levoleucovorin and Head-and-Neck-Neoplasms

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Cisplatin; Combined Modality Therapy; Deoxycytidine; Doxorubicin; Etoposide; Femoral Neoplasms; Gemcitabine; Head and Neck Neoplasms; Humans; Ifosfamide; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoadjuvant Therapy; Osteosarcoma; Palliative Care; Salvage Therapy; Scalp; Skin Neoplasms; Thoracotomy

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

Many randomized trials have investigated the effect on survival of induction chemotherapy; none however, has demonstrated improved survival. A study of the Department of Veterans Affairs Laryngeal Cancer Study Group demonstrated the feasibility of induction CDDP/5-FU plus surgical salvage as an alternative to initial laryngectomy, but it did not include a radiation-alone treatment arm. Thus, a three-arm trial (R 91-11) was needed to compare the regimen of induction chemotherapy plus surgical salvage treatment with radiation alone and with concurrent chemo-radiation, to determine whether the addition of chemotherapy led to better results than conventional radiation alone. R 91-11 data revealed that concurrent chemo-radiation significantly increased the time to laryngectomy and chemotherapy suppressed distant metastasis, but there was no difference in overall survival. Single-agent docetaxel is known to induce a response in 22-45% of patients with recurrent squamous cell cancer of the head and neck. When used in combination with CDDP, response rates of between 40 and 54% have been reported. Increased expression the epidermal growth factor receptor (EGFR) is reported in head and neck cancer. Anti-EGFR monoclonal antibody is associated with decreased cell proliferation, inhibition of metastasis and angiogenesis, and it has a synergistic effect with chemotherapy or radiotherapy. It is hoped that further advances will lead to greater realization of the therapeutic potential of these compounds as anticancer agents.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cisplatin; ErbB Receptors; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoadjuvant Therapy; Randomized Controlled Trials as Topic; Survival Rate

Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the main preclinical and clinical results of raltitrexed/5-FU-based combination chemotherapy regimens in anticancer therapy. Promising results include: response rates of 25 and 23% with combinations of raltitrexed/5-FU/levofolinic acid (LFA) as first-line treatment and oxaliplatin/raltitrexed/5-FU/LFA as second-line treatment of metastatic colorectal cancer, respectively; and a 67% response rate in a phase I study of cisplatin/raltitrexed/5-FU/LFA as first-line treatment of advanced head and neck cancer, including a 100% response rate at the recommended dose. These combinations were well tolerated, with neutropenia as the main dose-limiting toxicity, allowing the drugs to be combined at the doses used in monotherapy. These results suggest a role for raltitrexed within combination regimens in colorectal cancer therapy, as well as other tumors such as head and neck cancer. A further potential application of raltitrexed in combination therapies is within multidisciplinary chemo-radiotherapy strategies, mainly in rectal cancer. Phase II studies are planned/ongoing to investigate these interesting possibilities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Rectal Neoplasms; Thiophenes

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 results from preclinical studies using murine tumor models show that the combination of docetaxel (Taxotere) and fluorouracil (5-FU) is highly synergistic. Phase I studies in patients with advanced solid tumors indicate that 60 mg/m2 of docetaxel administered as a 1-hour intravenous infusion followed by a daily intravenous bolus of 300 mg/m2 of 5-FU on days 1 through 5 is the recommended dose for phase II studies. Preliminary results from another phase I study using a continuous infusion regimen for 5-FU suggest that 85 mg/m2 of docetaxel administered as a 1-hour intravenous infusion followed by continuous infusion of 750 mg/m2 per day of 5-FU on days 1 through 5 may be the recommended dose for phase II studies. As expected, dose-limiting toxicities included neutropenia and mucositis. Ongoing phase I/II and II studies are investigating the combination of docetaxel with continuous infusion of 5-FU in patients with metastatic breast cancer and with cisplatin (Platinol) and continuous infusion of 5-FU, with and without leucovorin, in patients with head and neck cancer. Preliminary results are encouraging and warrant further study.

Topics: Adult; Aged; Animals; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Docetaxel; Dose-Response Relationship, Drug; Drug Synergism; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Mice; Middle Aged; Mucous Membrane; Neoplasms; Neutropenia; Paclitaxel; Taxoids

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

Topics: Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Immunologic Factors; Interferons; Leucovorin; Methotrexate

Many clinical trials with 5-fluorouracil and leucovorin have been reported. This combination therapy seems to play an important role in untreated advanced colorectal cancer. In other neoplasms (gastric, head and neck, breast cancer) further studies are required.

Topics: Adenocarcinoma; Breast Neoplasms; Colorectal Neoplasms; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Meta-Analysis as Topic; Stomach Neoplasms

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

Topics: Administration, Oral; Animals; Biological Transport; Central Nervous System; Drug Resistance; Folic Acid; Folic Acid Antagonists; Gene Amplification; Head and Neck Neoplasms; Humans; Kinetics; Leucovorin; Leukemia, Lymphoid; Lung Neoplasms; Methotrexate; Neoplasms; Osteoma, Osteoid; Thymidylate Synthase; Tissue Distribution

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: Animals; Antineoplastic Agents; Cisplatin; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Mice

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

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

Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN.. In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT.. Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%]. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS.. Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival.. ClinicalTrials.gov Identifier: NCT04397341 , May 21, 2020, retrospectively registered.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Docetaxel; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Induction Chemotherapy; Leucovorin; Male; Middle Aged; Progression-Free Survival; Prospective Studies; Squamous Cell Carcinoma of Head and Neck

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

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

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

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

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

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 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

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 purpose of the study was to assess response rate, clinical outcome, organ/function preservation and toxicity in head and neck cancer patients treated with induction chemotherapy followed by concomitant chemoradiotherapy and, when necessary, limited surgery. The study design was a phase II non-randomized trial in hospitalized patients setting. The treatment plan consisted of 3 cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), l-leucovorin and interferon alpha2b (PFL-IFN) followed by 7 cycles of 5-FU, hydroxyurea and concomitant radiation for 5 days (FHX) for a total radiation dose of 70 Gy. 13 Cis-retinoic acid was added to treatment regimen for chemoprevention and a systematic prophylaxis of mucositis was administered to all patients during FHX. Conservative surgical resection was reserved to patients with no optimal response (PR > or =70%), whereas radical surgery was performed as salvage treatment. Twenty-six patients were treated at one institution: more than 90% had stage IV disease and only 19.2% had laryngeal cancer. Eighty-one percent of patients had performance status 0 and 23.1% of patients had >5% weight loss at the start of treatment. Nineteen patients were analyzed for response to PFL-IFN: 3/19 (15.8%) patients achieved a CR and 7/19 (36.8%) achieved a PR for an ORR of 52.6%. FHX was administered on protocol to 12 patients: 6 patients (50%) had CR, 1 patient (8.3%) had PR for an ORR of 58.3%, 2 patients (16.7%) had SD and 3 patients (25%) had PD. At the completion of FHX, no patient underwent local therapy according to treatment plan. At a median follow-up time of 13.5 months (range 1-28+) at June 2001, among 26 patients enrolled 12 (46.1%) were still alive and 9 (75%) of them were progression-free. The median duration of response was 9 months (range 0-25+), the median progression-free survival was 10.5 months (range 0-28+), the median overall survival time was 9 months (range 1-22). The toxicity was significant and consisted mainly of mucositis and, to a lesser extent, neutropenia/thrombocytopenia. In the present study, the low serum levels of leptin and the high serum levels of proinflammatory cytokines in advanced stage cancer patients were confirmed. In conclusion, this sequential induction chemotherapy and chemoradiotherapy program has been found moderately active and significantly toxic; moreover, the long overall treatment duration must be taken into consideration. For these reasons, this regimen could not be rec

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cytokines; Dose-Response Relationship, Radiation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Inflammation; Interferon-alpha; Leptin; Leucovorin; Male; Middle Aged; Quality of Life; Treatment Outcome

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

To evaluate the feasibility of combined high dose leucovorin plus 5-fluorouracil infusion for head-neck and digestive tract cancers.. Fifty-six patients with head-neck and digestive tract cancer were treated by combined high dose leucovorin (HD-CF) plus 5-fluorouracil (5-Fu) 48 hour continuous infusion with each patient receiving an average of 3.8 cycles (2-6 cycles). Twenty-five of these 56 patients were untreated and 31 recurrent. Their clinical stages were II 4, III 13 and IV 39.. The over all response rate (CR + PR) was 35.7% and the clinical beneficial response rate was 80.4%. The main side effects were peripheral phlebitis, suppression of bone marrow, oral ulcer, nausea and vomiting of grade I to II.. High dose leucovorin plus 5-fluorouracil 48 hour continuous infusion is useful with favorable cost/utility ratio for head-neck and digestive tract cancer patients. Further studies are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Digestive System Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Treatment Outcome

We have recently evaluated the combination of raltitrexed, levofolinic acid (LFA) and 5-fluorouracil (5-FU) in advanced head and neck and colorectal cancer, and we have shown that this combination is well tolerated and has clinical activity. Clinical combination studies have shown that raltitrexed and anthracyclines can be combined at full doses without unexpected toxicities. Based on these observations, we started a phase I study of mitoxantrone plus raltitrexed administered on day 1, followed by LFA and 5-FU on day 2 in patients with advanced solid tumors.. Mitoxantrone was given at a starting dose of 6 mg/m2, raltitrexed at a fixed dose of 3 mg/m2, LFA at a fixed dose of 250 mg/m2, and 5-FU at a starting dose of 750 mg/m2. Mitoxantrone and 5-FU doses were subsequently escalated alternately up to dose-limiting toxicity. Treatment was repeated every 14 days.. Four dose levels were tested in 18 patients. All three patients treated at the fourth dose level had grade 4 neutropenia after the first cycle. Therefore, this level was defined as the maximum tolerated dose and the dose level immediately below (mitoxantrone 7 mg/m2 and 5-FU 900 mg/m2) was selected for further evaluation. Neutropenia was the main toxic effect. Nonhaematologic side effects were mild. One complete response and five partial responses (all but one in patients with head and neck cancer) were observed, for an overall response rate of 33% (95% confidence interval, 13% to 59%).. Mitoxantrone, raltitrexed and 5-FU can be combined at doses which are close to those used in monotherapy. The observed activity is encouraging, especially in the subset of patients with head and neck cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Mitoxantrone; Neoplasms; Quinazolines; Thiophenes

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 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

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

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

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

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

The Oncopaz Cooperative Group designed a chemotherapy regimen to modulate UFT (Tegafur and Uracil) with leucovorin. The regimen consisted of a high intravenous dose of leucovorin, followed by oral UFT and oral leucovorin twice daily for 14 days. Based on the promising results obtained with this regimen in patients with advanced colorectal cancer, the Oncopaz group performed several phase II trials using this combination with other drugs to treat advanced gastric, lung, head and neck, and breast cancers. When combined with etoposide in gastric cancer, the regimen was shown to be active and well tolerated. However, when used with cisplatin to treat non-small cell lung cancer, a low response rate and high toxicity precluded its recommendation for further study. The addition of carboplatin in the treatment of head and neck cancer demonstrated moderate activity with low toxicity. In an ongoing trial of advanced breast cancer, preliminary results indicate that the combination of idarubicin, UFT, and leucovorin is active, with moderate, primarily hematologic toxicity. Trials of new combinations are warranted to take advantage of the pharmacokinetic properties and oral bioavailability of UFT and leucovorin.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Etoposide; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Middle Aged; Stomach Neoplasms; Tegafur; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin

The feasibility and effectiveness of a combined chemo-radiotherapy treatment modality for locally advanced head and neck cancer was tested in a phase II trial. Between 1990 and 1993, 74 patients (20 female/54 male) with head and neck cancer stage III (n = 12) and IV (n = 62) were treated with accelerated radiotherapy (72 Gy) and simultaneous chemotherapy (5-FU, folinic acid, mitomycin C). The median follow-up time was 43 months (1-72). Complete remission (CR) was absent in 76% (56/74) of patients and, after subsequent resection of residual lymph nodes, another 8 patients achieved CR. The cumulative local control rate was 72% and disease-specific survival rate was 59% at 4 years. Two patients died with treatment-related conditions (pancytopenia, larynx oedema). By multivariate analysis, only lymph node status was an independent parameter for local control (P = 0.04). This treatment was feasible and toxicity was not a treatment-limiting factor. As a consequence, a German multicentre phase III trial was initiated in 1995.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Multivariate Analysis; Prognosis; Remission Induction

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

To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells.. Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found.. L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasms, Squamous Cell; Recombinant Proteins; Stereoisomerism; Tetrahydrofolates

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

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

To determine survival rates and the pattern of failure in head and neck cancer patients treated with induction chemotherapy, limited surgery and concomitant chemoradiotherapy.. Three cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), leucovorin, and interferon alfa-2b (PFL-IFN) were followed by optional surgery, and seven or eight cycles of 5-FU, hydroxyurea, and concurrent radiation for 5 days (FHX) for a total radiation dose of 65 to 75 Gy. Surgical resection was performed with the intent to spare organ function.. Seventy-one patients were treated at three institutions. Sixty-five patients (91%) had stage IV disease with N2/3 in 46. Thirty-three patients (51%; 95% confidence interval, 39% to 63%) achieved a clinical complete response (CR) to PFL-IFN. Local therapy consisted of surgery in 37 and/or FHX in 55 patients. With a median follow-up duration of 37 months, there have been 20 recurrences (15 local, four distant, and one both local and distant), and 29 deaths, 15 in patients with disease progression and 14 not directly related to the primary tumor. Four patients have developed second malignancies. At 3 years, 69% (+/- 6%) are progression-free and the overall survival rate is 60% (+/- 6%). Toxicity of PFL-IFN included severe or life-threatening mucositis (54%) and myelosuppression (60%). Five patients died of toxicity. During FHX, 70% of patients had grade 3 or 4 mucositis.. PFL-IFN is highly active, producing clinical CRs in 51% of patients, and, when followed by FHX, resulting in high local and distant control and overall survival rates. Second malignancies and intercurrent medical disease emerge as major risks to long-term survival. In view of the high toxicity and long treatment duration, further modifications of this approach are required.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Proportional Hazards Models; Recombinant Proteins; Remission Induction; Survival Rate

Cisplatin-fluorouracil (PF) is the most frequently used combination as induction chemotherapy (CT) for the treatment of locally advanced squamous cell head and neck cancer. This study was designed to evaluate the role of leucovorin (L) in the modulation of the therapeutic activity of PF continuously infused for 4 days. Between June 1990 and June 1992, stage III and IV previously untreated patients received PFL induction chemotherapy followed by surgery, radiotherapy, or both. The chemotherapy consisted of P 25 mg/m2, F 1000 mg/m2 both continuously infused for 4 days and L 250 mg/m2 infused for 2 hours before each daily infusion of PF. PFL was administered every 3 weeks for 4 cycles. The overall response rate at the completion of PFL was 91%, with 54% CR and 37% PR. Locoregional treatment was performed on 68 patients, 11 (16%) underwent surgery, 20 (29%) surgery plus radiotherapy, and 37 (54%) radiotherapy. Complete response status after both induction and locoregional therapy was 71%. Biopsies of the primary tumor or definitive resection specimens immediately after PFL therapy were available in 25 patients in CR. Pathological CR was found in 11 (44%). With a maximum follow-up of 44 months, the overall survival rate is 51% and the median survival has not been reached. PFL is highly active as induction chemotherapy. A randomized comparison between PF and PFL is necessary to define the place of leucovorin modulation in the treatment of head and neck cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Time Factors; Treatment Outcome

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

To increase the activity of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) through further biochemical modulation and study the pharmacologic interaction of 5-FU and interferon alfa-2b (IFN).. Escalating doses of IFN (0.5 to 4.0 x 10(6) U/m2/d x 6) were added to cisplatin 100 mg/m2, continuous infusion 5-FU 800 or 640 mg/m2/d x 5, and leucovorin 100 mg orally every 4 hours. Forty-eight previously untreated patients with locoregionally advanced head and neck cancer received up to three cycles of PFL-IFN.. Twenty-one patients were treated during a phase I cohort study. Dose-limiting mucositis was seen with 800 mg/m2/d of 5-FU and 0.5 x 10(6) U/m2/d of IFN. After decreasing the 5-FU dose to 640 mg/m2/d, the maximally tolerated dose (MTD) of IFN was 2.0 x 10(6) U/m2/d. Mucositis and myelosuppression were dose-limiting. Of 34 patients treated at this MTD, 56% (95% confidence interval, 39% to 73%) had a complete remission. There was no correlation between 5-FU clearance and IFN dose. Pharmacodynamic analyses at the MTD showed that older age, female sex, and higher 5-FU area under the time versus concentration curve (AUC) were associated with lower nadir counts and/or increased mucositis. Seven patients with diabetes mellitus had significantly increased myelosuppression, serum creatinine, hypocalcemia, higher 5-FU concentrations, and lower 5-FU clearance compared with nondiabetics.. The recommended doses for PFL-IFN are 640 mg/m2/d for 5-FU and 2.0 x 10(6) U/m2/d for IFN. Sex, age, 5-FU AUC, and diabetes mellitus may have an impact on the pharmacodynamics of this regimen.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Diabetes Complications; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Multivariate Analysis; Recombinant Proteins; Regression Analysis; Treatment Outcome

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

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

Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1-5, 600 mg/m2 5-FU given i.v. daily by continuous infusion (c.i.) on days 1-5, escalating doses of cisplatin starting at 10 mg/m2 daily given by c.i. on days 1-5, and involved-field XRT carried out on days 1-5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3-4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1-5, 400 mg/m2 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o.4 h on days 1-5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m2 daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m2 daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors particularly non-small-cell lung cancer and head and neck cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Leucovorin; Lung Neoplasms; Male; Middle Aged; Platinum

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

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

The ongoing evaluation of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in several tumors prompted a phase I clinical trial of cisplatin with 5-FU modulated by leucovorin. A total of 26 patients were treated with varying doses of 5-FU by continuous i.v. infusion for 5 days; 200 mg/m2 leucovorin was given by daily bolus injection for 5 days; and 20 mg/m2 cisplatin was infused over 2 h on each day of treatment. Courses were repeated every 21-28 days. The starting dose of 5-FU was 300 mg/m2. Poor-risk patients (extensive prior radiation, performance status of 2 or worse) did not tolerate the initial dose; the maximum tolerated dose of 5-FU in this group was 200 mg/m2 daily. Good-risk patients tolerated 300 mg/m2, but a majority had excessive toxicity at higher doses. The dose-limiting toxicity was gastrointestinal (mucositis/diarrhea) and/or myelosuppression; additional side effects included were nausea and vomiting (less than or equal to grade 2) and ataxia (one patient). Among 13 patients with colorectal cancer, 4 partial responses were observed. The marked reduction in the tolerable dose of 5-FU occasioned by the addition of modulating doses of leucovorin is noteworthy. The responses observed support further investigation of this regimen in phase II trials.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Prognosis

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

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Injections, Intramuscular; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; 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

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

A randomized prospective clinical trial involved 259 cases of advanced recurrent Stage III and IV epidermoid cancers of the head and neck. The cases were randomized among three treatment programs evaluating two dose schedules and a combination treatment of methotrexate. The treatments consisted of: weekly methotrexate, biweekly methotrexate with leucovorin rescue (ML), and biweekly ML combined with cyclophosphamide and cytosine arabinoside (MLCC). Equivalent overall drug-related toxicity was produced with a 5% drug-related fatality rate. Methotrexate alone produced significantly more skin and mucosal toxicity, and the combination (MLCC) resulted in more hematologic toxicity than other treatments. Complete and partial objective responses were achieved in 26%, 24%, and 18% by each treatment. Methotrexate alone produced a median duration of response and 105 days compared with 42 and 49 days from the other treatments. Duration of response was significantly longer and survival was better in the methotrexate-alone group. Response was markedly stage dependent; 40% of Stage III patients achieved response, whereas only 17% of Stage IV patients responded. Presence of visceral metastases decreased response rates and the likelihood of response was particularly compromised by pulmonary metastatic spread; only seven of 54 such patients responded. Decreased survival was related to non-ambulatory performance status, disease-free intervals of less than one year and weight loss. Survival differences between Stage III and IV patients could not be shown. This study demonstrates the therapeutic superiority of weekly i.v. treatment with methotrexate but failed to support claims of an improved therapeutic index for high-dose methotrexate with leucovorin rescue. As the only randomized prospective clinical trial of chemotherapy in advanced head and neck cancer, this study reinforces the weekly i.v. schedule of methotrexate as the standard against which other drug schedules and drug combinations should be compared.

Topics: Adult; Aged; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Prognosis; Prospective Studies

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

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

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

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

Docetaxel-cisplatin and 5-fluorouracil (TPF) chemotherapy (days 1-21) represents a standard but toxic regimen for advanced head and neck cancer (HNC). We report a retrospective monocentric study evaluating the safety and the efficacy of a dose-dense modified TPF (mTPF) regimen (days 1-14) in patients with stage III-IV HNC.. Thirty-seven patients retrospectively included from May 2011 to May 2014 were treated with a bimonthly dose-dense mTPF regimen (40 mg/m(2) docetaxel, 40 mg/m(2) cisplatin or AUC2 carboplatin, folinic acid 400 mg/m(2) for 2 h, bolus 5-FU 400 mg/m(2) for 10 min and 5-FU 1,000 mg/m(2)/day) by continuous infusion over 46 h).. Chemotherapy was used as induction or palliative treatment in 12 and 25 patients, respectively, with a median age of 60 years (range 46-83). Median follow-up time was 7.4 months (2.53-16.7 months). There was no intestinal toxicity in 25 patients (68 %). Grade 3-4 hematological toxicity was noticed for 5 (13.5 %) patients. Granulocyte-colony stimulating factor was used as primary prophylaxis in 30 patients (81 %). After at least 4 delivered cycles, complete responses, partial responses and stable diseases were reported in 5 (15 %), 13 (39 %) and 5 (15 %) of the 33 evaluable patients, respectively, yielding an objective response rate of 54.5 % (39 % for palliative chemotherapy and 90 % for induction chemotherapy).. Dose-dense mTPF (days 1-14) is safe and seems to be as effective as TPF (days 1-21). Future prospective trials are required to confirm our results.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Docetaxel; Feasibility Studies; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Head and Neck Neoplasms; Humans; Induction Chemotherapy; Leucovorin; Male; Middle Aged; Palliative Care; Remission Induction; Retrospective Studies; Taxoids; Treatment Outcome

The objective was to investigate the feasibility of using buccal iontophoresis for the simultaneous delivery of chemotherapeutic agents with a view to developing a new approach to treat head and neck cancers. Short duration cathodal iontophoresis of 5-fluorouracil (5-FU; 20mM) and leucovorin (LV; 10 mM) at 1 mA/cm(2) for 10 or 20 min from aqueous solution and a 2% hydroxyethyl cellulose gel at pH 7.6 was evaluated using bovine mucosa in vitro. Iontophoresis resulted in a statistically significant increase in the mucosal deposition of both drugs as compared to passive diffusion (Student's t-test, α=0.05); in each case, drug delivery was selective for deposition with no permeation being observed. After 20 min of iontophoresis, there was an ~ 8-fold enhancement for 5-FU (1.46 ± 0.86 and 11.93 ± 3.81 μg/cm(2), respectively) and a 3-fold increase for LV (8.31 ± 2.44 and 25.08 ± 6.89 μg/cm(2), respectively) when using aqueous solutions. The same trend was observed when the gel was applied for 10 min; passive delivery of 5-FU from the gel resulted in non-detectable levels in the mucosa, while 4.62 ± 1.76 μg/cm(2) were deposited in the mucosa following iontophoresis. Similarly, iontophoretic delivery of LV from the gel resulted in ~ 3-fold higher deposition as compared to passive diffusion (6.71 ± 1.36 and 21.12 ± 9.94 μg/cm(2), respectively). No drug permeation was observed in either case. In conclusion, iontophoresis can be used for targeted topical delivery of chemotherapeutics to the buccal mucosa and may enable less invasive local therapy of head and neck cancers.

Topics: Administration, Buccal; Animals; Antimetabolites, Antineoplastic; Cattle; Diffusion; Fluorouracil; Head and Neck Neoplasms; In Vitro Techniques; Iontophoresis; Leucovorin; Mouth Mucosa; Permeability; 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

Patients with advanced head and neck (H/N) and esophageal squamous cell carcinoma (SCC) often have a poor performance status and a dire prognosis. Our aim was to evaluate the feasibility, activity and quality of life (QOL) of an outpatient chemotherapy regimen consisting of cisplatin, 5-fluorouracil and leucovorin (CFL).. Prospective phase II study conducted at a Brazilian public institution.. Fifteen patients with residual, recurrent or metastatic SCC of the H/N or esophagus received bolus infusions of leucovorin 20 mg/m(2)/day and 5-fluorouracil 370 mg/m(2)/day on days 1-4, and 90 minutes of infusion of cisplatin 25 mg/m(2)/day on days 1-3, every 21 to 28 days, depending on hematological recovery. We also evaluated QOL by applying the European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC QLQ-C30) before each cycle.. The overall response rate was 36%, and the mean overall survival and progression-free survival were six and three months, respectively. We observed grade 3 or higher hematological toxicity in seven patients and one patient had grade 3 nausea and vomiting. One patient died because of neutropenic fever. Seven out of the 12 patients who could be evaluated regarding QOL presented an improvement in their overall health status and functional QOL scores over the course of the treatment.. CFL is an active outpatient protocol with tolerable toxicity and a favorable QOL impact. Larger studies are warranted, in order to confirm these results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cost-Benefit Analysis; Epidemiologic Methods; Esophageal Neoplasms; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Outpatients; Quality of Life; Young Adult

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

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

The relationship of thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on 5-fluorouracil (FU) sensitivity was tested on 19 human cancer cell lines (head and neck, breast, digestive tract) in the absence and presence of folinic acid (FA) supplementation. Thymidylate synthase polymorphisms in the 5' promoter region (double or triple tandem repeats) and 3' untranslated region (6-bp deletion) were analysed by PCR. The C677T and A1298C MTHFR polymorphisms were determined by melting curve analyses (LightCycler). Thymidylate synthase activity and intracellular concentration of the reduced folate 5-10 methylenetetrahydrofolate (CH(2)FH(4)) were measured (biochemical assays). Thymidylate synthase activity was significantly different according to 5' TS genotype, heterozygous cell lines (2R/3R) exhibiting higher TS activities than homozygous ones (P=0.05). However, whether in the absence or presence of FA, FU sensitivity was not statistically associated with either 5' or 3' TS polymorphism. Basal CH(2)FH(4) cellular concentrations were lowest in C677T homozygous wild-type (wt) (C/C) cell lines. FU sensitivity was not linked to C677T polymorphism. In contrast, there was a marked trend for a greater FU efficacy in mutated A1298C variants (C/C+A/C) as compared to wt homozygous cell lines (A/A) (P=0.055 and 0.085 without and with FA supplementation, respectively). These results suggest for the first time a potential role of A1298C MTHFR polymorphism on fluoropyrimidine sensitivity.

Topics: Antimetabolites, Antineoplastic; Breast Neoplasms; Fluorouracil; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Pharmacogenetics; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic; Thymidylate Synthase; Tumor Cells, Cultured

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

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Combined Modality Therapy; ErbB Receptors; Fluorouracil; Gefitinib; Head and Neck Neoplasms; Humans; Leucovorin; Organoplatinum Compounds; Palliative Care; Quinazolines; Salvage Therapy; Time Factors

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

The authors reviewed experimental and clinical data (ie, cell kinetics and its circadian control by cyclins, circadian expression of clock genes, chronotolerance to anticancer agents.) justifying to consider the temporal dimension in the medical treatment of human head and neck cancer. A complex infusional chronotherapyschedule (with 5-fluorouracil, folinic acid and carboplatin) was administered to 48 patients. Excellent tolerance and interesting tumour outcome allowed to conclude to an optimised therapeutic index.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Case Management; Chronotherapy; Circadian Rhythm; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; 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

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Paclitaxel; Taxoids

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

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

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

Effects of lipophilic thymidylate synthase (TS) inhibitor AG337 on human head and neck squamous cell carcinoma (HNSCC) cell lines and CCRF-CEM human leukemia cells and sublines with acquired methotrexate (MTX) resistance were assayed using continuous or intermittent drug exposure. During 120-h continuous exposure, HNSCC cell lines A253 and FaDu are equally MTX sensitive (EC50 equals approximately 15nM); AG337 is less potent (EC50 approximately equals 1 microM). A253 is intrinsically resistant to 24-h intermittent MTX exposure (EC50 equals approximately 17 microM; FaDu, EC50 equals approximately 0.3 microM); both HNSCC cell lines are resistant to 24-h AG337 exposure (EC50 >100 microM). CCRF-CEM shows MTX (EC50 =14 nM) and AG337 (EC50 equals approximately 0.6 microM) sensitivity in continuous exposure similar to HNSCC; however, AG337 retains potency against CCRF-CEM cells in intermittent exposure (24-h, EC50 equals approximately 2 microM; 6-h, EC50 equals approximately 48 microM). The reduced folate leucovorin (LV) at > or = 0.1 microM fully protects from growth inhibition by continuous MTX exposure, but growth inhibition by AG337 is reversed only slightly by < or = 100 microM LV. Thymidine fully protects A253 and FaDu against growth inhibition by AG337, while hypoxanthine alone is without effect, suggesting inhibition is TS-specific. CCRF-CEM sublines with acquired MTX-resistance resulting from DHFR overexpression, defective MTX transport, or defective MTX polyglutamylation retain full sensitivity to AG337 in continuous exposure (all EC50 =0.4 microM). These data indicate that AG337 may be useful in therapy of tumors that have acquired resistance to MTX by most common mechanisms.

Topics: Cell Cycle; Cell Division; Culture Media; Drug Resistance; Enzyme Inhibitors; Fetal Blood; Head and Neck Neoplasms; Humans; Hypoxanthine; Inhibitory Concentration 50; Leucovorin; Leukemia; Methotrexate; Quinazolines; Thymidine; Thymidine Phosphorylase; Thymidylate Synthase; Tumor Cells, Cultured

Thymidylate synthase (TS), an essential enzyme in DNA synthesis, is a target for the fluoropyrimidines, an important group of antineoplastic agents used widely in the treatment of head and neck cancer.. We evaluated relationships between the level and/or pattern of tumor TS expression and response to fluorouracil (5-FU)-based neoadjuvant chemotherapy in patients with advanced head and neck cancer.. Tumor specimens from 86 patients were available for this retrospective analysis. The patients were enrolled in four consecutive phase II studies that tested combinations of 5-FU, leucovorin, and cisplatin with or without added methotrexate plus piritrexim or interferon alfa-2b (IFN alpha-2b). TS protein expression in the tumors was assessed by use of the TS 106 monoclonal antibody and standard immunohistochemical staining techniques. TS immunostaining was classified according to its level of intensity (TS 0-1 = low, TS 2 = intermediate, and TS 3 = high) and according to its extent (focal pattern = less than 25% of tumor cells positive; diffuse pattern = greater than or equal to 25% of tumor cells positive). Data from 79 patients were available for an analysis of tumor TS expression and patient/tumor characteristics; 70 patients were assessable for their response to neoadjuvant chemotherapy.. There was a statistically significant association between the level of tumor TS expression and the degree of tumor differentiation; a higher proportion of patients whose tumors exhibited TS 0-1 immunostaining had undifferentiated or poorly differentiated tumors than patients whose tumors exhibited TS 2 or TS 3 immunostaining (P = .04, Jonckheere-Terpstra trend test). Among the 70 patients who were assessable for response to neoadjuvant chemotherapy, TS 3 tumor immunostaining was associated with a lower rate of complete response (i.e., complete disappearance of clinically detectable disease for a minimum of 4 weeks from time of initial determination) than was TS 2 or TS 0-1 immunostaining, but this association was not statistically significant (P = .09, exact trend test); among the 39 patients who were treated with regimens that included 5-FU, leucovorin, cisplatin, and IFN alpha-2b, this inverse association between TS immunostaining intensity and response was statistically significant (P = .02, exact trend test). Tumor TS immunostaining intensity and overall survival were not found to be associated. Patients with tumors exhibiting a focal pattern of TS immunostaining have experienced significantly longer survival than patients with tumors exhibiting a diffuse pattern; for the 53 patients with diffuse tumor TS immunostaining, the median survival was 24.7 months, whereas the median survival has not yet been reached for the 22 patients with focal tumor TS immunostaining (P = .04, two-tailed logrank test). However, the survival advantage for the focal versus diffuse TS immunostaining pattern was limited to patients whose tumors also exhibited a TS 3 level of immunostaining intensity.. Characterization of tumor TS expression may be of value in identifying patients with advanced head and neck cancer who would benefit from fluoropyrimidine-based neoadjuvant chemotherapy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Dihydrouracil Dehydrogenase (NADP); Fluorouracil; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Immunohistochemistry; Interferon alpha-2; Interferon-alpha; Leucovorin; Oxidoreductases; Predictive Value of Tests; Recombinant Proteins; Remission Induction; Retrospective Studies; Thymidylate Synthase; Treatment Outcome

Thymidylate synthase (TS) inhibitor effects on growth of human head and neck squamous cell carcinoma (HNSCC) cell lines and CCRF-CEM human leukemia cells and sublines with acquired methotrexate (2,4-diamino-10-methylpteroylglutamic acid) (MTX) resistance were studied. During 120-h treatment, HNSCC cell lines A253 and FaDu are equally sensitive to MTX, whereas the polyglutamylatable TS inhibitors ZD1694 and BW1843U89 are 5- to 35-fold more potent than MTX and the lipophilic AG331 is approximately 10(2)-fold less potent than MTX. A253 is intrinsically resistant to intermittent (24 h) MTX and BW1843U89 exposure (higher EC50 values and shallower slopes of concentration-response curves relative to FaDu); AG331 and ZD1694 largely overcome this intrinsic resistance to intermittent exposure. Thymidine (TdR) protects against growth inhibition by these inhibitors, confirming that TS is their target in HNSCC; at high AG331 levels, TdR only partially protects, implying that a second site of action exists. Growth inhibition of HNSCC by ZD1694 and BW1843U89 is protected by leucovorin (LV) at > or = 10(-7) and > 10(-3) M, respectively; 10(-4) M LV cannot protect HNSCC cells against AG331. Results similar to protection studies are obtained if LV addition is delayed < or = 24 h after ZD1694 or BW1843U89 exposure. CCRF-CEM sublines with acquired MTX resistance resulting from dihydrofolate reductase (DHFR) overexpression, defective MTX transport, or defective MTX polyglutamylation retain full sensitivity to AG331. Cells with defective MTX transport are highly cross-resistant to ZD1694 and BW1843U89, implicating the reduced folate/MTX carrier in their transport. Minor cross-resistance of the DHFR overexpressing line to ZD1694 and BW1843U89 is observed. A subline with highly defective MTX polyglutamylation is cross-resistant to 120-h exposure to ZD1694, but not to BW1843U89, suggesting a profound contribution of polyglutamylation to the mechanism of action of ZD1694.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Division; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Inhibitors; Growth Inhibitors; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia; Methotrexate; Thymidylate Synthase; Tumor Cells, Cultured

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

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

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

The clinical use of the fluorouracil (FU)-folinic acid (FA) combination is hampered by the still open choice of the optimal schedule, with marked controversy as concerns the optimal FA dose. This in vitro study on FU-FA combinations in 17 human cancer cell lines, representative of tumour types responding to FU-FA treatment, reassesses the notion of the optimal FA concentration. Cells were exposed for 5 days to various FU-FA concentrations (0.07-77 microM, 14 concentrations, for FU; and 0.0025-100 microM for FA). The growth inhibition was assessed by the MTT test. The investigated cell lines exhibited FU IC50 ranging from 0.4 to 38.9 microM (median 3.7 microM). In six out of 17 cell lines investigated, the addition of FA did not result in a substantial enhancement of FU cytotoxicity (group 1). For the remaining 11 cell lines responding to FA supplementation (group 2), the maximal enhancement factor ranged from 3 to 8, meaning that in the presence of optimal FA concentration, the efficient FU concentration (IC50) was reduced by between 3 and 8 as compared to the efficient FU concentration without FA supplementation. For cell lines responding to FA supplementation, the optimal FA concentrations ranged from 10(-7) to 4 x 10(-4) M (4000-fold range) with a median value at 9.6 x 10(-7) M. Distribution of cell doubling time was not significantly different between group 1 and group 2. In contrast, the FU IC50 were significantly different (P = 0.02) between group 1 (median 7.4 microM) and group 2 (median 2.2 microM), thus indicating that cell lines with the greatest FU cytotoxicity enhancement by FA were those intrinsically sensitive to FU and vice versa.

Topics: Breast Neoplasms; Cell Division; Digestive System Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; 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

The objective of the present in vitro study was to determine an optimal timing of the irradiation in the combination cisplatin (CDDP) and 5-fluorouracil-folinic-acid (5-FU-FA) allowing a maximal cytotoxic effect on a human cell line derived from a head and neck carcinoma (CAL 27 cells). The various tested chemoradiotherapy sequences were applied in parallel to human keratinocytes in culture (SVK 14 cells). This was done in order to define the best sequence allowing the achievement of an optimal selectivity of the cytotoxic effects. The drug sequence was: CDDP over 2 h then fresh medium was added including the tandem 5-FU-d,I FA applied 6 h after CDDP, for 5 days. Irradiation was applied only once and at various times within the drug sequence. The cytotoxicity effects of the different chemoradiotherapy combinations were assessed by the MTT semi-automated test. The part taken by the 5-FU-FA combinations in the overall cytotoxicity was examined; an effect was apparent on CAL 27 cells only. The evolution of the radiation effect (RE = cell survival after drugs/cell survival after drugs plus irradiation) was analysed as a function of the different times of irradiation within the given drug sequence. Clearly, the RE values were dependent upon time at which the radiation dose in the chemoradiotherapy regimen was administered. For CAL 27 cells, irradiation effects were maximal at the first irradiation time tested after the end of the CDDP exposure (i.e. t = 3.5 h). In contrast, this optimal chemoradiotherapy timing for better cytotoxicity on CAL 27 cells did not correspond to that of SVK 14 cells. Consequently, it was possible to establish that the best time for the selectivity index was located shortly after the CDDP exposure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Time Factors; Tumor Cells, Cultured

Twenty-two patients with advanced head and neck carcinoma were treated with 5FU 400 mg-2 m-1 week and folinic acid 500 mg m-2 week-1 plus CDDP in escalating doses from 20 to 40 mg m-2 week-1 without forced diuresis. Reduced glutathione at the dose of 1.5 g m-2 was employed to protect patients from CDDP-related nephrotoxicity. The aims of the study were: a) to evaluate the therapeutic efficacy of this schedule, and b) to evaluate reduced glutathione as uroprotector. Out of 20 evaluable patients 14 (70%) had a major objective response. A CR with a mean duration of 9.0+ months was achieved in 15% of the patients, a PR of 5.8+ months in 55% of the patients, while 3 patients had stable disease and 4 progressed. It was possible to escalate CDDP up to 35 mg m-2 week-1, but at the dose of CDDP 40 mg m-2 week-1 the occurrence of grade 2 renal toxicity provoked a severe reduction of dose-intensity. Overall, this treatment has been very well tolerated by most patients with few cases of grade 3 gastrointestinal or hematological toxicity. In conclusion, the schedule seems effective and may be safely given to patients with advanced head and neck cancer on outpatient basis. Reduced glutathione seems to be able to reduce, at least partially, CDDP-related nephrotoxicity permitting the delivery of higher CDDP doses.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Glutathione; Head and Neck Neoplasms; Humans; Kidney Diseases; Leucovorin; Male; Middle Aged

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

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Evaluation; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Leucovorin; Male; Middle Aged

A 56-year-old female underwent treatment with leucovorin and 5-fluorouracil for extensive metastatic moderately differentiated transitional cell carcinoma (TCC) of the renal pelvis. This resulted in a complete response for 20+ months. This combination has not been reported before in TCCs of the urinary tract and requires further exploration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Kidney Pelvis; Leucovorin; Lymphatic Metastasis; Middle Aged; Remission Induction

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

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Remission Induction; Stereoisomerism

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

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

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

As part of a clinical trial of cisplatin, 5-fluorouracil (5-FU), and leucovorin (LV) for treatment of patients with advanced head and neck cancer, patients received 100 mg of LV (d,l-5-formyltetrahydrofolate) orally every 4 hours for 5 days. On days 2 and 4 of treatment, plasma samples were obtained 2 hours after (peak) and 30 minutes before (trough) a dose of LV. Total LV and 5-methyltetrahydrofolate (THF) concentrations were measured with high-performance liquid chromatography (HPLC) analysis. LV stereoisomer concentrations were determined by chiral HPLC on a bovine serum albumin-bonded silica column. Thus far, plasma folate levels have been analyzed for ten cycles of treatment administered to 7 patients (40 samples). Administration of LV in divided oral doses approximates a plasma steady state with no significant differences noted between peak and trough concentrations. Mean (+/- SD) plasma concentrations for all samples were (mumol): LV, 3.2 +/- 1.3; l-LV, 0.28 +/- 0.21; d-LV, 2.9 +/- 1.2; and THF, 4.25 +/- 2.5. Plasma levels of d-LV and THF tended to be approximately 10% higher on day 4 than day 2, although mean differences were not significantly different due to substantial interpatient variability. Of note was that the sum of THF and l-LV exceeds that of d-LV which was consistent with selective absorption of the l-isomer of LV. Mean ratios of d-LV/l-LV and d-LV/l-LV and THF were 13.7 +/- 10 and 0.88 +/- 0.68, respectively. The authors conclude that oral administration of LV in divided dose (1) simulates a continuous intravenous infusion; (2) produces plasma levels of l-reduced folates in a range known to potentiate 5-FU cytotoxicity; and (3) results in low ratios of d/l-reduced folates that may be important in maximizing the effectiveness of 5-FU-LV chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Stereoisomerism; Tetrahydrofolates

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

In advanced inoperable head and neck cancer radiotherapy alone is unsatisfying. Better results can be obtained by simultaneous 5-Fluorouracil/Cisplatin-chemotherapy and irradiation. The cytotoxicity of 5-Fluorouracil can be enhanced synergistically by adding Folinic Acid in excess. In a clinical phase II trial 62 previously untreated patients suffering from unresectable AJCC-stage III (4 pts.) and IV (58 pts.) squamous cell carcinoma of the head and neck were treated with a simultaneous chemoradiotherapy consisting of high-dose Folinic Acid in addition to a 5-Fluorouracil/Cisplatin combination and of accelerated split-course radiotherapy. As results, three pts. died from tumor arrosion bleeding during the treatment. Median follow up time of the surviving pts. is 27 + months (range 18-44 months). 48/62 pts. (77%) achieved complete remission, 11/62 pts. (18%) partial remission. Presently, 32 pts. (52%) are without evidence of disease. Actuarial three years overall survival rate (Kaplan-Meier method) out of 62 pts. in 53%. Actuarial disease free survival and local tumor control rates at three years are 58% and 72%. Mucositis was severe but tolerable, bone marrow depression was moderate to marked. In conclusion, this combined simultaneous modality approach is highly effective in locally advanced head and neck cancer. It seems to provide superior survival and local control rates as compared to conventional radiotherapy or sequential chemo-radiotherapy or as compared to simultaneous 5-Fluorouracil/Cisplatin and non-fractionated radiotherapy. A comparative phase III study is required.

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

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

Topics: Asparaginase; Folic Acid; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate

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

The results of treatment of 30 patients with advanced unresectable squamous cell carcinoma of the head and neck (stage III and IV) are presented. These patients were treated in a pilot study using kinetically based combination chemotherapy and split course radiotherapy from July 1977 until December 1979. Twenty-three patients (76%) achieved a local response (53% complete and 23% partial) and the median survival was 16 months. The two-year survival was 43%. Although no significant increase in acute radiation morbidity was seen, 43% of the patients developed chronic symptomatic complications. Seven patients (23%) developed second primary cancers, of which five were bronchogenic carcinomas and two were esophageal carcinomas. The regimen adopted produced a high local control rate with permanent local control in 50% of patients treated, but this was achieved at the expense of a high chronic toxicity rate. The incidence of second primary malignancies, presumably because of on-going environmental factors, remains a continuing concern.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Head and Neck Neoplasms; Humans; Hydrocortisone; Leucovorin; Male; Methotrexate; Radiotherapy Dosage; Vincristine

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

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

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

Neoadjuvant induction chemotherapy with cisplatin, methotrexate, and bleomycin appears to improve the results of treatment of advanced stage IV head and neck cancer, compared with results in historical control subjects. Patients treated with induction chemotherapy and radiation therapy had a 29 percent overall survival rate at 3 years, which represents approximately a twofold improvement in the survival rate. Patients who were treated with chemotherapy and radiation therapy followed by surgery had more than a threefold increase in the survival rate (49 percent at 3 years), compared with historical data from our institution and elsewhere for such patients [9-11]. Distant metastases developed in 25 percent of the patients, and it thus appears that long-term, effective consolidation and maintenance chemotherapy [12,13] need to be developed for patients who receive combination therapy before surgery for head and neck cancer.

Topics: Actuarial Analysis; Adult; Aged; Bleomycin; Cisplatin; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Premedication

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

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

Since 1968 we have treated with antiblastic drugs 164 malignant tumors recurrent or incurable by surgery or radiotherapy in 151 cases. Different therapeutic methods were employed. Today we have the possibility of selecting alternative options with incipient or relatively delimited carcinomas, principally the substitution of radical surgery by initial associated physical and chemical treatment, so that if there is a cure the consequences of radical surgery can be avoided. We emphasize the curve of two primary cancers of the uvula with 300 mg bleomycin exclusively and the results observed in oropharyngeal and laryngeal carcinomas by using three intermittent Schabel cycles and 4,000 rad Telecobalt, avoiding a radical surgery.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Therapy, Combination; Head and Neck Neoplasms; Hodgkin Disease; Humans; Infusions, Intra-Arterial; Leucovorin; Mechlorethamine; Methotrexate; Neoplasm Recurrence, Local; Prednisone; Procarbazine; Prognosis; Vinblastine; Vincristine

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

A study was performed in 110 rats to investigate the effect of an LD50 dose of MTX, rescued with leucovorin treatment in 24 hours, on the ability of surgical wounds to tolerate bacterial contamination. The results of this study would indicate that the optimal time to ensure normal wound healing would be an interval of 10 to 14 days following the administration of large doses of this drug. This information would suggest that the use of methotrexate as a preoperative adjuvant, and radiation therapy following the surgical removal of the tumor, might be a reasonable approach to the adjuvant treatment of head and neck cancer without increasing the risk of wound infections.

Topics: Animals; Disease Models, Animal; Head and Neck Neoplasms; Humans; Lethal Dose 50; Leucovorin; Leukocyte Count; Male; Methotrexate; Preoperative Care; Radiotherapy, High-Energy; Rats; Staphylococcal Infections; Surgical Wound Infection; Time Factors; Wound Healing

Methotrexate (MTX) in high doses (3 to 7.5 g/m2) with leucovorin rescue (HDMTX-LCV) can be delivered on a weekly basis in a setting of proper pharmacologic monitoring. Myelosuppression occurs in 28 per cent of the patients and in 8 per cent of the courses and usually results from delayed MTX excretion secondary to mild reversible nephrotoxicity. The incidence of tumor regression was 50 per cent in head and neck cancer; 59 per cent in non-Hodgkin's lymphoma; 40 per cent in small cell lung cancer; 24 to 50 per cent in breast cancer and 50 per cent in osteogenic carcinoma, for an over-all response rate of 39 per cent (70 of 178) in patients with disseminated cancer. HDMTX-LCV is not recommended for the conventional treatment of metastatic cancer because of the potential for toxicity and the fact that the response rates cited are probably not superior to those which can be achieved by conventional doses of MTX. However, the relative lack of myelosuppression and mucositis, when compared to conventional unrescued MTS, and the achievement of therapeutic concentrations of MTX in the central nervous system with the HDMTX-LCV program have led to its incorporation into clinical trials of combination chemotherapy.

Topics: Adult; Bone Marrow; Bone Neoplasms; Breast Neoplasms; Drug Administration Schedule; Female; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Kidney; Leucovorin; Lung Neoplasms; Lymphoma; Methotrexate; Neoplasms; Urogenital Neoplasms

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

A 67-year-old man with malignant lymphoma, nodular, poorly differentiated lymphocytic type, developed meningeal lymphomatosis. Repeated high-dose methotrexate-citrovorum factor treatment (1 g/m2 in 24 hours) rendered the patient free of disease. The administration of vincristine at 23 hours consistently increased the concentration of methotrexate in the cerebrospinal fluid 2.5-fold above baseline values.

Topics: Aged; Drug Interactions; Head and Neck Neoplasms; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Time Factors; Vincristine

Topics: Child; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Kinetics; Leucovorin; Lymphoma; Methotrexate; Neoplasm Staging

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

High dose methotrexate followed by citrovorum factor reversal has been utilized in twenty-six patients with advanced cancer. Four of 10 patients with head and neck cancer had an objective response. One of 7 patients with metastatic osteosarcoma to the lungs had stabilization with twenty treatments over 23 months. One patient with acute lymphocytic leukemia developed marrow aplasia but did not attain remission. The regimen was well tolerated when meticulous attention was paid to hydration, urine alkalinization, renal function and third space fluid accumulation. Life-threatening or lethal toxicity was encountered when these phenomena were not scrupulously observed.

Topics: Adolescent; Adult; Aged; Female; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Neoplasms; Osteosarcoma

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

Topics: Adult; Aged; BCG Vaccine; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging

The present review aims at developing a perspective for surgeons of the role of chemoimmunotherapy in the management of head and neck cancer. The biochemical pharmacology of high dose methotrexate with leucovorin "rescue" is also discussed. The need for a combined modality approach in the treatment of patients with this cancer is emphasized.

Topics: Antineoplastic Agents; BCG Vaccine; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Infusions, Intra-Arterial; Leucovorin; Methotrexate; Mycobacterium bovis

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

Topics: Animals; Asparaginase; Breast Neoplasms; Carboxypeptidases; Child; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia; Lung Neoplasms; Lymphoma; Melanoma; Methotrexate; Neoplasms; Osteosarcoma; Tetrahydrofolates; Thymidine

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

Although experience with drug therapy of advanced or recurrent squamous cell carcinoma of the head and neck is limited, several agents have produced convincing and reproducible tumor regression in these patients. Methotrexate has had the widest usage, and produces 30-50% response rates; bleomycin, hydroxyurea, and adriamycin appear to be somewhat less effective. Location of the malignancy and previous x-ray treatment appear to be important determinants of responsiveness to methotrexate, while degree of differentiation has not yet been shown to be an important factor for response to this drug. Attempts to improve the response rate and duration of chemotherapeutic response by utilizing combinations of drugs, or use of drugs to sensitize the tumor to x-ray treatment, or to reduce the bulk of tumor before x-ray treatment, are reviewed; they have been only moderately encouraging. Intra-arterial chemotherapy appears to have a therapeutic advantage over intravenous treatment; however, the morbidity associated with the former approach limits its usefulness for routine usage. The use of drugs as adjuncts following surgery and/or radiation therapy or immunotherapy are newer approaches that have not been investigated sufficiently, but are promising areas for investigation.

Topics: Bleomycin; Dinitrochlorobenzene; Doxorubicin; Drug Therapy, Combination; Fluorouracil; Head and Neck Neoplasms; Humans; Immunotherapy; Infusions, Parenteral; Injections, Intra-Arterial; Leucovorin; Methotrexate; Mouth Neoplasms; Recurrence

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: 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: Breast Neoplasms; Choriocarcinoma; Female; Head; Head and Neck Neoplasms; Humans; Leucovorin; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Pregnancy; Remission, Spontaneous; Uterine Cervical Neoplasms

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: 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: Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Leucovorin; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Paranasal Sinus Neoplasms; Sarcoma; Thiotepa; Vinblastine

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

Topics: Brain Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Melanoma; Methotrexate; Neoplasms; Palliative Care; Pelvic Neoplasms

Topics: Head; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Mouth Neoplasms; Neoplasms

Topics: Arteries; Folic Acid; Folic Acid Antagonists; Head and Neck Neoplasms; Injections, Intramuscular; Leucovorin; Methotrexate

Topics: Arteries; Folic Acid; Folic Acid Antagonists; Head and Neck Neoplasms; Injections, Intramuscular; Leucovorin; Methotrexate