mg/m(2) in combination with 100 mg/m(2) cisplatin intravenous bolus, and 2,800 mg/m(2) 5-FU continuous infusion and 2,000 mg/m(2) leucovorin continuous infusion with prophylactic growth factors and antibiotics. Patients who achieved a complete (CR) or partial (PR) response to three cycles received definitive twice-daily radiation therapy. A total of 97 cycles were administered to 34 patients. The major acute toxicities were neutropenia and mucositis. The MTD of docetaxel was 90 mg/m(2) . Seventy-seven of 97 cycles of were administered on an outpatient basis. The overall clinical response rate to opTPFL was 94%, with 44% CRs and 50% PRs. The MTD of opTPFL is 90 mg/m(2) docetaxel. Outpatient administration of opTPFL is tolerable, feasible, and does not alter the ability to administer definitive radiation therapy on schedule.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Docetaxel; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Paclitaxel; Taxoids

The objective of this study was to determine the toxicity and the efficacy of the combination of cisplatin, etoposide, 5-fluorouracil (5-FU) and folinic acid in the treatment of patients with advanced squamous cell carcinoma of the esophagus. Patients received cisplatin 80 mg/m(2) i.v. on day 1, etoposide 125 mg/m(2) i.v. on day 1 and etoposide 200 mg/m(2) p.o. on days 3 and 5, 5-FU 375 mg/m(2)/day continuously i.v. combined with folinic acid 30 mg p.o. 6 times per day on days 1--4. Courses were repeated every 4 weeks until progression or up to a maximum of 6 courses. Patients were evaluated for response after every two courses. Sixty-nine patients received a total of 291 courses (median 4, range 1--6). The hematological toxicity consisted of leukocytopenia grade 3 or 4 in 17 and 16% of patients, respectively. Leukocytopenic fever was seen in 19% of patients. Thrombocytopenia grade 3 or 4 was seen in 13 and 7% of patients, respectively. Non-hematological toxicity consisted of nausea/vomiting grade 3 in 32%, diarrhea grade 3 in 6% and mucositis grade 3 or 4 in 23% of patients. The overall response rate was 34% (complete response 4%, partial response 30%) and the median time to progression was 7 months in 13 patients who received no additional treatment. The median survival for all patients was 9.5 months with a 1-year survival rate of 36%. Ten patients with initially locally unresectable disease (N=2) or celiac or supraclavicular lymph node metastases (N=8) who received additional treatment (esophageal resection in seven patients and radiotherapy in three patients) after they had responded to chemotherapy had a 3-year survival of 50%. We conclude that the combination cisplatin and etoposide combined with 5-FU and folinic acid is a safe and active regimen for patients with advanced squamous cell carcinoma of the esophagus. Mucositis is the most prevalent toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disease-Free Survival; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN).. Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity.. One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10--37%).. UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Disease-Free Survival; Fatigue; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Pain; Palliative Care; Tegafur; Treatment Outcome; Uracil

The effectiveness of neoadjuvant treatment (NT) prior to resection of squamous cell carcinoma of the esophagus (SCCE) in terms of prolonged survival has not been proven by randomized trials. Facing considerable financial expenses and with concerns regarding the consumption of the patient's remaining survival time, this study aims to provide rationales for pretreating resection candidates.. From March 1986 to March 1999, patients undergoing resection for SCCE were documented prospectively. Since 1989, NT was offered to patients with mainly upper and middle third T3 or T4 tumors or T2 N1 stage who were fit for esophagectomy. Until 1993, NT consisted of chemotherapy. Since that time chemoradiation has also been applied. The parameters for expense and benefit of NT are costs, pretreatment time required, postoperative morbidity and mortality, clinical and histopathological response, and actuarial survival.. Two hundred and three patients were treated, 170 by surgery alone and 33 by NT + surgery. Postoperative morbidity and mortality were 52% to 30% and 12% to 6%, respectively (p = n.s.). The response to NT was detected in 23 patients (70%). In 11 instances (33%), the primary tumor lesion was histopathologically eradicated. Survival following NT + surgery was significantly prolonged in node-positive patients with a median survival of 12 months to 19 months (p = 0.0193). The average pretreatment time was 113 +/- 43 days, and reimbursement for NT to the hospital amounted to Euro 9.834.. NT did not increase morbidity and mortality. Expenses for pretreatment, particularly time and costs, are considerable. However, taking into account that the results are derived from a non-randomized study, patients with regionally advanced tumor stages seem to benefit, as seen by their prolonged survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Cost-Benefit Analysis; Drug Therapy; Epirubicin; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prospective Studies; Radiotherapy Dosage; Survival Analysis; Tomography, X-Ray Computed

The combination of cisplatin (CDDP) and 5-fluorouracil (5-FU) can be regarded as a reference regimen in squamous cell carcinoma of the head and neck (SCCHN). Raltitrexed (Tomudex) is a direct and specific thymidilate synthase (TS) inhibitor, which has shown clinical activity against SCCHN in a previous phase I study, when combined with 5-FU and levo-folinic acid (LFA). Preclinical data support the combination of CDDP and raltitrexed. The aim of the present study was to evaluate the combination of cisplatin, raltitrexed. LFA and 5-FU in a phase I-II study.. Patients with locally advanced or metastatic SCCHN were treated with a combination of cisplatin at the starting dose of 40 mg/m2. followed by raltitrexed at the starting dose of 2.5 mg/m2 on day 1; levo-folinic acid at fixed dose of 250 mg/m2, followed by 5-fluorouracil at the starting dose of 750 mg/m2 on day 2. Doses of the three cytotoxic agents were alternately escalated up to dose-limiting toxicity (DLT). Treatment was recycled every two weeks and given up to a maximum of eight courses; after chemotherapy, patients with locally advanced disease received a locoregional treatment.. Forty-five patients were entered into the study. Six dose levels were tested. At CDDP 50 mg/m2, raltitrexed 3 mg/m2, 5-FU 900 mg/m2, four out of six patients showed DLT, which was in all cases grade 4 neutropenia. Therefore, this dose level was defined as maximum tolerated dose (MTD). CDDP 60 mg/m2, raltitrexed 2.5 mg/m2, LFA 250 mg/m2, 5-FU 900 mg/m2 was the dose level recommended for phase II. CDDP, Raltitrexed and 5-FU mean actually delivered dose intensities at the selected dose level were 26, 1.05, and 378 mg/m2/week, respectively. Neutropenia was the main side effect and was observed even at the lowest dose levels. Nonhematologic side effects were mild. Nine complete responses (20%) and twenty-one partial responses (47%) were observed, for an overall response rate of 67% (95% confidence interval (95% CI): 51%-80%), according to intention to treat analysis. Fifteen of fifteen patients (100%) treated at the dose level selected for phase II had an objective response (5 complete responses, 10 partial responses).. The results of our dose escalation clearly demonstrate that it is possible to combine CDDP, raltitrexed, and modulated 5-FU at effective doses, without unexpected toxicities. The response data point to an impressive clinical activity, which will be better defined by an ongoing large phase II study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Quinazolines; Thiophenes; Treatment Outcome

The objective of this phase II prospective study was to determine the efficacy and the toxicity of a new schedule of neoadjuvant chemotherapy in locally advanced squamous cell carcinomas of the head and neck (SCCHN). Thirty-three patients were included in this study (13 stage III and 20 stage IV). Cisplatin (CDDP: 35 mg/m2), 5-fluorouracil (FU: 2 g/m2) and folinic acid (FA: 500 mg/m2) were administered by continuous i.v. infusion for 24 h, once every 7 days. Six cycles of neoadjuvant chemotherapy were planned before definitive locoregional treatment. A total of 195 cycles were analysed for toxicity: mucositis was observed in 11/195 cycles; 12/195 showed diarrhea and vomiting occurred in 10/195. The myelosuppression was low (neutropenia: 4/195, thrombopenia: 3/195). One treatment-related death was observed after grade IV neutropenia at the fourth cycle. Thirty-two patients were evaluated for response. The objective response rate was 87%, with 50% complete response (CR) and 37% partial response. Failure rate was 13% (stable disease). There was no progressive disease. Survival and DFS duration were significantly higher in cases of CR or in laryngeal localization. The average peak plasma levels for the 6 courses of CDDP, 5-FU, dl-FA and mTHF were 4.9+/-0.76 microM, 4.1+/-0.54 microM, 29.1+/-2.4 microM and 4.8+/-0.31 microM respectively. Therefore, the administration of the 3 drugs by a 24 h continuous i.v. infusion reached an efficient level for drug modulation. This new weekly schedule is as active as other standard therapy in the disease but significantly less toxic as neoadjuvant chemotherapy in advanced untreated SCCHN. With the low toxicities observed with this schedule, additional treatment (surgery and/or radiotherapy) is warranted to evaluate the impact on overall survival of SCCHN.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Gastrointestinal Diseases; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Life Tables; Male; Middle Aged; Neoplasm Staging; Neutropenia; Remission Induction; Risk Factors; Stomatitis; Survival Analysis; Thrombocytopenia; Treatment Outcome

Micrometastasis (MM) and tumor cell microinvolvement (TCM) in the lymph node were immunohistochemically evaluated using the cytokeratin (CK) antibody between a surgery group (n=20; 929 lymph nodes) and a chemotherapy group (n=20; 1052 lymph nodes). The incidence of MM+/-TCM in the surgery and chemotherapy groups was 50.0 (10/20) and 55.0% (11/20), respectively. Limiting the analysis to TCM alone revealed that the incidence in the chemotherapy group (10.0%; 2/20) was significantly lower than that in the surgery group (40.0%; 8/20; P=0.032). Preoperative chemotherapy in this regime was not effective, except for some patients with TCM alone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Survival Rate; Treatment Outcome

This is an open-label, nonrandomized phase I study to determine the maximum tolerated dose and dose-limiting toxicity of UFT plus leucovorin when given concomitantly with hyperfractionated radiotherapy in patients with head and neck cancer. The study period is determined by the course of radiotherapy, which is given as 1.7 Gy per fraction twice daily for 5 days (Monday to Friday) in 2 consecutive weeks, followed by 1 week of rest, and subsequently another 2 weeks of radiotherapy (Monday to Friday plus Monday to Thursday). Total duration of therapy will be 5 weeks.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Tegafur; Uracil

We designed two sequential trials of induction chemotherapy followed by definitive radiation in patients with potentially resectable head and neck cancer to determine whether organ preservation is feasible without apparent compromise of survival Study Design Both trials were Phase II studies.. Two clinical trials were conducted sequentially at the University of Michigan. Fifty-two patients enrolled in the first study and were treated with a planned three cycles of carboplatin and 5-fluorouracil. Patients who achieved at least 50% reduction in the size of the primary tumor received definitive radiation therapy, to a dose of 6600 to 7380 cGy. Patients with minimal response or progression had immediate salvage surgery. Thirty-seven patients enrolled in the second trial, in which the chemotherapy consisted of carboplatin, 5-fluororuracil, and leukovorin. Responders were treated with accelerated radiation therapy, to a total dose of 7120 cGy delivered in 41 fractions over 5.5 weeks.. Toxicity and response were similar in both trials; therefore, the results are reported first separately and then combined for all 89 patients. Tumor sites included: oropharynx, 55 patients; hypopharynx, 34 patients. Eighty-three percent of patients tolerated all three cycles of chemotherapy and toxicity was mild. Response to chemotherapy was: 48% complete response at the primary tumor site, and 34% partial response at the primary tumor site. Initial organ preservation at individual tumor sites was: oropharynx, 58%; hypopharynx, 59%. Median survival was 28 months, and survival at 3 and 5 years was 40% and 24%, respectively.. These two regimens were well tolerated, and survival did not appear to be compromised by organ preservation treatment compared with historical controls. This approach warrants further investigation, particularly in those patients for whom surgery could be functionally debilitating.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carboplatin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Humans; Hypopharyngeal Neoplasms; Leucovorin; Male; Middle Aged; Oropharyngeal Neoplasms; Radiotherapy Dosage; Survival Analysis

Induction chemotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) might improve survival with respect to radiation therapy alone. Furthermore, chemotherapy represents the only therapeutic option in metastatic head and neck carcinoma.. To improve further the results that could be obtained with an induction regimen of cisplatin (CDDP) plus 5-fluorouracil (5-FU), the authors treated 50 patients with locally advanced or metastatic SCCHN with a combination of CDDP 65 mg/m2 on Day 1, methotrexate 500 mg/m2 on Day 1, levofolinic acid 250 mg/m2 on Day 2, and 5-FU 800 mg/m2 on Day 2. Cycles were repeated every 2 weeks. The authors' aim was to increase the activity of CDDP plus 5-FU (PF) using a regimen that combined the three most active drugs in SCCHN and provided an adequate biochemical modulation of 5-FU, which was administered as an intravenous bolus infusion.. Forty objective responses were observed among 50 evaluable patients (80%; 95% confidence interval [C.I.], 66-90%), including 7 complete responses (14%; 95% C.I., 5-27%), and 33 partial responses (66%; 95% C.I., 51-79%). Locoregional treatment, consisting of radiotherapy or surgery, was given at the end of chemotherapy. On completion of induction chemotherapy and locoregional treatment, 42 of 46 patients (91%) were rendered disease free. After a median follow-up of 20 months, the median duration of response was 10 months, the median failure free survival was 10 months, and the median overall survival was 21 months. The treatment was generally well tolerated. Grade 3-4 neutropenia occurred in 25 patients (50%), but it was febrile in only 3 patients. Nausea and vomiting were well managed with serotonin-3 blocking agents. Severe mucositis was seldom observed and easily manageable, and it never required hospitalization.. The high level of activity, the manageable toxicity, and the noteworthy survival data of this regimen compare favorably with most of the drug combinations used worldwide to treat similar patient populations, with the additional advantage of significantly lower cost.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Radionuclide Imaging; Survival Analysis

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disease Progression; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Ontario; Severity of Illness Index; Treatment Outcome

To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).. Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4.. Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively.. TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Middle Aged; Mouth Mucosa; Nausea; Paclitaxel; Stomatitis; Taxoids

In vitro studies have shown a schedule-dependent synergism between Tomudex and 5-fluorouracil (5-FU). Incubation of different types of head and neck and colorectal cancer cells with levofolinic acid (LFA) plus 5-FU for 4 or 24 h, after 24-h incubation with Tomudex, produces a clear synergism. The purpose of this study was to evaluate the tolerability and activity of a combination of Tomudex, LFA, and 5-FU in advanced head and neck and colorectal cancer. Furthermore, the potential for 5-FU pharmacomodulation by Tomudex was also evaluated through an intrapatient assessment of dihydropyrimidine dehydrogenase (DPD) activity and 5-FU AUC with and without pretreatment with Tomudex. Eligible patients were treated with Tomudex at the starting dose of 1.5 mg/m2 on day 1, LFA at a fixed dose of 250 mg/m2 on day 2, immediately followed by bolus 5-FU at the starting dose of 600 mg/m2. Tomudex and 5-FU doses were alternately escalated. Courses were repeated every 2 weeks. In the second course, LFA and 5-FU were administered on day 1 and Tomudex on day 2; further treatment was given according to the sequence used in the first course. Plasma 5-FU concentrations were analyzed on courses 1 and 2 using a high-performance liquid chromatography assay with UV detection. DPD activity was measured in peripheral blood mononuclear cells on courses 1 and 2 using incubation of cytosol with [14C]FU and quantitation of metabolite formation. Fifty-eight patients were enrolled in the study. Dose escalation was stopped at step 8, because of the occurrence of dose-limiting toxicity in two of three patients. The dose level immediately before (3 mg/m2 Tomudex, 1050 mg/m2 5-FU) was selected for further evaluation. Tomudex and 5-FU mean dose intensities actually delivered at the seventh step were 1.32 and 462 mg/m2/week, respectively. Six of 40 patients with metastatic colorectal cancer obtained an objective response (15%; 95% confidence interval, 6-30%). In particular, three complete responses and three partial responses were observed. Six of 17 patients with locally advanced or metastatic head and neck cancer obtained an objective response (1 complete response + 5 partial responses; 35%; 95% confidence interval, 14-62%). Median duration of response in colorectal cancer patients was 12 months. 5-FU AUC was not significantly different between the two courses (median intrapatient difference, 9.3%; P = 0.28). DPD activity in course 1 was significantly higher than course 2 (P = 0.041) in the 16

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Thiophenes

A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer.. Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43.. From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant).. Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Survival Analysis

A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).. Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed.. Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor.. TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Docetaxel; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Middle Aged; Paclitaxel; Taxoids

Forty-one patients with locally advanced hypopharyngeal carcinomas were followed for at least 3 years (median, 60 months) after simultaneous radiochemotherapy. Conventionally fractionated radiotherapy was administered as 5 x 2 Gy/week to a total dose of 30 Gy within 3 weeks. From the fourth week an accelerated hyperfractionated schedule was used as 2 x 1.4 Gy/day five days weekly given exclusively to the first order target volume of macroscopic tumor (adding up to a total dose of 72 Gy in six weeks). The second and third order target volumes received conventional fractionation only to 60 Gy and 50 Gy, respectively. The moderate acceleration of the concomitant boost scheme in the second half was counterbalanced during the first week by the introduction of a 5-fluorouracil bolus of 350 mg/M2 with 200 mg/M2 folinic acid and a subsequent continuous infusion using the same dose each 24 h for 5 days. Additionally, a Mitomycin-C bolus of 10 mg/M2 was infused at the fifth day and on the first day of the sixth week. Six weeks after treatment the patients were restaged. In cases with residual carcinoma salvage surgery was performed (11 patients). Late effects of therapy were analyzed according to the Lent-Soma index and life quality according to the European Organisation for Research and Treatment of Cancer-Module. Late effects of treatment were tolerable and were controlled locally. The 3-year-survival rate was 39%, with a local-regional recurrence-free control rate of 71%. Fifty-two percent of all cases of death were caused by distant metastases, secondary carcinomas or other diseases not related to tumor recurrence. The poor prognosis of hypopharyngeal carcinomas despite acceptable local tumor control may be due to specific biological factors present in affected patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Hypopharyngeal Neoplasms; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Staging; Radiotherapy, Adjuvant; Survival Rate

To determine tumor response rate, patterns of failure, toxicity, and survival in advanced squamous head and neck cancer after a combined treatment program that consists of induction chemotherapy, organ-sparing surgery, and concurrent chemoradiation. Long-term outcome data are presented.. Between July 1991 and March 1993, 93 patients received three cycles of induction chemotherapy that consisted of cisplatin, fluorouracil (5-FU), l-leucovorin, and alpha-interferon2b (PFLl-alpha) followed by optional limited surgery and six to eight cycles of 5-FU, hydroxyurea, and concurrent radiation (FHX) to a total radiation dose of 65 to 75 Gy.. Ninety-three patients were entered onto this study and 97% had stage IV disease, with 66 patients who were N2 or N3. Sixty-one patients (66%) achieved a clinical complete remission (CR) after induction therapy. Thirty-four patients underwent surgery. Seventy-nine patients proceeded to FHX. With a median follow-up time of 43 months for surviving patients, 20 patients have had disease progression (13 local, two distant, five both), and there have been 35 deaths (18 from disease, six treatment-related, two from a second primary, and nine for other medical reasons). At 5 years, progression-free survival is 68%, and overall survival is 62%. Surgery was organ-preserving, as only a single laryngectomy and no glossectomies were performed in primary management. Acute toxicity related to PFLl-alpha consisted of severe or life-threatening mucositis in 57% and leucopenia in 65% of patients. During FHX, 81% of patients had grade 3 or 4 mucositis.. PFLl-alpha is a highly active regimen that induced clinical CR in two thirds of patients. When followed by limited surgery and FHX, resultant local and distant disease control, organ preservation, and overall 5-year survival are very promising in high-risk stage IV patients. Based on these local control and survival data, further evaluation of this treatment sequence, induction chemotherapy followed by concurrent chemoradiation, is warranted. Identification of similarly active but less toxic regimens is a high priority.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Interferon alpha-2; Interferon-alpha; Leucovorin; Levoleucovorin; Male; Middle Aged; Radiotherapy Dosage; Recombinant Proteins; Remission Induction; Survival Rate

For patients with advanced, unresectable head and neck (HN) cancer, surgery and/or radiotherapy are the standard treatments but have poor results. A phase II trial of a continuous infusion of cisplatin, 5-FU, and high dose folinic acid (PFL) as induction chemotherapy in patients with previously untreated, locally advanced HN cancer was performed in an attempt to confirm the encouraging results reported by Dana Farber investigators using an identical regimen. Forty-five consecutive patients with unresectable HN cancer were treated every 28 days with a continuous infusion of cisplatin 25 mg/m(2)/day (days 1-5), 5-FU 800 mg/m(2)/day (days 2-6), and folinic acid 500 mg/m(2)/day (days 1-6). After three courses of chemotherapy, patients were treated with surgery and/or radiotherapy. Objective responses were observed in 26 of 38(69%) evaluable patients with 14(37%) clinical complete responses. Grade III-IV toxicity was important and consisted mainly of mucositis and neutropenia that were found in 47 and 18%, respectively , of patients after the first course. There was one toxic death. PFL is an active, toxic induction regimen for far-advanced HN cancer, yielding a response rate in the range of the widely used cisplatin and 5-FU (PF) schedule; a comparative trial is warranted before concluding that PFL is superior to the latter combination.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cause of Death; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Mucous Membrane; Neutropenia; Remission Induction; Survival Rate

The prognosis of patients with locally advanced esophageal cancer (LAEC) remains poor when treated with local modalities. An intensive preoperative program with chemoradiotherapy was used to evaluate the curative resection rate, pathologic response, and survival of patients with LAEC.. Ninety patients with LAEC were treated preoperatively with chemotherapy (three courses of fluorouracil, leucovorin, etoposide, and cisplatin [FLEP]) followed by concurrent chemoradiotherapy (one course of cisplatin plus etoposide in combination with 40 Gy of radiation). Transthoracic esophagectomy was performed 4 weeks after the end of radiation.. Seventy-two patients were included in this evaluation. Forty-four (61%) underwent a complete tumor resection, and 16 (22%) had no tumor in the resected specimen (pathologic complete response [PCR]). The operative mortality rate was 15%. At a median follow-up time of 22 months (range, 12 to 41), the median survival duration of all 72 patients was 17 months (range, 1 to 41+). The calculated survival rates at 3 years were 33%, 42%, and 68% for all patients, patients after complete resection, and patients with PCR, respectively.. This combined treatment modality is active in LAEC, with a PCR in 33% of the patients undergoing surgery. The results appear improved compared with those reported with surgery alone, by approximately doubling the 3-year survival rate. The high efficacy of preoperative chemoradiation warrants evaluation of the role of surgery in LAEC.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cause of Death; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Preoperative Care; Survival Analysis; Treatment Failure

The addition of leucovorin to 5-fluorouracil (5-FU) has been shown to improve the response rate in recurrent colon cancer. The combination of low-dose leucovorin and 5-FU was previously tested by the Gynecologic Oncology Group (GOG) and did not produce response rates greater than rates using 5-FU alone. From June 1990 to April 1992, 55 patients with unresectable recurrent squamous cervical cancer received high-dose leucovorin at 200 mg/m2 i.v. bolus, followed by 5-FU at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses. Subsequent courses were given every 5 weeks. The median number of courses delivered was two (range 1-15). Fifty patients were evaluable for toxicity and 45 for response. Prior radiotherapy had been given to 43 patients and prior chemotherapy to 38. The overall response rate was 8.8% (95% confidence interval, 2.5-21.2%). There were two complete responses (4.4%) and two partial responses (4.4%). One response was in the pelvis and three were outside the pelvis. None of the extrapelvic responses had received irradiation at the site of measurable disease. The major adverse effect was granulocytopenia, with 15/50 (30%) experiencing GOG grade 3 or 4 granulocytopenia. The median white blood count for patients experiencing leukopenia was 2,000 (range 400-3,800). Grade 3 or 4 gastrointestinal toxicity was seen in 12 patients (24%). In this pretreated population, patients receiving high-dose leucovorin with 5-FU had moderate toxicity but only minimal activity.

Topics: Antidotes; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

Cisplatin (P) and 5-fluorouracil (5FU) have demonstrated activity for the treatment of squamous cell carcinoma of the esophagus. Previous studies have shown that leucovorin (L) may potentiate the antitumoral activity of 5FU, so we tested the combination P-5FU-L in 31 patients with inoperable squamous cell esophageal carcinoma. Chemotherapy consisted of P 20 mg/m2 in 4 h, followed by L 200 mg/m2 in 2 h and 5FU 600 mg/m2 in 18 h. This schedule was repeated for 5 days every 4 weeks. The treatment plan included three courses of chemotherapy followed by radiotherapy. The overall response rate was 58% (95% CI = 39-76%), with one complete remission (3%), and 61% of patients reported an improvement in dysphagia. Gastrointestinal toxicity was the main side effect: grade 3-4 mucositis appeared in 19% of patients, grade 3-4 nausea/vomiting in 13%, and grade 3-4 diarrhea in 6.5%. There was one toxic death caused by neutropenia and sepsis. Nineteen patients received local radiotherapy after chemotherapy, which increased the overall response rate to 63% (5% complete responses). Dysphagia improved in 75% of them. The median survival for all patients was 11 months. This study shows that sequential therapy with P-5FU-L and radiotherapy achieves a high response rate as well as adequate symptomatic relief in patients with inoperable esophageal cancer. The results justify further evaluation of P-5FU-L in patients with earlier-stage disease.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Deglutition Disorders; Diarrhea; Drug Administration Schedule; Drug Synergism; Enzyme Inhibitors; Esophageal Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucous Membrane; Nausea; Radiotherapy, Adjuvant; Remission Induction; Survival Rate; Thymidylate Synthase; Vomiting

Eighty patients with advanced squamous carcinoma of the head and neck were entered into a study using a 2-day, inpatient, intravenous regimen. Folinic acid 200 mg/m2, 5-fluorouracil (5-FU) 500 mg/ m2 bolus followed by 5-FU 500 mg/m2 in a 22-hour infusion were given on days 1 and 2, with carboplatin 300 mg/m2 on day 2. The whole was repeated every 21 days. Forty-three patients had advanced disease with no prior treatment; 37 had recurred following radical treatment. Fifty-eight patients were male and the median age was 60 years. In total, 275 cycles of chemotherapy were given. The major toxicity was haematological, which delayed 65 cycles of chemotherapy and contributed to the death of two patients. Non-haematological toxicity was mild, with less than 8% of patients experiencing any toxicity greater than WHO grade 2. The patients who had had no previous treatment had a 65% response rate (95% confidence interval (95% CI) 48-80). Those who had been previously treated had a 37% response rate (95% CI 21-55). The overall response rate was 52% (95% CI 40-64), of whom 5% were complete responders. The median survival time was 36 weeks (95% CI 29-45), with the majority of patients dying with progressive disease. We conclude that this chemotherapy regimen was well tolerated and produced minimal toxicity, while maintaining an acceptable response rate of 52%.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis

Cisplatin-based induction chemotherapy has been extensively tested in nasopharyngeal carcinoma for the improvement of local and systemic control and survival of this disease. In this study, we report the results of the treatment with induction chemotherapy in 40 patients with locally advanced carcinoma of the nasopharynx (LANPC) with four courses of cisplatin (P) 25 mg/m2 per day and 5-fluorouracil (F) 1000 mg/m2 per day both in a 4-days continuous infusion, with or without leucovorin (L) 250 mg/m2 per day in 2-hour infusion at the beginning of daily administration of PF, followed by sequential radiotherapy. All except one were in stage IV. The overall response after induction chemotherapy was 93%, with 55% CR and 38% PR. Definitive overall response after radiotherapy was 98%, with 80% CR and 18% PR. At a maximum follow up of 11 years, the overall survival rate is 55%. Induction chemotherapy with continuous infusion of PF with or without leucovorin followed by radiotherapy is a highly active regimen for the treatment of locally advanced nasopharyngeal carcinoma with response and survival rates comparable to other combinations of sequential or simultaneous chemotherapy and radiotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Life Tables; Male; Middle Aged; Nasopharyngeal Neoplasms; Remission Induction; Survival Rate; Treatment Outcome

To evaluate prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the reduction of chemotherapy-induced oral mucositis.. Twenty patients with stage IV squamous cell carcinoma of head and neck were studied. Two-cycles (periods) of identical doses of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) chemotherapy with cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d, leucovorin 90 mg/m2/d by 96-hour continuous intravenous infusion every 3 weeks were given to each patient. After PFL chemotherapy, GM-CSF 4 micrograms/kg subcutaneously from days 5 to 14 or no therapy was given by a randomized self-controlled crossover study design. Oral mucositis was graded with modified Radiation Therapy Oncology Group criteria.. In the first cycle of PFL chemotherapy, GM-CSF significantly reduced the incidence, mean duration, and mean area under the curve (AUC) of severe oral gross mucositis (grade > or = 3) compared with no therapy. These beneficial effects continued into the second cycle of PFL chemotherapy after crossover to no GM-CSF. The incidence of severe mucositis was reduced when GM-CSF was given in the second cycle of PFL. Analysis of variance indicated significant direct GM-CSF treatment effects on the mean AUC of gross/functional scores and duration of moderate gross mucositis (grade > or = 2) over both periods. There was a significant period effect in favor of giving GM-CSF in the first cycle of chemotherapy.. GM-CSF can significantly reduce the severity and duration of chemotherapy-induced oral mucositis after PFL chemotherapy.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Cross-Over Studies; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Head and Neck Neoplasms; Hematologic Diseases; Humans; Leucovorin; Male; Middle Aged; Mouth Mucosa; Prospective Studies; Stomatitis

Eighteen patients with invasive periadventitial tissue (T4) or distant lymph node metastatic (M1,LYM) squamous cell carcinoma were entered into a pilot study of neoadjuvant chemotherapy with etoposide (50 mg/m2/day, days 1-5), leucovorin (30 mg/body/day, days 2-5), 5-fluorouracil (5-FU; 400 mg/m2/day, days 2-5) and cisplatin (100 mg/m2/day, day 1) (ELFP). The overall response rate was 56%. The response rates in the T4 tumor and M1,LYM patients were 56 and 50%, respectively. Radical esophagectomies were performed on six of 17 patients who had completely recovered from the chemotherapy, a resectability of 35%. Histologically, the primary tumor was moderately to slightly effective, and the lymph nodes markedly to moderately effective. Histologic responses in the lymph nodes were different from those in the primary tumors and in each node. There were four chemo-surgically related deaths. Median survival times in responding and non-responding patients were nine and three months, respectively. In conclusion, neoadjuvant chemotherapy with ELFP appears to be effective against esophageal squamous cell cancer with periadventitial tissue invasion or distant lymph node metastasis. Chemo-surgically related deaths were however, 22%, showing neoadjuvant chemotherapy to necessitate extremely careful attention to the medical and surgical management of patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Esophagectomy; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Pilot Projects; Survival Rate

To analyze clinical and pharmacokinetic data of cisplatin (CP)/fluorouracil (FU)/l folinic acid (l FA) chemotherapy administered as first-line treatment to locally advanced head and neck cancer patients.. Thirty-nine patients (35 men and four women; median age, 60 years; six stage III and 33 stage IV) received CP on day 1 (100 mg/m2) followed by l FA (200 mg/m2/d x 5) plus FU (500 mg/m2/d x 5) administered by continuous venous infusion (three cycles planned). Mean plasma concentrations of FU, l FA, and 5-methyltetrahydrofolate (5MTHF) over the cycle were computed.. Clinical response was assessable for 33 patients. Response rates on the primary tumor site (n = 33) were 63.7% complete responses (CRs), 24.2% partial responses (PRs), and 12.1% treatment failures. Response rates on lymph nodes (n = 27) were 40.7% CRs, 37.1% PRs, and 22.2% treatment failures. The most frequent toxicity was mucositis (36.2% of cycles grade 3 to 4). Grade 3 to 4 nausea-vomiting, diarrhea, neutropenia, and thrombocytopenia occurred in 6.7%, 1.9%, 13.3%, and 1% of cycles, respectively. Pharmacokinetic analysis showed a wide interpatient variability for both FU (mean, 1.01 mumol/L; range, 0.16 to 2.09), l FA (mean, 1.89, mumol/L; range, 0.52 to 7.88) and 5MTHF plasma concentrations (mean, 3.85 mumol/L; range, 1.30 to 8.11). A significant correlation was demonstrated between FU concentration and hematologic toxicity grade, mucositis grade, and nausea-vomiting/diarrhea grade. Regarding tumor response, patients who failed to respond significantly exhibited lower FU and total folate concentrations than patients with a CR or PR.. This study highlights the efficacy of CP/FU/l FA in head and neck carcinoma and establishes the clinical importance of coupled FU/FA pharmacokinetics to predict pharmacodynamic variability.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Humans; Hypopharyngeal Neoplasms; Laryngeal Neoplasms; Leucovorin; Male; Middle Aged; Nose Neoplasms; Oropharyngeal Neoplasms; Tetrahydrofolates

In order to investigate the medical treatment of anal canal carcinoma (ACC), 27 patients (pts) were treated with cisplatin, fluorouracil and radiotherapy, in an alternating schedule. Eleven pts received mitomycin C, fluorouracil and radiotherapy, in a concurrent scheme. Finally, six pts were included in a new outpatient scheme with cisplatin, fluorouracil, leucovorin, mitomycin C and concurrent radiotherapy. Within the first schedule, 25 pts were evaluable and 18 achieved complete response. All of them are disease free until now. With the second scheme, 7/10 pts had a complete response and 5 of them are alive and disease free. All the pts included in the last schedule (6/6) achieved complete remission. There were no deaths related to toxicity. Our experience is one of the earliest in oncology using cisplatin as a first line drug, in the non-surgical treatment of ACC. We think that the use of cisplatin is feasible, its toxicity is manageable, and its effectivity is similar to other schedules, as observed in our last scheme.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Clinical Protocols; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Time Factors

Recurrent squamous cell carcinoma of the head and neck is poorly responsive to chemotherapy in most patients; therefore, the development of new approaches is essential. Edatrexate is a new antifolate with improved preclinical antitumor activity when compared to methotrexate. The purpose of this study was to define the feasibility and efficacy of combining edatrexate with another active single agent, carboplatin in chemotherapy-naive recurrent disease. Carboplatin was given as an outpatient on day 1 at a dosage based on the formula: Dose (mg/m2) = (0.091) (creatinine clearance) (body surface area) (desired percentage change in platelet count) + 86. Edatrexate (80 mg/m2) was given on days 1, 8, and 15 of a 21 day cycle. Calcium leucovorin 15 mg was given orally every 6 h for 4 doses after edatrexate. Of the 26 patients entered on the study, 1 was invaluable for toxicity or response and 3 patients were evaluable for toxicity only. Grade 3 or 4 neutropenia occurred in 2 patients each, and grade 3 or 4 thrombocytopenia occurred in 2 and 4 patients, respectively. Grade 3 stomatitis occurred in only two patients. Overall, major responses occurred in 2 of 22 evaluable patients (9%). The combination of carboplatin and edatrexate was not superior to the results expected with either agent alone.

Topics: Adult; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local

38 patients with advanced oesophageal carcinoma were treated with intravenous (i.v.) folinic acid (300 mg/m2), 5-fluorouracil (500 mg/m2), etoposide (100 mg/m2), and cisplatin (30 mg/m2) (FLEP), on days 1, 2 and 3, every 22-28 days. 26 patients had locally advanced disease (LAD) and 12 had metastatic disease (M1). Oesophagectomy was planned for patients with LAD in case of tumour regression after chemotherapy, while patients with M1 disease received chemotherapy only. The overall remission rate was 45% (17/38) including four clinical and two pathologically confirmed complete remissions. 16 patients underwent oesophagectomy, 12 after response to FLEP, and 4 after FLEP and subsequent irradiation +/- 5-fluorouracil/mitomycin. Toxicity was mainly haematological, with WHO grade 3 and 4 leukocytopenia in 50% and thrombocytopenia in 31% of the patients. Two treatment-related deaths were observed; one due to chemotherapy and one postoperatively. Median survival time of LAD patients was 13 months, and actuarial 2-year survival was 31%. Patients with complete tumour resection after FLEP had a median survival time of 18 months and a 2-year survival rate of 42%. Median survival of M1 patients was 6 months. FLEP is an active combination for oesophageal cancer, especially when used preoperatively in LAD.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Remission Induction; Thrombocytopenia; Treatment Outcome

To evaluate the activity and toxicity of the drug combination cisplatin, fluorouracil by continuous infusion, and high-dose oral leucovorin calcium (PFL) as induction chemotherapy in patients with advanced and untreated squamous cell head and neck (SCHN) cancer.. Nonrandomized, prospective trial.. Referral center (comprehensive cancer center).. Twenty-two patients with stage III (n = 7) and IV (n = 15) M0 SCHN cancer of the larynx (n = 13), hypopharynx (n = 7), and oropharynx (n = 2) whose standard treatment would have required total laryngectomy.. Three cycles of PFL were administered prior to local-regional therapy (concomitant cisplatin and radiation and/or neck dissection, with total laryngectomy reserved for nonresponse or relapse). Chemotherapy included cisplatin (100 mg/m2) on day 1 by short intravenous infusion; fluorouracil (800 mg/m2) on days 1 through 5 by continuous infusion; and leucovorin (100 mg) every 4 hours by mouth for 30 doses. The PFL combination was administered every 21 days.. Clinical response to chemotherapy and observed toxic effects during chemotherapy.. Five patients were inevaluable for response, with three early deaths (infection in two and sudden death in one), one cerebrovascular accident, and one patient declining further chemotherapy. Of the remaining 17 patients, 10 had a major response to chemotherapy, but in only five patients (29%) was this complete (95% confidence interval, 8% to 51%). Other significant toxic effects included grade 3 to 4 mucositis in eight patients and grade 3 to 4 neutropenia in 10.. While PFL is active in patients with SCHN cancer, we were unable to reproduce the high complete response rates reported by other centers. Its use can be associated with significant toxic effects. We do not recommend the use of PFL for the treatment of patients with SCHN cancer outside the context of a clinical trial until there is further critical assessment of its activity and toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Fluorouracil; Humans; Laryngeal Neoplasms; Leucovorin; Middle Aged; Pharyngeal Neoplasms; Prospective Studies

Systemic disease progression occurs in the majority of patients with locally advanced nasopharyngeal carcinoma (NPC). Although a variety of chemotherapeutic drugs have had tumoricidal activity, the roles of chemotherapy and optimal regimens must be further defined. Based on high response rates of Cisplatin, 5-Fluororacil and Leucovorin (PFL) in patients with advanced squamous cell cancers of the head and neck, we tested a new outpatient PFL chemotherapy program in patients with advanced NPC.. Patients with NPC and 1) previously untreated, locally advanced disease; 2) local regional recurrence (LR) after radiotherapy; or 3) metastatic disease were eligible for study. Cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d and Leucovorin 90 mg/m2/d were administered simultaneously by continuous 96-hour intravenous infusion every three weeks. Patients were evaluated for response, survival, and toxicity.. Thirty-five patients were studied. The response rates of PFL therapy were 100% (15% complete response [CR], 85% partial response [PR]) in 20 patients with locally advanced or locally recurrent disease, and 80% (13.3% CR, 67.7% PR) in 15 patients with metastatic disease. The overall median survival was 20 months after therapy (range, 2-21). The median survival rate for previously untreated, locally advanced patients was not reached. The median survival rate for previously treated, local recurrence was 34 months and for metastatic patients was 14 months. Mucositis and leukopenia were the dose-limiting toxicities (20-23%, grade III) and occurred more frequently in patients previously irradiated. No treatment-related deaths occurred.. Outpatient PFL chemotherapy is active, safe, and convenient for advanced stage nasopharyngeal carcinoma patients, and the overall toxicities are tolerable.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms

Authors carried out a review of 40 cases of recurrent and/or metastatic nasopharyngeal carcinoma (NPC) treated with cisplatin-based chemotherapy at the Division of Othorhinolaryngology and the Service of Chemotherapy of the University of Palermo between July 1984 and July 1992. All patients were treated with regimens comprising high dose cisplatin (80-100 mg m-2). Histologically there were 29 squamous cell and 11 undifferentiated NPC. Thirty-nine patients were evaluable for response and toxicity. The overall response rate was 64%, with a 20.5% complete response rate and a 43.5% partial response rate. The mean duration of complete responses was 10.2+months, while that of partial responses was 8.6+months. The mean survival of the whole group was 11.4+months, with four patients alive after 2 years of follow-up. No statistically significant difference in response rate and survival was found between patients with metastatic disease and those with locoregional recurrency, and between patients with squamous cell NPC and those with undifferentiated histology. The employed regimens have been generally well tolerated. These data confirm that NPC is a neoplasm highly responsive to chemotherapy. However, duration of objective response and survival are still largely unsatisfactory.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies

The majority of patients with head and neck cancer die of locoregional recurrence of disease following surgery and/or radiotherapy.. Our purpose was to administer induction chemotherapy, perform surgery, and administer concomitant chemoradiotherapy in rapid sequence and to evaluate their impact on locoregional and distant tumor control.. Sixty-four patients with previously untreated, locoregionally advanced head and neck cancer received two cycles of cisplatin, bleomycin, and methotrexate (PBM) (33 patients) or cisplatin, fluorouracil (5-FU), and leucovorin (PFL) (31 patients). PFL was given to patients who were unable to receive bleomycin. Local therapy consisted of surgery and/or concomitant chemoradiotherapy with 5-FU, hydroxyurea, leucovorin, and radiotherapy (FHX-L), all administered every other week.. Complete and overall induction response rates were 21% and 79%, respectively, for PBM and 29% and 81%, respectively, for PFL. At completion of local therapy, 81% of the patients were disease-free. With a median follow-up of 35 months, the median survival and time to progression are 22 and 17 months, respectively, for PBM and have not been reached for PFL. Locoregional recurrence of disease is 30% for PBM and 26% for PFL. Distant disease progression is 24% for PBM and only 3% for PFL.. The sequencing of induction chemotherapy and concomitant chemoradiotherapy is feasible and results in a high local control rate and in an encouraging survival rate with PFL. The high distant failure (i.e., outside the head and neck area) rate of PBM suggests insufficient systemic activity for that regimen.. Concomitant FHX-L chemoradiotherapy may improve regional control rates of advanced head and neck cancer. Effective systemic therapy may be needed to control systemic micrometastases. PFL, but not PBM, appears to be suitable to accomplish that goal.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Leucovorin; Male; Methotrexate; Middle Aged; Radiography; Time Factors; Treatment Outcome

Twenty-eight patients with recurrent squamous carcinoma of the cervix not amenable to cure by further surgery or radiation therapy were entered into a Phase II trial utilizing i.v. leucovorin 20 mg/m2 followed by 5-fluorouracil 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. One patient never received therapy, and three are inevaluable for response; therefore, 27 patients were evaluable for toxicity and 24 for response. Twenty-three patients had received prior radiotherapy, and 16 had received prior chemotherapy. There was one partial response 4.2% (95% confidence intervals for a response of 0 to 21%). Although toxicity was acceptable with 11 of 27 (41%) grade 3 or 4 leukopenia, 1 of 27 (4%) grade 3 thrombocytopenia, and 3 of 27 (11%) grade 3 or 4 gastrointestinal toxicity, this dose schedule of 5-fluorouracil and leucovorin has minimal activity in recurrent squamous carcinoma of the cervix.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Recurrence; Uterine Cervical Neoplasms

Thirty-five patients with advanced epidermoid carcinoma of the esophagus were treated with 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin 20 mg/m2, day 1-5 every 28 days. Six patients had a partial response (95% confidence limit, 7-35%) with a median response duration of 32 weeks. The median survival time of the patients on study was 14 weeks. The toxicity was acceptable, with only two patients experiencing severe hematologic toxicity and one patient experiencing severe nausea and vomiting. The addition of leucovorin at this dose level in this population of patients with advanced disease does not appear to enhance the activity of 5-FU for patients with squamous cell cancer of the esophagus. Since only a small percentage of patients experienced significant toxicity, a higher response rate could be achieved in patients treated with the maximally tolerated dose.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Evaluation; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Remission Induction; Survival Analysis

To increase the complete remission (CR) rate achieved with two cycles of cisplatin, continuous infusion fluorouracil (5-FU) and oral leucovorin (PFL) we added two antifolate drugs, methotrexate (MTX) and the lipophilic piritrexim (PTX), to the combination (PFL-MP). Twenty-eight patients with previously untreated Stage IV squamous cell carcinoma of the head and neck received 2 cycles of cisplatin 100 mg/m2 on day 1 followed by a 5-day continuous infusion of 5-FU at 800 mg/m2/day and 100 mg of leucovorin administered orally every 4 hours. MTX was administered at 40 mg/m2 IV on day 15 and PTX at 75 mg orally twice daily on days 22 to 26, with cycle 2 starting on day 36. After 2 of the first 5 patients had tumor progression between days 15 and 35, the regimen was intensified to MTX 50 mg/m2, PTX 100 mg twice daily and a cycle duration of 28 days. Local therapy consisted of surgery and/or radiotherapy with concomitant 5-FU and hydroxyurea (FHX) administered every other week. Eleven patients (39%, 95% confidence intervals 21-57%) had a CR, 9 (32%) had a PR, and four patients had no response. Four patients were unevaluable for response to PFL-MP. Patients with poor performance status or N3 disease were less likely to achieve a CR. Mucositis following PFL was the dose-limiting toxicity. Local therapy included surgery in 15 patients and FHX chemoradiotherapy in 19 patients. The administration of FHX in this setting proved feasible and the regimen was given near the intended dose intensity in the majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Pyrimidines

Between 1983 and 1986, the National Institute for Cancer Research in Genoa and affiliated institutions conducted a randomized study to compare two different ways of combining chemotherapy (CT) and radiation therapy (RT). One hundred sixteen patients were randomized to receive neoadjuvant CT followed by definitive RT (treatment arm A) or alternating CT and RT. In treatment arm A, RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction, five fractions per week. In treatment arm B, RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each, 2 Gy/fraction, ten fractions/2 weeks alternated with four courses of CT. CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly, day 1; methotrexate 200 mg intravenously, day 2; leucovorin rescue, day 3. CT was repeated every 2 weeks up to four courses. The same CT was used in both treatment arms of the study. Fifty-five patients were entered in treatment arm A and 61 in treatment arm B. Complete responses were 7/48 and 19/57 in treatment arms A and B, respectively (P less than 0.03). Four-year progression-free survival was 4% in treatment arm A and 12% in treatment arm B (P less than 0.02), and four-year survival was 10% in A and 22% in B (P less than 0.02). Mucosal tolerance was significantly worse in treatment arm B (P less than 0.00004). The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Mouth Mucosa; Neoplasm Staging; Radiotherapy Dosage; Remission Induction; Stomatitis; Survival Rate; Vinblastine

A retrospective analysis was performed of 39 patients with locally advanced nasopharyngeal cancer treated with combined chemotherapy and radiation therapy during the last five years at our departments. There were 26 men and 13 women with median age 55 (24-75) years. Histology was squamous cell carcinoma in 6 patients and undifferentiated carcinoma in the remaining 33 patients. Induction chemotherapy consisted of either regimen A (cisplatin 100 mg/m2 day 1, 5-FU 1,000 mg/m2 days 2-6 as continuous infusion, bleomycin 15 mg days 15 and 29 i.m., mitomycin 4 mg/m2 day 22 and hydroxyurea 1,000 mg/m2 daily days 23-27) or regimen B (carboplatin 300 mg/m2 day 1, 5-FU 1,000 mg/m2 days 1-5 as continuous infusion and methotrexate 1.2 g/m2 day 14 with leucovorin rescue). After completion of induction chemotherapy 13 patients (33%) had complete remission (CR) and 19 (49%) partial remission (PR). The CR rate was increased after radiation therapy to 72%. Survival rates were 88% at 12 and 78% at 24 months. Median time to progression was 29.5 months. In conclusion, induction chemotherapy with a platinum-based regimen followed by radiation therapy achieved a high rate of local control. If the treatment also prolongs survival must, however, be studied by randomized trials.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Retrospective Studies

Between August 1983 and December 1986, 116 previously untreated patients with squamous cell carcinoma of the head and neck were randomized to receive induction chemotherapy followed by radiotherapy given in conventional fractions (55 patients, arm A) or an alternating chemotherapy and radiotherapy (3 courses of 20 Gy, 10 daily fractions each; 61 patients, arm B). The same chemotherapy was used in both arms: 6 mg/m2 vinblastine sulfate, hour 0; 30 mg bleomycin, hour 6; 200 mg methotrexate, hours 24 to 26; 45 mg leucovorin, hour 48. Forty-five patients had stage III disease and 71 had stage IV disease. All patients were evaluated for survival, 112 for toxicity, and 105 for analyses of response and time from the start of treatment until progression of disease. At the end of the combined treatment, we observed an overall response rate of 52% in arm A and an overall response rate of 64.9% in arm B. The incidence of mucositis was more relevant in arm B compared to arm A (P less than .00004). The difference in complete response, progression-free survival, and survival was statistically significant, with an advantage for arm B (P less than .03, P less than .02, and P less than .03, respectively). The analysis at a median follow-up of 36 months (range = 19 to 59) demonstrates a higher effectiveness for the alternating program.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Chi-Square Distribution; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Randomized Controlled Trials as Topic; Survival Rate; Vincristine

Patients suffering from locally advanced squamous cell carcinoma of the head and neck were treated with three courses of simultaneous radio-chemotherapy. Chemotherapy consisted of cis-platinum, 60 mg/m2 i.v. on day 2; 5-FU, 350 mg/m2 i.v. bolus on day 2; leucovorin calcium, 50 mg/m2 i.v. on day 2; 5-FU, 350 mg/m2/24 hrs continuously infused over 96 hrs from day 2 to day 5 and leucovorin calcium, 100 mg/m2/24 hrs continuously infused over 96 hours from day 2 to day 5 each course. Radiotherapy was administered from day 3 to day 11. 23.4 Gy were given in 13 fractions, twice a day with a minimum interval of four hours. This schedule was repeated on days 22 and 44. The total radiation dose amounted to 70.2 Gy/51 days. From 1984 to 1986, 62 patients were entered in this prospective trial. Three patients deceased due to massive hemorrhage during therapy, one patient was not eligible due to a second malignancy. 5/58 evaluable patients had a UICC-Stage III cancer, 53/58 had a UICC-Stage IV cancer. 48/58 (81%) showed a clinically complete response to therapy, 10/58 (17%) achieved partial response three months after the end of treatment. In 16/58 patients loco-regional cancer was not controlled (minimum follow-up 2 years), in 12/58 distant metastases occurred. Loco-regional control rate is estimated at 66% +/- 7% (Kaplan Maier).

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Germany, West; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Prospective Studies

Randomized trials comparing high-dose methotrexate (HDMTX) plus leucovorin (LV) with standard-dose methotrexate (SDMTX) have not detected a therapeutic advantage for the HDMTX arm despite compelling evidence from experimental systems. We hypothesized that these negative trials might reflect modulation of the antitumor effect of methotrexate (MTX) by LV. To test this we randomized 61 patients with locally advanced and recurrent squamous cell head and neck cancer to receive SDMTX (40 mg/m2 weekly for 8 weeks) and either LV or placebo "rescue" starting 24 hours later. Of the 61 randomized patients, there were protocol violations in two cases, leaving 59 patients evaluable for response using standard criteria, and for toxicity using the Eastern Cooperative Oncology Group (ECOG) scale. Of the 29 patients randomized to MTX plus LV, there were five responders (17.2%) compared with 11 of 30 (36.7%) patients randomized to MTX plus placebo (P = .047). Response was influenced independently by age, gender, and by previous treatment. Toxicity overall was more severe in patients randomized to MTX plus placebo (P = .016). This was accounted for primarily by differences in toxicities related to bone marrow function (neutrophil and platelet counts), stomatitis, and elevations of liver function tests. MTX therapy was more often interrupted for toxicity in the placebo group (P = .007) and discontinued for progressive disease in the LV group (P = .07). These results indicate that at the doses of MTX and LV used, LV modulates the antitumor effect as well as the toxicity of MTX in patients with head and neck cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Placebos; Prospective Studies; Randomized Controlled Trials as Topic; Remission Induction

58 patients with locally advanced or relapsed squamous cell head and neck cancer were treated on 5 consecutive days with DDP 20 mg/m2/d IV-push, followed by CF 100 mg/m2/d IV-bolus and Fura 400 mg/m2/d IV-push 60 minutes later. Treatment was recycled on day 22(-29), according to toxicity. CF was added to the widely used DDP/Fura combination, because recent studies showed enhancement of Fura-activity by CF. 45/58 patients had no prior therapy and 13/58 pts were relapsed after chemotherapy and/or radiation therapy. All patients were evaluable for toxicity and response. After 3 courses of induction chemotherapy 23/45 pts in the previously untreated group had a complete response (CR); 20/45 a partial response (PR), 2/45 were restaged as no change (CR + PR: 95%). Induction chemotherapy was followed by radical surgery and postoperative radiation therapy. In the pretreated group 4/13 pts had a complete response; 6/13 a partial response; no change in 3/13 pts. Median duration of remission (MDR) has not been reached in the primarily untreated group, whereas in pretreated patients the MDR was 3.8 months (range 2.3 - 11.7 months). Hematologic and gastrointestinal toxicity was substantial but manageable and therapy was performed on an outpatient basis. The combination of DDP, CF and Fura has high activity in untreated and pretreated head and neck cancer patients. The obtained results are comparable to the widely used DDP/Fura continuous infusion regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging

Progress in the treatment of advanced squamous cell cancer (SCC) of the head and neck (H & N) has included the development of combination chemotherapeutic regimens that achieve impressive complete response (CR) rates using two to three courses therapy with minimal toxicity and good patient tolerance. Further improvements in these results will require intensification of induction regimens. Therefore, a five course, alternating combination chemotherapy induction trial was initiated in an attempt to test the feasibility and toxicity of a prolonged, intensive induction regimen in patients with advanced SCC of H & N. Courses 1, 3, and 5 consisted of fluorouracil as a 120-hour infusion (5FU-I) with cisplatin (CACP) as an intravenous (IV) bolus. Courses 2 and 4 consisted of 3 weekly doses of high-dose methotrexate (HDMTX) followed by 5FU (5FU-b) and leucovorin rescue (LR). Forty-six stage IV patients with SCC of H & N (85% T4 and 58% N3) were entered. Thirty-one patients completed the study and 15 did not. Twenty-one of the 46 patients (46%) achieved a CR. Twenty-five of the 46 patients had N3 neck disease, ten of these 25 achieved a CR (40%), and eight did not complete therapy. Of the 15 patients not completing this study, one patient achieved a CR and eight achieved a partial response (PR). Eight of 46 (17%) were removed from study for reasons of toxicity (6% to 13%) or tumor progression (2% to 4%). The remaining seven were removed due to intercurrent medical conditions (four uncomplicated pneumonias and one gun shot wound) or lost to follow-up (2). Myelosuppression, mucositis, and skin toxicity increased in frequency by the end of the trial but were acceptable and reversible. The activity of this five-course regimen is promising given the advanced disease status of patients treated. Consideration of concurrent medical conditions, patient compliance, intensity of medical, nutritional and social support, and levels of acceptable toxicity will be necessary in the design of future, intensive induction trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Random Allocation; Statistics as Topic

We evaluated postoperative complications in a randomized series of patients with head and neck cancer who received preoperative chemotherapy. Forty-two patients with advanced squamous carcinoma of the head and neck were randomized to receive either high-dose methotrexate with leucovorin calcium rescue (23 patients) or no chemotherapy (19 patients) prior to definitive conventional treatment. The two groups of patients were balanced by sex, disease site, stage, histologic grade, and prior therapy. Sixteen of the 23 patients receiving preoperative chemotherapy had postoperative complications, whereas only eight of 19 patients not receiving chemotherapy had postoperative complications. Surgical complications included wound infections, orocutaneous fistulas, and flap necrosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Neoplasm Staging; Postoperative Complications; Random Allocation; Retrospective Studies

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Clinical Trials as Topic; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Prognosis; Random Allocation

This prospective study has established the effectiveness and safety of two courses of a combination of vincristine, bleomycin, methotrexate, 5-FU, and hydrocortisone with a folinic acid "rescue" given over 24 hours on Days 1 and 14 prior to surgery and/or radiotherapy in 93 patients with advanced (stage III and IV) untreated epidermoid cancer of the head and neck. Of 91 patients evaluated on Day 28 for chemotherapy response, 58 (64%) had a partial remission and 33 (36%) were classified as nonresponders, although 12 had a minimal response of 20%-30%. After completion of local therapy, 73% of the chemotherapy responders achieved complete remission compared with only 48% of the nonresponders (P = 0.005). Forty-seven percent of the patients achieving complete remission were alive at 5 years compared with only 4% of those with residual disease after local therapy. Response to chemotherapy is a good prognostic sign. Side effects were minimal and there was 100% patient compliance.

Topics: Adult; Aged; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Hydrocortisone; Leucovorin; Male; Methotrexate; Middle Aged; Prognosis; Prospective Studies; Vincristine

In order to determine whether combination chemotherapy offered any advantage over single-agent therapy in cases of metastatic non-small cell bronchogenic carcinoma, we performed a randomized study in 56 patients comparing combination chemotherapy (cyclophosphamide, doxorubicin, methotrexate, procarbazine, leucovorin--CAMP-L) with a regimen in which the same drugs were given sequentially (methotrexate/leucovorin followed by cyclophosphamide/doxorubicin at progression). Of the patients receiving the combination, 52% (14 of 27) had either a partial response or stable disease, compared to 17% (5 of 29) in the sequential group. Of the patients with adenocarcinoma, those in the combination group had a significantly longer survival than those treated in the sequential group (medians, 10.0 vs 2.8 months; P less than 0.01); such a difference could not be demonstrated for patients with squamous carcinoma. Patients who achieved a partial response had a median survival of 15.3 months; those with stable disease survived a median of 10.0 months; and those with no response survived a median of 2.5 months (P less than 0.0001). Four patients died from chemotherapy-related complications: three from methotrexate toxicity and resultant infection and one from pneumonia associated with neutropenia. We conclude that the short survival of non-responding patients and the survival benefit accompanying response or stabilization make early aggressive combination therapy useful for patients with metastatic non-small cell lung cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Cyclic AMP; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Procarbazine

Eighty patients with recurrent squamous cell cancer of the head and neck were randomized to cisplatin (80 mg/m2) every 3 weeks or cisplatin plus weekly methotrexate (250 mg/m2) with leucovorin. The overall response rate to cisplatin was 18%, with 10% complete responses. The overall response to the combination was 33% with 18% complete responses (P = 0.11). There was no difference in response duration, time to progression, or survival. There was no difference in renal toxicity between the 2 arms (creatinine greater than 2 mg/dl in 6% of the patients). There was significantly more leukopenia (64%), thrombocytopenia (18%), anemia (18%), and mucositis (33%) in the combination arm. This combination of two of the best agents for head and neck cancer did not improve response, but resulted in added toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; California; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Neoplasm Recurrence, Local; Probability; Random Allocation

A clinical trial of moderate dose methotrexate (MTX)-CF rescue was conducted in 12 institutions. Thirty-seven patients with head and neck carcinoma entered this trial, of which 32 were evaluable. MTX was administered 350 mg/m2 (500 mg/body) by i.v. drip over 6 hours. Three hours after completion of MTX infusion, CF rescue was started. There was no complete response in 32 patients. Nine patients showed partial response with the response rate of 28%. The response rates were 21% for the group of patients treated previously, and 75% for the group untreated previously. MTX concentration in plasma was determined at 6, 24, 48 and 72 hours after the initiation of MTX infusion, and the assay results revealed a safe range. GI disturbances were seen at the rates of 11 to 38%. Bone marrow suppression was mild and no renal toxicity was observed. We concluded that the moderate dose MTX-CF rescue therapy was useful for head and neck carcinoma. As a next step, we are planning to conduct a clinical trial of high-dose MTX.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Middle Aged

Patients presenting with Stage III-IV squamous carcinoma of the head and neck often relapse following aggressive surgery and/or radiotherapy. In an attempt to increase survival in this high risk group of patients, HD-MTX, 3 gm./m2/dose, given weekly, was administered to 21 inoperable patients with Stage III/IV squamous carcinoma of head and neck prior to, and for 1 month after, definitive surgery and/or radiotherapy. Six of 11 patients (55%) who showed a significant response (greater than 50% reduction in tumor volume) to HD-MTX are alive and free of tumor greater than 38 months following treatment (p = 0.6) (Fisher Exact Test). Responder median survival is greater than 38 months while non-responder median survival is 15 months (p = .02) (Log Rank Test). For the entire treatment group, at a mean duration of 44.2 months following initiation of therapy, 7 patients (33%) remain alive and free of tumor. Patients responding to induction MTX-LCV more often become eligible for combined modality approach than did the non-responder group. This "downstaging" of the tumor prior to aggressive surgery or radiotherapy may be responsible for the increased survival rate seen in those patients who responded to MTX-LCV.

Topics: Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

Fifty-eight patients with advanced squamous cell cancer of the head and neck have been randomized on a study comparing three different weekly methotrexate (MTX) dose levels followed at 24 hours by standardized folinic acid rescue. Eighteen patients received MTX 5 g/m2, 24 patients received 500 mg/m2, and 16 patients received 50 mg/m2. The initial response rate according to treatment were 50%, 21% and 31%, respectively. Six patients crossed from low- to medium-dose MTX after failing to respond (four) or relapsing, and one in each group had a tumor response. Eleven patients crossed over from initial medium-dose to high-dose MTX after failing to respond (ten) or relapsing, and one in each group had a tumor response. The median time to maximum response was 3.5 weeks. There were only two complete responders, and one is disease free more than 19 months after starting treatment and more than 15 months after stopping treatment. The high-dose MTX treatment was significantly more toxic than lower doses, and there were four drug-related deaths (three in the high-dose group). The preliminary results of this study support the notion of a dose-response relationship to MTX in advanced squamous cell cancer of the head and neck.

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Random Allocation

Eight patients with epidermoid carcinoma of the penis received methotrexate, five with high-dose methotrexate, 250--1500 mg/m2 with citrovorum rescue Q 2--4 weeks, and three with low-dose methotrexate, 0.5--3.0 mg/kg weekly. Three (38%) patients achieved a complete or partial remission which persisted for 11, 3 and 2 months, respectively. Methotrexate appears to be an active agent in the treatment of advanced penile cancer.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Penile Neoplasms; Remission, Spontaneous; Time Factors

Topics: Adult; Aged; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Laryngeal Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Mouth Neoplasms; Pharyngeal Neoplasms

Twenty-three patients with advanced recurrent head and neck carcinoma were randomized to receive either high dose methotrexate with calcium leucovorin rescue (HDMTX) or HDMTX in combination with bacilli Calmette Guerin (HDMTX/BCG). An additional eight patients were treated with escalating doses of HDMTX ranging from 1 to 7 g of methotrexate. Of 12 patients receiving HDMTX, one complete response and two partial responses were noted. Of 11 patients in the HDMTX/BCG group, one complete response and two partial responses were observed. Only one partial response was noted in eight patients receiving escalating doses of the drug. Responses were brief and no significant difference in response duration was seen in any particular group. Toxicities in all groups were tolerable. BCG did not improve response rate, median duration of response, or median survival in these patients. Reported experiences with high dose methotrexate have been reviewed and again, responses to "high dose methotrexate" were found to be of brief duration. Despite acceptable toxicity, the brief duration of response and cost of such therapy raises serious question on the usefulness of chemoimmunotherapy utilizing high dose methotrexate with leucovorin rescue and BCG in the management of advanced recurrent carcinomas of the head and neck region.

Topics: Adult; Aged; BCG Vaccine; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Middle Aged; Stomatitis

Topics: Adult; Aged; Carcinoma, Squamous Cell; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Leucovorin; Methotrexate; Middle Aged; Ovarian Neoplasms; Vincristine

Since January 1974, 95 patients with anterior tongue and floor of the mouth cancers were included in a randomized trial. After stratification according to staging and initial treatment, one-third of the patients received chemotherapy for 2 years (methotrexate 400 mg followed by citrovorum factor 100 mg + bleomycin 60 mg/week, during the first 15 weeks), one-third of the patients received immunotherapy with weekly C. parvum injections during 2 years, while the remaining third did not receive any treatment. If adjuvant treatment seems to delay recurrence it did not significantly decrease the recurrence rate. Survival is also not signigicantly modified by adjuvant treatment and was better for patients with small tumors. Patients who previously received radiotherapy did not benefit from adjuvant therapy.

Topics: Antigens, Bacterial; Bleomycin; Carcinoma, Squamous Cell; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Mouth Floor; Mouth Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Propionibacterium acnes; Random Allocation; Tongue Neoplasms

The application of some basic principles derived from studies of the cell cycle and proliferative kinetics of normal and malignant cells has provided a rational basis for designing cancer treatment protocols. Using this approach in advanced head and neck cancer it is possible (a) to increase the response rate, (b) to reduce toxicity and (c) to reduce in-patient hospital stay time. Seventy-one patients with advanced carcinoma of the head and neck were randomized for treatment between two combination schedules, one with and the other without adriamycin. Responses (more than 50% tumour regression) were 74% overall with 70% responding to the combination without adriamycin and 82% responding to the schedule containing it. The increase in response rate seen with adriamycin is not statistically significant. Prior radiotherapy significantly reduced the likelihood of response to chemotherapy. These results have major implications for adjuvant chemotherapy and suggest a possible way of increasing the survival time in this group of diseases.

Topics: Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Doxorubicin; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplastic Cells, Circulating; Vincristine

Thirty patients with operable epidermoid carcinoma of the head and neck were treated with intravenous high dose methotrexate and leucovorin rescue prior to resection. Their clinical courses were compared with those of thirty randomly selected patients matched for tumors site and clinical stage who were treated by surgery alone. No medical or surgical complications associated with methotrexate were encountered. An objective decrease in tumor size (primary lesion or nodal metastases) was noted prior to resection in twenty-three patients (77 per cent). The number of recurrences in the two groups was similar. However, these was a significantly greater disease-free interval in the methotrexate-treated patients (p less than 0.05). No significant differences in survival have been noted to date between the two groups. In view of the absence of complications, the regressions in tumor size, and the increase in postoperative disease-free interval in this trial, evaluation as preoperative adjuvants of higher doses of methotrexate and of other chemotherapeutic agents in combination with methotrexate appears warranted.

Topics: Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Neoplasm Recurrence, Local; Postoperative Complications

Topics: Adult; Aged; Carcinoma, Squamous Cell; Clinical Trials as Topic; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Mouth Neoplasms

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli's disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour a

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Female; Fluorouracil; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Tongue Neoplasms

The standard chemotherapy treatment protocol for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) requires as long as 56 days of hospitalization over six months. Where the 5-Fluorouracil (5-FU) pump is available, most treatment will be on outpatient bases, however patients will still be under chemotherapy treatment for a comparable period of time (around 50 days).. A modified protocol was assessed to decrease hospitalization and/or chemotherapy treatment time without sacrificing outcomes, to potentially increase patient quality of life.. A retrospective analysis (2005-2018) of recurrent/metastatic HNSCC patients with a modified treatment protocol was performed. Treatment consisted of cisplatin, cetuximab, 5-fluorouracil bolus and leucovorin administered on day 1 of a 2-week cycle, and a continuous infusion of 5-fluorouracil on days 1-2 of the cycle. Outcomes were measured by progression-free survival, overall survival, and patient hospitalization time. Analysis was done using the Kaplan-Meier survival function curve. The study cohort consisted of 27 patients. The modified treatment protocol resulted in a median progression-free survival of nine months and median overall survival of 14 months, while hospitalization time was reduced by almost 80% in the first six months of treatment.. Modification of the cisplatin, cetuximab, 5-FU and leucovorin protocol to a bi-weekly regimen utilizing alternative drug delivery methods, significantly reduced patient hospitalization from 56 days to 12 days in the first 6 months of treatment. This was achieved without compromising treatment outcome, while significantly reducing the days patients were exposed to chemotherapy, and thus potentially improving quality of life.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cetuximab; Cisplatin; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Recurrence, Local; Quality of Life; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome

The optimal dose in esophageal cancer patients treated with definitive chemoradiation (CRT) remains debated. We herein report on the dosimetric results, treatment-related toxicities and long-term outcomes of escalated dose up to 60Gy delivered with intensity-modulated radiotherapy (IMRT).. All consecutive patients that received a definitive CRT>50Gy for an unresectable esophageal carcinoma between 2010 and 2015 were retrospectively evaluated for this study. Methodology included data base search, delayed toxicity grading, statistical testing including frequency analysis and survival analysis.. A total of 51 patients were irradiated for a squamous cell carcinoma (86.3%) or an adenocarcinoma (13.7%). The median age at diagnosis was 62 years. Seven patients were simultaneously irradiated for another synchronous primary tumor. Forty-six patients (90.2%) received concurrent platin-based chemotherapy. The median prescribed doses were 60Gy (54-66) and 48Gy (44.8-56) delivered in 30 (27-35) fractions to the high and the low risks PTV respectively. The mean dose delivered to the lungs was 11.4Gy (IC 95%: 4.8-19.8), the median volumes receiving up to 20Gy (V20) and 30Gy (V30) were 13.5% (3.0-46.0) and 4.6% (0.7-19.8) respectively. The mean dose delivered to the heart was 13.9Gy (IC 95%:0.3-31.3) with a median V40 of 3.3% (0.0-25.0). One treatment-related death occurred within days after RT completion (neutropenic aplasia). After a median follow-up of 2.7 years (95% CI: 1.9-4.3), the 2-year overall survival, disease free survival and loco-regional control rates were 53.6%, 42.0% and 72.8% respectively. Delayed treatment related-toxicities ≤grade 3 occurred among 25 patients (62.5%) mostly esophageal stricture (79.2%).. We demonstrated in this study that dose escalation using IMRT in combination with platin-based chemotherapy as a definitive treatment for esophageal carcinoma is safe and results in higher loco-regional and control survival when compared to previously reported data.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Disease-Free Survival; Dose Fractionation, Radiation; Esophageal Neoplasms; Esophageal Stenosis; Female; Fluorouracil; Heart; Humans; Leucovorin; Lung; Male; Middle Aged; Organoplatinum Compounds; Organs at Risk; Radiation Tolerance; Radiotherapy, Intensity-Modulated; Retrospective Studies; Time Factors; Treatment Outcome

The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. This is a case report of a 70-year-old female with a history of skin squamous cell carcinoma presenting with occult hematochezia. Colonoscopy and biopsy results confirmed a microsatellite stable (MMS) adenocarcinoma in the ascending colon, and subsequent computed tomography (CT) scans identified a 3.2 cm right colonic mass and a 5.0 cm mass in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) confirmed the presence of pancreatic ductal adenocarcinoma (PDAC). The patient underwent neo-adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) chemotherapy prior to the simultaneous distal pancreatectomy and right hemicolectomy for both pancreatic and colonic tumors. The pathology diagnoses included moderately differentiated pancreatic ductal carcinoma (PDAC) with histiocyte-like features (tumor stage: ypT3N1M0) and moderately differentiated colonic adenocarcinoma, intestinal type (tumor stage: ypT3N0M0). To the best of our knowledge, this is the first documented case of synchronous primary colonic adenocarcinoma and PDAC in the English literature.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasms, Multiple Primary; Oxaliplatin; Pancreatic Neoplasms; Skin Neoplasms

Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.. We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy - essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin - in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers.. Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval [CI], 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations.. FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Biomarkers, Tumor; Carcinoma, Squamous Cell; Female; Fluorouracil; Follow-Up Studies; Genomics; High-Throughput Nucleotide Sequencing; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

5-fluorouracil (5-FU) and cisplatin (CDDP) are common chemotherapy drugs used in the treatment of patients with advanced esophageal cancer. We investigated the efficacy of adding a continuous infusion of a large dose of a common adjuvant, citrovorumfactor (CF), to the traditional 5-FU/wCDDP regimen. 50 patients with advanced esophageal cancer were treated with a continuous infusion of CF, 5-FU, and CDDP, and the short-term effects, adverse reactions, and survival periods after treatment were analyzed. Overall, the treatment was effective in 58% of patients, and the therapeutic effects of the first-line of chemotherapy were significantly better than the second-line (u = 4.121, p < 0.05). Patients experienced severe nausea and vomiting in 18.7% of the treatment cycles and experienced severe hair loss or leucopenia in 1.9% of the treatment cycles. The majority of the treatment cycles produced only mild side effects. The median survival period following chemotherapy treatment was 10.6 months (95% confidence interval was 8.146 ~ 13.054 months), with the median survival time of patients with a Karnofsky Performance Status (KPS) score ≥ 80 being significantly longer than that of patients with KPS scores < 80 (χ

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chi-Square Distribution; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Karnofsky Performance Status; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Risk Factors; Time Factors; Treatment Outcome

We aimed to investigate the efficacy of second line treatment with modified FOLFOX6 (mFOLFOX6) following cisplatin- plus 5-fluorourasil (CF) chemotherapy in patients with metastatic esophagus cancer (mEC).. In our oncology clinic, between March 2011 and September 2014, we reviewed patients admitted with progressive mEC following first line CF chemotherapy and those with >60 kanofsky performance status performed second line mFOLFOX6 regimen.. A total of 242 patients with mEC were evaluated. 94 of 242 patients (38.8%) had received second-line chemotherapy treatment. All of these patients had received mFOLFOX6 regime. Median age was 53 years (range: 28-71). The received median number of chemotherapy cycles was 6 (2-12). Objective response rate (ORR) was obtained in 39 of 94 (41.4%) patients, 6 (6.3%) of these had complete response (CR) and 33 (35.1%) had partial response (PR). Stable disease (SD) was obtained in 20 (21.3%) patients and progression was observed in 35 (37.3%) patients. Grade ¾ toxicity was observed in 67 (71.2%) patients. The hematologic toxicity was found as the most common toxicity (69.1%).. mFOLFOX6 regimen as a second line treatment can be applied to the mEC patients with progressive disease following CF chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Squamous Cell; Cohort Studies; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome

To compare chemotherapy first (group 1) versus self-expanding metal stent first (group 2) for the management of malignant dysphagia in unresectable oesophageal or gastro-oesophageal junction cancer.. Patients from two university hospitals with severe malignant dysphagia (dysphagia score ≥ 2) uneligible for surgery or radiochemotherapy were evaluated retrospectively.. Forty-two patients were included in group 1, and 29 in group 2. After 4 weeks, dysphagia scores improved by at least 1 point in 67% of patients in group 1 versus 93% in group 2 (p=0.01); 48% of patients in group 1 were able to eat solid food versus 68% in group 2 (p=0.054). In group 1, a self-expanding metal stent was secondarily placed in 18 patients (42.9%), whereas in group 2 dysphagia required a second self-expanding metal stent placement in 33.3% of patients.. Chemotherapy as the first treatment may be a valid option, avoiding self-expanding metal stent insertion in half of the patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Deglutition Disorders; Endoscopy, Gastrointestinal; Esophageal Neoplasms; Esophageal Stenosis; Esophagogastric Junction; Esophagoscopy; Female; Fluorouracil; Gastroscopy; Humans; Leucovorin; Male; Metals; Middle Aged; Organoplatinum Compounds; Palliative Care; Quality of Life; Retrospective Studies; Severity of Illness Index; Stents

Basaloid squamous cell carcinoma (BSCC) is a high-grade variant of squamous cell carcinoma usually localized in the aerodigestive tract, with a poor prognosis. Surgical resection is generally recommended, even if no standard treatment has been established yet.. Here, we report the case history of a patient diagnosed with BSCC at the esophagogastric junction who was successfully treated with chemotherapy alone, leading to a durable complete response.. The presented case illustrates the diagnostic challenges associated with BSCC of the esophagus and reports an unexpected chemosensitivity of this histotype to the combination of a platinum salt plus 5-fluorouracil, which could represent an optimal treatment strategy in unfit patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Esophagogastric Junction; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Rare Diseases; Stomach Neoplasms; Treatment Outcome

Limited literature on the role of intraarterial chemotherapy as first-line therapy for penile squamous cell carcinoma is available.. From 2005 to 2013, a total of 12 patients with various stages of penile squamous cell carcinoma received intraarterial chemotherapy. The chemotherapeutic agents used were methotrexate, mitomycin C, bleomycin, cisplatin, and 5-fluorouracil. Surgery was followed by the tumour responses.. An objective tumour response was noted in 10 of 12 patients (83%, 4 complete responders and 6 partial responders). In node-negative patients (n=7), the response rate was 100% (4 complete responders and 3 partial responders). Even in advanced penile squamous cell carcinoma with nodal invasion, a response rate of 60% could be achieved. Grade 2 anorexia was the most frequent chemotherapy-related toxicity and no toxic death was noted. Recurrence-free survival was significantly better in patients without lymph node invasion (log-rank test, P=0.041).. Neoadjuvant intraarterial chemotherapy displayed excellent responses for penile squamous cell carcinoma. This therapy could effectively shrink the tumour burden or even achieve complete response before surgery. It could be used as first-line strategy for penile cancer treatment because of low toxicity.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carboplatin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Fluorouracil; Humans; Infusions, Intra-Arterial; Inguinal Canal; Leucovorin; Lymph Node Excision; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Mitomycin; Neoadjuvant Therapy; Penile Neoplasms; Retrospective Studies

Topics: Adenocarcinoma; Aged; Anemia; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Carcinoma, Squamous Cell; Cecal Neoplasms; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Fibrinogen; Fibrinolysis; Fluorouracil; Heart Diseases; Hemorrhage; Humans; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Multiple Organ Failure; Neoplasms, Multiple Primary; Organoplatinum Compounds; Postoperative Complications; Thrombosis; Tranexamic Acid; Vulvar Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Mitomycin; Multimodal Imaging; Neoadjuvant Therapy; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy, Intensity-Modulated; Rectal Neoplasms; Tomography, X-Ray Computed

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Carcinoma, Squamous Cell; Cecal Neoplasms; Chemotherapy, Adjuvant; Colectomy; Fluorouracil; Humans; Laparoscopy; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Central Venous Catheters; Esophageal Neoplasms; Extravasation of Diagnostic and Therapeutic Materials; Fluorouracil; Humans; Iatrogenic Disease; Leucovorin; Male; Mediastinitis; Mediastinum; Organoplatinum Compounds; Oxaliplatin

Cervical oesophagus represents a critical location for squamous cell carcinoma, which usually requires extensive surgery (pharyngo-laryngo-oesophagectomy). In the last decade, neoadjuvant chemo-radiotherapy was reported to be beneficial in the treatment of locally advanced squamous cell oesophageal cancer.. Between November 1997 and January 2012, 55 patients with locally advanced (T3-4) squamous cell oesophageal cancer received preoperative chemo-radiotherapy, where the tumour was localized in the upper third. Patients received preoperative irradiation of 3960 cGy in 180 cGy fractions and simultaneously Cisplatin and 5-FU chemotherapy. Restaging was carried out after four weeks and patients considered operable were underwent surgery.. In patients with cervical oesophageal cancer 35 of 55 (64%) underwent oesophageal resection or pharyngo-laryngectomy. In 16 out of 35 resected specimens (46%) complete histopathological remission (pCR) was observed. Perioperative mortality and anastomotic leaks were the same: 5/35 (14%). R0 resection rate was 82% and the 2- and 5 years survival rates were 41% and 18%. In 19 cases a larynx preserving pharyngo-oesophagectomy was performed and a free jejunal graft was used for reconstruction after a pharyngo-laryngectomy in 11 cases.. The high rate of pCR (46%) confirmed that upper third oesophageal cancer has superior sensitivity to multimodal treatment. In 30 cases neoadjuvant chemo-radiotherapy was able to achieve tumour regression and render pharyngo-laryngo-oesophagectomy unnecessary.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Disease Progression; Dose Fractionation, Radiation; Drug Administration Schedule; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Laryngectomy; Length of Stay; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Pharyngectomy; Radiotherapy, Adjuvant; Treatment Outcome

To review the experience with and evaluate the treatment plan for helical tomotherapy for the treatment of oropharyngeal cancer.. Between November 1, 2006 and January 31, 2009, 10 histologically confirmed oropharyngeal cancer patients were enrolled. All patients received definitive concurrent chemoradiation with helical tomotherapy. The prescription dose to the gross tumor planning target volume, the high-risk subclinical area, and the low-risk subclinical area was 70 Gy, 63 Gy, and 56 Gy, respectively. During radiotherapy, all patients were treated with cisplatin, 30 mg/m(2), plus 5-fluorouracil (425 mg/m(2))/leucovorin (30 mg/m(2)) intravenously weekly. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. Several parameters, including maximal or median dose to critical organs, uniformity index, and conformal index, were evaluated from dose-volume histograms.. The mean survival was 18 months (range, 7-22 months). The actuarial overall survival, disease-free survival, locoregional control, and distant metastasis-free rates at 18 months were 67%, 70%, 80%, and 100%, respectively. The average for uniformity index and conformal index was 1.05 and 1.26, respectively. The mean of median dose for right side and left side parotid glands was 23.5 and 23.9 Gy, respectively. No Grade 3 toxicity for dermatitis and body weight loss and only one instance of Grade 3 mucositis were noted.. Helical tomotherapy achieved encouraging clinical outcomes in patients with oropharyngeal carcinoma. Treatment toxicity was acceptable, even in the setting of concurrent chemotherapy. Long-term follow-up is needed to confirm these preliminary findings.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Oropharyngeal Neoplasms; Parotid Gland; Radiodermatitis; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Stomatitis; Tumor Burden

Our aim was to report the outcomes of base of tongue cancers treated with chemoradiotherapy.. Between 1990 and 2004, 127 patients with stage III or IV base of tongue cancer were treated with chemoradiotherapy on protocol. Indications included nodal involvement, T3/T4 tumors, positive margins, those patients refusing surgery, or were medically inoperable. The most common regimen was paclitaxel (100 mg/m2 on day 1), infusional 5-fluorouracil (600 mg/m2/day × 5 days), hydroxyurea (500 mg prescribed orally [PO] 2 × daily [BID]), and 1.5 Gy twice daily irradiation followed by a 9-day break without treatment.. Median follow-up was 51 months. The median dose to gross tumor was 72.5 Gy (range, 40-75.5 Gy). Five-year locoregional progression-free survival, overall survival, and disease-free survival was 87.0%, 58.2%, and 46.0%, respectively.. Concurrent chemoradiotherapy results in promising locoregional control for base of tongue cancer. As distant relapse was common, further investigation of systemic therapy with novel agents may be warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Female; Fluorouracil; Humans; Hydroxyurea; Interferon alpha-2; Interferon-alpha; Irinotecan; Leucovorin; Male; Middle Aged; Neck Dissection; Paclitaxel; Radiotherapy Dosage; Radiotherapy, Adjuvant; Radiotherapy, Intensity-Modulated; Recombinant Proteins; Tongue Neoplasms

Combined treatment modality, e.g., definitive surgery followed by radiotherapy (RT) and definitive RT with concurrent chemotherapy, has been applied for advanced maxillary sinus squamous cell carcinoma (MSSCC) patients to obtain a better survival with organ preservation in Japan.. The outcome of 40 patients with MSSCC between 1991 and 2007 in our institute was analyzed retrospectively. There were 36 males and 4 females, the average age being 59.5 years (ranging from 34 to 81 years). The median follow-up time was 66.1 months. All the patients had received a combined treatment consisting of definitive surgery, RT, and intra-arterial or systemic chemotherapy. The chemotherapeutic regimen was different depending on the performance status and/or complications of the patients. Since 1998, concurrent chemoradiotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin regimen (CCRT-PFML) instead of neo-adjuvant chemotherapy has been applied.. The overall 5-year survival rate was 59.2%, the 5-year disease-specific survival rate was 71.7%, and the 5-year organ preservation survival rate was 42.4%. In the group receiving CCRT-PFML, the overall 5-year survival rate was 60.0%, the 5-year disease-specific survival rate was 76.0%, and the 5-year organ preservation survival rate was 60.3%.. CCRT-PFML for advanced MSSCC patients is feasible to preserve the organs without reducing the survival rate.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Maxillary Sinus; Methotrexate; Middle Aged; Neoadjuvant Therapy; Organ Preservation; Paranasal Sinus Neoplasms; Retrospective Studies; Tegafur; Treatment Outcome; Uracil

Malignant transformation in a mature cystic teratoma of the ovary is rare. The most common malignancy is squamous cell carcinoma, which consists of about 75% of malignant transformations. In the present report, we describe a case of advanced-stage squamous cell carcinoma arising in a mature cystic teratoma. A postmenopausal 63-year-old woman with squamous cell carcinoma arising in a mature cystic teratoma is presented. The initial investigation by ultrasound showed a left adnexal mass with mixed echo pattern, which arose the suspension of malignancy. She underwent a laparotomy and left oophorectomy. Histopatholog was compatible with squamous cell carcinoma arising in a mature cystic teratoma. After a few episodes of intestinal obstruction and colostomy, she underwent partial resection of the ileum and sigmoid colon four months after the initial oophorectomy. Histopathologic study showed metastatic poorly-differentiated squamous cell carcinoma. Subsequently, she underwent two courses of combination chemotherapy with cisplatin, leucovorin, and 5-fluorouracil with no response. She died from progression of the disease nine months after the initial operation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Colostomy; Fatal Outcome; Female; Fluorouracil; Humans; Ileal Neoplasms; Intestinal Obstruction; Leucovorin; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms; Ovariectomy; Sigmoid Neoplasms; Teratoma; Ultrasonography; Vitamin B Complex

To determine the efficacy and safety profile of the combination of cisplatin and 5-fluorouracil modulated both by methotrexate and leucovorin in metastatic/recurrent squamous cell carcinoma of the head and neck.. Twenty-eight patients were treated with cisplatin 40 mg/m2/day continuous infusion for 24 hours on day 1; high-dose 5-fluorouracil 2,000 mg/m2/day and leucovorin 100 mg/m2/day continuous infusion for 48 hours on days 1 and 2; methotrexate 40 mg/m2/day as a bolus infusion 4 hours before 5-fluorouracil and leucovorin on day 1. The treatment was repeated every 2 weeks in a cycle.. The overall response rate was 25%, and 14% of the patients achieved stable disease status. Subgroup analysis demonstrated significantly improved overall survival in the disease-control group (12.0 months vs. 5.3 months, p<0.001). Only 3 (10.7%) patients developed grade 3-4 neutropenia, and none developed grade 3-4 non-hematologic toxicity.. This multiagent-containing regimen has an excellent safety profile and improved survival in disease-control group of patients with metastatic/recurrent squamous cell carcinoma of the head and neck.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Treatment Outcome; Vitamin B Complex

A 52-year-old woman was referred to our hospital for treatment of urachal cancer. She complained of supurapubic dull pain and gross hematuria. Computed tomography and magnetic resonance imaging showed a non-papillary sessile tumor, which was located on the dome of the bladder and invaded the small intestine. The tumor was diagnosed as Sheldon's stage IIIC urachal cancer. After three courses of neoadjuvant chemotherapy with FOLFOX4 (oxaliplatin, 5-FU and leukovolin), the tumor was reduced from 7 x 6 cm to 5.5 x 5 cm in size. Consequently, the patient underwent an en-bloc resection of the urachal tumor with the dome of the bladder and the parts of the ileum invaded by the tumor. One course of adjuvant chemotherapy (FOLFOX4) was performed. Surgical specimen revealed histologically well differentiated squamous carcinoma and invasion to the propria of the ileum. The surgical margins were negative for the cancer. For 1.5 years after the surgery, no local recurrence or distant metastasis has been observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Fluorouracil; Humans; Ileal Neoplasms; Leucovorin; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Organoplatinum Compounds; Treatment Outcome; Urachus; Urinary Bladder Neoplasms

5-Fluorouracil, usually in combination with folinic acid, is widely used in the treatment of both colorectal and head and neck squamous cell cancer patients. Since 5-fluorouracil plus folinic acid and the antifolate thymidylate synthase inhibitor; raltitrexed have distinct mechanisms of action and toxicity profiles, we have evaluated the potential synergistic antitumor interaction between these two agents combined with a sequential schedule of administration in KB (wt-p53) and Cal27 (mut-p53) head and neck squamous cell carcinomas, and LoVo (wt-p53) and HT29 (mut-p53) colorectal cell lines. The combination between a 24-h exposure to raltitrexed followed by a 4-h exposure to 5-fluorouracil plus folinic acid was globally synergistic, as assessed by the median effect principle and combination index. A specific contribution of folinic acid to the cytotoxic effect of the raltitrexed/5-fluorouracil combination was clearly demonstrated by the evaluation of the potentiation factor. In all cell lines, a 1.5- up to 17-fold reduction in the IC50 of both raltitrexed and 5-fluorouracil plus folinic acid was observed in the combination setting compared with the concentrations of the each drug used alone. Moreover, we demonstrated that raltitrexed/5-fluorouracil plus folinic acid induced a distinct S-phase block of the cell cycle, as well as a potentiation of the apoptotic cell death, compared with 5-fluorouracil plus folinic acid or raltitrexed/5-fluorouracil combination. This preclinical work represents, at least to our knowledge, the first demonstration of a synergistic interaction between raltitrexed and 5-fluorouracil modulated by folinic acid, and could represent a rationale for further clinical investigation of raltitrexed/5-fluorouracil plus folinic acid combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Fluorouracil; Head and Neck Neoplasms; Humans; Inhibitory Concentration 50; Leucovorin; Quinazolines; Thiophenes

The purpose of treatment in patients with advanced and metastatic esophageal cancer is to improve symptoms and maintain quality of life. Recently, the regimen including epirubicin, cisplatin, and 5-FU (ECF) has been used with protracted venous infusion (PVI), and has been reported to be an effective treatment for advanced and metastatic esophagogastric cancer. However, complications and the inconvenience associated with PVI cannot be justified for the treatment of advanced esophageal cancer. Therefore, we provided treatment with oral UFT and leucovorin instead of 5-FU PVI to improve convenience and catheter related complications.. Thirty-seven patients with advanced esophageal cancer were admitted between March 2002 and April 2005. The treatment schedule was as follows: epirubicin 50 mg/m2 iv on d 1, cisplatin 60 mg/m2 iv on d 1, oral UFT 300 mg/m2 and leucovorin 75 mg for 21 consecutive days of treatment followed by a 7-d treatment-free interval.. The response rate was 45.9% including one complete response (95% CI: 29.8%-62%). The median survival was 13 mo (95% CI: 10-16 mo). Four patients had adenocarcinoma. Interestingly, their response rate was 75% including one complete response. Myelosuppression was the most important toxicity. Other toxicities were tolerable.. The combination of epirubicin, cisplatin, UFT, and leucovorin (EPUL) could be another alternative to ECF in patients with advanced esophageal cancer. And this treatment might be more effective in adenocarcinoma of esophageal cancer.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Epirubicin; Esophageal Neoplasms; Female; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Survival Rate; Tegafur; Treatment Outcome; Uracil

This regimen of concurrent chemoradiotherapy was safe and well tolerated. In terms of larynx preservation, the present regimen appears to be useful for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and hypopharynx.. To evaluate the efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced resectable SCC of the larynx and hypopharynx, and to demonstrate the feasibility of larynx preservation.. Forty-six eligible patients were treated. The chemotherapy regimen consisted of a combination of four drugs: cisplatin (60 mg/m(2), day 4), 5-fluorouracil (5-FU) (600 mg/m(2) given continuously for 120 h, days 1-5), methotrexate (MTX) (30 mg/m(2), day 1), and leucovorin (LV) (20 mg/m(2), days 1-5). Two cycles of this regimen were given every 4 weeks during radiotherapy. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8-2.0 Gray, to a total dose of 66.6-70.2 Gray.. The 3-year disease-specific survival rates of patients with laryngeal or hypopharyngeal SCC were 81.3% and 78%, respectively. The 3-year disease-specific survival rates with larynx preservation of patients with laryngeal or hypopharyngeal SCC were 46.7% and 59%, respectively. The main toxicities were neutropenia, dermatitis, mucositis, and infection.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Female; Fluorouracil; Humans; Hypopharynx; Laryngeal Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Pharyngeal Neoplasms; Radiotherapy, Adjuvant; Survival Analysis; Treatment Outcome; Vitamin B Complex

A 56-year-old man was hospitalized for evaluation of left neck tumor. The biopsy of neck lymph node showed a squamous cell carcinoma. Since no primary lesion was detected, the diagnosis was primary unknown neck lymph node metastasis. The first course of our chemotherapeutic regimen consisted of CDDP, 5-FU, MTX and LV. After MTX infusion, the level of serum creatinine increased. Based on laboratory data, we diagnosed acute renal failure caused by MTX and added the infusion of Ringer and LV. The serum creatinine level decreased to the level before chemotherapy. In the second course, chemotherapy with only CDDP and 5-FU was administered, and the level of serum creatinine did not increase. In the present case, suitable intravenous drip infusion of Ringer's injection prevented irreversible renal dysfunction. Since the laboratory data did not show dysfunction of uriniferous tubule and renal glomerulus, we considered allergic nephritis as a possibility.

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Male; Methotrexate; Middle Aged

When surgical resections are performed for patients with locally advanced head and neck cancer, a critical consideration is which organs and functions of patients are sacrificed. In attempts to improve the organ preservation rate in patients with advanced squamous cell carcinoma of the head and neck (SCCHN), chemotherapy has been used either before(neoadjuvant or induction), with (concurrent or concomitant), after (adjuvant) radiotherapy, or as alternating treatment with radiotherapy. A recent systematic review using meta-analysis has revealed that concurrent chemotherapy with radiotherapy shows a significant benefit for the survival rate of patients with SCCHN when compared with radiotherapy alone, and is superior to neoadjuvant chemotherapy. However, no standard concurrent chemoradiotherapy regimen has been defined,although concurrent chemotherapy together with regimens including cisplatin has been considered to be most effective for SCCHN. We combined radiotherapy concurrently with chemotherapy including cisplatin, 5-fluorouracil, methotrexate, and leucovorin in patients with advanced resectable SCC of the hypopharynx to minimize the necessity of radical surgery and preserve the functional larynx. In conclusion, previous reports and our data show that an organ preservation treatment approach using concurrent chemoradiotherapy is feasible.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Larynx; Leucovorin; Male; Methotrexate; Middle Aged; Survival Rate

We encountered a patient with metastatic disease of the lung from oropharyngeal cancer who achieved a complete response to 3 cycles of chemotherapy with docetaxel, cisplatin, 5-FU and l-leucovorin (TPFL). A 72-year-old man was found to have metastatic disease of the lung 32 months after treatment of oropharyngeal squamous cell carcinoma. Chemotherapy was initiated with TPFL and the patient obtained a complete response after 3 cycles. Twelve months after chemotherapy he had no recurrence. We conclude that the use of docetaxel cisplatin, 5-FU and l-leucovorin for metastatic squamous cell carcinoma of the head and neck is a viable option.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Docetaxel; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Oropharyngeal Neoplasms; Remission Induction; Taxoids

Topics: Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Fluorouracil; Humans; Hydroxyurea; Interferon-alpha; Leucovorin; Nasopharyngeal Neoplasms; Sample Size; Time Factors

The goal of the current study was to evaluate the efficacy and toxicity of paclitaxel, cisplatin (P), tegafur (T), and leucovorin (L) as a neoadjuvant chemotherapy (CT) for patients with advanced, unresectable squamous cell carcinoma of the head and neck.. From November 1999 to January 2001, 21 consecutive patients (Stage IV, 100%; T4, 86%; and N3, 41%) were treated with paclitaxel-PTL (Day 1: paclitaxel, 120 mg/m(2) intravenous infusion for 3 hours; Day 1: P, 50 mg/m(2); T, 800 mg; and L, 60 mg orally daily over a 14-day cycle). Evaluation after three cycles led to CT termination if primary tumor responses were less than partial responses. Otherwise, paclitaxel-PTL was continued for up to six cycles before commencement of locoregional therapy.. CT responses were analyzed on an intent-to-treat basis. Response rates (RR) for the primary tumors were 81% (17 of 21), with 28.6% (6 of 21) showing a complete response (CR). RR and CR rates for the neck lymph nodes were 85.3% (15 of 18) and 22% (4 of 18), respectively. The combined RR for primary tumors and neck lymph nodes was 81% (95% confidence interval, 62.9-99.3%) with a CR rate of 19%. Grade 3/4 toxicities according to World Health Organization criteria included leukopenia, 19.0%; emesis, 9.5%; asthenia, 9.5%; mucositis, 4.8%; and neuropathy, 4.8%. Both the overall and disease-free survival rates were 14.3% (3 of 21), with a median follow-up of 41 months.. The relatively low toxicities and encouraging response rates demonstrated in the current study suggested that paclitaxel-PTL merits future trials in the setting of resectable tumors with more favorable characteristics.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Prognosis; Salvage Therapy; Survival Rate; Tegafur; Treatment Outcome

The authors conducted a series of four Phase I-II trials of high-dose and intermediate-dose docetaxel, cisplatin, and 5-fluorouracil (TPF)-based induction chemotherapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). The chemotherapy regimens and response rates for each trial were published previously. In the current analysis, the authors report the data on long-term survival, patterns of failure, and morbidity among the patients who were treated at their institution.. A total of 101 patients with previously untreated, locally advanced, curable SCCHN were entered onto the studies. Overall, 68 patients (67%) had N2-N3 disease, and 86 patients (85%) had Stage IV disease. Patients were treated with combinations of TPF with or without leucovorin. Cycles were repeated every 21-28 days for a total of 3 cycles followed by hyperfractionated radiotherapy.. After a median follow-up of 49 months, 65 patients (64%) remain alive with no evidence of disease (NED), and 3 patients remain alive with disease, for an overall survival rate of 67% (68 patients). Twenty-six patients had locoregional recurrences (LRR), and 5 patients had both LRR and distant metastasis (DM). Only five patients had DM as the sole site of failure. Four patients underwent salvage surgery at the primary site and remain alive with NED. Excluding 17 patients with nasopharyngeal carcinoma, of 84 patients, 55 patients remain alive with NED (65%). Notably, 43 of 84 patients (51%) had oropharyngeal primary tumors, and 30 of those patients remain alive with NED (70%). Significant morbidity was low, with two treatment-related deaths. All but two of the surviving patients are able to swallow and had their feeding tubes removed.. These data suggest that docetaxel adds incrementally to the efficacy of cisplatin and fluorouracil. Local-regional failures continue to be the major impediment to cure in these patients. Given the increase in local-regional dose intensity with chemoradiation, sequential treatment plans that integrate induction chemotherapy and chemoradiotherapy seem to be the logical next step.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Docetaxel; Dose Fractionation, Radiation; Fluorouracil; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Head and Neck Neoplasms; Humans; Leucovorin; Paclitaxel; Radiotherapy, Adjuvant; Survival Analysis; Taxoids; Treatment Failure; Treatment Outcome

Combination chemotherapy including 5-fluorouracil (5-FU) and nedaplatin (CDGP) with methotrexate (MTX) and leucovorin (LV) was administered for modulation in patients with head and neck cancer. We treated 19 patients with MTX.5-FU.CDGP consisting of 150 mg/body of MTX on day 1 followed by a 3-day continuous infusion of 5-FU at 3,500 mg/m2 and 17 injections of LV at 15 mg and infusion of CDGP at 100 mg/m2. Six patients had recurrent head and neck cancer, and 13 had newly diagnosed disease. Eleven of the new patients were concurrently treated with radiation therapy. Treatment-associated toxicity was significant, including mucositis and myelosuppression, but acceptable. Sixteen patients were eligible for evaluation of response. The overall complete response rate was 75.0% (12/16). Patients treated with radiotherapy had a 90.0% (9/10) overall complete response rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Organoplatinum Compounds; Radiography; Radiotherapy, Adjuvant; Remission Induction; Survival Analysis

A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and Leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Endothelial Growth Factors; Esophageal Neoplasms; Fluorouracil; Humans; Intercellular Signaling Peptides and Proteins; Leucovorin; Lymphatic Metastasis; Lymphokines; Male; Middle Aged; Organoplatinum Compounds; Tracheal Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The effect of preoperative chemotherapy on prognosis is still controversial. We have investigated the relationship between responses to preoperative chemotherapy and prognosis after curative operations in patients with esophageal squamous cell carcinoma. Thirty-nine patients received preoperative chemotherapy with continuous infusion of 500 mg/m2 of 5-fluorouracil (5-FU) and intravenous injection of 20 mg/m2 of leucovorin every 12 hours for 5 days. On the 5th day alone, 70 mg/m2 of cisplatin was also infused. The effect was evaluated approximately 14 days after the end of one course of chemotherapy. The rates of responders and non-responders were 64.1% and 35.9%, respectively. After an interval of 21-28 days, transthoracic esophagectomy was performed. Significant histological effect by chemotherapy was found in responders compared to non-responders (P < 0.05). Responders had a significantly better prognosis than non-responders by Log-rank test (P < 0.01). This suggests that preoperative chemotherapy may contribute to better prognosis when the tumor is sensitive to chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Case-Control Studies; Cisplatin; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Preoperative Care; Prognosis; Survival Rate; Time Factors

The relationship between the volumetric and histologic responses of metastatic cervical nodes to radiotherapy or chemotherapy in the oral and maxillofacial region is unclear. In this study, we evaluated the correlation between the initial volume and regression rate of metastatic nodes with their histologic response to preoperative radiotherapy or radiochemotherapy.. The volume of 54 metastatic nodes in 32 patients with squamous cell carcinoma in the oral and maxillofacial region was measured by ultrasonography before and after preoperative therapy, and the rate of the volume change was calculated. All surgically removed nodes were histologically classified as poor, good, or complete response according to their histologic features.. There was no significant difference in initial volume among the 3 response groups. Good and complete response nodes showed a significant increase in regression rate compared with poor response nodes. All 11 nodes showing no regression were poor response nodes, and 7 with a regression rate of more than 90% were good or complete response nodes. The remaining 36 nodes (regression rate, 0% to 90%) represented all 3 types of histologic response. Of these, 7 of 9 complete response nodes were found in 5 patients who received combination chemotherapy consisting of 5-fluorouracil, leucovorin, and cisplatin.. The initial nodal volume before therapy is not a good indicator for the response to radiotherapy and/or chemotherapy. A regression rate of more than 90% may be a useful predictor of the effectiveness of preoperative treatments, but it was difficult to define the cutoff values in regression rates for differentiating types of histologic response.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Mouth Neoplasms; Neck; Neoadjuvant Therapy; Remission Induction; Statistics, Nonparametric

For preservation of integrity of appearance and function in a 57-year-old male with a squamous cell carcinoma of his left big toe who had refused amputation, intra-arterial infusion with methotrexate was used.. To evaluate the effectiveness of arterial infusion with methotrexate in this uncommon big toe cancer.. Left external iliac arterial catheterization and infusion with methotrexate (50 mg) were used every 24 hours plus simultaneous intramuscular injection of 6 mg of leucovorin every 6 hours for 8 days.. At 7 years and 3 months after therapy, the patient was in sustained complete remission with a functionally normal left foot.. This case study suggests that intra-arterial infusion chemotherapy is a simple and effective method for big toe squamous cell carcinoma with the unique advantage of preservation of organ and function. It can be considered as an effective alternative treatment.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Hallux; Humans; Infusions, Intra-Arterial; Injections, Intramuscular; Leucovorin; Male; Methotrexate; Middle Aged; Skin Neoplasms

Nasopharyngeal carcinoma (NPC) is one of the dominant cancers in South China and Taiwan. Although NPC is highly chemosensitive, the use of chemotherapy for treating patients with recurrent or metastatic NPC has not been very successful. The emergence of drug resistance may be one of the major reasons. However, the mechanisms of drug resistance of NPC have never been addressed before. In this study, we sought to clarify the role of classical drug resistance markers in predicting the chemosensitivity and the prognosis of patients with advanced NPC.. In a cohort of 202 consecutive patients diagnosed at the Department of Pathology of the National Taiwan University Hospital, 44 patients with adequately preserved pretreatment tumor tissues and complete clinical information regarding the details of chemotherapy and tumor response were identified. The expression of multidrug resistance (MDR1), glutathione-S-transferase-pi (GSTpi), and p53 were determined by immunohistochemistry. Tumor response to chemotherapy and survival of the patients were the endpoints of this analysis.. Thirty-four patients received cisplatin-based regimens, and 28 of them were enrolled in a prospective trial using a doxorubicin-containing regimen. The overall response rate was 70%. Expression of MDR1 was seen in only 5 cases (11%) and was associated with a significantly worse overall survival, yet did not appear to predict chemoresistance to the doxorubicin-containing regimen. Overexpression of p53 was seen in 22 patients, and surprisingly, was correlated with chemoresponse and a trend towards better survival. GSTpi expression was demonstrated in 13 cases (30%) and was not correlated with chemoresistance to cisplatin-containing regimens and overall survival.. In this relatively small cohort, positive MDR1 immunostaining predicted a poor overall survival for recurrent or metastatic NPC patients receiving chemotherapy. Overexpression of p53 by immunohistochemical staining, however, was associated with a better response rate to systemic chemotherapy and a trend towards better survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cisplatin; Doxorubicin; Female; Fluorouracil; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Immunoenzyme Techniques; Isoenzymes; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Survival Rate; Tumor Suppressor Protein p53

We treated a patient with hypopharyngeal carcinoma who achieved a complete response following three cycles of chemotherapy with docetaxel, cisplatin, 5-FU and levofolinate. A 77-year-old Japanese male with hypopharyngeal carcinoma had undergone a radical esophageal operation and subsequent radiation therapy in the lower neck and upper mediastinum in 1991 because of esophageal carcinoma. He refused radical total laryngopharyngotomy, and agreed to chemotherapy. Three cycles of chemotherapy with docetaxel, CDDP, 5-FU and l-LV were then administered and no other therapy was given. Sixteen months after this chemotherapy he had no recurrence and no metastasis. We conclude that chemotherapy using docetaxel, cisplatin, 5-FU, and levofolinate will be useful for treating head and neck cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Docetaxel; Drug Administration Schedule; Fluorouracil; Humans; Hypopharyngeal Neoplasms; Leucovorin; Male; Paclitaxel; Remission Induction; Taxoids

The aim of this study was to evaluate the effect of preoperative chemotherapy on metastatic lymph nodes and on the outcome of patients who underwent esophagectomy for advanced squamous cell carcinoma of the esophagus. Fifty-nine patients with potentially resectable squamous cell carcinoma of the esophagus were studied. Twenty patients (group A) were treated by preoperative chemotherapy with cisplatin, 5-fluorouracil, and leucovorin, followed by surgery. Thirty-nine patients underwent surgery alone (group B). A total of 2591 resected lymph nodes were histologically evaluated for metastasis and the effect of chemotherapy. The metastasis rate in the resected lymph nodes, the number of metastatic lymph nodes, and outcome of the patients were statistically analyzed between groups. In group A, the clinical and pathological response rates were 75% and 75% respectively. The metastasis rate in the resected lymph nodes was significantly higher in group B (P < 0.01). The mean number of metastatic lymph nodes was significantly lower in group A (P < 0.05). Furthermore, the mean number of metastatic lymph nodes was significantly lower in the chemotherapy responders than in non-responders. The survival rate in group A was better than in group B (P = 0.07). Preoperative chemotherapy reduced the number of metastatic lymph nodes and may contribute to improving the outcome of the patients who have undergone esophagectomy for squamous cell carcinoma of the esophagus.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Carcinoma, Squamous Cell; Case-Control Studies; Chemotherapy, Adjuvant; Cisplatin; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Preoperative Care; Probability; Prognosis; Statistics, Nonparametric; Survival Analysis; Treatment Outcome

A previous study of 371 patients with extracapsular spread (ECS) of cervical metastases from squamous cell carcinoma (SCCA) of the head and neck revealed a survival advantage for patients treated with adjuvant chemoradiation, compared with those treated with surgery and radiation or surgery alone. While all patients in the study were offered adjuvant chemotherapy, only 35% selected this option. Comorbidity was identified as a reason for declining chemotherapy. Recently, Piccirillo demonstrated that the Modified Medical Comorbidity Index (MMCI) is a valid instrument to classify and quantify severity of comorbidity. We applied this instrument to previously reported patients with ECS to determine 1) how comorbidity affected treatment selection, 2) whether the survival advantage of adjuvant chemoradiation persisted after controlling for comorbidity, and 3) the impact of comorbidity on outcome.. This was a nonrandomized, retrospective study.. Patients in the initial study underwent resection of the primary tumor and neck dissection. Eligible patients elected to receive chemoradiation, radiation, or no further treatment. Comorbidity scores were assigned according to the MMCI. Data were analyzed according to disease-specific survival and overall survival.. The study population consisted of 330 patients. More severe comorbidity was related to higher overall mortality rates after controlling for treatment. Adjuvant chemoradiation resulted in improved disease-specific and overall survival compared with adjuvant radiation after adjusting for severity of comorbidity.. These results substantiate the benefits of adjuvant chemoradiation for patients with SCCA of the head and neck. Furthermore, these results reinforce the importance of comorbidity as a prognostic indicator for this population of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Comorbidity; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Lymph Node Excision; Lymphatic Metastasis; Methotrexate; Radiotherapy, Adjuvant; Radiotherapy, High-Energy; Retrospective Studies; Severity of Illness Index; Survival Analysis

The purpose of this study was to evaluate the efficacy and toxicity of an induction chemotherapy schedule followed by high-dose radiotherapy and concurrent chemotherapy for locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Patients were treated with three courses of fluorouracil, leucovorin, etoposide, and cisplatin-containing induction chemotherapy followed by high-dose external beam radiotherapy to 65 Gy in 6 weeks for T4 and obstructing T3 tumors. Transversable T3 tumors received 60 Gy in 6 weeks by external radiotherapy, followed by two high-dose-rate esophageal brachytherapy fractions of 4 Gy in 5-mm tissue depth. Concurrent to radiotherapy, cisplatin and etoposide were given. Long-term survival of 22 patients was 41% and 31% at 2 and 3 years, respectively, with a median follow-up of 39 months. The probability of locoregional tumor recurrence was 60% at 3 years for all patients and 30% for those with a partial or complete response to induction chemotherapy. Acute toxicity of this schedule was moderate. Long-term survivors had a good swallowing function. This schedule offers a considerable chance of long-term survival for patients with locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Local in-field recurrences are the main risk after definitive radiochemotherapy. Dose escalation of radiotherapy is possible because of the observed low late toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carcinoma, Squamous Cell; Cisplatin; Cohort Studies; Combined Modality Therapy; Deglutition Disorders; Drug Administration Schedule; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Prognosis; Quality of Life; Survival Analysis

Cancer cell lines in standard cell culture medium or in animal models are surrounded by an environment with relatively high folate (HF) levels, compared with folate levels in human plasma. In the present study we adapted 4 colon cancer (C26-A, C26-10, C26-G and WiDr) and 3 squamous cell carcinoma of the head and neck (HNSCC) cell lines (11B, 14C and 22B) to culture medium with low folate (LF) levels (2.5, 1.0 and 0.5 nM, respectively) and investigated whether folate depletion had an effect on sensitivity to antifolates and which mechanisms were involved. All LF cell lines showed a higher sensitivity to 5-fluorouracil (5-FU) alone or in combination with leucovorin (LV) (2-5-fold), to the thymidylate synthase (TS) inhibitors, AG337 (2-7-fold), ZD1694 (3-49-fold), ZD9331 (3-40-fold), LY231514 (2-21-fold) or GW1843U89 (4-29-fold) or to the dihydrofolate reductase (DHFR) inhibitor PT523 (2-50-fold) compared with their HF variants cultured in standard medium containing up to 8 microM folic acid. LV could only increase sensitivity to 5-FU in HNSCC cell lines 14C and 14C/F. The differences in sensitivity could partially be explained by a 2-7-fold increased transport activity of the reduced folate carrier (RFC) in LF cell lines, whereas no significant change in folylpolyglutamate synthetase (FPGS) activity was observed. Furthermore, the protein expression and catalytic activity of the target enzyme TS were up to 7-fold higher in HF colon cancer cells compared with the LF variants (p < 0.05). Although the TS protein expression in LF HNSCC cells was also lower than in HF variants, the TS catalytic activity and FdUMP binding sites were up to 3-fold higher (p < 0.05). Thus, changes in TS levels were associated with differences in sensitivity. These results indicate that folate depletion was associated with changes in TS and RFC levels which resulted in an increase in sensitivity to 5-FU and antifolates. The folate levels in LF medium used in this study are more representative for folate levels in human plasma and therefore these data could be more predictive for the activity of 5-FU and antifolates in a clinical setting than results obtained from cell lines cultured in HF medium or in animal models.

Topics: Animals; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Carrier Proteins; Colonic Neoplasms; Fluorouracil; Folic Acid; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Membrane Proteins; Membrane Transport Proteins; Mice; Multienzyme Complexes; Neoplasms; Peptide Synthases; Reduced Folate Carrier Protein; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Tumor Cells, Cultured

Most nonendocrine pancreatic neoplasms are adenocarcinomas of ductal cell or acinar origin. Primary carcinomas of the pancreas with squamous differentiation are rare enough to warrant a search for other primary tumors. In the past few decades, well-documented individual reports and large series reviews support the view that these squamous neoplasms are indeed of pancreatic origin and not uncommonly exhibit cystic degeneration. Late manifestation and unfavorable prognosis seem to be uniform features. We report a case with many of these features.

Topics: Abdominal Pain; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Squamous Cell; Cholangiopancreatography, Endoscopic Retrograde; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Jaundice; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Cyst; Pancreatic Neoplasms; Tomography, X-Ray Computed

The efficacy of chemotherapy for unresectable recurrent or metastatic squamous cell carcinomas of the head and neck can not be proved by survival periods. However, the efficacy of chemotherapy has been observed in some select patients. We investigated the effect of chemotherapy for unresectable recurrent squamous cell carcinomas of the head and neck. Four patients with a good performance status (PS) were treated with high-doses of leucovorin (LV), cisplatin (CDDP), and 5-fluorouracil (5-FU). The regimen consisted of 25 mg/m2 of CDDP on days 1-5; 600 mg/m2 of 5-FU of days 2-6; and 200 mg/m2 of LV on days 1-6. Patients received 3 cycles of this regimen at 28-day intervals. Ten patients with a poor PS were treated with low-doses of CDDP and tegafur.uracil upon admission. The regimen of seven poor PS patients consisted of 8 mg/m2 of CDDP on days 1-5 and 8-12, and 400 mg/body of tegafur.uracil administered orally on days 1-14. The other three patients received chemotherapy on an outpatient basis for ten weeks. The weekly regimen consisted of 7.5 mg/m2 of CDDP on days 3 and 6 and 400 mg/body of tegafur.uracil administered orally on days 1-7. With respect to the LV + CDDP and 5-FU treatment, complete remission was obtained in one patient. Two patients showed no change (NC), while one patient developed a progressive disease (PD). This regimen is highly toxic, has severe side effects including myelosuppression, oral mucositis, and diarrhea, and has a survival period of between 16 and 32 weeks. The low-dose CDDP + tegafur.uracil treatment produced a partial response in three patients, NC in three patients, and four patients developed a PD. This regimen doses not have any severe side effects and has a survival period of between 4 and 67 weeks.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Survival Rate; Treatment Outcome

We conducted a prospective study on neoadjuvant treatment for squamous cell carcinoma of the esophagus, modifying the chemotherapy protocol by adding l-folinic acid and giving bifractionated radiotherapy with a cis-diaminedichloroplatinum (CDDP) injection before each fraction. Thirty-two patients, 30 men, 2 women, mean age 56.2-8.9 years, with resectable squamous celi carcinoma of the esophagus (TNM stage I = 4, IIA = 4, IIB = 13, III = 11) were included. Chemotherapy, CDDP (80 mg/m2: D2), 5-fluorouracil (5-FU; 600 mg/m2, D1-4), and 1-folinic acid (200 mg/m2, DI-4), was given in two sessions with a 3-week interval during which the patients received radiotherapy (45 Gy), two fractions per day (150 cGy/fraction). A 3-mg Injection of CDDP was given prior to each fraction. Patients underwent surgery 4 to 7 weeks after neoadjuvant therapy. No severe side effects were observed in 12 patients. Grade 3 effects (WBC, platelests, mucosite's) occurred in 16 patients and grade 4 effects (platelets, mucositis) in four including 1 death due to septicemia with an infected catheter. Surgery was performed in 29 patients; 26 had resectable tumors (81%). Operative mortality was 10%. The 26 surgical specimens showed complete response (n = 18), persistent microscopic residues (n = 4), or not significant modification (n = 4). Survival at 1, 3, and 5 years was 82, 47, and 47% and disease-free survival was 77, 47, and 47% respectively. This new therapeutic combination is aggressive and associated with a high postoperative mortality but has a remarkable histological effect since complete response was achieved in 56% (95% CI: 39-73%) of the patients and 5-year survival reached 47%, a very high rate in our experience.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prospective Studies; Radiotherapy Dosage; Radiotherapy, Adjuvant; Survival Analysis; Treatment Outcome

In the present study, the expression of cyclin D1, as detected by immunohistochemistry, was compared with other prognostic variables and its prognostic impact was evaluated in a group of 172 patients with squamous cell carcinoma (SCC) of the esophagus who underwent potentially curative resection therapy and in a second group of 38 patients with SCC of the esophagus who were treated by combined modality therapy (radiochemotherapy +/- surgery). Expression of cyclin D1 in surgically treated carcinomas correlated negatively with tumor differentiation (p = 0.026) but positively with mitotic activity (p = 0.0199) and nodal status (p = 0.040). There were no significant correlations with pT category. Patients with cyclin D1-positive carcinomas showed significantly worse overall survival than patients with cyclin D1-negative carcinomas, both in univariate (p = 0.0016) and in multivariate survival analyses (p = 0.0038). Expression of cyclin D1 in carcinomas with multimodal treatment was correlated with poor response to chemotherapy (p = 0.026) but not with overall survival. We thus consider expression of cyclin D1 to be an important parameter, predicting an unfavorable overall survival of surgically treated esophageal cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Cyclin D1; Epirubicin; Esophageal Neoplasms; Esophagus; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucous Membrane; Prognosis; Survival Rate

Oxygen/drug supply to cancer cells is an important factor defining response to radiotherapy and chemotherapy. Although tumor angiogenesis is considered an important prognostic marker, its role in the outcome of chemotherapy and radiotherapy is unknown. In the present study we examined the possible correlation of the degree of angiogenesis with response to cytotoxic therapy in locally advanced squamous cell head and neck cancer (HNC). Vascular grade (VG) was assessed immunohistochemically using the JC70 monoclonal antibody (MAb) in tumor specimens from 76 patients treated with platinum/5-fluorouracil (with or without methotrexate) induction chemotherapy (ICT) (n = 37) or concurrent chemoradiotherapy (CCRT) with cisplatin or carboplatin (n = 39). Seventeen of 76 analyzed patients had an overall microvessel score of < 11 (VGI), 25/76 of 11-30 (VG2), 16/76 of 31-50 (VG3) and 18/76 of > 50 (VG4). Complete response rate after ICT or after CCRT was higher in cases with an intermediate vascularization (VG2,3). Both local relapse-free and overall survival were significantly better in the VG2 group. Patients treated with CCRT had a better survival compared to those treated with ICT. This was mainly observed in VG1 tumors. Multivariate analysis showed that VG and treatment modality were independent prognostic factors for local relapse and survival. Intratumoral angiogenesis correlation with the cytotoxic therapy outcome is likely to follow a bell-shaped relation, the response being better in cases with an intermediate VG. This may be the consequence of 2 vasculature-dependent factors, i.e., the drug/oxygen availability and the ability of cancer cells to undergo rapid repopulation in optimally oxygenated conditions. Our pilot study stresses the importance of individualization of therapy according to VG.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Neovascularization, Pathologic; Oxygen; Pilot Projects; Remission Induction; Survival Analysis; Treatment Outcome

A 63-year-old male with an esophageal cancer invading the bronchus was treated with radiation therapy (70 Gy) from November 1995, resulting in the disappearance of the lesion. He was later readmitted due to dysphagia from the recurrence of the esophageal cancer. We diagnosed, by endoscopic and chest CT scan findings, that the esophageal cancer was invading the right bronchus. We inserted an expandable metallic stent endoscopically, and the patient could eat well. We performed two courses of FLEP chemotherapy (consisting of 5-FU, leucovorin, etoposide and cisplatin) from November 12, 1997. He then suffered from an esophagobronchial fistula, but was cured by a covered expandable metallic stent replacement. No esophageal stenoses or recurrences were seen endoscopically and he could eat well on December 7, 1998. The standard modality of treatment for patients with advanced esophageal cancer invading adjacent structures is not yet established, and the prognosis for such patients remains quite poor. We performed combination therapy with an expandable metallic stent replacement and FLEP chemotherapy, and improved the patient's quality of life. This form of therapy was thus proved useful for patients with esophageal cancer invading adjacent structures.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bronchial Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Etoposide; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Stents

A 67-year-old man was diagnosed as having a type 3 advanced esophageal carcinoma by barium swallow and endoscopy. Biopsy specimens showed well-differentiated squamous cell carcinoma with positive immunostaining for p53, C-erb B-2 and negative for bcl-2. Two courses of chemotherapy using 5-FU, leucovorin and CDDP were performed before operation. Because no cancer cells were present in the surgical specimens, the effect was evaluated as grade 3. This neoadjuvant chemotherapy may be effective for esophageal carcinoma with a possible apoptosis mechanism.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Esophageal Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Preoperative Care

The purpose of this trial was to examine the feasibility of intensive, sequential chemo- and radiochemotherapy followed by surgery in patients with locally advanced carcinomas of the lower oesophagus and the gastro-oesophageal junction (GO junction). The chemotherapy consisted of two courses of 6 weekly administrations of 5-fluorouracil (5-FU) (2.0 g/m2, 24 h infusion) and folinic acid (FA) (500 mg/m2, 2 h infusion) combined with twice weekly cisplatin (50 mg/m2, 1 h infusion). Irradiation of 30 Gy was given concurrently with one course of cisplatin and etoposide. 25 patients with locally advanced (T3-T4 NX M0) squamous cell or adenocarcinoma of the lower oesophagus and GO junction were included and evaluated. Toxicity was usually mild to moderate (WHO grade 1 and 2) with mucositis as the most important side-effect of the pre-operative treatment. Of the patients, 94 and 88% completed the chemo- and radiochemotherapy according to the protocol, respectively. A major response (= partial remission with subjective improvement) to chemotherapy was achieved in 6/10 patients with squamous cell carcinoma and 10/15 with adenocarcinoma. 19 patients had subsequent surgery and complete resection was achieved in 16 (3 patients had intra-abdominal metastases observed at laparotomy). The operative mortality rate was 16% (3/19). 10 of the 16 patients with tumour resection had a pathological complete response. 15 patients (43%) remain alive at a median follow-up of 20 months and the median survival exceeds 16+ months. Our data suggest that this intensive pre-operative chemoradiotherapy programme is feasible and remarkably effective in patients with locally advanced carcinomas of the lower oesophagus or GO junction.

Topics: Adenocarcinoma; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Esophagogastric Junction; Etoposide; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Preoperative Care; Survival Analysis; Treatment Outcome

We conducted a prospective study of neoadjuvant treatment for squamous cell carcinoma of the esophagus, modifying the chemotherapy protocol by adding l-folinic acid and giving bifractionated radiotherapy with a cis-diaminedichloroplatinum (CDDP) injection before each fraction.. Thirty-two patients, 30 men, 2 women, mean age 56.2+/-8.9 years, with resectable squamous cell carcinoma of the esophagus (TNM stage I=4, IIA=4, IIB=13, III=11) were included. Chemotherapy, CDDP (80 mg/m2 D2), 5-fluorouracil (5-FU; 600 mg/m2, D1-4), and l-folinic acid (200 mg/m2, D1-4), was given in two sessions with a 3-week interval during which the patients received radiotherapy (45 Gy), two fractions per day (150 cGy/fraction). A 3-mg injection of CDDP was given prior to each fraction. Patients underwent surgery 4 to 7 weeks after neoadjuvant therapy.. No severe side effects were observed in 12 patients. Grade 3 effects (WBC, platelets, mucositis) occurred in 16 patients and grade 4 effects (platelets, mucositis) in four including 1 death due to septicemia with an infected catheter. Surgery was performed in 29 patients; 26 had resectable tumors (81%). Operative mortality was 10%. The 26 surgical specimens showed complete response (n=18), persistent microscopic residues (n=4), or not significant modification (n=4). Survival at 1, 2, and 3 years was 81, 61, and 51.6% and disease-free survival was 75, 59, and 54% respectively.. This new therapeutic combination is aggressive and associated with a high postoperative mortality but has a remarkable histological effect since complete response was achieved in 56% (95% CI: 39-73%) of the patients and 3-year survival reached 52%, a very high rate in our experience.

Topics: Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Radiotherapy Dosage; Treatment Outcome

Primary unresectable and locally advanced recurrent rectal cancer presents a significant clinical challenge. Local failure rates are high in both situations. Under such circumstances, there is a significant need to safely deliver tumoricidal doses of radiation in an attempt to improve local control. For this reason, we have incorporated a new approach utilizing high dose rate intraoperative radiation therapy (HDR-IORT).. Between 11/92-12/96, a total of 112 patients were explored, of which 68 patients were treated with HDR-IORT, and 66 are evaluable. The majority of the 44 patients were excluded for unresectable disease or for distant metastases which eluded preoperative imaging. There were 22 patients with primary unresectable disease, and 46 patients who presented with recurrent disease. The histology was adenocarcinoma in 64 patients, and squamous cell carcinoma in four patients. In general, the patients with primary unresectable disease received preoperative chemotherapy with 5-fluorouracil (5-FU) and leucovorin, and external beam irradiation to 4500-5040 cGy, followed by surgical resection and HDR-IORT (1000-2000 cGy). In general, the patients with recurrent disease were treated with surgical resection and HDR-IORT (1000-2000 cGy) alone. All surgical procedures were done in a dedicated operating room in the brachytherapy suite, so that HDR-IORT could be delivered using the Harrison-Anderson-Mick (HAM) applicator. The median follow-up is 17.5 months (1-48 mo).. In primary cases, the actuarial 2-year local control is 81%. For patients with negative margins, the local control was 92% vs. 38% for those with positive margins (p = 0.002). The 2-year actuarial disease-free survival was 69%; 77% for patients with negative margins vs. 38% for patients with positive margins (p = 0.03). For patients with recurrent disease, the 2-year actuarial local control rate was 63%. For patients with negative margins, it was 82%, while it was 19% for those with positive margins (p = 0.02). The disease-free survival was 47% (71% for negative margins and 0% for positive margins) (p = 0.04). Prospective data gathering indicated that significant complications occurred in approximately 38% of patients and were multifactorial in nature, and manageable to complete recovery.. HDR-IORT using our technique is versatile, safe, and effective. The local control rates for primary disease compare quite well with other published series, especially for patients with negative margins. For patients with recurrent disease, locoregional control and survival are especially encouraging in patients with negative resection margins. Further follow-up is needed to see whether these encouraging data will continue.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Intraoperative Period; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy Dosage; Rectal Neoplasms

Cisplatin and leucovorin heighten the activity of 5-fluorouracil by increasing the intracellular concentration of reduced folates. Therefore, we treated the recurrent oropharynx carcinoma case, who had received concurrent chemotherapy with low-dose cisplatin and radiotherapy, with continuous infusion high-dose leucovorin with cisplatin and 5-fluorouracil. Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2, days 1 through 5); 5-fluorouracil (600 mg/m2, days 2 through 6); and leucovorin (200 mg/m2, days 1 through 6) administered once about every 4 weeks. Three cycles were performed, and a complete response was achieved. Grade 3 to 4 mucositis, nausea-vomiting, anemia, neutropenia, and thrombocytopenia occurred. Continuous infusion high-dose leucovorin with cisplatin and 5-fluorouracil was effective for this recurrent head and neck carcinoma. However, one must be cautious when comparing this chemotherapy in terms of toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Oropharynx; Pharyngeal Neoplasms

A cytomorphic, stereological study was made by computerized image analysis of six nuclear morphometric variables and one stereological nuclear variable. Variables were measured on 150 randomly selected tumor cells in oropharyngeal biopsies from 44 patients with oropharyngeal cancer who had not responded completely to induction chemotherapy. The nuclei of tumoral cells were larger (mean nuclear area, perimeter, and volume), more rounded, and had a less irregular nuclear contour index.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cisplatin; Fluorouracil; Humans; Immunosuppressive Agents; Leucovorin; Male; Middle Aged; Oropharyngeal Neoplasms; Oropharynx; Retrospective Studies

A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA).. One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed.. Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%.. PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Remission Induction; Survival Analysis; Treatment Outcome

To determine the effectiveness of selective neck dissection for management of the clinically negative neck in head and neck squamous cell carcinoma.. A retrospective comparison of patients treated electively with selective neck dissection and comprehensive neck dissection.. Academic tertiary referral center.. Patients with clinically negative necks and previously untreated head and neck squamous cell carcinoma.. Elective neck dissection, surgical treatment of the primary lesion, and postoperative radiotherapy as indicated.. Regional recurrence, distant metastasis, and disease-free survival.. Selective neck dissection was as effective as comprehensive procedures for staging the clinically negative neck. Occult metastases had a statistically significant effect on patient outcome as measured by distant metastasis.. Elective neck dissection provides invaluable staging information, which guides the decision for adjuvant therapy.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Decision Making; Disease-Free Survival; Elective Surgical Procedures; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Lymph Node Excision; Lymph Nodes; Methotrexate; Middle Aged; Neck; Neck Dissection; Neoplasm Recurrence, Local; Neoplasm Staging; Radiotherapy, Adjuvant; Retrospective Studies; Treatment Outcome

Available data concerning the treatment of patients with advanced T4 esophageal carcinoma are limited. A consecutive series of 42 patients with advanced T4M0 epidermoid carcinoma of the esophagus were studied from June 1987 to July 1992. The aim of this study was to evaluate the efficacy of various therapeutic modalities, and further evaluate the therapeutic options. The various therapeutic modalities included the following: Group I, feeding jejunostomy or endoesophageal intubation, 6 patients; Group II, palliative subtotal esophagectomy only, 8 patients; Group III, bypass procedures without tumor resection, 9 patients; Group IV, nutritional support and then treatment with irradiation (n=8) or concurrent radio-chemotherapy (n=4), 12 patients; Group V, subtotal esophagectomy, followed by aggressive concurrent radiochemotherapy, 7 patients. The total prescribed irradiation dose was 60 Gy (10 Gy/5 fractions/week). A combination regimen of chemotherapy consisted of cisplatin, 5-fluorouracil, and leucovorin (PFL regimen). For the patients undergoing esophagectomy or bypass procedures (n=24), the rates of operative complication and mortality were 45.8% and 25%, respectively. Side effects of adjuvant therapy (n=24) consisted of main airway irritation (100%), mucositis or gastrointestinal symptoms (83.3%), hematologic toxicity (79.2%), esophagitis or gastric ulcer (62.5%), alopecia (37.5%), and pneumonia (20.8%). The mortality due to toxicity of adjuvant therapy was 21.1% (4/19 patients). The mean survival times for each of the different groups was 1.9+/-0.5 months for Group I, 4.8+/-1.6 months for Group II, 5.2+/-1.2 months for Group III, 7.3+/-2.0 months for Group IV, and 20.3+/-2.5 months for Group V, respectively. Compared with patients of Groups I--IV, the Group V patients had a significantly superior one-year survival rate (P<0.01). Our results demonstrated that esophagectomy followed by concurrent irradiation and PFL combination chemotherapy may provide a significant improvement in the quality of life and survival for appropriate patients with advanced T4M0 epidermoid carcinoma of the esophagus. Furthermore, more than one cycle of PFL regimen chemotherapy may result in a better prognosis. During the performance of such an aggressive treatment, the utmost care must be taken with the patient's nutrition and to prevent pulmonary complications.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Radiotherapy, Adjuvant; Survival Rate

The results of conventional radiotherapy in patients with inoperable recurrence of laryngeal cancer after total laryngectomy are bad. Therefore experimental methods including neutron therapy and combination of chemo- and radiotherapy have been used. This presentation evaluates results of different treatment modalities in patients with inoperable recurrences of laryngeal cancer after total laryngectomy.. Forty-two patients with inoperable recurrences of laryngeal cancer after total laryngectomy were treated. Thirty patients received radiotherapy alone, and 12 patients received multidrug chemotherapy and radiotherapy. Patients were irradiated with cobalt-60 beam, neutron beam and with mixed cobalt-60 and neutron beam. The tumor dose in cobalt-60 therapy was 60 Gy in 20 to 30 fractions. In 8 patients additional dose of 10 to 20 Gy in 5 to 10 fractions was given to the reduced field. The doses used in neutron irradiation varied from 10 to 13 Gy in 5 to 20 fractions.. In 20 patients (47.6%) complete regression after therapy was observed, but only 9 (21.4%) patients survived without evidence of disease at 2 years after radiotherapy. In patients treated with radiotherapy alone the 2-year disease-free survival was observed in 16.7% and in patients who received induction chemotherapy with Cisplatin followed by radical irradiation the 2-year disease-free survival was observed in 40%.. The results of therapy of inoperable recurrence of laryngeal cancer after total laryngectomy remain bad. Radiotherapy combined with multidrug chemotherapy including cisplatin may contribute to some improvement of the patients survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Cobalt Radioisotopes; Combined Modality Therapy; Disease-Free Survival; Humans; Laryngeal Neoplasms; Laryngectomy; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neutrons; Radiotherapy Dosage; Time Factors; Vincristine

The aim of this study was to establish the feasibility, evaluate the response rate, and assess the impact on local control and survival in locally advanced (bulky nodal) squamous cell carcinoma of the head and neck (SCCHN) patients treated with neoadjuvant chemotherapy consisting of cisplatin followed by continuous infusion of vindesine and fluorouracil with intermittent i.v. folinic acid. Eligibility criteria included histologically proven SCCHN, previously untreated locally advanced stage III-IV with measurable or evaluable disease, no distant metastases, an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2, patient age of at least 18 years, and adequate bone marrow, hepatic, and renal functions. The protocol consisted of three cycles (day 1, day 21, day 42) of Cisplatin (CDDP) 100 mg/m2/day i.v. on day 1 immediately followed by 4 days (96 h) of continuous infusion of vindesine 0.8 mg/m2/day and 5-fluorouracil (5-FU) 600-700 mg/m2/day with folinic acid 150 mg/m2 i.v. every 6 h x 16 doses before locoregional treatment with radiotherapy preceded by radical surgery when appropriate. Twenty-nine patients were enrolled in this study, and 28 were evaluable for activity; an objective response rate of 55% (four complete responses, 12 partial responses) was achieved. Leukopenia and mucositis were the most frequent and severe toxicities. The addition of vindesine did not improve the activity of the CDDP-FU-folinic acid combination, but this may be partly because of the particularly poor prognosis of the present patient population, with 75% of stage IV bulky nodal disease (N2c-N3).

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Remission Induction; Survival Rate; Vindesine

A 62-year-old patient on long-term haemodialysis who developed an inoperable T2N3Mo squamous-cell carcinoma of the larynx was treated with weekly low-dose methotrexate (MTX) after failing to respond to radiotherapy. The patient was initially given one dose of 10 mg MTX (6 mg/m2) as a 1-h infusion, then he received three further i.v. doses of 20 mg (12 mg/m2). Haemodialysis was performed 15-18 h after each dose and the patient received folinic acid (30 mg i.v.q 6 h) until the MTX concentration was < 0.1 mumol/l. The MTX concentration was measured regularly until it reached < 0.1 mumol/l, and additional samples were withdrawn pre- and post-dialysis. The MTX elimination rate constant and half-life were estimated with the patient on and off dialysis. The patient failed to respond to treatment but did not experience MTX-related toxicity. The elimination half-life ranged from 22 to 42 h when he was off dialysis but fell to a median of 5.5 h during dialysis. Low-dose MTX was given to a patient on regular haemodialysis without evidence of toxicity. The rate of MTX elimination was increased during haemodialysis, although high MTX concentrations persisted for several days and prolonged rescue with folinic acid was required.

Topics: Antimetabolites, Antineoplastic; Area Under Curve; Carcinoma, Squamous Cell; Fatal Outcome; Humans; Infusions, Parenteral; Injections, Intravenous; Kidney Failure, Chronic; Laryngeal Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Palliative Care; Renal Dialysis; Terminal Care

The biochemical modulation (BCM) of the antitumor effect of 5-fluorouracil (5-FU) by leucovorin (LV) was studied with xenografts (MC-1, MC-3, MPC-2) by transplanting human tumors to nude mice and by human tumor clonogenic assay (HTCA). For human tumor transplantation to nude mice, the dose of 5-FU was set at LD50 x 0.6 or LD50 x 0.8 and LV was given in three doses, 0.45, 0.15, 0.06 mg/body. Antitumor effects of combined administration of 5-FU and LV at the same time, as compared with that of administration of LV one hour before 5-FU, were examined. The relationship between the rate of inhibition of thymidylate synthetase (T.S) activity and 5-FU concentration in the neoplastic tissues was also examined. In HTCA the antitumor effects of 5-FU were examined by two methods: 1) limited contact for one four, and 2) continuous contact for two weeks. In the human tumor transplantation to nude mice, the BCM of the antitumor effect of 5-FU by LV was demonstrated in MC-1 and MPC-2. This BCM function of LV was enhanced by administering it one hour before 5-FU. The suitable LV dose was between 0.15 and 0.45 mg/body. Although there was a tendency for the rate of inhibition of T.S to be proportional to the tissue concentration of 5-FU, there was no significant relationship between the T.S inhibition rate and the antitumor effect. In HTCA, the BCM function of LV was suggested by the two-week-continuous contact method with MC-1 and MPC-2. Depending on the method of administering LV, the antitumor activity was higher with two-week continuous contact than with one-hour contact. In conclusion, the BCM effect of LV on the antitumor effect of 5-FU was revealed in MC-1 and MPC-2 strains. Further studies are needed to establish a standard for appropriate dosage and administration of LV.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Screening Assays, Antitumor; Female; Fluorouracil; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Transplantation, Heterologous

Between 1989 and 1992, 38 patients with advanced squamous cell carcinomas of the head and neck were treated by an accelerated hyperfractionated split-course radiochemotherapy (SCRC). This therapy was carried out at the ENT department and department of radiooncology of the University of Heidelberg. Within 51 days, 70.2 Gy were applied in three courses. In every course, simultaneous chemotherapy with cisplatin (60 mg/m2/week)/5 Fu (bolus: 350 mg/m2/d)/Leucovorin (bolus: 50 mg/m2 + 100 mg/m2/24 h) was carried out. Between 1992 and 1994, 50 patients suffering from advanced head and neck cancer (stage III, V) were also treated with an accelerated hyperfractionated concomitant-boost radiochemotherapy (CBRC) at the same departments. A total dose of 66 Gy, was applied within 33 days. The patients were also treated with simultaneous chemotherapy with carboplatin (70 mg/m2/24 h) in the first and fifth week.. In about 50% of the patients treated with SCRC, the therapy was more than 10 days longer than the scheduled period. The lack of compliance due to toxicity was considered as one of the main reasons for this delay. After the first course of SCRC, eight of 38 patients showed mucositis of the upper aerodigestive tract (WHO grade > 3); after the second course, 11 of 38 patients; and after the third course, 15 of 38 patients. Fifty-two percent of the patients developed emesis, 10% leucopenia < 1 nl, 10% nephrotoxicity, 3% pancreatitis, 3% thrombosis, 3% gastritis, and 3% auditory threshold shifts of about more than 10 dB. In about 7.5% of the patients treated with CBRC, the therapy was more than 10 days longer than the scheduled period. The mucositis of the upper aerodigestive tract (50% of the patients showed WHO-grade > 3) was considered to be the main reason for this. In four patients a neutropenia < 1 nl was detected, in one patient anemia < 7 g/dl and n 33 patients thrombocytopenia < 100/nl.. In conclusion, the concomitant boost radiochemotherapy showed a lower toxicity and higher acceptance than the split-course radiochemotherapy. This is documented in lower protocol delays and better results in the two-years survival time in case of concomitant boost radiotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Radiation-Sensitizing Agents; Radiotherapy Dosage; Radiotherapy, High-Energy

Continuous infusions of 5-fluorouracil (5-FU) are increasingly used in the treatment of cancer. Their optimal use, however, has still to be determined since the availability of suitable animal models is limited. We studied continuous infusions in mice using subcutaneously implanted pellets that release 5-FU over a period of 3 weeks. At the maximum tolerated dose (MTD) (based on the systemic toxicity in healthy animals) we assessed the antitumour activity, haematological toxicity, inhibition of thymidylate synthase (TS) in tumours and the concentration of 5-FU in plasma during the 3-week period. We also studied the addition of leucovorin in different schedules. The dose-limiting toxicity was weight loss, and at the MTD of 10 mg of 5-FU released in 21 days per mouse myelosuppression was tolerable (nadir for leucocytes and thrombocytes was approximately 40% of pretreatment levels). In several independent experiments using the 5-FU-resistant Colon 26 tumour, a good antitumour activity was observed during the first part of the infusion, but thereafter the growth of the tumours resumed; the overall effect of continuous infusions was thus comparable to that of bolus injections. Coadministration of leucovorin did not enhance the therapeutic results; depending on the schedule used, it proved ineffective or only increased toxicity. Similar results were obtained with head and neck squamous cell carcinomas and with the 5-FU-sensitive tumour Colon 38. In Colon 26 tumours the TS activity (FdUMP-binding assay) initially decreased to 20-30% of controls and returned to normal after 11 days. In the catalytic TS assay a slight inhibition was observed for the continuous infusion, followed after 11 days by a marked (4-fold) increase in activity. 5-FU plasma levels varied from 0.1 to 1 microM following a circadian rhythm (with a peak at 6 h after light onset), and were maintained during the entire period. Subcutaneously implanted pellets represent a suitable model to study prolonged administration of 5-FU in mice and to evaluate the effect of modulating agents in laboratory animals before transferring data obtained in vitro to the clinic.

Topics: Animals; Carcinoma, Squamous Cell; Circadian Rhythm; Colonic Neoplasms; Delayed-Action Preparations; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Thymidylate Synthase; Transplantation, Heterologous

We designed a trial of intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction to assess tumor response and operability after neoadjuvant chemotherapy and to determine the impact of trimodality therapy on longterm survival.. Thirty-two patients with resectable (clinical stage IIa, n = 17; IIb, n = 1; III, n = 14) squamous cell cancer (n = 15) or adenocarcinoma (n = 17) were treated with neoadjuvant chemotherapy (cisplatin, 5-fluorouracil, leukovorin), resection, and postoperative chemoradiotherapy (hydroxyurea, 5-fluorouracil; 50-66 Gy).. Use of neoadjuvant chemotherapy yielded the following results: a measurable clinical response in 22 patients, stable disease in eight patients, disease progression in one patient, and death in one patient. Thirty-one patients underwent resection, with the following results: two operative deaths (6.5%) and nonfatal morbidity in 17 (59%); the median hospital stay was 13 days. Pathologic staging was stage 0, n = 1; I, n = 2; IIa, n = 11; IIb, n = 5; III, n = 7; and IV, n = 5. Postoperative chemoradiotherapy was completed in 23 patients with one death, for an overall treatment-related mortality rate of 12.5% (four of 32). At a mean follow-up of 22.5 months, median survival is 19.7 months and 14 patients are alive and disease free.. Neoadjuvant therapy for cancer of the esophagus and cardia results in good tumor response. Esophagectomy in this setting can be accomplished with acceptable morbidity and mortality. Results of an interim analysis of survival are encouraging and suggest that further investigation of this regimen is warranted.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Follow-Up Studies; Humans; Hydroxyurea; Leucovorin; Male; Middle Aged; Neoplasm Staging; Postoperative Care; Radiotherapy, Adjuvant; Remission Induction; Survival Rate

From March 1992 to May 1994, 105 patients with esophageal carcinoma patients were treated with CF/5-Fu-DDP (group A, n = 40) or 5-Fu-DDP (group B, n = 65) protocol. The response rate (CR+PR) was 80% in group A and 60% in group B. (P < 0.01) Induction chemotherapy was followed by surgery or radiation therapy. The incidence of nausea, vomiting, cardiotoxicity and leukopenina was higher in group A than in group B. Buccal mucositis, diarrhea, abdomenal pain and skin pigmentation were noted only in group A. However, the toxic effects were tolerable. The results suggest that the CF/5-Fu-DDP regimen is more effective than 5-Fu-DDP regimen and may be one of the best chemotherapy regimens for the treatment of esophageal carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nausea; Vomiting

To evaluate the feasibility and effectiveness of a concurrent radio-chemotherapy regimen for locally advanced carcinomas of the pharynx and floor of the mouth.. Since January 1990, 97 patients with locally advanced carcinomas of the naso-, oro-, hypopharynx and the oral cavity in UICC stages III and IV were treated according to an accelerated hyperfractionated radiotherapy schedule with concurrent chemotherapy. The primary tumor and positive lymph nodes received a total dose of 72 Gy in 6 weeks. In the first 3 weeks, large fields were irradiated 5 times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving 2 daily fractions of 1.4 Gy with minimal intervals of 6 hours. Target volumes were reduced after 49.6 and 59.4 Gy, excluding clinically uninvolved lymph node regions of low and high risk. On day 1, 350 mg/m2 5-FU and 50 mg/m2 folinic acid were given as intravenous bolus followed by continuous infusion of 350 mg/m2 5-FU and 100 mg/m2 folinic acid, days 1 to 5. 10 mg/m2 mitomycin C was given on day 5 and 36 of the treatment. Salvage surgery was offered for residual disease 5 to 6 weeks after the end of radiotherapy.. 70 male, 27 female; age: 27 to 81 years; T2/T3/T4: 7/30/60; N0/N1/N2/N3: 20/18/53/6; nasopharynx/oropharynx/hypopharynx/oral cavity: 16/33/36/12. Median follow-up is 26 months.. Overall survival and recurrence-free survival at 2 years were. Overall survival and recurrence-free survival at 2 years were 68 +/- 5% and 74 +/- 5%. Multivariate analysis revealed a significant influence of the geometric mean neck node diameter or the N-stage on loco-regional control and survival. T-stage, tumor volume, or tumor localisation did not become significant. Acute toxicity of this schedule was acceptable but required optimised supportive care. Treatment related grade 4+ late toxicity of mucosa, soft tissue and bone were observed with a cumulative frequency of 13% at 2 years. Two patients died during a phase of severe leuko- or thrombocytopenia.. This phase I to II trial shows favourable results using an intensified treatment radio-chemotherapy protocol. A phase III study is now planned, comparing this regime with an accelerated hyperfractionated radio-therapy alone to an increased total dose of 77.6 Gy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Mouth Neoplasms; Neoplasm Staging; Particle Accelerators; Pharyngeal Neoplasms; Pilot Projects; Radiotherapy Dosage

Topics: Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Time Factors; Tumor Cells, Cultured

The principal aim of our policy in the cytotoxic treatment of advanced squamous cell carcinoma of the head and neck (SCCHN) is to reduce toxicity, to maintain or increase the response rate and consequently to improve the quality of life for these patients. In locally advanced disease the aim is to reduce the volume of the tumor and to treat micrometastases in order to achieve a better outcome of the subsequent local treatment (i.e., surgery and/or radiotherapy). In these patients the aim is to prolong survival.. We have employed 3 different multi-drug regimens with 5-FU+FA combination in 87 consecutive patients with SCCHN. Two regimens (B1, C) have been used for recurrent and/or metastatic disease and only one (B2) for previously untreated patients with locally advanced SCCHN. Regimen B1: cisplatin (P) 30 mg/m2 i.v., 5-fluorouracil (5-FU) 500 mg/m2 i.v., folinic acid racemic form (d, 1-FA) 200 mg/m2 i.v., bleomycin (B) 15 mg im 1st and 2nd day; Regimen C: P 60 mg/m2 1st day, 5-FU 500-750 mg/m2 continuous infusion, FA 50 mg po every 4 hours, B 15 mg im 2nd and 3rd day; Regimen B2 is similar to the B1 but lasts 3 consecutive days (instead of 2) and for every 3 weeks (instead of 4). It consists of 3 cycles before surgical treatment or radiotherapy.. There are no statistical differences in the Objective Response (OR) for the regimens B1 (39%) and C (34%). Grade 3-4 toxicity is higher in regimen B1 (50%) than in regimen C (< or = 8%).. Regimen C is less toxic regimen B1 with no significant difference in the OR. The primary treatment study is still ongoing but the preliminary results are promising: the remission rate is 92% (22/24, 1CR + 21 PR) and the median survival is 18 months (range 3-38+).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Italy; Leucovorin; Male; Middle Aged; Remission Induction

In a 4-year period (1988-1991) 122 patients with a squamous cell carcinoma of the esophagus were studied prospectively and analysed. 64 patients of them could be primary resected (primary resectability rate 52%), 36 patients were in general inoperable and 22 patients had an advanced stage of cancer with local inoperability. Due to a preoperative combined radiotherapy and chemotherapy 16 of the 22 patients with local inoperability had a clinical remission of the tumor (73%). 11 patients (50%) showed a histological verified down staging and 3 cases of them a complete remission (no primary tumor was found, no infiltration of the regional lymphnodes and no metastatic disease). Curative resection was possible in 14 of 16 patients with clinical remission (2 patients refused surgical treatment). So the resectability rate now increases from 52 to 63%. We conclude that there was no increased rate of postoperative complications or mortality in the combined radio-/chemotherapy group compared with the primary resected patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Esophagus; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Neoplasm Staging; Preoperative Care; Radiotherapy Dosage; Survival Rate

Recently, esophageal carcinoma has shown a wide variation in spread, from carcinoma in situ to the far-advanced type. Therefore, the treatment must be performed on the basis of accurate clinical stagings, and not only the prognosis but also the quality of life of patients should be considered. Surgical resection has been regarded as standard treatment for patients with advanced carcinoma, but in some cases, preoperative treatments should be added to perform curative resections. Our objectives in preoperative (neoadjuvant) chemotherapy with cisplatin and other chemotherapeutic agents are three-fold: 1) To reduce the extent of direct invasion of neighboring structures (e.g., aorta, trachea or bronchus). 2) To reduce the degree of lymph node metastasis. 3) To preserve the larynx in cases of cervical esophageal carcinoma. For the past 4 years, we treated 13 cases of advanced esophageal carcinoma with this chemotherapy method preoperatively. Two of 13 patients showed a partial clinical response, including one with no viable carcinoma cells pathologically, and 4 had a minor clinical response. However, the impact on overall survival must be further investigated. We conclude that this multimodality treatment is effective for local tumor control, but should be applied for selected patients with careful management of its side effects.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Preoperative Care; Survival Rate

Between December 1988 and August 1992, 68 patients with adenocarcinoma (n = 39) and squamous carcinoma (n = 29) of the esophagus were entered prospectively in a treatment protocol to receive two cycles of cisplatin, 5-fluorouracil, etoposide, leucovorin, and 3,000 cGy of radiation to the involved esophagus and adjacent mediastinum, followed by resection. There were four deaths during chemotherapy, and 7 patients had a decline in condition or were denied operation. Fifty-six patients have come to operation, and 1 awaits resection. Twenty-two patients had transhiatal esophagectomy and 29 patients had esophagogastrostomy with a combined abdominal and right thoracic approach. Five patients did not undergo resection at operation. There was one hospital death (2%). A complete response to preoperative therapy was seen in 12 patients (21%): 5 of 20 with squamous cancer (25%) and 7 of 36 with adenocarcinoma (19%). Average follow-up is 19 months. Median survival in these patients after entrance in the protocol is 24 months. Actuarial survival at 12, 18, and 24 months is 72% (confidence limits, 66% and 78%), 53% (confidence limits, 46% and 60%), and 51% (confidence limits, 44% and 58%). Significantly better survival was associated with adenocarcinoma (p = 0.041). There is no survival advantage based on complete response to preoperative therapy. This neoadjuvant regimen is effective in patients with squamous carcinoma and adenocarcinoma. These preliminary results demonstrate an improved median and actuarial survival compared with historical controls in 137 patients operated on between 1966 and 1985 at our institution.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Postoperative Complications; Prospective Studies; Radiotherapy Dosage; Survival Rate

A 62-year-old man diagnosed as Stage IIIB advanced non-resectable squamous cell carcinoma of the lung was treated with a sequential combination of 5-fluorouracil (5-FU) and cisplatin (CDDP), with concurrent administration of leucovorin and dipyridamole as a biochemical modulator for 5-FU. After 3 cycles, the mass reduced in size more than 70% in CT scan and the patient underwent a thoracotomy. Histologically, the primary lesion was completely necrotized and of the 10 metastatic regional lymph nodes, only one lymph node contained a small amount of viable cells and 3 additional cycles were conducted. The patient is still alive 30 months after initial chemotherapy. This regimen appears to be potentially useful for non-small-cell lung cancer and warrants further clinical study.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Dipyridamole; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Remission Induction

We evaluated the efficacy of folinic acid (Leucovorin, LV) on cell lethality induced by 5-fluorouracil (FU) alone or in combination with cisplatin (DDP) by using the HEp-2 laryngeal squamous carcinoma multicellular tumor spheroids (MTS) system. For LV, non-toxic concentration of 10(-5) M was used. For cells in the monolayer, 6 and 24 h exposure to LV increased FU-induced cell lethality approximately 7- and 2-fold, respectively, whereas LV did not influence the effect of FU for MTS. LV's lack of effect on cells in MTS may be interpreted to mean that LV cannot penetrate the MTS. For the monolayer, simultaneous exposure to 3 drugs, DDP, FU and LV, produced synergistic interaction. However, sequential exposures were marginally synergistic or antagonistic, irrespective of sequence of DDP first or last. In contrast, DDP followed by FU plus LV was most synergistic for MTS. Simultaneous exposure was also synergistic, however, FU plus LV followed by DDP was antagonistic. These results suggest that LV is unable to penetrate into the MTS core to potentiate FU activity. DDP appears to have enhanced LV penetration into the MTS core. The exploration of means to overcome limited penetration of LV appears important for successful treatment of head and neck carcinoma.

Topics: Carcinoma, Squamous Cell; Cell Count; Cell Death; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Screening Assays, Antitumor; Drug Synergism; Fluorouracil; Humans; Laryngeal Neoplasms; Leucovorin; Tumor Cells, Cultured

A group of 60 patients with advanced head/neck cancer were treated with high-dose folinic acid (500 mg/m-2/week-1) plus 5-fluorouracil (400 mg/m-2/week-1 on day 1, and cisplatin (20 mg/m-2/week-1) 24 h after folinic acid infusion was completed. Out of 55 evaluable patients, 10 patients (18%) experienced a complete response with a mean duration of 11.4+ months, 25 patients had a partial response (45%) of 6.7+ months, 6 patients (11%) showed a stabilization of 4.8+ months, and 14 (25%) progressed. The overall response rate was 63.6% (95% confidence limits 56.5%-69.5%). Patients pretreated with radiotherapy had a 67% overall response rate, while those pretreated with chemotherapy showed a 54% overall response rate. All patients with cancer of the oropharynx had a major response, while patients with cancer of the oral cavity had the lowest response rate. The mean survival of patients who attained a complete response was 14.5+ months. Partial responders had a mean survival of 10.6+ months, while patients who progresses survived a mean of 3.6+ months. The treatment has been very well tolerated with few cases of grade 3 gastrointestinal toxicity. Grade 1-2 leukopenia was recorded in 64% of cases, grade 1-2 nausea/vomiting in 85%. In one case therapy was stopped because of persistent diarrhoea.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Cystadenocarcinoma; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

Thirty-six patients with advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with a regimen including cisplatinum (CP) 30 mg/m2 i.v., 5-fluorouracil (5-FU) 500 mg/m2 i.v. bolus, folinic acid (FA) 200 mg/m2 i.v. in a continuous one-hour infusion, and bleomycin (B) 15 mg i.m. on the first and second days and repeated every 28 days. Thirty-three patients (25 with recurrent disease and 8 untreated) are evaluable for objective response. Of these, 4 (12%) achieved CR and 15 (45%) PR. All of the untreated patients responded. The mean duration of response in the patients with recurrent or metastatic disease was 5.5 months (range 2-10+). Remission of symptoms, such as pain and dysphagia, was obtained in 58% and in 44%, respectively. Subjective remission occurred almost exclusively in objectively responsive patients. The major side effects were leukopenia (55%) and nausea/vomiting (58%). This regimen is active in the treatment of advanced SCCHN. The quality of life may be improved in responsive patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging

Folinic acid (FA) and cisplatin (CDDP) both potentiate the cytotoxicity of 5-fluorouracil (5-FU). The activity of various drug combinations including 5-FU, CDDP and FA was tested on two human cell lines derived from squamous cell carcinomas of the head and neck. Cytotoxicity was assessed by the semi-automated colorimetric MTT test. The drugs were tested in clinically achievable conditions (concentrations and duration of exposure). The dose response curves for 5-FU (0-100 ng ml-1) associated with FA (10(-7)-10(-5) M) reflected a progressive increase in 5-FU cytotoxicity with increasing FA concentrations. When CDDP (0-5 micrograms ml-1) was associated with 5-FU, CDDP-mediated enhancement of 5-FU cytotoxicity was apparent only when CDDP was given before 5-FU. The triple association CDDP, 5-FU and FA was also tested. In this case, for an identical final cytotoxicity, the presence of FA (10(-6) M) permitted reduction of the 5-FU concentration between 24.2 and 42% and reduction of the CDDP concentration between 13.8 and 72.7%. These observations may be beneficial for the design of more rational therapeutic trials associating CDDP, 5-FU and FA.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Tumor Cells, Cultured

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (FUra) by stabilizing the fluorodeoxyuridine monophosphate:thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro tetrazolium colorimetric (MTT) cytotoxic assay, we tested the effects of FUra and 5-fluorodeoxyuridine (FUdR) with and without leucovorin (LV) on a panel of 7 human lung cancer cell lines. LV at a concentration of 20 microM enhanced the cytotoxicity of FUra and of FUdR in all of the cell lines. Quantitatively, LV had a higher degree of enhancement on FUdR than on FUra cytotoxicity in 6 cell lines. There was equivalent enhancement in the only remaining line. The differential effects of LV on the cytotoxicity of FUra vs. FUdR in these lung carcinoma lines contrasts with a quantitatively similar enhancement of cytotoxicity between FUra and FUdR in colon cancer lines previously reported from our laboratory. This suggests that the metabolism of FUra may be different in these lung cancer cell lines.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Carcinoma, Squamous Cell; Cell Line; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Tumor Cells, Cultured

To study the activity of continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin (PFL) as induction chemotherapy in patients with previously untreated, advanced squamous cell carcinoma of the head and neck.. Nonrandomized, prospective trial.. A comprehensive cancer center.. Thirty-five patients (4 patients [11%], stage III; 31 patients [89%], stage IV [MO]), all evaluable for response and toxicity.. Two to three cycles of PFL before definitive, local-regional therapy (surgery and radiation therapy or radiation therapy alone). Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2 body surface area daily, days 1 through 5); 5-fluorouracil (800 mg/m2 body surface area daily, days 2 through 6); and leucovorin (500 mg/m2 body surface area daily, days 1 through 6) administered once every 28 days. Pathologic response was evaluated by surgical resection or biopsy. Serum-reduced folates were measured before and 18 hours after the initiation of chemotherapy.. A clinical response to PFL was achieved in 28 of 35 (80%) patients: 23 (66%) patients had a complete response (90% CI, 50% to 79%) and 5 (14%) patients, a partial response. A complete response was confirmed pathologically in 14 of 19 (74%) patients. The most common toxicity was mucositis (grade 2 to 3; 94% of patients). Dose reduction for toxicity was necessary in 11 (31%) patients. There were no treatment-related deaths. Serum levels of leucovorin and (6S)5-methyltetrahydrofolate were measured in 7 patients. After 18 hours, the mean leucovorin level (+/- SD) was 34.3 +/- 1.5 mumol/L, of which only 8.0 +/- 0.5% was the active 6S isomer. The mean serum (6S)5-methyltetrahydrofolate was 9.2 +/- 0.6 mumol/L.. Continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin is a new and highly active chemotherapy regimen that can achieve clinical and pathologically confirmed complete responses in a substantial proportion of patients with advanced, local-regional squamous cell carcinoma of the head and neck. Further studies are needed to confirm the activity of PFL and to determine its potential impact on local tumor control and disease-free and overall survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Staging; Tetrahydrofolates

Experimental and clinical data support the concomitant use of 5-fluorouracil (5-FU) and high-dose folinic acid (HDFA). To verify the role of such a combination in far advanced head and neck cancer, we performed a phase II study employing weekly HDFA, 500 mg/m2 in 2-h infusions, and 5-FU, 600 mg/m2 bolus injection. Twenty-seven evaluable patients with recurrent disease entered the study. One complete response, seven partial responses, 10 stable disease, and nine progressions were observed: the overall response rate was 29.6%. Oral mucositis and diarrhea were major side effects; five patients discontinued the treatment due to toxicity; no deaths correlated to the treatment were detected. Considering the characteristics of our patients, the 5-FU/HDFA combination has shown a satisfactory antitumoral activity, but toxicity was similar to other chemotherapy regimens.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Remission Induction

Based on an animal model to improve the antitumor activity of 5-fluorouracil (FUra), a Phase I study of N-(phosphonacetyl)-L-aspartate, methotrexate, FUra, and leucovorin was conducted on 44 patients. Methotrexate was given in an intermediate dose (250 mg/m2) to overcome potential drug resistance, and N-(phosphonacetyl)-L-aspartate was given at a low dose (250 mg/m2) in order to allow escalation of FUra to toxicity. These two drugs were given 24 h before FUra to enhance maximal incorporation of FUra into RNA. Two schedules of administration were used; one every other week and one weekly for 2 weeks. The every other week schedule was well tolerated, with minimal gastrointestinal and hematological toxicity. However, the weekly for 2 weeks schedule was more toxic with increased mucositis, diarrhea requiring therapy, and decreased performance status of 20% in 4 of 6 patients. There were no responders in the every other week schedule. There was one partial response and three patients with stable disease in four evaluable patients on the weekly for 2 weeks schedule. At 24 h post-N-(phosphonacetyl)-L-aspartate-methotrexate treatment, PRPP levels were doubled in bone marrow biopsies, and increased 2.5- to 25-fold in tumor biopsies. We have currently added uridine rescue to this combination with the hope of further escalating the dose of FUra.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Bone Marrow; Carcinoma, Squamous Cell; Colorectal Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Pentosephosphates; Phosphonoacetic Acid; Phosphoribosyl Pyrophosphate

The growth inhibitory effects of the fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) against a human squamous cell carcinoma cell line (SQ-1) were studied in the absence and presence of deoxynucleosides and/or N5-formyl-tetrahydrofolate (leucovorin). Inhibition of cell growth by the fluoropyrimidines was less when undialyzed rather than dialyzed fetal bovine serum was used. Leucovorin, in concentrations of 10(-6) to 10(-4) M potentiated the growth inhibition of FU and FdUrd; deoxyguanosine and deoxyinosine in concentrations of 10(-5) M also enhanced the growth inhibition produced by these fluoropyrimidines. In the presence of leucovorin addition, deoxyguanosine (10(-5) M) caused a further synergistic inhibition of cell growth produced by FdUrd but not FU. In contrast, addition of deoxyinosine at 10(-5) M resulted in further potentiation of FU but not FdUrd inhibition of cell growth in the presence of leucovorin. The synergy obtained with these combinations encourage the exploration of modulation of fluoropyrimidine by leucovorin and deoxynucleosides in vivo.

Topics: Carcinoma, Squamous Cell; Culture Media; Deoxyribonucleosides; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Tumor Cells, Cultured

In a clinical phase-II trial, 62 previously untreated patients suffering from unresectable stage III (4 patients) and IV (56 patients) squamous cell carcinoma of the head and neck were treated with a simultaneous chemoradiotherapy consisting of a 5-fluorouracil/folinic acid/cis-platinum combination and of an accelerated split-course radiotherapy. As results, 3 patients died from tumor arrosion bleeding during the treatment. The median follow-up time of the surviving patients is 27+ months (range 18-44 months). Forty-eight out of 62 patients (77%) achieved complete remission, and 11/62 patients (18%) partial remission. Presently, 32 patients (52%) are without evidence of disease. The actuarial 3-year overall survival rate (Kaplan-Meier method) out of 62 patients is 53%. The actuarial disease-free survival and local tumor control rates at 3 years are 58% and 72%. Toxicity on oral mucosa was severe but tolerable, bone marrow depression was marked but not life-threatening. In conclusion, this combined simultaneous modality approach is highly effective in locally advanced head and neck cancer. It appears to provide superior survival and local control rates as compared to conventional radiotherapy or sequential chemo-radiotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Evaluation; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Middle Aged

Both cisplatin and leucovorin may increase the activity of 5-fluorouracil (5-FU) by increasing the intracellular concentration of reduced folates. Therefore, a Phase I study was conducted in patients with recurrent or metastatic head and neck cancer in which high doses of oral leucovorin were added to the combination of cisplatin and 5-FU. Patients received intravenous cisplatin 100 mg/m2 on day 1, followed by a continuous intravenous infusion of 5-FU at 600 mg/m2/day for 5 days. Leucovorin 50 mg/m2 orally was administered from the start of the cisplatin infusion and then every 6 hours throughout the 5-FU infusion. The dose of 5-FU was increased to 800 mg/m2/day and 1 g/m2/day according to observed toxicity. In a second phase of the study, the dose of leucovorin was increased to 50 mg/m2 orally every 4 hours. Twenty-five patients were registered: 23 had recurrent head and neck cancer after extensive treatment; two had newly diagnosed metastatic disease. The maximum tolerated dose of 5-FU was 800 mg/m2/day with leucovorin administered every 6 hours. Toxicities at that level included mild-to-moderate myelosuppression. Mucositis in the previously irradiated field prevented the further increase of the 5-FU dose to 1 g/m2/day. Identical toxicities were observed when administering 5-FU at 800 mg/m2/day with 50 mg/m2 of leucovorin every 4 hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who had previously received cisplatin and 5-FU as induction chemotherapy). Eight patients did not respond. The median survival for all 25 patients was 6.5 months. It was concluded that the combination of cisplatin, 5-FU, and leucovorin is active in the treatment of recurrent head and neck cancer. The maximum tolerated dose of 5-FU in previously treated patients is 800 mg/m2/day, with mucositis being the dose-limiting toxicity. Further investigation of this regimen as neoadjuvant chemotherapy in previously untreated patients with locally advanced head and neck cancer is in progress.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local

In a phase II study, patients with locally advanced squamous cell carcinoma of the head and neck were treated with simultaneous chemoradiotherapy. Treatment was divided into three courses. Chemotherapy consisted of cis-diamminedichloroplatinum (II) (cisplatin [cis-DDP]) 60 mg/m2 intravenously (IV), fluorouracil (5-FUra) 350 mg/m2 IV, and folinic acid (leucovorin calcium [FA]) 50 mg/m2 IV on day 2 as bolus, and 5-FUra 350 mg/m2 over 24 hours and FA 100 mg/m2 over 24 hours on days 2 through 5. Radiotherapy consisted of 23.4 Gy over nine days divided into 13 fractions of 1.8 Gy each delivered twice a day from day 3 through day 11. This regimen was repeated on days 22 and 44. Total radiation dose amounted to 70.2 Gy over 51 days. Between August 1984 and October 1986, 62 (modified AJCC stage III, four; IV A, eight; IV B, 50) consecutive patients were entered in the study. Three patients died during treatment due to tumor hemorrhage. Of 59 patients, 48 (81%) achieved a clinically complete response (cCR); 11 (19%) achieved a partial response (cPR). Mean follow-up of the surviving patients was 29+ (24 to 44) months. Actuarial 2-year survival probability is 52%, including three early deaths from tumor bleeding. Tumor and neck nodes control rates at 2 years were 92% for stage III and IV A patients and 65% for stage IV B patients. Patients with cCR had a significantly better 2-year tumor and neck nodes control probability compared with patients who achieved cPR after therapy (P less than .001). Six patients developed distant metastases. Overall toxicity was tolerable, mucositis particularly was not a limiting factor.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Radiotherapy Dosage; Remission Induction

A small group of 46 previously untreated patients out of about 260 in all who have received Price Hill Schedule A cytotoxic chemotherapy, achieved apparent complete clinical regression (ACCR) of their disease before local treatment. Forty patients were classified T3 or T4, over half having clinically positive nodes at the start of treatment. A determinate survival rate of 70 per cent disease free at three years was obtained and 74 per cent achieved quality relief of all symptoms. Two patients declined local treatment and survived three years disease free after chemotherapy alone. No recurrence has occurred to date in seven patients achieving apparent complete histological regression (ACHR) in their surgical specimens. Although ACCR does not automatically improve prognosis it is likely that it does enhance the complete remission rate, especially for those also achieving ACHR. Benefits to patients obtaining ACCR with this minimally toxic chemotherapy schedule are listed.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydrocortisone; Leucovorin; Male; Methotrexate; Middle Aged; Remission Induction; Vincristine

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

Sixty untreated patients with advanced carcinoma of the head and neck (stages III = 11 and IV = 49) were treated simultaneously with three cycles of polychemotherapy and radiation. Chemotherapy consisted of cisplatinum (DDP) 60 mg/m2 after prehydration with saline and mannitol, 5-fluorouracil (5-FU) 350 mg/m2 and folinic acid (FA) 50 mg/m2 on day 2 as a bolus and a continuous infusion of 5-FU 350 mg/m2/24 h and folinic acid (FA) 100 mg/m2/24 h from day 2-5. Concomitantly, accelerated hyperfractionated radiation was administered from day 3-11. Two fractions per day with 1.8 Gy each were given, 13 fractions in 9 days. This cycle was repeated two times on day 22 and 44 with an interval without treatment from day 16-21 and 34-43. Total radiation dose was 70.2 Gy in 51 days. Acute toxicities (WHO grade II and III) consisted mainly of leucopenia (75%), thrombopenia (15%), weight loss (mean 5.8 +/- 3.7%) and mucositis (66%). Grade IV was never reached. Except for 3 patients, who died during treatment due to fatal tumor bleeding or carotid rupture, all were able to finish the treatment with reduction in chemotherapy in only 95% (DDP) and 98% (5-FU) with no changes in the radiation protocol. Evaluation of tumor response at 3 months after end of treatment showed 68% complete and 32% partial responses. 5 patients developed distant metastases. Survival with local control after 12 months was 80.8% and 71.3% after 24 months. 1 and 2 years disease-free survival was 70.8% and 62.1%. Total survival irrespective of cause of death was 77.9% and 57.2% after 1 and 2 years. This particular simultaneous radio-polychemotherapy protocol appears to be well tolerable and highly effective in terms of tumor control and survival of advanced stages of head and neck cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Staging

The effects of extracellular folate concentration on intracellular folate and phosphoribosylpyrophosphate (PRPP) levels and the cytotoxicity of methotrexate and 5-fluorouracil were studied in human KB cells grown in fetal bovine serum-supplemented Eagle's minimum essential medium, which contained standard high folic acid levels (2.3 microM) (standard or S medium), or folic acid-free serum-supplemented medium containing approximately 4 nM 5-methyltetrahydrofolate (physiological or P medium), a folate level and form more comparable to that in normal human serum. Macrocytosis and prolongation of the doubling time by 150% were observed after 5-10 serial passes in P medium, but after 10-15 serial passes, KB cells became "adapted" to P medium with return of size and doubling time to values indistinguishable from cells maintained in S medium. Cellular folate levels fell, and marked elevations in PRPP levels from 68 +/- 43 to 642 +/- 287 pmol/mg cell protein (mean +/- SD) were observed as KB cells were serially passed through P medium. Human leukemia HL-60 and K562 cells and MJY-alpha mouse mammary tumor cells serially passed in P medium also exhibited 10- to 20-fold elevations in PRPP levels. Glucose consumption, glucose decarboxylation, thymidine and adenosine specific uptake, thymidine incorporation into DNA, and 5-fluorouracil uptake were studied in KB cells with elevated and control PRPP levels. As determined by clonal assay, despite elevated PRPP levels, KB cells cultured in P medium were less sensitive to 5-fluorouracil than cells cultured in S medium unless exogenous folate was added. These data support the concept that endogenous folate levels may be inadequate for optimal 5-FU pharmacological action in KB cells with a modulated increase in PRPP levels.

Topics: Adenosine; Carcinoma, Squamous Cell; Cell Survival; Fluorouracil; Folic Acid; Glucose; Humans; KB Cells; Leucovorin; Leukemia, Myeloid, Acute; Methotrexate; Nasopharyngeal Neoplasms; Pentosephosphates; Phosphoribosyl Pyrophosphate; Thymidine

Thirty patients with epidermoid carcinoma of the anus, ranging in age from 40 to 89 years, were treated with combined chemotherapy (CT) and radiation therapy (RT) in lieu of abdominoperineal resection. Two courses of 5-FU (1000 mg/m2/day X four days) by continuous infusion and mitomycin-C (10-15 mg/m2 IV bolus on day 1 of each course) were given 3 to 4 weeks apart simultaneously, with whole pelvis RT to 4140 to 4500 cGy. Twenty-one of 28 patients had T3-T4 primaries and ten had positive nodes (N1). Two of the 30 patients were treated for local recurrence following surgical excision and one was treated immediately after local excision. Twenty-six of the 30 patients attained biopsy-confirmed complete remission. Four of the 30 patients demonstrated residual disease at completion of therapy but all subsequently achieved complete remission with additional nonsurgical treatment. One patient, initially treated for local recurrence following excision failed locally at four years and was salvaged with chemotherapy followed by abdominoperineal resection. No patient has experienced distant failure. Twenty-seven of 30 patients were alive and disease free after 9 to 76 months of follow-up and three died, disease-free, of unrelated causes. Acute toxicities were mild and did not necessitate interruption of treatment. A brisk perineal reaction and diarrhea were noted in all patients. Late complications were unusual. All patients were treated in a community-based, private practice setting. The authors conclude that combined CT-RT, as employed herein, represents a first-line curative treatment for the majority of patients with epidermoid anal carcinoma. For patients who demonstrate residual disease following this therapy, salvage regimens such as 5-FU infusion and cisplatin, or sequential MTX-5-FU-Leucovorin with additional synchronous RT should be employed before resorting to radical surgery.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Mitomycins; Neoplasm Recurrence, Local; Radiotherapy, High-Energy

Concomitant application of chemotherapeutic agents and radiotherapy increases the tumoricidal effects. In this report the biochemical, cell-kinetic and radiobiological interactions of the simultaneous radio-polychemotherapy are discussed. Systemic chemotherapy consisted of cis-dichlorodiammineplatinum (II) (cis-DDP; 60 mg/sqm), 5-fluorouracil (5-FU; 350 mg/sqm) and folinic acid (FA; 50 mg/sqm) on day 2 and 5-FU 350 mg/sqm/24 hrs and FA 100 mg/sqm/24 hrs on days 2-5. Radiotherapy was applied in 13 fractions of 1.8 Gy delivered twice daily from days 3-11. The regimen was repeated on days 22 and 44, reaching the final dose of 70.2 Gy in 8 weeks. With this protocol, optimal tumor regression was achieved in very advanced squamous cell carcinoma of the head and neck. Survival rate after 2 years was 76.8% with 28/32 complete and 4/32 partial remissions. Using an intensive adjuvant treatment, the overall toxicity was tolerable allowing the application of the full therapeutic dosage in 95% without any interruptions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Middle Aged; Radiotherapy Dosage

We treated 20 patients with squamous cell carcinoma of the esophagus with the following regimen: cisplatin = 100 mg/m2 i.v. day 1, HDFA = 200 mg/m2 i.v. day 1 to 5, 5-fluorouracil = 370 mg/m2 i.v. day 1 to 5 repeated every 28 days. Among the 17 evaluable patients, 4 (23%) had a partial remission, 6 had stable disease while 7 progressed. The median survival for all patients was 6+ months. Grade III or IV toxicity included 2 patients with grade III leukopenia, 1 with grade III thrombocytopenia, 1 patient with grade IV and 3 patients with grade III oral mucositis, 3 patients with grade III diarrhea. The regimen did not seem particularly active in the treatment of squamous cell carcinoma of the esophagus and had manageable but substantial toxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Remission Induction

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Time Factors; Uterine Cervical Neoplasms

In patients with locally advanced head and neck cancer, the results of standard definitive treatments of surgery, radiotherapy, or both were disappointing. The local and regional recurrence rates were high, despite adequate surgical resection with negative margins and postoperative radiotherapy to all known or possible disease areas. Combination cisplatin chemotherapy given initially before definitive treatments produced a high overall antitumor response and up to 50 percent clinical complete response. Before answering the question of value of chemotherapy as part of the multimodality treatment, it is important to identify the safest and most form of chemotherapy. The degre of chemotherapy effectiveness is defined by the incidence of clinical and, most important, histologic complete response. To assess this effectiveness, chemotherapy was given before definitive treatments to patients with measurable disease. From our 10 year experience we have concluded that continuing the development of induction chemotherapy, including investigating the timing of such effective treatment and assessing the value of such therapy, is of the utmost importance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Vincristine

A case of severe oral ulceration, following administration of combination chemotherapy which included methotrexate, is reported. Topically applied folinic acid was effective in facilitating resolution of the oral lesions.

Topics: Administration, Topical; Carcinoma, Squamous Cell; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Mouth Diseases; Mouth Neoplasms; Ulcer

Thirty-two patients (only two had previously untreated disease) with squamous cell carcinoma of the head and neck were treated with alternating combination chemotherapy. The regimen consisted of cisplatin (50 mg/m2) and bleomycin (30 units) given iv on Days 1 and 2, alternated with 1 hour of sequential methotrexate (200 mg/m2) and 5-FU (600 mg/m2) given iv, plus oral leucovorin rescue on Day 22. The entire cycle was repeated every 5 weeks (less than or equal to five cycles). Objective tumor regression was obtained in 33% of the 30 evaluable patients, with 13% complete regression. The median duration of response was only 3 months. Evidence of response occurred within one cycle, and was maximal after two cycles. Toxicity was very mild. Alternating combination chemotherapy is not more effective than either combination chemotherapy alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Neoplasm Recurrence, Local; Neoplasm Staging; Time Factors

Despite good results of polychemotherapy in head and neck cancer, monochemotherapy retains a valuable role in managing patients with advanced disease. In a palliative setting, lower toxicity and simpler handling of therapy with single agents are outlined by the Authors, who review results of most active drugs in their different schedules.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

Fifteen patients with advanced squamous cell carcinoma of the anal canal were treated with a combination of bleomycin, vincristine, and high-dose methotrexate (BOM) with leucovorin rescue. Three out of twelve patients with measurable disease had objective responses of 1, 2, and 5 months. Five of the fifteen patients had severe or life-threatening complications as a result of this treatment regimen. The narrow therapeutic index of the BOM therapy makes it a less than ideal drug combination for the treatment of advanced squamous cell carcinoma of the anal canal.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Bleomycin; Carcinoma, Squamous Cell; Drug Evaluation; Female; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Vincristine

One hundred consecutive patients with previously untreated advanced squamous cell carcinoma of the head and neck were treated with induction combination chemotherapy followed by definitive surgery and/or radiotherapy, and were evaluated for radiotherapy related toxicity. The induction regimen consisted of cisplatin, bleomycin and methotrexate/leucovorin. Acute toxicity consisted predominantly of mucositis and weight loss, and was mild or moderate by degree in 94% of patients. Six percent of patients experienced severe or life threatening acute toxicities. Two acute toxic deaths were noted in this series, one from a combination of mucositis, weight loss and infection and one from hypoglycemia of unknown origin. Thirty-five percent of patients had radiation treatment interrupted briefly because of acute toxicity. Toxicity was greatest in patients who were nonresponders to induction chemotherapy and such may have been related to the continued presence of advanced tumor. Radiotherapy dose, surgical intervention and age did not have an impact on the presence or degree of acute toxicity. Late toxicities included: hypothyroidism in 32% of patients tested: osteoradionecrosis in 5% of patients, associated primarily with a composite resection (4 of 5 cases); and soft tissue ulcerations in 3%. Taken together, these data indicate that induction combination chemotherapy did not significantly increase the toxicity of subsequent radiotherapy with or without surgery.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Body Weight; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Hypothyroidism; Leucovorin; Male; Methotrexate; Mucous Membrane; Osteoradionecrosis; Pneumonia; Radiotherapy; Time Factors; Ulcer

The multidisciplinary treatment results of 114 patients with advanced, untreated Stage III and IV squamous cell carcinoma of the head and neck region are reported. Induction chemotherapy with two cycles of cisplatin 20 mg/m2/day intravenous bolus days 1 through 5, bleomycin 10 mg/m2/day as a continuous infusion days 3 through 7, and methotrexate 200 mg/m2 intravenous bolus on days 15 and 22 with leucovorin rescue was utilized before definitive surgery and/or radiation therapy. The total response rate was 78% with 30 (26%) patients achieving complete response and 59 (52%) patients achieving partial response. Patient age, performance status, histologic grade of tumor, and tumor site did not predict response to chemotherapy. Induction chemotherapy was well tolerated with myelosuppression and nephrotoxicity being dose-limiting in a few patients. The toxicity of subsequent local treatment with surgery and/or radiation is reported with an analysis of local treatment failures. A strong correlation was noted between local control of tumor and postchemotherapy tumor size before local treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged

Fifty-nine patients with stage IV head and neck squamous cell cancer were treated with an intensive induction chemotherapy consisting of high-dose methotrexate-leucovorin, bleomycin, and cisplatin. Forty-five patients had recurrent disease following surgery and/or radiation therapy. The response rate in this group was 22%, with a median response duration of 10 weeks and a median survival of 19 weeks. The median survival in responders was 20 weeks and in nonresponders 18 weeks. Fourteen previously untreated patients (13 T4 and one T2) received identical chemotherapy followed by radiation and/or surgery. The response to chemotherapy in previously untreated patients was impressively higher (93%). These patients had a median survival of 48 weeks, and 30% survived 2 years. The initial chemotherapy did not compromise the succeeding radiation therapy or surgery. Toxicities were frequent, but generally well tolerated. It is concluded that prior surgery and/or radiation therapy compromises the efficacy of subsequent chemotherapy in head and neck cancer. Responses to intensive chemotherapy prior to surgery and/or radiation therapy are excellent in patients with T4 tumors and provides a basis for further intensive treatment in attempts to augment cure rates.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged

A phase II trial of cyclophosphamide and adriamycin was carried out in 26 patients with recurrent squamous cell carcinoma of the head and neck, previously treated with cis-diamminedichloroplatinum-based regimens. The overall response rate was 46% (12/26 patients) with the median duration of response being 6.5 months. Cyclophosphamide and adriamycin is an active combination in patients with previously treated squamous cell carcinoma of the head and neck.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged

MTX 250 mg./m2 was administered via i.v. push, followed 1 hour later by a 5-Fu 600 mg./m2 i.v. push. 24 hours after methotrexate, oral leucovorin-rescue started with 15 mg. Every 6 hours for a total of 5 doses. The courses were repeated at weekly intervals, if the toxicity permitted such repetition. 28 patients could be evaluated for response. The overall response rate was 39.2%, with 17.8% (5/28) complete response. The mean duration of complete and partial remissions was 30,8 and 24 weeks, respectively. Subjectively, the patients tolerated the treatment very well. Objective toxicity was moderate, and the major side effect was a generally mild myelosuppression. Thus, in our experience, this regimen can be recommended in the palliative treatment of rSCCHN.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Otorhinolaryngologic Neoplasms; Prognosis

From January to November, 1981, 28 patients with unresectable squamous cell carcinoma of the esophagus were treated with two cycles of chemotherapy combining vincristine (V), methotrexate (M), folinic acid rescue, and cisplatin (P) on days 1 and 21. Split-course radiation therapy was delivered thereafter from day 42 on. Hematologic, renal, and neurologic tolerance was acceptable, but most of the patients experienced nausea and vomiting. Results evolution at day 40 showed a 61% partial response (PR) rate and a 7% complete response (CR) rate. One month after the end of radiation therapy, 43% PR and 32% CR were obtained. Median response duration was 8 months. Median survival was 11.6 months for patients overall, yielding 12.9 months for responders and 5.9 months for nonresponders. Based on the response rate obtained with combined chemotherapy, a randomized trial of VMP initial chemotherapy is currently being undertaken by our cooperative group to study whether such an initial treatment could improve resectability and radiation-mediated local control along with survival rate.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Evaluation Studies as Topic; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nausea; Time Factors; Vincristine; Vomiting

Between January 1975 and December 1981, 160 patients with metastatic non-oat cell bronchogenic carcinoma (MNOBC) were treated with cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP), or with a CAMP-like regimen. Forty-two (26%) of these patients demonstrated an objective response to the chemotherapy with a median survival of 61 weeks. Thirty-nine (24%) patients had stable disease (SD) with a median survival of 45 weeks. Seventy-nine patients (49.4%) were nonresponders with a median survival of 15 weeks. There was a significant difference in survival times between the responders and the SD patients, and between the responders and SD patients and the nonresponders. Responses were seen in 11% of the patients with squamous cell carcinoma and in 37% of the patients with adenocarcinoma. There was a significant difference in the response and SD categories in favor of adenocarcinoma over squamous cell carcinoma. Once a response was achieved, the median survival of the patients with adenocarcinoma was not significantly longer than that of the patients with squamous cell carcinoma.

Topics: Actuarial Analysis; Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Procarbazine

A prospectively designed program employing surgery, radiotherapy, and maintenance chemotherapy was initiated for patients with histologic evidence of extracapsular spread of tumor in cervical metastases. Postoperative radiotherapy consisted of 6,000 rad of cobalt 60 administered in 180- to 200-rad fractions. Chemotherapy was initiated two to four weeks following radiotherapy. Methotrexate sodium (250 mg/sq m), fluorouracil (600 mg/sq m), and leucovorin calcium were administered one day per week, two weeks of three, for a total of 18 treatments in six months. Thirty-two patients have been in the therapeutic program. Toxic reaction has been minimal and self-limiting. One patient stopped chemotherapy because of toxic reaction. One patient (3%) was noncompliant. All patients have been followed up for 18 to 33 months. Twenty-one patients remain alive and free of disease (81% determinate survival). This compares with a 36% (9/25) disease-free survival for concurrent controls and 39% survival for historic controls.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Patient Compliance; Prospective Studies; Risk; Sex Ratio

This paper reviews the role of chemotherapy in advanced squamous cell carcinoma of the head and neck region (SSCHN). Two different areas of administration are discussed separately: (1) Palliative therapy in recurrent disease, and (2) chemotherapy as additional measure in first line treatment of advanced SSCHN aiming at an increase of the disease-free survival and the cure rate. Overall response rates of 80% and complete clinical remissions in about 40% of the cases can be achieved in locally untreated tumors. On the other hand, recurrent SSCHN respond not as well to chemotherapy; nevertheless, a good temporary palliative effect is reached in more than half of the patients. As example for the numerous combination programs studied in the last few years, we report some data of the two protocols evaluated at our clinic, cis-diamminedichloroplatinum/adriamycin and methotrexate/5-fluorouracil, respectively.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Doxorubicin; Drug Administration Schedule; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Neoplasm Recurrence, Local; Neoplasm Staging; Palliative Care; Prognosis

A new concept of chemotherapy scheduling was evaluated in 20 patients with inoperable squamous cell lung cancer. The complete plus partial response rate was 85%, with 15% complete responses. The drugs utilized included vinblastine, bleomycin, methotrexate, 5-FU, cisplatin, and leucovorin. The hypothesis leading to the chosen drug schedule was that impaired rbc deformability (RBCD) found in cancer patients may produce stasis of flow in tumor capillary beds and decrease drug delivery to cancer cells. Drug schedules were designed to take advantage of chemotherapy-induced improvement in RBCD. After an initial drug treatment, a second treatment was given when RBCD increased at least 25% over pretreatment values (usually 4-6 days after the first chemotherapy dose). Drug doses were weighted so that more drug was given when RBCD was greatest. Treatment toxicity was predominantly hematopoietic and renal. This type of chemotherapy approach opens up new avenues of investigation in squamous cell cancer and other common neoplasms.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Erythrocytes; Fluorouracil; Hematopoiesis; Humans; Kidney; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Vinblastine

Fourteen patients with advanced or locally recurrent squamous cell carcinoma of the uterine cervix were treated with bleomycin, vincristine, and moderately high dose methotrexate with citrovorum rescue. Two patients (14%) had a partial response; no patient had a complete response. Two patients were felt to have significant bleomycin associated pulmonary toxicity. This chemotherapy regimen is not felt to be clinically useful in our patient population.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Female; Humans; Leucovorin; Lung Diseases; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms; Vincristine

A clinical trial of high dose methotrexate (MTX)-CF rescue was conducted in 17 institutions. Forty-seven patients with head and neck cancer entered this trial, of which 29 were evaluable. In this series, the patients were divided into 2 groups (Arm I, Arm II), according to physician's selection. MTX was administered 700 mg/m2 (1000 mg/body) in Arm I and 1750 mg/m2 (2500 mg/body) in Arm II by i.v. drip over 6 hours. Twenty-four hours after initiation of MTX infusion, CF rescue was started. There was no complete response in 29 patients. Four patients showed partial response with an overall response rate of 13.8%. There were 4 partial responders out of 21 patients in Arm I, with a response rate of 19%, whereas there was no partial responders out of 8 patients in Arm II. These results showed no apparent dose response. MTX concentrations in plasma were determined at 6, 24, 48 and 72 hours after initiation of MTX infusion. The assay results revealed a safe range in Arm I, but exceeded in 3 cases of Arm II. GI disturbances were seen at the rate of 78%. Bone marrow suppression was remarkable and hepatic toxicity was observed as the rate of 41%. No renal toxicity was observed. The results of high dose MTX-CF rescue therapy were not better than those of moderate dose therapy, so that we concluded that MTX should be used as one agent at low or moderate dose in combination chemotherapy as far as Japanese patients with head and neck cancer are concerned.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged

Fifteen patients with advanced or recurrent gynecologic malignancy were treated with high-dose methotrexate (HDMTX) (1-8 g/M2) and citrovorum factor rescue (10-100 mg/M2). One complete response (13%) and two improved responses occurred in eight patients (25%) with squamous cell carcinoma and one of seven patients (14%) with nonsquamous nontrophoblastic carcinoma had stable disease for 7 months. The median duration of survival in the squamous group was 9 months and in the nonsquamous groups 6.5 months. Mean serum MTX concentrations were proportional to the doses administered and typical two compartment plasma disappearance curves were seen. Adverse toxic reactions were not observed at serum MTX levels less than 7.8 X 10(-7) M at 24 hr and 1 X 10(-7) M at 48 hr post-MTX. Hematopoietic toxicity occurred most frequently with leukopenia observed in 19.5% of courses. Hepatic, renal, gastrointestinal, and dermatologic toxicities were observed infrequently. Drug-induced nephrotoxicity occurred in one patient and possibly related leukoencephalopathy occurred in another patient. On the basis of the relatively low response rate observed in this trial and the high expense of HDMTX therapy, the value of such therapy may be limited in advanced nontrophoblastic gynecologic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Drug Evaluation; Female; Genital Neoplasms, Female; Hematologic Diseases; Humans; Kidney Diseases; Kinetics; Leucovorin; Methotrexate; Middle Aged; Nausea; Time Factors

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Floxuridine; Fluorouracil; Humans; Iliac Artery; Infusions, Intra-Arterial; Leucovorin; Male; Melanoma; Methotrexate; Middle Aged; Ovarian Neoplasms; Pelvic Neoplasms; Prostatic Neoplasms; Urinary Bladder Neoplasms; Uterine Cervical Neoplasms

Since experimental data strongly suggest a synergistic cytotoxic effect when methotrexate (MTX) and 5-fluorouracil (5-FU) are administered sequentially, we investigated antitumor effects and toxicity with sequential MTX/5-FU followed by leucovorin rescue in 52 patients with carcinoma of the head and neck. MTX (200 mg/m2) was given as an i.v. infusion over 1 hr. At 2 hr, 5-FU (600 mg/m2) was started as an i.v. infusion for 2 hr. At 24 hr, the leucovorin rescue was started. The chemotherapy course was repeated every week until toxicity (mainly gastrointestinal) occurred, after which the interval between courses was prolonged to 2 wk. Toxicity was mild and usually disappeared when the interval between the chemotherapy courses was prolonged to 2 wk. The regression rate was 15% for complete and 48% for partial regression (response rate, 63%). In 31 of the patients not previously treated, the objective response rate was 74%. About the same results were obtained for tumors of different anatomic sites of the head and neck. Radiotherapy could be added sequentially without measurable escalation of toxicity. We conclude that sequential MTX/5-FU treatment, which produces a very mild toxicity to normal tissue, is effective in inducing antitumor response in patients with carcinoma of the head and neck.

Topics: Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Therapy, Combination; Endoscopy; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Lymphatic Metastasis; Methotrexate; Neoplasm Staging

Thirty-six patients with squamous cell carcinoma of the head and neck were treated with sequential methotrexate-5-fluorouracil followed by leucovorin rescue. The frequency of objective tumor regression obtained was 64% (complete response + partial response) with 19% complete regression. In 20 not previously treated patients, the objective response rate was 70%. Approximately the same result was obtained for tumors of different anatomical sites of the head and neck. The degree of differentiation of the squamous cell carcinoma did not seem to be of prognostic importance for the initial tumor response. Toxicity was very mild and usually disappeared when the interval between the chemotherapy courses was prolonged from 1 to 2 weeks. Radiotherapy could be added sequentially to the treatment without measurable escalated toxicity.

Topics: Carcinoma, Squamous Cell; Drug Therapy, Combination; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

Thirty-three patients with locally advanced squamous cell carcinoma of the head and neck were scheduled to receive two courses of chemotherapy prior to radical radiotherapy. Chemotherapy consisted of moderate-dose methotrexate with leucovorin rescue, bleomycin by infusion, and cisplatin. Loss of body weight and the duration of membrane formation at a specified region of the oral cavity during radiation therapy were used as indices of radiation toxicity: there was no excessive loss of body weight or mucosal reaction in patients who received combined treatment compared to patients in a nonrandomized control group who received radiotherapy alone. Twenty patients (60%) had a greater than or equal to 50% decrease of measurable disease prior to starting irradiation, but only eight patients (24%) are alive and disease-free at a median followup of 16 months. Aggressive chemotherapy does not prevent delivery of subsequent full-dose radiotherapy for squamous cell carcinoma of the head and neck, but this study does not suggest that chemotherapy has a great beneficial effect on long-term survival.

Topics: Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Prognosis; Radiotherapy

Twenty-seven evaluable patients with advanced head and neck squamous carcinoma were treated with a polychemotherapeutic regimen described in 1975 by Price et al. Chemotherapy consisted of vincristine, adriamycin, bleomycin, methotrexate, 5-fluorouracil, hydroxyurea, 6-mercaptopurine and citrovorum factor administered sequentially. One complete remission, 4 partial remissions, 7 minor responses were obtained for a total of 12/77 (44%) objective responses. Toxicity was acceptable. The results obtained were not better than those observed with less complicated regimens administrable on an outpatient basis.

Topics: Adult; Aged; Bleomycin; Carcinoma, Squamous Cell; Doxorubicin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Leucovorin; Male; Mercaptopurine; Methotrexate; Middle Aged; Vincristine

Optimal therapy for stage III and stage IV squamous carcinoma arising in the head and neck requires a multidisciplinary approach, including chemotherapy. Advances have identified several chemotherapeutic agents and combinations of agents that show substantial antitumor activity in this disease. While antitumor activity can be documented, experience indicates the duration of antitumor effect is short, and the toxicity may limit further therapy. To date, studies have not shown an advantage of combination chemotherapy over single agents. Theoretically, combination chemotherapy should increase patient survival through regression of the primary tumor as well as ablation of distant metastases. An analysis of recent trials with patients who received induction chemotherapy before definitive local treatment suggests that regression of tumor in stage III and stage IV lesions before definitive therapy may increase local treatment for regional disease. Randomized trials are needed to confirm or disprove the efficacy of combination chemotherapy for advanced squamous carcinoma of the head and neck.

Topics: Carcinoma, Squamous Cell; Cisplatin; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

A new intensive methotrexate regimen for the treatment of advanced squamous carcinoma of the head and neck is presented, employing twice-weekly parenteral low-moderate doses of methotrexate and a single parenteral dose of leucovorin 24 hours following methotrexate. Toxicity and therapeutic results in 20 patients treated with this regimen favorably with results of weekly high-dose methotrexate-leucovorin in 36 patients treated immediately before initiation of the new regimen. Moderate nephrotoxicity and mild gastrointestinal/mucosal toxicity were common to both, while myelotoxicity was rarely seen with the low dose regimen and was more frequent with the high-dose regimen. Partial response was observed in 60% of patients treated on the intensive low-moderate dose schedule, and 50% of patients previously untreated with methotrexate on the weekly high-dose schedule. None of 12 patients previously failing low-moderate doses of methotrexate responded to high doses administered in this trial. The characteristics of antitumor response with low-moderate and high-dose schedules were similar except for the median dose required to attain response (50 mg/m2 vs. 3 g/m2) and the lesser toxicity of intensive lower dose therapy with leucovorin.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Administration Schedule; Female; Gastrointestinal Diseases; Head and Neck Neoplasms; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Middle Aged; Myeloproliferative Disorders; Prognosis

200 mg/m2 methotrexate given intravenously in a running drip for 6 h has been used as an initial adjuvant therapy in 38 patients with advanced head and neck cancer. The response rate is as high as 80%, with 21% achieving complete remission. Histologically, specimens were tumor free in 3 patients. Toxicity in 38 patients included leukopenia (4), mucositis (6) and diarrhea (1). This particular dose of methotrexate appears to be safe and usually does not need leucovorin rescue. Also, when given as initial treatment, it is effective in reduction of tumor bulk. A prolonged randomized trial is essential to determine its role in improving long-term survival.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Diarrhea; Female; Head and Neck Neoplasms; Humans; Leucovorin; Leukopenia; Male; Methotrexate; Middle Aged; Mucous Membrane

Split course radiation and kinetically based combinations of chemotherapy as suggested by Price, et al have been used for treatment of Stage III and Stage IV squamous cell carcinoma of the head and neck region. Twenty-nine patients were eligible for evaluation. Twenty-three out of 29 patients had complete remission of their primary tumor, three patients presented with N1 of which all had complete remission. Fourteen patients who presented with N2 neck nodes--three had complete regression and seven had partial response. Five patients who presented with lung lesion at the beginning; proved to be a second primary rather than metastases from the head and neck cancer. Subsequently, three patients had lung resection. At one year these three patients have remained free from recurrence from both the primaries. Toxicities had been noted due to combinations of two modalities which however had been within acceptable limits. Eighteen out of 29 patients had considerable persistent soft tissue edema in the irradiated area.

Topics: Alopecia; Bleomycin; Carcinoma, Squamous Cell; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Vincristine

Fifteen patients with advanced squamous cell carcinoma of the head and neck were treated with the six-drug Price-Hill regimen (vincristine, bleomycin, methotrexate, hydrocortisone, 5-fluorouracil, and leucovorin). Only two partial remissions were obtained, and the regimen produced moderate toxicity. Our results are not as favorable as those of Price and Hill.

Topics: Adult; Aged; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Drug Therapy, Combination; Fluorouracil; Head and Neck Neoplasms; Humans; Hydrocortisone; Leucovorin; Methotrexate; Middle Aged; Time Factors; Vincristine

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Child; Drug Evaluation; Drug Therapy, Combination; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Leucovorin; Leukocyte Count; Melanoma; Neoplasms; Platelet Count; Pyrimethamine; Sarcoma

In cases with inoperable tumours of the head and neck some benefit may still be derived from cytostatics and radiotherapy. One treatment concept is based on intraarterial infusion therapy (bleomycin, methotrexate), while the systemic intravenous application of cytostatic substances (bleomycin, cyclophosphamide) is considered as an alternative of the intra-arterial approach is ruled out. Of the 31 intra-arterially and the 30 intravenously treated patients (all except 2 had squamous cell carcinomas), 64,5% and 20%, respectively, went into remission. This documents the validity of our treatment concept.

Topics: Adult; Aged; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Catheterization; Cyclophosphamide; Dacarbazine; Doxorubicin; Female; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Injections, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Vincristine

Topics: Adult; Aged; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Female; Glycoproteins; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Injections, Intramuscular; Leucovorin; Leukocyte Count; Male; Methotrexate; Middle Aged; Neoplasm Staging; Rosette Formation; T-Lymphocytes

Thirty-four patients with advanced squamous cell carcinoma of the head and neck have been treated with sequential combination chemotherapy consisting of Cytoxan, methotrexate, oncovin, bleomycin and adriamycin, followed by Leucovorin (COMBAL). All patients had undergone extensive prior radiation and/or surgery. All the patients had recurrent cancer. Toxicity included two deaths from drug induced pancytophenia and one from sepsis. Treatment was well tolerated and could be given in the outpatient clinic. No bleomycin pulmonary or adriamycin cardiac toxicity was seen. Results include 4 patients who achieved complete remission, objective improvement in measurable lesions in 6 others, stabilization of disease for 1 to 3 mo. in 5, and progression of disease in 13. Survival has ranged from 1 to 19+ months with a median of 10.7 mo. for patients that were evaluated. We conclude that COMBAL produces objective evidence of improvement in approximately 45% of patients with far advanced, previously treated squamous cell carcinoma of the head and neck.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Vincristine

A new combined modality treatment in advanced squamous cell carcinoma of the head and neck, is presented. It consists of surgery, or radiotherapy, followed by adjuvant chemotherapy with MTX and CF rescue, cis-DDP, Bleomycin, Cyclophosphamide, given sequentially. Toxic effects were not very severe and did not cause an interruption of therapy.

Topics: Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Cyclophosphamide; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

Advanced squamous carcinoma of the head and neck remains refractory to the best combinations of surgery and radiotherapy. Weekly methotrexate in high doses with leucovorin "rescue" is able to produce significant remissions in a majority of patients treated palliatively for recurrent disease yet is associated with little or no toxicity. We have attempted to improve the cure of patients with advanced disease by the use of high dose methotrexate (3-7.5 g/M2) and leucovorin prior to and following definitive surgery and/or radiotherapy. In a series of 24 patients we have achieved a response rate of 52%, with minimal toxicity during chemotherapy, and no apparent potentiation of toxicity with radiotherapy. Survival free of disease appears to be prolonged in patients with response to this chemotherapy. Multimodality approaches to locally advanced squamous carcinoma of the head and neck may soon yield improved cure rates.

Topics: Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged

A case of extensive metastatic epidermoid carcinoma of the penis is reported. Disseminated disease developed after penectomy and lymphadenectomy and it continued to progress while the patient received radiation therapy. Chemotherapy with high dose methotrexate followed by citrovorum factor rescue was instituted. After completion of 10 weekly cycles of treatment there was biopsy-proved complete regression of all lesions, which lasted 9 months when the patient suddenly died of pneumonia completely unrelated to the tumor or chemotherapy treatment. This chemotherapeutic approach deserves additional trial in patients with advanced stages of penile carcinoma.

Topics: Carcinoma, Squamous Cell; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Penile Neoplasms

Thirteen patients with metastatic squamous cell cancer of the lung were treated, in a nonrandomized study, with an oral high-dose methotrexate and citrovorum factor rescue regimen. There was some response and/or stabilization of disease for at least three months in six (46%) of 13 cases. The median survival time of the study group was double (365 vs. 180 days) that of a retrospectively matched control group. This suggests a possible therapeutic effect of this treatment program in metastatic squamous cell cancer of the lung.

Topics: Administration, Oral; Adult; Aged; Carcinoma, Squamous Cell; Drug Therapy, Combination; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Middle Aged; Neoplasm Metastasis; Remission, Spontaneous; Time Factors

Our initial experience with weekly high dose methotrexate with leucovorin rescue (MTX-LCV), in advanced recurrent or metastatic squamous cell carcinoma of the head and neck with a 77% tumor response rate and high therapeutic index, prompted a trial of MTX-LCV as initial adjuvant therapy in high risk nonmetastatic patients. Results in 11 patients are presented and confirm the high response rate to MTX-LCV and the low incidence of myelotoxicity and mucositis, when concurrent urinary alkalinization is employed. Initial MTX-LCV administrations has not compromised subsequent optimum aggressive combinations of surgery and radiation therapy. Cytoreduction with MTX-LCV may be safely used initially in combined therapy for high risk squamous cell carcinoma of the head and neck.

Topics: Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Therapy, Combination; Head and Neck Neoplasms; Leucovorin; Methotrexate

A series of 17 patients with stage III and IV head and neck cancer received three cycles of methotrexate and leucovorin calcium during an interval of two weeks prior to surgery and/or radiotherapy. The dosage of methotrexate was sequentially escalated to produce mucositis (the usual dose-limiting toxicity). All patients have been followed up for a minimum of two years (range, 24 to 44 months). Two recurrences and two second primary tumors occurred in seven patients with stage III cancer, and one recurrence and one postoperative death (pulmonary embolism) occurred in ten patients with stage IV cancer. Seventy-six percent of patients survived, with 71% disease free. Mucositis occurred in 88% but was transient and prevented oral fluid intake in only one patient. Bone marrow suppression was usually mild and did not delay surgery. Escalation of dosage was thought to be important in achieving these encouraging results. A controlled trial is under way to better define the degree of efficacy of this regimen of adjuvant chemotherapy.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

Fourteen patients with advanced localized gynecologic cancer were treated with 44 courses of intraarterial pelvic infusion chemotherapy. All patients received methotrexate with folinic acid rescue; 9 patients also received vincristine. Tumor regression was observed in 3 of 14 patients (21.4%). In 5 patients there were major complications related to 28 intraarterial catheter placements. Two patients developed leukopenia following chemotherapy. The value of intraarterial infusion chemotherapy in gynecologic cancer is limited. Its use in gynecologic oncology is discussed.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Catheterization; Female; Genital Neoplasms, Female; Humans; Infusions, Intra-Arterial; Leucovorin; Methotrexate; Middle Aged; Pelvis; Uterine Cervical Neoplasms; Vincristine

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Cycle; Cell Survival; Drug Therapy, Combination; Humans; Kinetics; Leucovorin; Lung Neoplasms; Methotrexate

Eighty-six adults with malignant disease were given high doses of methotrexate with folinic acid rescue, with acceptable toxicity. Protocal violations in two cases led to death. The results of therapy in some diagnostic groups are encouraging.

Topics: Adult; Carcinoma, Squamous Cell; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Lymphoma; Methotrexate; Neoplasms

Combination chemotherapy in advanced squamous carcinoma of the head and neck resulted in objective remission in 5 of 8 patients, with a median duration of 9 months. In 4 patients, the intravenous chemotherapy was supplemented by regional intra-arterial short-time infusion chemotherapy, by which one patient obtained a partial remission and 3 a static disease. The most important results of the methods used were the subjective improvements of the patients. The side-effects were acceptable, and no serious complications were observed.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Injections, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Vincristine

Methodichlorophen was given to 26 patients with terminal malignant disease. Eight patients received adequate doses, and five of them showed objective evidence of tumour regression while three failed to respond. Those who responded included four out of five patients with lung cancer (three with squamous-cell carcinoma and one with oat-cell carcinoma) and a patient with hypernephroma. Two patients with testicular teratomas and one with acute myeloid leukemia failed to respond. The drug may be given safely by mouth to outpatients if certain precautions are taken.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Bone Marrow Diseases; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chlorobenzenes; Drug Therapy, Combination; Erythema; Headache; Humans; Kidney Neoplasms; Leucovorin; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pyrimethamine; Pyrimidines; Teratoma; Testicular Neoplasms

Experience with chemotherapy in advanced gynecologic malignancies is limited. In 6 patients, 2 of 4 with carcinoma of the cervix, and 1 patient with carcinoma of the ovary achieved partial remission when treated with a regimen of high dose methotrexate (240 mg/m2) followed by leucovorin rescue. On patient with metastatic trophoblastic disease achieved complete response (greater than 24 months). The number of doses of leucovorin 'rescue' was based on creatinine clearance. The advantage of rapid response and moderate toxicity indicate the need for further study of this regimen in the treatment of gynecologic malignancies.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Genital Neoplasms, Female; Humans; Leucovorin; Methotrexate; Middle Aged; Ovarian Neoplasms; Pregnancy; Trophoblastic Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms

The inadequacies of traditional methods for control of advanced oral carcinomas at their sites of origin prompted evaluation of combined chemotherapy and cryosurgery in seventy-three patients treated since 1969. Our experience with thirty-nine unlikely candidates for salvage by other therapy is the subject of this report. The majority had recurrent disease after other therapy. The observed morbidity potential of combined chemotherapy and cryosurgery with earlier experience led to abbreviations and refinements of method that are described and consist mainly of the following. (1) A two day postcryosurgical infusion (intra-arterial) of 5-fluorouracil (1 gm per twenty-four hours, or less) in lieu of methotrexate, the systemic toxicity and therapeutic efficacy of which seem less predictable with cryosurgery. (2) Electrosurgical subtotal tumor resection at the time of initial cryosurgery to reduce swelling and magnitude of in situ tissue slough. (3) Use of a flexible copper mesh cryoprobe that enhances feasibility of in-depth wide field cryosurgery. (4) Systematic use of multiple marginal wound biopsies as a principal guide to repetitive cryosurgery or other therapeutic adjunct selection. A special warning that available toxicologic data for independent drug therapy may not be applicable in patients after cryosurgery is given. Current experience indicates that negative biopsy after such combined therapy may be 85 per cent reliable in foretelling lesion outcome. Among the thirty-nine patients reported, twenty remain alive from six months to six years, only two of whom have clinically evident recurrent disease. If such could be reasonably accomplished, comparative evaluation of single methods should precede attempts to combine two or more modes of therapy. Since neither chemotherapy nor cryosurgery, as known today, can eliminate nodal metastases, each must be regarded as potentially adjunctive to other methods for achieving the ultimate goal of a cancer-free patient. It is within this context that combined chemotherapy and cryosurgery have been applied to unfavorable candidates for cure with seemingly worthwhile gains. Potential applicability for patients with less formidable stages of disease cannot be extrapolated from this experience. Large scale controlled clinical trials must provide the ultimately conclusive test of efficacy for such combined forms of therapy before decisive revision of traditional standards of practice might result.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cryosurgery; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Male; Methods; Methotrexate; Middle Aged; Mouth Neoplasms; Neoplasm Recurrence, Local; Ohio; Tongue Neoplasms

Surgical techniques for the selective administration of anti-cancer drugs is presented. These isolated-perfusion or intra-arterial infusion procedures have achieved significant palliation for many patients with advanced cancer. When used in conjunction with surgical excision of certain early skin cancers, such as aggressive forms of malignant melanoma of the extremities, improved cure rates may be achieved.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Extremities; Female; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Leucovorin; Male; Melanoma; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Sarcoma; Sarcoma, Kaposi; Skin Neoplasms

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Bleomycin; Carcinoma, Squamous Cell; Catheterization; Cyclophosphamide; Glutamates; Head and Neck Neoplasms; Humans; Hydroxyurea; Infusions, Parenteral; Injections, Intravenous; Leucovorin; Methotrexate; Mouth Neoplasms; Pteridines; Remission, Spontaneous

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Synergism; Female; Head; Head and Neck Neoplasms; Humans; Injections, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Carotid Artery, External; Carotid Artery, Internal; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lymphatic Metastasis; Maxillary Artery; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Nose Neoplasms; Paranasal Sinus Neoplasms

Topics: Adenocarcinoma; Adult; Bone Marrow Diseases; Carcinoma, Squamous Cell; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Radiography

Topics: Aged; Blood Platelets; Carcinoma, Squamous Cell; Female; Head; Head and Neck Neoplasms; Hematocrit; Hemoglobins; Humans; Laryngeal Neoplasms; Leucovorin; Leukocyte Count; Male; Methotrexate; Middle Aged

Topics: Adult; Aged; Anemia; Carcinoma, Squamous Cell; Cell Division; Drug Eruptions; Drug Synergism; Facial Neoplasms; Female; Head and Neck Neoplasms; Humans; Laryngeal Neoplasms; Leucovorin; Leukopenia; Lip Neoplasms; Male; Methotrexate; Middle Aged; Mouth Neoplasms; Mucous Membrane; Palatal Neoplasms; Pharyngeal Neoplasms; Tongue Neoplasms

Topics: Adenocarcinoma; Administration, Oral; Aged; Carcinoma, Adenoid Cystic; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cystadenoma; Ear Neoplasms; Female; Head; Head and Neck Neoplasms; HeLa Cells; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Mouth Neoplasms; Osteosarcoma

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Child, Preschool; Choriocarcinoma; Chorionic Gonadotropin; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Methotrexate; Middle Aged; Pregnancy; Teratoma; Testicular Neoplasms

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Catheterization; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Fluorouracil; Follow-Up Studies; Head; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Mechlorethamine; Methotrexate; Neoplasms; Pelvic Neoplasms; Thoracic Neoplasms

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Jaw Neoplasms; Laryngeal Neoplasms; Leucovorin; Leukopenia; Male; Methotrexate; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Neoplasms; Paranasal Sinus Neoplasms; Pharyngeal Neoplasms; Salivary Glands; Thrombocytopenia; Tongue Neoplasms; Tonsillar Neoplasms

Topics: Adenocarcinoma; Arteries; Brain Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Catheterization; Chloramphenicol; Facial Neoplasms; Fever; Fluorouracil; Head and Neck Neoplasms; Humans; Infections; Infusions, Parenteral; Leucovorin; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Neoplasm Metastasis; Palliative Care; Penicillins; Stomach Neoplasms; Thoracic Neoplasms

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Child; Female; Humans; Injections, Intra-Arterial; Leucovorin; Male; Maxillary Neoplasms; Mechlorethamine; Mesenchymoma; Methotrexate; Middle Aged; Palatal Obturators; Paranasal Sinus Neoplasms; Radiotherapy Dosage; Temporal Arteries

Topics: Aged; Carcinoma, Squamous Cell; Hand; Humans; Injections, Intra-Arterial; Leucovorin; Male; Methotrexate; Middle Aged

Topics: Adenocarcinoma; Blood Cell Count; Blood Chemical Analysis; Bone Marrow Examination; Carcinoma; Carcinoma, Papillary; Carcinoma, Squamous Cell; Drug Therapy; Facial Neoplasms; Hematopoiesis; Hemoglobinometry; Infusions, Intra-Arterial; Injections, Intra-Arterial; Injections, Intramuscular; Intestinal Neoplasms; Leucovorin; Methotrexate; Mouth Neoplasms; Myxosarcoma; Toxicology; Urine; Urogenital Neoplasms

Topics: Carcinoma; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Laryngeal Neoplasms; Leucovorin; Maxillary Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasms; Orbital Neoplasms; Palatal Neoplasms; Temporal Arteries; Tongue Neoplasms; Toxicology