levoleucovorin and Bone-Neoplasms

To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue.. A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects.. Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue.. Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

Topics: Bone Neoplasms; Child; Humans; Leucovorin; Methotrexate; Neurotoxicity Syndromes; Osteosarcoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Cystic fibrosis (CF) is a multisystem disease affecting the gastrointestinal (GI) tract as well as the lungs. As survival has increased significantly over the past few decades, complications not seen previously have become apparent. There is an overall increased rate of malignancy in CF, particularly from the GI tract and in the post-transplant population. The most common sites of malignancy are the pancreatico-biliary and digestive tract, as well as an increased rate of testicular cancer. Using an illustrative case of metastatic oesophageal malignancy which initially appeared to be hepatic in origin, we have reviewed the literature surrounding malignancy in CF with a particular focus on the GI tract.

Topics: Adenocarcinoma, Clear Cell; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cystic Fibrosis; Esophageal Neoplasms; Fatal Outcome; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds

Major advances have been achieved in the treatment of osteosarcoma with the discovery of several chemotherapeutic agents that were active in the disease. These agents comprise high-dose methotrexate with leucovorin rescue, Adriamycin, cisplatin, ifosfamide and cyclophosphamide. The agents were integrated into various regimens and administered in an effort to destroy silent pulmonary micrometastases which are considered to be present in at least 80% of patients at the time of diagnosis. Their efficacy in achieving this goal was realized and their use was further extended to the application of preoperative (neoadjuvant) chemotherapy to destroy the primary tumor and achieve safe surgical resections. Disease free survival was escalated from <20% prior to the introduction of effective chemotherapy to 55-75% and overall survival to 85%. Further, the opportunity to perform limb salvage was expanded to 80% of patients. Of interest also was an attempt in one series to treat the primary tumor exclusively with chemotherapy, and abrogation of surgery. Adding to these advances, varieties of subsequently discovered agents are currently undergoing investigations in patients who have relapsed and/or failed conventional therapy. The agents include Gemcitabine, Docetaxel, novel antifolate compounds, and a liposome formulation of adriamycin (Doxil). A biological agent, muramyl tripeptide phosphatidyl ethanolamine (MTPPE) was also recently investigated in a 2x2 factorial design to determine its efficacy in combination with chemotherapy (methotrexate, cisplatin, Adriamycin and ifosfamide).In circumstances where the tumor was considered inoperable, chemotherapy and radiotherapy were advocated for local control. High dose methotrexate, Adriamycin and cisplatin and Gemcitabine interact with radiation therapy and potentiate its therapeutic effect. This combination is also particularly useful in palliation. Occasionally, the combination of radiation and chemotherapy may render a tumor suitable for surgical ablation. Samarium153, a radio active agent, is also used as palliative therapy for bone metastases.However, despite the advances achieved with the multidisciplinary application of chemotherapy, radiotherapy and surgical ablation of the primary tumor over the past 3(1/2) decades, the improved cure rate reported initially has not altered. Particularly vexing is the problem of rescuing patients who develop pulmonary metastases after receiving seemingly effective multidisciplinary

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Humans; Leucovorin; Methotrexate; Osteosarcoma

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

An antifolate first introduced into the clinic about half decades ago, Methotrexate is effective against a variety of human cancers, when administered alone or in combination with leucovorin rescue at wide-ranging doses and by many different schedules. We know much more about MTX and its molecular and cellular pharmacology and mechanisms of anti-cancer action in light of current knowledge of the biochemistry of folate. This understanding has stimulated novel approaches to the clinical application of the drug and has greatly enhanced its therapeutic efficacy.

Topics: Antidotes; Antimetabolites, Antineoplastic; Bone Neoplasms; Drug Synergism; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasms; Osteosarcoma

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Cyclophosphamide; Disarticulation; Doxorubicin; Europe; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Recurrence, Local; Osteosarcoma; Survival Analysis; Treatment Outcome; Vincristine

Topics: Amputation, Surgical; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Humans; Ifosfamide; Leucovorin; Lung Neoplasms; Mesna; Osteosarcoma; Survival Analysis; Tennessee; Treatment Outcome; Vincristine

Topics: Acidosis, Renal Tubular; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Doxorubicin; Humans; Ifosfamide; Leucovorin; Mesna; Methotrexate; Osteosarcoma; Postoperative Care; Preoperative Care; Radionuclide Imaging; Retrospective Studies; Salvage Therapy; Thallium Radioisotopes; Treatment Outcome

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Extremities; Humans; Leucovorin; Methods; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Prostheses and Implants; Random Allocation

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Cell Division; Child; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Radiotherapy, High-Energy; Time Factors

Topics: Adolescent; Adult; Alkalies; Aminopterin; Animals; Bone Marrow; Bone Neoplasms; Drug Therapy, Combination; Female; Folic Acid Antagonists; Humans; Kidney; Kidney Failure, Chronic; Leucovorin; Leukemia L1210; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Thymidine; Vincristine

Topics: Adjuvants, Pharmaceutic; Adult; Animals; Bone Neoplasms; Child; Doxorubicin; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Humans; Immunotherapy; Leucovorin; Methotrexate; Neoplasm Metastasis; Osteosarcoma

Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naïve metastatic CRC population.. A total of 1202 patients from the Spanish VISNÚ-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNÚ-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients.. Interestingly, 41% of the population studied presented ≥3 bCTC count. bCTC count ≥3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels.. In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naïve metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors.. VISNU 1 ClinicalTrials.gov ID: NCT01640405/ VISNU 2 ClinicalTrials.gov ID: NCT01640444.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Bone Neoplasms; Camptothecin; Cell Count; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Oxaliplatin; Prognosis; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins B-raf; ras Proteins; Risk Assessment; Young Adult

Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC.. In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments.. In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively.. Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed.. ClinicalTrials.gov (NCT01896531).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Esophagogastric Junction; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Male; Middle Aged; Organoplatinum Compounds; Piperazines; Progression-Free Survival; Proto-Oncogene Proteins c-akt; Pyrimidines; Stomach Neoplasms

Epidemiologic and preclinical data suggest isoflavones have anticancer activity in colorectal malignancy prevention and treatment. This is the first clinical trial assessing safety and tolerability of Genistein in combination with chemotherapy in metastatic colorectal cancer.. Patients who had histologically confirmed metastatic colorectal cancer and had not received previous treatment were eligible to enroll. Subjects were treated with FOLFOX or FOLFOX-Bevacizumab as per the investigator choice. Genistein was administered orally for 7 days every 2 weeks, beginning 4 days prior to chemotherapy and continuing through days 1-3 of infusional chemotherapy. Primary endpoint was safety and secondary endpoints included cycle 6 response rate, best overall response rate (BOR), and median progression-free survival (PFS).. Thirteen patients received chemotherapy with Genistein in this trial. The most common adverse events related to Genistein alone were mild and included headaches, nausea, and hot flashes. One subject was observed to have grade 3 hypertension. No increase in chemotherapy-related adverse events was observed when Genistein was added. BOR and median PFS were 61.5% and 11.5 months, respectively.. We observed that adding Genistein to FOLFOX or FOLFOX-Bevacizumab was safe and tolerable. Efficacy results are notable and warrant verification in larger clinical trials.. The study was registered at ClinicalTrials.gov Identifier: NCT01985763.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Genistein; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxaliplatin; Peritoneal Neoplasms; Pilot Projects; Prognosis; Survival Rate

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

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

Despite median survival of less than 6 months, there is a significant proportion of advanced pancreatic cancer patients who progress on gemcitabine that remains fit, and these patients are candidates for second-line treatment.. The objective of this study is to evaluate the efficacy and safety of oxaliplatin plus 5-fluorouracil and folinic acid in patients with gemcitabine-pretreated advanced pancreatic cancer.. Thirty patients with advanced pancreatic cancer who were pretreated with gemcitabine received oxaliplatin (85 mg/m(2)) on days 1 and 15 followed by leucovorin (20 mg/m(2)) and 5-fluorouracil (500 mg/m(2)) on days 1, 8, and 15. The cycle was repeated every 3 weeks.. The majority of patients (80 %) had locally advanced disease. Median age was 63 years, and 60 % were males. The liver was the most common site of metastasis. Partial response was observed in 2 patients (6.7 %) and stable disease in 6 patients (20 %), while 12 patients progressed (40 %). Improved performance status was reported in 10 patients (33.3 %). The median duration of response was 13 weeks, and median overall survival was 22 weeks. There was no grade 4 toxicity apart from grade 4 neutropenia in 6.6 % of patients. Neutropenia (46.5 %) and neuropathy (43.2 %) were the most common toxicities, while hand-foot syndrome was the least frequent one (20 %). There were no treatment-related deaths. The 6-month survival rate was 30 %.. This regimen is feasible and active with an acceptable toxicity; however, further investigation in phase III trial is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate

We conducted a retrospective cohort study to compare 2 different chemotherapy regimens for advanced biliary tract cancer (BTC).. Records of patients consecutively treated in our institution for advanced BTC from 2001 to 2006 were retrieved. Chemotherapy treatment with FOLFOX-4 regimen was routinely offered as first option; gemcitabine (GEM) as single agent was proposed as an alternative option to patients who refused central venous catheter implantation. Toxicity, overall response rate, progression-free survival (PFS), and overall survival (OS) obtained with the 2 treatments were evaluated.. Twenty-two patients were treated with FOLFOX-4, whereas 18 patients received GEM. In the FOLFOX-4 group, the overall response rate was 13.6% (95% confidence interval [CI], 4.7-33.3), with 1 complete response and 2 partial responses, and 54.5% (95% CI, 34.7-73.1) of disease control rate (complete response+partial response+stable disease). Median OS was 14.1 months (95% CI, 9.1-18.8) and median PFS 5.44 months (95% CI, 3.2-6.3). In the GEM group, we observed no objective response, whereas 27.7% (95% CI, 12.5-50.9) obtained disease control. Median OS was 8.3 months (95% CI, 4.7-12.9) and median PFS 3.9 months (95% CI, 2.2-5.4). Toxicity, mainly hematological, was acceptable for both treatments. On a multivariable Cox model including a propensity score, only the performance status and chemotherapy regimen were confirmed as strong predictors of OS, with an hazard ratio of 0.49 (95% CI, 0.24-0.99) in favor of FOLFOX-4.. The combination chemotherapy with oxaliplatin and 5-fluorouracil is well tolerated and seems to provide prolonged survival than GEM alone in advanced BTC treatment, but further randomized trials are warranted.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Bone Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Retrospective Studies; Survival Rate; Young Adult

FOLFIRI is one of the current standard first-line regimens for advanced colorectal cancer, but its administration is onerous. Because the replacement of 2-day-infusional 5-fluorouracil (5-FU) of FOLFIRI with oral tegafur-uracil/leucovorin (UFT/LV) would be highly beneficial for clinical management, we performed a phase I trial using oral UFT/LV and a pharmacokinetic evaluation.. Treatment consisted of infusional irinotecan (100 mg/m)/l-LV (15 mg/m) and a bolus injection of 5-FU (500 mg/m) on day 1, and oral UFT (300 mg as tegafur/m/d)/LV (75 mg/d) on days 1-5 (level 1), days 1-7 (level 2), or days 1-10 (level 3). Cycles were repeated every 14 days. After determination of the recommended UFT/LV administration period, irinotecan was dose-escalated (level 4: 125 mg/m; level 5: 150 mg/m).. Nineteen patients were enrolled. One dose-limiting toxicity (DLT), grade 4 neutropenia lasting for > or =4 days was observed at level 2. At level 3, one DLT of treatment delay of > or =8 days occurred due to prolonged neutropenia, and 2 patients refused to continue the treatment because of prolonged grade 2 anorexia. Therefore, a 7-day administration of UFT/LV was recommended. No DLT was observed at levels 4 and 5. Pharmacokinetic evaluation suggested continuous exposure to 5-FU by means of oral UFT/LV administration in this combination.. The recommended administration period was 7 days for oral UFT/LV, and the recommended dose of irinotecan was 150 mg/m. A phase II study is ongoing to validate the clinical outcome.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Survival Rate; Tegafur; Tissue Distribution; Treatment Outcome

To evaluate the antitumor activity and toxicity of 5-fluorouracil (FU)/leucovorin (LV) and capecitabine (C) given with either oxaliplatin (OX) or camptothecin (CPT-11) in the treatment of chemotherapy naive patients with metastatic colorectal cancer.. The outpatient treatment, consisted of 2 consecutive days of LV, 200 mg/m(2), 5-FU 400 mg/m(2), and C 2000 mg/m(2) that, in one cycle, was preceded by 2 days of OX 50 mg/m(2), and, in the subsequent cycle, by CPT-11, 90 mg/m(2).. All 54 patients were assessable for toxicity and response. Thirty-two patients responded, giving an overall response rate of 59.3%. Median progression-free survival was 12.3 months and median survival was 20.5 months. Toxicity included grade 3 to 4 neutropenia in 43% of patients, grade 3 diarrhea in 7% of patients, and grade 2 neurotoxicity in 6% of patients.. The alternating, bimonthly schedule of OX and CPT-11 plus 5-FU/LV/C has substantial antitumor activity and is well tolerated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; Treatment Outcome

The association between oxaliplatin and 5-fluorouracil (5-FU) has been extensively reported to improve prognosis of gastric cancer patients. The present study is aimed at evaluating response rate and the toxicity profile of the association with oxaliplatin, 5-FU/lecovorin and epirubicin in gastric cancer patients with locally advanced or metastatic disease. Thirty-six patients have been enrolled and 35 evaluated. The treatment schedule was oxaliplatin (100 mg m(-2)), 5-FU (400 mg m(-2)), leucovorin (40 mg m(-2)) and epirubicin (60 mg m(-2)) intravenously. administered every 3 weeks for 6 months, for a total of 185 therapy cycles . Response rate and toxicity were assessed according to the international WHO criteria. Every patient received a mean of 5.3 therapy cycles in a day-hospital setting. Sixteen of 35 patients (46%) showed an objective response, two complete response and 14 partial response. Median time to progression was 33 weeks with an overall median survival of 49 weeks. During the study, anaemia grade 3 and neutropenia grade 3 were observed in 9 and 11% of patients respectively. A grade 3 periferic sensorial neuropathy was observed in 6% of patients. No life threatening or cardiac toxicity was recorded. The regimen used showed anticancer activity against gastric carcinoma, a tolerable toxicity profile and excellent patient compliance.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Colorectal Neoplasms; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

More than two-thirds of patients with gastric cancer present with metastatic disease and their curative options are limited. This phase II study assessed the efficacy and tolerability of cisplatin, epirubicin, tegafur-uracil (UFT) and leucovorin in patients with metastatic gastric cancer (MGC). Thirty-nine patients with previously untreated metastatic or unresectable gastric cancer received intravenous cisplatin 60 mg/m2 and epirubicin 50 mg/m2 on day 1 of a 28-day cycle; UFT 300 mg/m2 was administered with oral leucovorin 30 mg/day in divided doses on days 1-22, followed by a 7-day rest. Two patients achieved a complete response, 13 had a partial response (overall response rate 38%; 95% confidence interval [CI] 24-52%) and 16 patients (41%) had stable disease. Median time to progression was 6.5 months (95% CI 5.5-7.5 months); overall survival was 9.5 months (95% CI 8.5-13.5 months). Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 20%, 8%, and 3% of patients, respectively; two patients experienced febrile neutropenia. Grade 3 diarrhea occurred in three patients. The combination of cisplatin, epirubicin, UFT, and leucovorin has significant activity and tolerable toxicities in patients with MGC and represents a convenient treatment option for these patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Epirubicin; Female; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Peritoneal Neoplasms; Stomach Neoplasms; Survival Analysis; Tegafur; Time Factors; Treatment Outcome; Uracil

Conventional systemic chemotherapy for metastatic urothelial carcinoma (UC) such as methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) or cisplatin, methotrexate, and vinblastine (CMV) is associated with significant dose-limiting toxicities and even treatment-related death. The authors developed a regimen that was designed to maintain efficacy, while reducing toxicities.. Between January 1998 and July 2003, 35 patients (median age, 71 yrs) with metastatic UC were treated with 4-week cycles of P-HDFL (cisplatin 35 mg/m(2), high-dose 5-fluorouracil [5-FU] 2,600 mg/m(2), and leucovorin 300 mg/m(2), on Days 1 and 8, all given by 24-hr infusion). On Day 15, only HDFL was given again.. Among the 32 patients treated with > or = 2 cycles, 9 (28.1%) and 11 (34.4%) were complete and partial responders, respectively, with an overall response rate of 62.5% (95% confidence interval [CI], 45.9-79.2%). The median overall and progression-free survival was 12.3 months (95% CI, 8.2-16.4 mos) and 10.5 months (95% CI, 8.4-12.6 mos), respectively. Toxicity in a total of 121 courses (mean, 3.5 per patient) was modest, with WHO Grade 3 or 4 leukopenia and thrombocytopenia noted in only 1 and 0 patients, respectively. Grade 3 or 4 nausea, vomiting, mucositis, and diarrhea were noted in 3, 2, 0, and 2 patients, respectively. In general, patients tolerated the regimen very well.. P-HDFL is a moderately active and considerably low-toxic regimen for metastatic UC. The excellent toxicity profile makes it a viable option for patients with poor general conditions. To reach any conclusion, randomized trials comparing P-HDFL with traditional cisplatin-based regimens are necessary.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Survival Rate; Treatment Outcome; Urinary Bladder Neoplasms

Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously.. Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin.. One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy).. Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Methotrexate; Neoadjuvant Therapy; Osteosarcoma; Survival Analysis; Treatment Outcome

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A - vinorelbine 30 mg/m2 i.v. weekly; Arm B - leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 5, q 28 days; Arm C - mitoxantrone 12 mg/m2 i.v. only day 1 + leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 3, q 28 days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3-4 toxicities. Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Salvage Therapy; Soft Tissue Neoplasms; Survival Rate; Treatment Failure; Vinblastine; Vinorelbine

To assess the activity of paclitaxel in combination with 5-fluorouracil (5-FU) and leucovorin in breast cancer, a phase II trial was conducted in women with metastatic disease. Toxicity, response rate, median survival, median duration of response, and median time to disease progression were measured. Between January 1994 and May 1996, 47 patients with metastatic breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 who had previously been treated with chemotherapy received 175 mg/m2 paclitaxel over 3 hours on day 1. After paclitaxel administration, 300 mg intravenous (i.v.) leucovorin over 30 minutes was administered followed by 350 mg/m2 i.v. push 5-FU. Both 5-FU and leucovorin were given on days 1-3. Treatment was repeated every 28 days for a minimum of 6 cycles per patient. Two (4%) patients had a complete response and 21 (45%) patients had a partial response for an overall response rate of 49% (95% confidence interval: 35%-63%). The median survival was 17.7 months, median duration of response was 8.6 months, and median time to disease progression was 6.3 months. There was no statistical difference in survival or time to progression between anthracycline-naive, anthracycline-sensitive, and anthracycline-resistant patients. Nine (19%) patients had grade 3 or 4 neutropenia, and no patient required blood or platelet transfusion. The most frequently observed nonhematologic toxicities were arthralgia and myalgia. Pharmacokinetic data were obtained on 19 patients. Responders had higher peak plasma concentrations of paclitaxel than nonresponders (4.46 vs. 2.9 micrograms/mL; P = 0.02). Paclitaxel/5-fluorouracil/leucovorin is an active, well-tolerated regimen for patients with metastatic breast cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Drug Monitoring; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Paclitaxel; Proportional Hazards Models; Soft Tissue Neoplasms; Survival Analysis; Time Factors; Treatment Outcome; Viscera

High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patients, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Stereoisomerism

There is no known effective salvage chemotherapy for patients with refractory or relapsed urothelial tumors after methotrexate/cisplatin-based regimen. We report the results of a phase II trial with the FIFO regimen that includes from day 1 to 5: fluorouracil 350 mg/m2, folinic acid 20 mg/m2, and ifosfamide 1000 mg/m2, Q4W. Fifteen patients with metastatic measurable urothelial cancer were enrolled in this trial. Previous therapy included M-VAC regimen in 11 patients, CMV regimen in 3 patients, and both regimens in 1 patient. Thirty-one courses were delivered. Toxicity was moderate, including encephalopathy grade 2 in 2 patients and hematological toxicity grade 3 in 2 others. However, an early death occurred on day 1 in a patient who progressed rapidly and died from hepatic insufficiency after initial encephalopathy. No objective response was seen. Twelve patients progressed during FIFO therapy and 3 patients experienced a stable disease. Despite almost encouraging results of fluorouracil and ifosfamide in the literature, their combination according to our schedule is not active in urothelial cancer.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Transitional Cell; Fluorouracil; Hepatic Encephalopathy; Humans; Ifosfamide; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retroperitoneal Neoplasms; Salvage Therapy; Treatment Failure; Urologic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Clinical Protocols; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Humans; Leucovorin; Life Tables; Methotrexate; Osteosarcoma; Survival Rate; Treatment Outcome; United States

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Humans; Leucovorin; Methotrexate; Osteosarcoma; Survival Rate; Treatment Outcome; United States; Vincristine

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Feasibility Studies; Female; France; Humans; Ifosfamide; Leucovorin; Male; Methotrexate; Osteosarcoma; Survival Rate; Treatment Outcome; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Humans; Leucovorin; Life Tables; Methotrexate; Osteosarcoma; Treatment Outcome; Vincristine

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Cyclophosphamide; Disarticulation; Doxorubicin; Europe; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Recurrence, Local; Osteosarcoma; Survival Analysis; Treatment Outcome; Vincristine

Topics: Amputation, Surgical; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Humans; Ifosfamide; Leucovorin; Lung Neoplasms; Mesna; Osteosarcoma; Survival Analysis; Tennessee; Treatment Outcome; Vincristine

60 patients with metastatic breast cancer were entered in a phase II study using folinic acid, 5-fluorouracil bolus and infusion and mitoxantrone with or without cyclophosphamide. 47 had measurable visceral metastases and 13 had exclusively bone metastases. 36 had received previous adjuvant or metastatic treatment (33/36 with anthracycline-based regimens). Overall response rate in visceral metastatic patients was 57.1% [95% confidence interval (CI) 35.4-78.8%]; 45.5% and 70% in previously and non-previously treated patients, respectively; duration of response was 9 and 13 months, respectively. 10 out 13 patients with exclusive bone metastases improved for a median time of 18 months. Median survival was 22 months for the 60 patients; 18 and 31 months for previously and non-previously treated patients, respectively. Cyclophosphamide was scheduled only in the absence of nadir grade 4 neutropenia. However, this toxicity occurred in the first 7 patients. For this reason, we chose to avoid cyclophosphamide in patients over 60 years, or with a performance status of 1-2, or who had received previous chemotherapy. Overall, cyclophosphamide was stopped due to nadir grade 4 neutropenia in 17/24 patients for whom this drug was planned. When mitoxantrone, 5-fluorouracil and folinic acid were used at the doses scheduled, the addition of cyclophosphamide appeared feasible in only about 25% of the patients. Furthermore, survival was identical for patients receiving or not receiving cyclophosphamide. Therefore, cyclophosphamide does not contribute substantially to this regimen. This study confirms the value of folinic acid, 5-fluorouracil and mitoxantrone in metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Neutropenia; Prognosis

Nine adult patients with Ki-1-positive large-cell anaplastic lymphoma were treated with MACOP-B. Two suffered from relapsed disease and had previously received chemotherapy; a third patient had received a single dose of 100 mg/m2 cisplatin before initiation of MACOP-B. The stage of lymphoma was determined according to the Ann Arbor Conference criteria and was II in one, III in two and IV in six patients. All patients had constitutional symptoms. Five patients had achieved complete remission 4 weeks after termination of the protocol and there were two partial remissions. One patient died of massive pulmonary embolism during the 4th week of treatment; another patient, who had received MACOP-B as salvage therapy, died of progressive lymphoma 1 month after completion of the regimen. Maximal observed toxicities according to WHO were mucositis grade 3 (n = 3) and there were three cases with thromboembolic complications, including a fatal pulmonary embolism in a young patient. However, MACOP-B appears an effective, fairly well-tolerated and feasible therapy for patients with Ki-1-positive large-cell anaplastic lymphoma.

Topics: Adult; Aged; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Ki-1 Antigen; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Prednisone; Remission Induction; Vincristine

In this study, 30 patients with metastatic breast cancer were treated with 5-Fluorouracil (5-FU) and high-dose Folinic acid, using a new sequential dosing schedule. Our treatment consisted of one day i.v. infusion of 500 mg/m2 of Folinic acid over two hours. One hour after the beginning of Folinic acid infusion, 5-FU (500 mg/m2) was given by i.v. bolus injection. The complete and partial response rates achieved (CR+PR) were 21% in a population of patients pretreated with chemotherapy including 5-FU. Cutaneous and bone metastasis responded best to our treatment. There were no treatment related deaths or withdrawals from the study. The drug related toxicities observed in this study were usually mild to moderate and easily controllable. Thus preliminary results of our study suggest that response rate, quality of life and time to disease progression for the responders improved by this sequential treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Remission Induction; Skin Neoplasms

High dose of methotrexate (HDMTX) with leucovorin rescue requires over-hydratation to avoid nephrotoxicity; nevertheless the relationship between hydratation and plasma MTX levels is unknown. We compared the effects of two different types of hydratation (2 lt/m2 vs 1.5 lt/m2) on plasma MTX levels in two groups of patients with osteosarcoma of the extremities and treated with HDMTX (8 g/m2 IV). Samples were obtained at the end of infusion of MTX and 14 and 38 hours after the start of MTX infusion. At the end of infusion of MTX the medium plasma MTX levels proved significantly higher in the group with low hydratation than in the group with high hydratation (585.5 microns/l vs 427.7 microns/l P less than 0.001). The values obtained at 14 and 38 hours, did not show significant differences. No significant differences were seen between the two groups in term of late elimination of MTX and correlated toxicity. These data show that a low hydratation regime allows higher plasma MTX levels at the end of infusion of HDMTX and does not increase the incidence of late elimination of MTX compared to a high hydratation regime.

Topics: Adult; Bone Neoplasms; Child; Extremities; Female; Fluid Therapy; Glucose Solution, Hypertonic; Humans; Infusions, Intravenous; Kidney; Leucovorin; Male; Methotrexate; Osteosarcoma

The authors propose alternative chemotherapy of osteosarcoma and Ewing's sarcoma in children. The aim of this proposal was elaboration of effective and, at the same time, less expensive and less toxic therapeutic regimens. The authors recommend open surgical biopsy with doxorubicin for 3 consecutive days as a protection against the released circulating neoplastic cells. After completion of histopathologic examination, one of two types of chemotherapy is chosen randomly. In osteosarcoma, there was induction chemotherapy for 4 or 9 weeks (according to the type of operation--conservative amputation or limb salvage surgery). In the I type of induction chemotherapy, high doses of methotrexate with vincristine and citrovorum factor rescue are administrated weekly, in the II type--the combination of BCD (bleomycin, cytoxan, actinomycin D) and CDDP (cisplatin). On the regimen of intensification chemotherapy decides the degree of tumour response to induction chemotherapy assessed as tumour necrosis in histopathologic examination. Maintenance chemotherapy is the same in two types of regimen and is continued for the period up to 2 years. The authors elaborated concomitantly the regimen of high methotrexate doses administration with rescue procedure in the case of elevated serum methotrexate levels, and regimen of cisplatin administration aiming at maximal patients protecting against the toxic effects of both drugs. In Ewing's sarcoma the randomisation differentiates between T-9 Rosen's regimen of chemotherapy and own modification of Memphis group regimen. The primary tumour is treated by radiotherapy with lower doses adjusted to the tumor response to induction chemotherapy (30-50 Gy or 50 Gy) and the irradiation port limited to the residual bone lesion plus a 2-3 centimeter margin. Surgical excision of bone with tumor depends on special tumor localisation as the clavicula, rib or fibula. The results of discussed treatment regimens will be subsequently published.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Humans; Leucovorin; Methotrexate; Organoplatinum Compounds; Osteosarcoma; Sarcoma, Ewing; Vincristine

Chemotherapy with leucovorin (100 to 200 mg) and 5-fluorouracil (30 mg/kg) every 2 wk produced four (three complete) objective responses among a group of eight patients with early metastatic pancreatic primary and unknown cancers. Complete remissions were associated with exceptionally long durations of survival, one in a patient failing prior combination chemotherapy. This treatment warrants testing because of its ease, scientific rationale, and the large population of patients with early metastatic pancreatic cancer for whom there is no accepted treatment. Early metastatic disease is defined as small metastatic lesions not immediately life threatening found in a physiologically intact patient. Controlled trials, demonstrating benefit associated with other 5-fluorouracil-containing regimens for patients with nonmetastatic stages of pancreatic cancer, provide a rationale for extending testing of leucovorin and 5-fluorouracil to other early stages of pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasms, Unknown Primary; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis

Adjuvant chemotherapy comprising Adriamycin (ADM) and Methotrexate (MTX) with Citrovorum Factor (CF) was administered on a randomization basis to 2 groups of patients with osteosarcoma after surgical ablation of the primary tumor. One group received high dose MTX (regimen I) and the other moderate dose MTX (regimen II). In both groups a short period of heparin treatment was also administered to prevent neoplastic emboli during surgery. All patients were free of metastasis at the beginning of therapy. The efficacy of therapy was determined by recording the percentage of continuously disease-free patients. This was compared to the disease-free survival in 132 patients previously treated with other ADM or ADM-MTX regimens and to a group of 39 patients treated during this period with amputation only. The latter did not receive adjuvant chemotherapy for a variety of reasons and are equated to a concurrent control group. Over the ensuing 27-66 months, 31 of 56 patients (55%) treated with regimen I and 25 of 50 (50%) treated with regimen II were disease-free. The overall disease-free survival in both regimens was 53%. This is similar to the 132 patients treated with previous adjuvant chemotherapy protocols (45-50%). However, the percentage of continuously disease-free patients treated with adjuvant chemotherapy was significantly better than the 39 patients (12%) treated contemporaneously with surgery only (P less than 0.0005). Survival in the latter is similar to that of historical control patients. These results do not suggest any change in the natural history of osteosarcoma and reveal benefits which may accrue with adjuvant chemotherapy. These results also demonstrate that in adjuvant treatment of osteosarcoma performed with ADM and MTX the high and the moderate doses of MTX are equally efficacious.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Doxorubicin; Drug Evaluation; Extremities; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Random Allocation

A randomized two-arm study was undertaken to determine relative tumoricidal effects of intra-arterial cis-diamminedichloroplatinum II (I/A-CDP) and high-dose methotrexate with citrovorum factor rescue (MTX-CF) in the treatment of the primary tumor in patients with osteosarcoma. Responses were evaluated by clinical, radiographic, angiographic, and pathologic parameters. Fifteen patients were randomized to receive MTX-CF and 15 to I/A-CDP. In the MTX-CF arm there were four responses (three complete responses, one partial response) whereas in the I/A CDP arm there were nine responses (seven complete responses, two partial responses). Two patients who failed MTX-CF and requested alternative treatment with I/A-CDP also responded. The total I/A-CDP response was 11/17.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Humans; Infusions, Intra-Arterial; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma; Random Allocation

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Extremities; Humans; Leucovorin; Methods; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Prostheses and Implants; Random Allocation

The treatment-associated toxicity in 189 patients entered in the COSS-80 Study was analyzed. The sequential use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and cis-platinum may be additive or synergistic in causing renal toxicity. However, evaluation of the 48-h serum methotrexate level and the incidence of elevated serum creatinine levels throughout treatment failed to indicate prolonged methotrexate elimination or severe kidney damage from this regimen where an interval of 3 weeks between cis-platinum administration and the next course of HDMTX was mandatory. The treatment-related mortality was 3.2% (6 out of 189 patients). Three patients died of septicemia during chemotherapy-induced bone-marrow depression following treatment with adriamycin or the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). Three deaths occurred following the use of high-dose methotrexate with citrovorum factor rescue. Two of these deaths were associated with delayed excretion of methotrexate. The toxicity is within the range reported in the literature.

Topics: Acute Kidney Injury; Adolescent; Adult; Antineoplastic Agents; Body Weight; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Leukopenia; Male; Methotrexate; Osteosarcoma

Topics: Bone Neoplasms; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma

Thirty-nine patients with extremity osteogenic sarcoma and no discernible metastases were treated with amputation and postoperative adjuvant high-dose methotrexate with leucovorin rescue. One half of the patients were also randomized to receive bacillus Calmette-Guérin by a multiple-puncture technique. Results have been analyzed with a minimum followup of 10 months and a median followup of 27 months. Actuarial analysis estimates that 38% of current protocol patients remain continuously free of disease for 24 months compared to only 17.4% of historical control patients (P = 0.029; one-sided generalized Kruskal-Wallis test). Bacillus Calmette-Guérin administered by a multiple-puncture technique had no effect on disease-free interval. Minor differences between current protocol and historical control patients with regard to race, age, histologic type, and site and size of primary tumors do not affect the difference in disease-free interval between these two patient groups. However, current patients had somewhat lower grade lesions and consideration of the patients with grade III and IV lesions only, lessens the difference between current and historical control patients (P = 0.11; one-sided generalized Kruskal-Wallis test). High-dose methotrexate was administered with virtually no morbidity and no deaths. The small differences observed in this study between protocol patients treated with surgery plus high-dose methotrexate and historical control patients treated with surgery alone point to the need for a prospective randomized study to establish the role of high-dose methotrexate in the adjuvant treatment of patients with osteogenic sarcoma.

Topics: Adolescent; Adult; Age Factors; BCG Vaccine; Bone Neoplasms; Child; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Osteosarcoma

Seventeen consecutive patients with osteogenic sarcoma participated in a prospective study to ascertain first, whether postoperative adjuvant chemotherapy or chemoimmunotherapy could reduce the incidence of distant metastases and second, whether in situ tumor cell destruction could be achieved with preoperative chemotherapy and radiation therapy. To date 14 of 17 patients (85%) are alive and free of disease for a median survival time of 11 months. Three patients developed recurrent disease, one with local recurrence in the tibia and two with pulmonary metastases. Limb salvage was attained in 12 patients by cadaver allografts and in one patient by radiation alone at 6 months.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Clinical Trials as Topic; Doxorubicin; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Recurrence, Local; Osteosarcoma; Postoperative Care; Preoperative Care; Time Factors

Topics: Adolescent; Bone Neoplasms; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Extremities; Female; Humans; Joint Prosthesis; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

Because of the great risk for development of pulmonary metastases following amputation for osteosarcoma, 24 consecutive patients with "clinically localized" osteosarcoma of an extremity were given adjuvant combination chemotherapy with adriamycin-cyclophosphamide-high-dose methotrexate-citrovorum factor. Thirteen of these patients remain free of tumor from 11 to 48 months following amputation. The median disease-free survival is estimated to be 18 months and the median survival 27 months. No relapses have been observed in any patients surviving free of disease beyond 23 months. Combination chemotherapy was also given to 16 patients whose disease was not localized; eight with pulmonary metastases at or following diagnosis, one with nodal metastases at diagnosis, two with osteosarcoma following radiation therapy for other malignant tumors, three with osteosarcoma of flat bones, one with parosteal osteosarcoma, and one with multifocal osteosarcoma. Three of this latter group of patients are surviving free of tumor at 8, 17, and 19 months from diagnosis. Two young patients died from complications of methotrexate and adriamycin toxicity.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Time Factors

Topics: Adolescent; Adult; Bone Neoplasms; Child; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Time Factors; Vincristine

Twenty-nine evaluable patients with nonmetastatic osteosarcoma were given sequential combination chemotherapy utilizing high-dose methotrexate with citrovorum factor rescue, vincristine, adriamycin, and cyclophosphamide. Fourteen (48%) of 29 patients are currently disease-free for 8--48 months from initiation of chemotherapy with a median disease-free survival of 21 months. The projected 4-year disease-free survival is 13%. At 4 years the projected overall survival is 57%. In this particular study, adjuvant chemotherapy does not appear to significantly prevent the development of overt metastases. In four patients, delayed onset of metastasis was observed at 18--43 months from initiation of treatment.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Cell Division; Child; Clinical Trials as Topic; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Radiotherapy, High-Energy; Time Factors

Topics: Amputation, Surgical; Bone Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Femoral Neoplasms; Follow-Up Studies; Humans; Injections, Intramuscular; Injections, Intravenous; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Time Factors; Vincristine

To evaluate the pattern of tumor relapse of pathological complete response (pCR) patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), and to identify predictive factors of distant metastasis in pCR patients after nCRT.. This was a retrospective analysis of 118 LARC patients who achieved a pCR following nCRT and TME from 2008 to 2015. Clinicopathological and therapeutic parameters were evaluated as possible predictors of distant metastasis-free survival (DMFS), and COX regression analysis was performed.. After a median follow-up of 57 months, the 5-year overall and disease-free survival rates were 94.7% and 88.1%, respectively. Overall, 6 patients (5.1%) died, no local recurrence occurred, 13 patients (11%) developed distant metastases, including lung (n = 5), liver (n = 2), bone (n = 3), lung and brain (n = 1), peritoneal (n = 1), and spleen (n = 1) metastasis. On univariate analysis, tumor distance from the anal verge (HR = 0.706, P = 0.039), acellular mucin pools (HR = 6.687, P = 0.002), and MUC1 expression (HR = 8.280, P < 0.001) were independently associated with DMFS. COX regression demonstrated that MUC1 expression (HR = 3.812, P = 0.041) remained to be an independent predictor of DMFS in pCR patients.. Distant metastasis still remained a major concern in pCR patients following nCRT and TME. Tumor distance from the anal verge, acellular mucin pools, and MUC1 expression were associated with distant metastasis in patients with pCR. MUC1 staining remained to be an independent risk factor for DMFS. Such information could facilitate treatment decision in these patients, such as adjuvant chemotherapy and follow-up.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Humans; Incidence; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Mesentery; Middle Aged; Mucin-1; Mucins; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Proctectomy; Proportional Hazards Models; Rectal Neoplasms; Remission Induction; Retrospective Studies; Splenic Neoplasms

Metastatic colorectal cancer (mCRC) combined with hyperbilirubinemia is typically considered a contraindication to irinotecan-based therapy, a proven first-line treatment of mCRC. Herein, we present 6 consecutive patients with mCRC combined with hyperbilirubinemia who underwent UGT1A1 genotyping before receiving FOLFIRI plus bevacizumab. Dose escalation of irinotecan was performed according to the results of UGT1A1 genotyping in all patients. Improvement in the serum total bilirubin level to a normal range was noted in all 6 patients. Disease control was 100%. The median progression-free survival was 7.5 months and the median overall survival was 8.5 months. FOLFIRI plus bevacizumab as a first-line chemotherapy may achieve effective disease control and be safe in patients with mCRC and hyperbilirubinemia based on UGT1A1 genotyping. More prospective clinical studies are necessary to evaluate the clinical benefits and safety of this treatment approach.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bilirubin; Bone Neoplasms; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Survival Rate

Glucarpidase rapidly reduces methotrexate plasma concentrations in patients experiencing methotrexate-induced renal dysfunction. Debate exists regarding the role of glucarpidase in therapy given its high cost. The use of reduced-dose glucarpidase has been reported, and may allow more institutions to supply this drug to their patients. This report explores the relationship between glucarpidase dosage and patient outcomes in pediatric oncology patients.. The authors evaluated data from 26 patients who received glucarpidase after high-dose methotrexate. Decrease in plasma methotrexate concentrations and time to renal recovery were evaluated for an association with glucarpidase dosage, which ranged from 13 to 90 units/kg.. No significant relationship was found between glucarpidase dosage (units/kg) and percent decrease in methotrexate plasma concentrations measured by TDx (P > 0.1) or HPLC (P > 0.5). Patients who received glucarpidase dosages <50 units/kg had a median percent reduction in methotrexate plasma concentration of 99.4% (range, 98-100) measured by HPLC compared to a median percent reduction of 99.4% (range, 77.2-100) in patients who received ≥50 units/kg. Time to SCr recovery was not related to glucarpidase dosage (P > 0.8).. The efficacy of glucarpidase in the treatment of HDMTX-induced kidney injury was not dosage-dependent in this retrospective analysis of pediatric oncology patients.

Topics: Acute Kidney Injury; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Drug Evaluation; Female; gamma-Glutamyl Hydrolase; Hematologic Neoplasms; Humans; Inactivation, Metabolic; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Methotrexate; Osteosarcoma; Recombinant Proteins; Recovery of Function; Retrospective Studies; Young Adult

We report a case of a 59 years old man affected by an adenocarcinoma of the rectum RAS wild type with synchronous liver metastases, diagnosed on October, 2011. The patient underwent a left hemicolectomy with left hepatic lobectomy. In view of the recurrence of the disease from 18.01.2012 to 13.7.2012 we practiced first line chemotherapy with FOLFOX plus bevacizumab for 12 total cycles, obtaining a complete response, so the patient underwent clinical follow-up controls that proved negative until January, 2013, when, following the appearance of pain in the pelvis to the left, a total body PET with 18FDG was performed that documented the presence of bone metastases (left hemipelvis), confirmed histologically. Therefore from 03.18.2013 to 29.03.2013 the patient underwent a left ischium radiotherapy (for a total of 30 Gy). On May, 2013, a CT scan showed a progression of disease in the liver and so the patient started a II line chemotherapy with FOLFIRI and aflibercept, treatment still ongoing. At 46 months after diagnosis, the patient is in good general condition, presenting a complete response of the disease, demonstrated by a total body CT scan, performed in April 2015, completely negative.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Camptothecin; Colorectal Neoplasms; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

Aggressive chemotherapy protocols for non-metastatic limb osteosarcoma have improved histological response without affecting prognosis. This study evaluated the toxicity and outcome of a dose-intensive, high-dose 3- to 5-drug pilot protocol, SCOS 89.. The cohort included 26 patients (14 male; ages 6.5-22 years) with non-metastatic limb osteosarcoma treated at a tertiary pediatric medical center between 1989 and 2013. Preoperatively, patients received two courses of once-weekly pulses of high-dose methotrexate (12-30 g/m(2)) for 2 weeks; doxorubicin (90 mg/m(2)) with dexrazoxane, combined with cisplatin (200 mg/m(2)), was added in week 3. Following methotrexate, 760 mg/m(2) of folinic acid was administered. Postoperative chemotherapy was continued to a total of 14 courses of methotrexate, doxorubicin (up to a total dose of 360 mg/m(2)), and cisplatin (up to a total dose of 560 mg/m(2)). If toxicity occurred or <90 % tumor necrosis, ifosfamide (12 g/m(2)) plus etoposide (500 mg/m(2)) was substituted for doxorubicin, cisplatin, or methotrexate. Toxicity and death rates were calculated.. All patients underwent definitive limb salvage surgery. Six patients died of infection, recurrent disease, or secondary malignancy. Median follow-up was 100 months (range 2-290). Event-free and overall survival rates, respectively, were 88 and 96 % at 2 years, 80 and 87.6 % at 5 years, 80 and 78 % at 10 years. Eleven patients required ifosfamide/etoposide substitution. One patient had a transient decreased left ventricular ejection fraction. Two patients developed acute nephrotoxicity during therapy, but no neurotoxicity. Seven patients had hearing impairment.. The SCOS 89 yields a high event-free survival rate with reduced nephro-/neuro-/cardiotoxicity in patients with non-metastatic limb osteosarcoma.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Substitution; Etoposide; Female; Follow-Up Studies; Hearing Loss; Humans; Ifosfamide; Kidney Diseases; Leucovorin; Male; Methotrexate; Osteosarcoma; Pilot Projects; Stroke Volume; Survival Rate; Treatment Outcome; Young Adult

A woman in her 60s showed positive results on a fecal occult blood test and consulted her doctor. Early-stage cancer of the lower rectum was diagnosed, and a transanal local excision was performed. Histopathological examination revealed that the depth of submucosal invasion was ≧1,000 mm, and the submucosal invasive part of the tumor was a poorly differentiated adenocarcinoma. Therefore, she was referred to our hospital for additional resection. Intersphincteric resection was performed 11 months after the initial operation. The cancer stage was T1N0M0, Stage Ⅰ(UICC 7th edition), and the cancer did not recur. The patient visited our hospital again, 78 months after the additional resection, because of left hip-joint pain. Positron-emission tomography revealed fluorodeoxyglucose uptake in the left acetabulum, para-aortic lymph nodes, and left external iliac lymph nodes; these findings indicated recurrence of the rectal cancer. The patient received radiation therapy (57 Gy) and FOLFIRI; bevacizumab was added from the third course onward. The therapy reduced the size of the tumor recurrence in the bone. This was a rare case of rectal cancer with submucosal invasion that showed recurrence in the bone and lymph nodes 78 months after the additional resection.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Camptothecin; Chemoradiotherapy; Female; Fluorouracil; Humans; Intestinal Mucosa; Leucovorin; Lymphatic Metastasis; Neoplasm Invasiveness; Neoplasm Staging; Rectal Neoplasms; Recurrence; Time Factors

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

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

Because the incidence rate of renal impairment is 2-10% for patients treated with high-dose methotrexate and renal impairment develops in 0-12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination.. Pooled analysis of efficacy data from four multicenter single-arm compassionate-use clinical trials using protocols from 1993 to 2007.. Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after high-dose methotrexate, 169 patients had at least one preglucarpidase (baseline) plasma methotrexate concentration greater than 1 μmol/L and one postglucarpidase methotrexate concentration measurement by high-performance liquid chromatography and were included in the efficacy analysis; renal recovery was assessed in 436 patients who had at least one recorded preglucarpidase and postglucarpidase serum creatinine concentration measurement.. Efficacy was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of 1 μmol/L or lower at all postglucarpidase determinations. Median age of efficacy-evaluable patients was 20 years (range 5 weeks-84 years). Osteosarcoma (36%), non-Hodgkin lymphoma (27%), and acute lymphoblastic leukemia (20%) were the most frequent underlying diagnoses. Median preglucarpidase serum methotrexate was 11.7 μmol/L. At the first (median 15 minutes) through the last (median 40 hours) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. A total of 64% of patients with renal impairment greater than or equal to Common Terminology Criteria for Adverse Events grade 2 recovered to grade 0 or 1 at a median of 12.5 days after glucarpidase administration.. Glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels and provided noninvasive rescue from methotrexate toxicity in renally impaired patients.

Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Bone Neoplasms; Compassionate Use Trials; Drug Administration Schedule; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Methotrexate; Osteosarcoma; Treatment Outcome

XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev) treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this study was to compare efficacy of first-line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC.. A total of 409 patients with mCRC who received chemotherapy were included and divided into 2 groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made in terms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity.. Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in 29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%) and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively. Median OS was 25 months (range 2-57 months, 95%CI; 22.2-27.7) for Group 1 and 20 months (range 1-67 months, 95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) for Group 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4% in Group 1 and 26.1% in Group 2 (p<0.001).. First-line XELOX-Bev is more effective with a better response rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Camptothecin; Capecitabine; Carcinoma; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Oxaloacetates; Retrospective Studies; Treatment Outcome

This study has been performed to examine the currently used doses of folinic acid (FA) and to determine the importance of the dose of FA in preventing subtle neurotoxicity. Thirty osteosarcoma patients were an appropriate population studied as they have no intrinsic neurological involvement. The neuropsychological and psychosocial status was tested in 2 groups of patients treated with similar protocols containing repeated doses of high-dose methotrexate, but different doses of FA. The patients received 300 to 600 mg/m or 120 to 250 mg/m FA in their protocols.. Eighteen tests or subtests of neuropsychological assessment were tested.. Eleven of 18 tests were significant at the P=0.025 level favoring the group treated with high dose of FA. There were no clear results in the psychosocial measures with only a single measure of self-esteem (understanding) being significantly higher (P=0.024) in the group treated with high dose of FA, other measures had no statistical significance.. A correlation between a higher dose of FA after high-dose methotrexate and a better neuropsychological status was clearly shown. The doses of FA used in the low FA group, 120 to 250 mg/m, were similar to those used by several groups treating children with leukemia; some have used even lower doses and report gross neurotoxicity.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Bone Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Leucovorin; Male; Methotrexate; Neuropsychological Tests; Neurotoxicity Syndromes; Osteosarcoma; Young Adult

To investigate prognostic factors for long-term outcomes in Chinese patients with high-grade osteosarcoma of the extremities or trunk treated by multidisciplinary combined therapy.. In total, 333 consecutive patients with non-metastatic or primary metastatic high-grade osteosarcoma of the extremities or trunk were retrospectively reviewed to analyze the correlation between survival and sex, age, site, histological type, clinical stage, alkaline phosphatase (ALP) level, preoperative chemotherapy or not, response to preoperative chemotherapy, postoperative chemotherapy cycles and manner of surgery. The combined therapy included preoperative and postoperative chemotherapy as well as limb salvage surgery or amputation.. The median survival time was 52 months for all 333 patients. Univariate analysis revealed that sex, ALP level, preoperative chemotherapy and cycle numbers of postoperative chemotherapy may influence the prognosis of high-grade osteosarcoma of the extremities or trunk. Multivariate analysis revealed that the female, a normal ALP level, preoperative chemotherapy with good response and ≥4 cycles of postoperative chemotherapy correlated with a better outcome.. Preoperative chemotherapy is important in high-grade osteosarcoma treatment and a good response to it is an important marker of prognosis. It should be given with ≥ cycles of postoperative chemotherapy after surgery.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Ifosfamide; Leucovorin; Limb Salvage; Male; Methotrexate; Middle Aged; Neoplasm Grading; Neoplasm Staging; Osteosarcoma; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; Young Adult

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Signet Ring Cell; Cetuximab; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Prostatic Neoplasms; Radiography; Treatment Outcome

A 48-year-old man with respiratory discomfort was diagnosed with rectal cancer with carcinomatous lymphangiosis, together with lung and sternum metastasis. As the patient's performance status(PS) was 2, mFOLFOX6+bevacizumab (Bmab)therapy with a 20% reduction in the dose was started. Three courses of this treatment resulted in improved respiratory function, and his PS dropped to 1. A chest computed tomography(CT) scan taken after four courses of this treatment indicated that pleural effusion had almost disappeared, and that the shadow on the lung had also reduced. However, after 20 courses of this treatment the disease had progressed. The regimen was changed to irinotecan (CPT-11)+Bmab administration. All of these chemotherapeutic treatments were administered on an outpatient basis. Sixteen months after the diagnosis of rectal cancer, the patient died. In recent years, combination chemotherapy for unresectable colorectal cancer has become recognized as a standard regimen, though adverse effects frequently occur. Thus, intensive chemotherapy is not always recommended for patients with poor PS. In this report, we presented a case of pulmonary metastases from rectal cancer, carcinomatous lymphangiosis, and sternum metastasis that was successfully treated with mFOLFOX6+Bmab.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms

Colorectal carcinomas are among the most common tumor types and are generally treated with palliative chemotherapy in case of metastatic disease. Here, we describe the case of a 58 year old woman with metastatic rectal carcinoma who developed severe gastrointestinal toxicity when the thus far well-tolerated intravenous 5-fluorouracil (5-FU)/leucovorin containing chemotherapeutic regimen was replaced by the same chemotherapeutic regimen in combination with the oral 5-FU prodrug capecitabine. This increased toxicity is probably due to the intracellular retention of polyglutamated folates induced by prior leucovorin therapy which, upon subsequent administration of capecitabine, will result in an enhanced and prolonged inhibition of the, for DNA synthesis important, enzyme thymidylate synthase, essentially creating a situation equivalent to overdosing.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Atorvastatin; Bisoprolol; Bone Neoplasms; Capecitabine; Colic; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Heptanoic Acids; Humans; Hypercholesterolemia; Ileus; Leucovorin; Lymphatic Metastasis; Middle Aged; Nausea; Pyrroles; Ventricular Premature Complexes; Vomiting

The purpose of this study is to evaluate the disease-free survival (DFS) and overall survival (OS) of patients with stage IIB osteosarcoma at a single institution for 20 years and to compare the results according to the chemotherapy protocols.. From Jan 1988 to Nov 2008, 167 patients with osteosarcoma were treated at our hospital and among them, 117 patients (67 males and 50 females) with stage IIB osteosarcoma were evaluable. Their mean age was 22.6 years (range, 8 months to 71 years). Seventy-eight cases underwent the modified T10 (M-T10) protocol (group 1), 23 cases underwent the T20 protocol (group 2) and 16 cases underwent the T12 protocol (group 3). The DFS and OS were calculated and compared according to the chemotherapy protocols.. At a mean follow-up of 78.9 months, 63 patients were continuously disease-free (63/117), 6 patients were alive after having metastatic lesions, 7 patients died of other cause and 41 patients died of their disease. The 5- and 10-year OS rates were 60.2% and 44.8%, respectively and the 5- and 10-year DFS rates were 53.5% and 41.4%, respectively. There was no significant difference of the OS and DFS between the chemotherapy protocols (p = 0.692, p = 0.113).. At present, we achieved success rates close to the internationally accepted DFS and OS. We were able to achieve the higher survival rates using the M-T10 protocol over the 20 years. However, there was no significant difference of results between the chemotherapy protocols. We think the M-T10 protocol will achieve more favorable results in the near future.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Humans; Infant; Kaplan-Meier Estimate; Leucovorin; Male; Methotrexate; Middle Aged; Neoadjuvant Therapy; Osteosarcoma; Survival Rate; Vincristine; Young Adult

Topics: Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Cisplatin; Diphosphonates; Female; Fluorouracil; Humans; Hypercalcemia; Imidazoles; Leucovorin; Middle Aged; Neoplasm Recurrence, Local; Treatment Failure; Vinblastine; Vinorelbine; Zoledronic Acid

Oxaliplatin is an anticancer agent only approved for treatment of colorectal cancer, but that has shown some activity in metastatic breast cancer in phase II studies. Herein, we examine the off-label use of oxaliplatin in unselected patients with metastatic breast cancer.. A retrospective review was performed of all patients with metastatic breast cancer treated with oxaliplatin at our hospital between February 2003 and November 2009. Data concerning patterns of use, safety and activity were collected from patient charts.. The cohort comprised 30 female patients with a median age of 49 (range, 34-68 years) and a median of two involved organs (range, 1-4). All patients had been pretreated for metastatic breast cancer (median number of previous lines: 3; range:1-6). Oxaliplatin was only given in association either with fluorouracil and folinic acid (n=23) or with gemcitabine (n=7). The most commonly used dose was 100 mg/m(2) given every other week or every 3 weeks. As of December 15, 2009, the median duration of treatment was 4 (range, 0.75-11) months. Most of the discontinuations occured due to disease progression (n=11) and adverse effects or worsening condition (n=8). Twelve (40%) patients presented side-effects related to oxaliplatin use including hematotoxicity (n=8), gastrointestinal disorders (n=4) and neuropathies (n=2). Among patients evaluable for antitumoral activity (n=15), one patient achieved a complete response and one patient demonstrated a partial response. Most of the patients (57%) continued to be treated by chemotherapy after oxaliplatin. Median overall survival for the evaluable patients was 10 (range, 1-51) months.. In our population of heavily pretreated women with metastatic breast cancer, off-label use of oxaliplatin was of little worth. This off-label treatment was not the last therapeutic option for most of these patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Off-Label Use; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Skin Neoplasms; Survival Rate; Treatment Outcome

We present the case of a 57-year-old patient who initially presented with a constellation of symptoms including intense pruritis, flushing and diarrhoea. Following several months clinical deterioration, the patient was investigated radiologically, where multiple hepatic tumours were identified. Liver biopsy confirmed the presence of a well-differentiated metastatic gastroenteropancreatic endocrine carcinoma with biochemical evidence of serotonin secretion. Over a period of six months, the clinical course of the patient's disease progressed whereby severe hypoglycaemia became the major manifestation. Subsequent biochemical investigations confirmed the diagnosis of an insulinoma. Extensive radiological investigation revealed a solitary primary pancreatic tumour, indicating the presence of a metastatic pancreatic endocrine tumour (PET) secreting both insulin and serotonin. The patient was treated with a chemotherapy regimen consisting of 12 cycles of 5-fluorouracil/oxaliplatin, responding clinically - improved World Health Organization performance score from 3 to 1, biochemically - significantly reduced plasma chromogranin A and cancer antigen 19-9 concentrations and improved liver function tests, and radiologically - reduced pancreatic and hepatic tumour size. This is the first report of a primary PET secreting insulin and serotonin. Due to the association of serotonin-secreting gastroenteropancreatic endocrine tumours (GEP-ETs) with multiple endocrine neoplasia type-1 (MEN1) and biochemical evidence of an insulinoma, MEN1 should also be considered in such cases. The case provides further evidence for the biological heterogeneity of GEP-ETs and the myriad secretory humoral products and resultant clinical syndromes arising from such tumours.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Fluorouracil; Humans; Hyperinsulinism; Hypoglycemia; Leucovorin; Liver Neoplasms; Malignant Carcinoid Syndrome; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Vitamin B Complex

We describe the safety, feasibility, and provide a cost-estimate of outpatient high-dose methotrexate administration (HDMTX) among an urban, underserved population.. A retrospective analysis of ambulatory HDMTX administration among osteosarcoma patients, at Montefiore Medical Center's Children's Hospital (Bronx, NY) was performed. HDMTX (12 g/m(2)) was given intravenously (IV) over 4 hr after urine alkalinization. Patients were discharged home to continue IV hydration and alkalinization delivered via a home infusion pump. Families were instructed to monitor urine pH overnight and management was adjusted according to our institution's treatment algorithm until MTX level ≤ 0.1 µmol/L. A cost estimate was performed to assess the difference in costs for outpatient versus hypothetical inpatient administrations.. Of the 97 ambulatory HDMTX administrations, 99% were successfully completed. One patient failed outpatient administration secondary to home infusion pump malfunction. This patient successfully completed subsequent courses as an outpatient. Most patients (72%) had a MTX level of < 10 µmol/L at 24 hr post-HDMTX. No patients were found to have a MTX level of > 50 µmol/L at 24 hr. About 26% of courses were associated with grade III or IV neutropenia, 4% were associated with grade III or IV thrombocytopenia and 1% were associated with grade III/IV leukopenia. Compared to a hypothetical hospital inpatient stay, the hospital costs for ambulatory HDMTX were an average of $1400 less per cycle.. Ambulatory HDMTX administration among an underserved, urban population is safe, feasible, and cost-effective.

Topics: Adolescent; Adult; Ambulatory Care; Antimetabolites, Antineoplastic; Bone Neoplasms; Child; Cost-Benefit Analysis; Costs and Cost Analysis; Female; Home Infusion Therapy; Hospital Charges; Humans; Infusions, Intravenous; Leucovorin; Male; Medically Underserved Area; Methotrexate; Osteosarcoma; Urban Population; Young Adult

Combined chemotherapy including 5-FU plus radiation treatment resulted in a synergistic effect has been reported. S-1 enhances a radiation response of colon cancer cell line xenografts. Also the effectiveness of S-1 + radiation therapy has been reported. A 66-year-old man underwent a low anterior resection for lower rectal cancer. Adjuvant chemotherapy was not performed due to Stage II rectal cancer. Twenty months after the operation, solitary sacral bone metastasis was found during the postoperative work-up. S-1 (120 mg/day) combined with radiotherapy was performed on days 1-14 and 21-35. Radiation (3 Gy) was administered a total of 45 Gy on days 1-5, 7-12 and 35-40. Moreover, the reduction was judged as complete response after 11 courses of mFOLFOX 6. There has been no sign of recurrence for 44 months. It suggested that local control therapy (S-1 + radiation) plus systemic chemotherapy (mFOLFOX6) was one of the promising effective therapies for single sacral bone metastasis of rectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Drug Combinations; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Oxonic Acid; Radiotherapy Dosage; Rectal Neoplasms; Sacrum; Tegafur

The goal of this study was to establish the population pharmacokinetics (PK) of high-dose methotrexate (HD-MTX) treatment in children with osteosarcoma and to explore the influence of patient covariates and between-occasion variability on drug disposition. Patient covariates and concentration-time data were collected. PK data analysis from 209 HD-MTX cycles from 14 patients was performed using the population approach (NONMEM V). Internal and external validations were performed to confirm the model. PK of methotrexate was best described by a 2-compartment open PK model with first-order elimination from the central compartment. Between-subject variability (BSV) was included in total plasma clearance (CL) and in central compartment distribution volume (V1) [coefficient of variation (CV) 11.9% and 8.9%, respectively]. The CV of BSV in the residual error was 25.5%. Between-occasion variability was only retained for CL (CV 8.2%). RE consisted of a proportional error of 41.6%. Age and body weight in CL and body weight in V1 were identified as the appropriate covariates. The final estimates of total CL and V1 were given by the equations CL = 88.5.(AGE/15) + 27.4 x (WGT/50) L/d and V1 = 11.0 + 5.6 x (WGT/50) L, respectively. Internal validation results showed that the 95% confidence interval covered all the observed MTX concentrations. Mean bias and precision of the individual predicted concentrations, calculated in a validation dataset, resulted in -1.36% and 19.71%, respectively. A population PK model was developed for HD-MTX in children with osteosarcoma. Validation studies confirmed the suitability of the model for further dose individualization by means of a Bayesian approach.

Topics: Adolescent; Antidotes; Antimetabolites, Antineoplastic; Bone Neoplasms; Child; Female; Fluorescence Polarization Immunoassay; Humans; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Models, Statistical; Osteosarcoma; Reproducibility of Results

A 78-year-old man was admitted to our institute with the symptom of melena. The patient was diagnosed as having advanced rectal cancer (T4N2M1) with multiple bone metastases. Chemoradiation therapy was chosen for the local control because our proposal of colostomy was rejected. Concurrent chemoradiation therapy [46 Gy/23 Fr+tegafur/uraci (l UFT 400 mg/m2)/calcium folinate (Leucovorin: LV 75 mg/body)] resulted in a good partial response and the patient became asymptomatic. UFT/LV were administrated and most of the bone metastases were diminished. After 3 years of disease remission with good quality of life, local tumor recurred with the symptoms of melena and bowel obstruction. Colostomy and additional radiotherapy were performed for the palliation. He died after 4 years from the initial treatment. In advanced rectal cancer with distant metastases, chemoradiation therapy for local control plus systemic chemotherapy could be an alternative to improve quality of life.

Topics: Aged; Bone Neoplasms; Combined Modality Therapy; Humans; Leucovorin; Male; Rectal Neoplasms

Nasopharyngeal carcinoma (NPC) is a disease that is highly responsive to various chemotherapeutic agents. In the metastatic setting, 2-drug combination chemotherapy generally provides a response rate of 55% to 75%, and median survival of 10 to 12 months. The objective of the current study was to assess the efficacy of a 3-drug combination followed by maintenance treatment in patients with metastatic NPC.. Patients with metastatic NPC were treated with a combination of gemcitabine at a dose of 1,000 mg/m(2), paclitaxel at a dose of 70 mg/m(2), and carboplatin at an area under the concentration-time-curve (AUC) of 2.5 on Days 1 and 8 every 21 days. Patients who achieved partial or complete response continued to receive weekly 5-fluorouracil at a dose of 450 mg/m(2) and leucovorin at a dose of 30 mg/m(2) for 48 weeks.. Twenty-eight patients were recruited. Twenty-two (79%) patients had >or=2 sites of disease. Toxicities were mainly from bone marrow suppression, with 79% grade 3/4 neutropenia, 32% grade 3/4 anemia, and 29% grade 3/4 thrombocytopenia (according to the National Cancer Institute Common Toxicity Criteria). The overall response rate to the 3-drug regimen was 86%, with a complete response rate of 11%. The median duration of response was 8 months and the median overall survival was 22 months.. This regimen of a 3-drug combination followed by maintenance is feasible and has demonstrated an encouraging response rate and overall survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carboplatin; Deoxycytidine; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Nasopharyngeal Neoplasms; Paclitaxel; Prognosis; Quality of Life; Survival Rate

A 10-year-old boy with osteosarcoma and normal renal function manifested laboratory evidence of impending renal toxicity and extreme elevation of aspartate aminotrasferase and alanine aminotransferase within 2 hours after the completion of a 4-hour infusion of high-dose methotrexate (MTX) (12 g/m2), and went on to develop acute renal failure with life-threatening hyperkalemia 29 hours later. Although his renal function recovered completely with high-dose leucovorin, hemodialysis, charcoal hemoperfusion, and carboxypeptidase G2, we present this case to emphasize that signs of renal toxicity may be present as early as 2 hours after the completion of a 4-hour MTX infusion, and to suggest that monitoring for MTX toxicity should perhaps begin within a few hours after the completion of 4-hour MTX infusion.

Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Bone Neoplasms; Child; Drug Monitoring; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma

We describe the safety and feasibility of an outpatient high dose methotrexate (HDMTX) regimen.. HDMTX (12 g/m(2)) is administered in a pediatric day hospital (PDH) intravenously (IV) over 4 hrs. Urinary alkalinization is achieved using an IV bolus of sodium bicarbonate and oral bicarbonate tablets. Daily visits to the PDH follow. Leucovorin is begun 24 hrs. after MTX at a standard dose of 10 mg orally (po) every 6 hrs. (q6h). The leucovorin dose is escalated between a range of 20 mg po q6h to 1 g as a continuous IV drip over 24 hrs. according to an institutional algorithm for levels above 10, 1, and 0.1 micromol/L at 24, 48, and 72 hrs. post-MTX. To evaluate our approach, we conducted a retrospective review of all HDMTX courses administered at the Memorial Sloan Kettering Cancer Center between 1996 and 2002.. Out of a total of 708 MTX courses, 82% were successfully completed as an outpatient. Forty-nine percent of the MTX courses were treated with standard dose leucovorin while 49% required a dose escalation, the majority of which was to 20-30 mg po q6h. Observed toxicity included mild (Grade 0-I) nephrotoxicity and reversible transaminitis in the majority of patients. Myelosuppression was manifested mainly as neutropenia, with Grade III-IV toxicity in 16% of patients.. Outpatient administration of HDMTX and the required supportive therapy is safe and feasible using the described approach. Approximately half of the patients will require leucovorin dose modification based on serial monitoring of MTX levels.

Topics: Adolescent; Adult; Ambulatory Care; Antimetabolites, Antineoplastic; Bone Neoplasms; Child; Drug Monitoring; Female; Humans; Infusions, Intravenous; Kidney; Leucovorin; Male; Methotrexate; Neutropenia; Osteosarcoma

A 63-year-old man had undergone a low anterior resection for rectal cancer with multiple liver metastases. Oral UFT (450 mg/day) administration alone was started after the operation. After 6 months post operatively, the patient was diagnosed as anastomosis recurrence because of ileus by abdominal X-ray. Transverse loop colostomy was performed by emergency surgery. After surgery, he suffered from paraplegia for lumbar vertebrae metastases. UFT+LV therapy was started. After chemotherapy a significant reduction of the lymph node and liver metastases and an apparent decrease in CEA and CA19-9 were observed. The patient left the hospital and showed no signs of tumor exacerbation for three months. The patient died of aggravation of primary disease afterwards. The therapy was safe and effective, and has successfully maintained the quality of life (QOL) of this patient.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Humans; Leucovorin; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Middle Aged; Rectal Neoplasms; Tegafur; Tomography, X-Ray Computed; Treatment Failure; Uracil

Cholangiocarcinoma is a malignant neoplasm arising from the biliary epithelium. The disease is notoriously difficult to diagnose and is usually fatal because of its late clinical presentation and the lack of effective nonsurgical therapeutic modalities. The overall survival rate, including in patients who underwent tumor resections, is poor, with less than 5% surviving more than 5 years. Over the past 5 years, several important studies have yielded new insight into the molecular mechanisms involved in the development and growth of these tumors. The tumor cells of the cholangiocarcinoma express an epidermal growth factor receptor which plays an important role in the pathogenesis of these tumors.. A 49-year-old woman with cholangiocarcinoma of the liver developed spinal metastases. The antiepidermal growth factor receptor (anti-EGFR) antibody was used successfully in combination with radiotherapy. The response to treatment was assessed by magnetic resonance imaging and positron-emission tomography.. The patient with cholangiocarcinoma had a response to cetuximab-based therapies. This may lead to another option for the treatment of hepatic cholangiocarcinoma.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bone Neoplasms; Cetuximab; Chemotherapy, Adjuvant; Cholangiocarcinoma; Combined Modality Therapy; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Liver Transplantation; Magnetic Resonance Imaging; Middle Aged; Positron-Emission Tomography; Radiotherapy, Adjuvant; Spinal Neoplasms; Thoracic Vertebrae

The patient was a 50-year-old woman who suffered from gastric discomfort. She was first diagnosed as intrahepatic cholangiocarcinoma with hepatic, paraaortic lymphnodal and bone metastasis. Initial systemic chemotherapy using gemcitabine (GEM) and 5-FU failed to control the disease activity. Then she was given GEM and cisplatin (CDDP) combination chemotherapy. The response was assessed as stable disease (SD), but grade 4 leukopenia was seen. Then systemic therapy using GEM, and hepatic arterial infusion therapy with CDDP, l-leucovorin and 5-FU were continued biweekly. Partial response (PR) was achieved six months later, and her disease status was maintained as SD. This hepatic arterial infusion chemotherapy would be safe and feasible as therapy for inoperable intrahepatic cholangiocarcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bone Neoplasms; Cholangiocarcinoma; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Middle Aged

Topics: Antimetabolites, Antineoplastic; Bone Neoplasms; History, 20th Century; Humans; Leucovorin; Methotrexate; Orthopedics; Osteosarcoma; Vitamin B Complex

We present a patient with colon carcinoma metastatic to the thyroid. Review of the literature reveals only a few reports of metastatic colorectal carcinoma to the thyroid. Metastatic tumors of the thyroid are no longer considered rare. Unfortunately, they often remain undetected because only a small minority of patients present with a mass lesion or enlargement of the gland. This is further evidenced by the fact that most reports come from autopsy series. Establishing this diagnosis is important because metastatic deposits in the thyroid can sometimes cause respiratory compromise as well as thyrotoxicosis.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Colectomy; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy; Rectal Neoplasms; Thyroid Neoplasms; Thyroidectomy; Treatment Outcome

A 54 year-old male was admitted for highly advanced ascending colon cancer with multiple bone and liver metastases and pleuritis carcinomatosa. He was treated with pharmacokinetic modulating chemotherapy (PMC) and low-dose CPT-11. UFT (400 mg) was orally administered daily and a 2-hour infusion of l-leucovorin (250 mg/m2/day) with a continuous infusion of 5-FU (600 mg/m2/24 h) was given once a week on an outpatient basis. CPT-11 (80 mg/body/2 h) was administered every 2 weeks. Partial response was obtained in the liver for 6 months and in the primary lesion for 9 months. Significant decrease of pain from the multiple bone metastases was observed for 4 months without severe side effects, which led to an improvement in performance status and quality of life for the patient. He survived more than 11 months after initial treatment. The duration of his stay at home was 288 days, accounting for 83% of the treatment period. This case suggests the efficacy of home anticancer therapy with PMC and low-dose CPT-11 for highly advanced colon cancer in terms of QOL.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pleurisy; Quality of Life; Tegafur; Uracil

We report a case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin (L-OHP), 5-FU, l-LV (l-Leucovorin). A 72-year-old man was examined at a certain hospital because of constipation and appetite loss. Chest computed tomography (CT) revealed lung metastases, and abdominal CT revealed liver metastases. He was then referred to our hospital. A colonoscopy revealed type 2 tumor in the colon, at the hepatic flexure. We diagnosed adenocarcinoma of the colon with metastases to the liver and lung. Resection of the primary lesion was performed, and chemotherapy consisting of systemic administration of CPT-11, 5-FU and l-LV was performed. After 2 courses of combined treatment with CPT-11/5-FU/l-LV, CT revealed considerable reduction of the metastatic tumors. However, after 3 courses of combined treatment, progressive disease was observed and new brain and bone metastases were detected. We imported and used a non-approved/pending drug, oxaliplatin from the Remedy and Health Corporation, with informed consent from the patient and his family and our clinical ethics committee. Chronotherapeutic schedules have been performed, from which the safety and activity of oxaliplatin against advanced colorectal cancer was reported. Our patient received a 5-day course of chronomodulated 5-FU and l-LV (750 and 300 mg/body/day, respectively; peak delivery rate at AM 4:00 hours) with L-OHP on the first day of each course (100 mg/body, as a 6-hour infusion). Each course was again repeated every 21 days. A partial response was observed in the liver and lung metastases. These results indicate that chronomodulated 5-FU and LV with L-OHP therapy could be an effective regimen for cases of irinotecan-resistant colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Chronotherapy; Colonic Neoplasms; Drug Evaluation; Drug Resistance, Neoplasm; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin

A 16-year-old girl with a distal femur osteosarcoma became pain-free with the first treatment of methotrexate 12.5 g/m(2) and folinic acid 760 mg/m(2). She was inadvertently given 1275 mg folinic acid after the third dose. Four days later, pain and swelling recurred. Appreciating that this was "over rescue" rather than drug resistance led to the successful use of a further 8 doses of high-dose methotrexate when a suboptimal response was achieved with cisplatinum, Adriamycin, and ifosfamide. This is the first time "over rescue" has been documented in humans from high-dose folinic acid after methotrexate.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Femur; Humans; Ifosfamide; Leucovorin; Methotrexate; Osteosarcoma

5 patients with colorectal cancer with multiple liver metastases underwent resection of primary lesions. We then evaluated the effects of hepatic arterial infusion chemotherapy with low-dose leucovorin and 5-FU. Weekly, dl-leucovorin of 30 mg/body or l-leucovorin of 25 mg/body was administered as a bolus, then 5-FU of 500 mg/body was administered for 1 hour through the hepatic artery from the subcutaneous reservoir on an outpatient basis. 2 of 5 patients achieved a CR of liver metastases, but later 1 of these 2 cases had metastases of bone and lung. No adverse effects, such as nausea, vomiting, diarrhea or bone marrow suppression, were seen after this treatment in any of the patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Colorectal Neoplasms; Drug Administration Schedule; Drug Evaluation; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged

Contemporary therapy for osteosarcoma is comprised of initial treatment with chemotherapy and surgical extirpation of the primary tumor in the affected bone. In view of the major advances forged by chemotherapy in the treatment of the primary tumor, an attempt was made to destroy the tumor exclusively with this therapeutic modality and abrogate surgery.. Thirty-one consecutive patients were treated. All had localized disease (absence of metastases) at the time of diagnosis. Initial treatment with chemotherapy was comprised of high-dose methotrexate and leucovorin rescue (MTX-LF) in 3 patients and intraarterial cisplatin in 28 patients. Clinical, radiologic, angiographic, radionuclide, and histologic investigations were utilized to assess the efficacy of treatment. After a response at 3 months, entry into the study was permitted and treatment was maintained for a total of 18-21 months with a combination of agents comprised of MTX-LF, intraarterial cisplatin, and doxorubicin. Patients were monitored closely for disease recurrence with the investigations outlined earlier. Two informed consents were required: one at the time of diagnosis and another at 3 months after the initial response had been attained.. Only 3 of 31 patients were cured with the administration of chemotherapy alone. Local recurrence and pulmonary metastases were not reported to develop in these 3 patients during a follow-up period of 204+ to 225+ months. Four other patients also possibly were cured with chemotherapy alone. At their request, several months after the cessation of chemotherapy, they underwent surgical extirpation of the tumor. No evidence of viable tumor was found. These patients remained free of disease for 192+ to 216+ months. Thus, only seven patients did not develop local recurrence and/or pulmonary metastases. Among the remaining 24 patients, 9 developed local recurrences without pulmonary metastases 14-74 months (median, 30 months) after the initial response. Eight of the nine patients were rendered tumor free by extirpation of the local recurrence. Two of these eight patients subsequently died, one of the acquired immunodeficiency syndrome (AIDS) and the other of varicella septicemia. The ninth patient refused amputation and died of metabolic complications. Three other patients developed local recurrences 20-69 months and pulmonary metastases 10-98 months after achievement of the initial response. These patients were rendered tumor free by extirpation of the local recurrence and metastasectomy. One of these patients also later died of AIDS. In the remaining 12 patients, local recurrences developed 5-29 months (median, 14 months) after the initial response was achieved. The patients also developed pulmonary metastases 11-60 months after the initial response. In eight patients the local recurrences were extirpated and metastasectomy was performed; however, these patients later died of recurrent pulmonary metastases. The remaining four patients refused to undergo extirpation of the local recurrence. The pulmonary metastases were not resected. They failed to respond to alternate therapy. Thus, the tumor-free survival rate was 23% (7 of 31 patients): 3 patients who were treated with chemotherapy only and 4 patients who were treated with chemotherapy plus surgery. The overall survival rate (patients who remained free of disease and those who underwent resection for local recurrence and metastasectomy) was 48% (15 of 31 patients). Prior to the deaths from AIDS and varicella septicemia, the overall survival was 58% (18 of 31 patients).. Utilizing the regimen employed in the current study, only 3 of 31 patients with osteosarcoma (10%) were cured exclusively with chemotherapy. Four additional patients who underwent extirpation of the primary tumor without disease recurrence and in whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50-65% with "conventional" sin whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50-65% with "conventional" strategies, the results of the current study do not justify the adoption of current forms of chemotherapy as exclusive treatments for osteosarcoma.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Disease-Free Survival; Follow-Up Studies; Humans; Leucovorin; Methotrexate; Neoplasm Recurrence, Local; Osteosarcoma; Survival Analysis; Treatment Outcome

Thirty-two women with untreated metastatic breast cancer were treated with 100 mg/M2 i.v. methotrexate (MTX), 600 mg/M2 5-fluorouracil (5FU) and leucovorin 15 mg orally every 6 hr, 24 hr after MTX (MFL) on days 1 and 8 every 28 days. Stratification was according to sites of metastases (mets), adjuvant (adj), chemotherapy (CTX), and/or hormonal therapy or no adj therapy (Tx). Treatment continued until documented radiographic or clinical disease was in progression. Toxicity was mild, consisting of only minimal elevations of transaminases and mild cytopenias. There was no pulmonary toxicity. There were no hospitalizations, treatment delays or cessations for toxicity. One patient with skeletal mets had a complete response and 7 had partial responses. The overall median progression free survival (PFS) was 13.8 months (mos). Eighteen patients with skeletal mets had PFS from 7-70 mos (median 15.9). Five patients with lung mets only had PFS from 6-20 mos (median 9.8 mos). Patients with liver alone or with other visceral mets showed progression within 2-5 mos. However, patients with bone and visceral mets without liver involvement had PFS from 8-50 mos (median 20.5). Of 21 adj Tx failures the median PFS was 8.8 mos (2-94). Six who received adj CTX had a median PFS of 7.6 mos (3-12) and 4 tamoxifen (tam) failures a median PFS of 11 mos (8-15). Eleven patients who received adj CTX+tam had a median PFS of 8.5 mos (2-94). Six patients received tam at adj failure and MFL at progression. These six had a median PFS of 19.8 mos (8-50). The patients (six, who received no prior adj Tx) had a median PFS of 24.3 (8-70). MFL is as effective in achieving clinical remissions in metastatic breast cancer, is inexpensive and is far less toxic than other CTX regimes. MFL should strongly be considered as first line Tx.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Mitoxantrone; Prospective Studies

A case featuring very late and unusual metastasis of gastric cancer is presented. A 49-year-old woman presented with metastatic disease in the seventh cervical vertebra 9 years after a total gastrectomy for gastric carcinoma. The resected primary tumor was a Borrman type III, poorly differentiated adenocarcinoma which had invaded the subserosal layer of the stomach and had generated lymph node metastases. The patient was treated for the metastatic tumor with sequential administration of cisplatin, calcium leucovorin and 5-fluorouracil and subsequent irradiation. Remission was achieved and she survived for a further 13 months without major symptoms.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Stomach Neoplasms

We report the results of a prospective Tunisian study using primary chemotherapy followed by conservative surgery in primitive limb osteosarcoma. From January 1988 to January 1998, 56 patients affected by limb osteosarcoma entered in a prospective study of neoadjuvant chemotherapy with the T10 protocol before surgery with a conservative intent. Initial work-up include: clinical exam with tumor measurements, chest and limb X-rays, limb CT-scan or MRI, chest CT-scan, bone scintigraphy and hematological and renal biological exams. Patients receive pre- and post-operative chemotherapy according to the T10 modified protocol. Fifty-six patients (33 M/23 F) with a mean age of 19 years (8 to 28) are included. Mean clinical and radiological tumor size is around 14 cm. Main histologic type is classic osteosarcoma (50% of cases) and 10 patients (9%) presented with initial metastasis; 42 patients on 56 receive the whole pre-operative protocol. Treatment is well tolerated excluding 18 episodes of mucositis, 29 of leucopenia (< grade 3), 7 of thrombopenia (< grade 3), 4 of cutaneous toxicity, 2 of pulmonary toxicity and 3 of nausea-vomiting. We observe 36% of good histological responders and 64% of bad responders to primary chemotherapy, 27 patients on 49 operated (53%) have a conservative surgery and 18 (47%) a radical surgery. With a median follow-up of 51 months (8 to 128), 29 patients remain alive free of disease (15/17 GR and 14/30 BR), 2 are alive with disease, 2 died by toxicity, 14 died by progressive disease and 9 are lost to follow-up with evolutive disease. Five year disease-free survival is 55% for the 46 non metastatic patients. In univariate analysis, seric alkaline phosphatase level (p = 0.0014) and histological response to chemotherapy (p = 0.0218) are significant factors for prognosis.

Topics: Adolescent; Adult; Alkaline Phosphatase; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Humans; L-Lactate Dehydrogenase; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Osteosarcoma; Prospective Studies; Survival Analysis; Tomography, X-Ray Computed; Vincristine

Hemodialysis, hemoperfusion, thymidine, and carboxypeptidase have been recommended together with high-dose (HD) leucovorin (LV) to treat patients at risk for methotrexate (MTX) toxicity. To elucidate the efficacy of high LV rescue as the sole salvage modality for severe MTX intoxication, we studied 13 patients who were treated in this fashion at Memorial Sloan-Kettering Cancer Center (New York, NY).. To identify patients at high risk for severe MTX toxicity, we performed a retrospective review of all patients with MTX levels greater than 100 micromol/L at 24 hours and greater than 10 micromol/L at 48 hours after HD MTX.. A total of 13 patients were identified. The median MTX concentration was 164 micromol/L at 24 hours (range, 102 to 940 micromol/L), 16.3 micromol/L at 48 hours (range, 10.5 to 190 micromol/L), and 6.2 micromol/L at 72 hours (range, 1.35 to 39 micromol/L). MTX levels remained greater than 0.1 micromol/L for an average of 11 +/- 3 days (mean +/- SD) (range, 7 to 17 days). In addition to supportive treatment with hydration and sodium bicarbonate administration, all patients were treated solely with HD LV, which was started within the first 24 hours in nine patients, 48 hours in three patients, and 72 hours in one patient in doses that varied from 0.24 to 8 g/d. Significant neutropenia (neutrophil count < 1,000/ microL) occurred in eight patients and lasted for 1 to 5 days. Thrombocytopenia (platelet count < 100,000/microL) occurred in seven patients and lasted for 5 to 10 days. Other toxic manifestations included mucositis of varying degrees, diarrhea, and neutropenic fever, but all patients recovered.. In the range of MTX levels observed, HD LV can be used as a sole therapy for MTX toxicity without the need for extracorporeal removal and with tolerable morbidity.

Topics: Antidotes; Antimetabolites, Antineoplastic; Bone Neoplasms; Child; Creatinine; Drug Administration Schedule; Female; Folic Acid Antagonists; Humans; Kidney; Leucovorin; Methotrexate; Neutropenia; Osteosarcoma; Retrospective Studies; Thrombocytopenia

The purpose of this study was to evaluate the prognostic significance of variables in osteosarcoma. We performed a retrospective analysis of 35 patients with non-metastatic limb osteosarcoma that were treated between 1973 and 1994. The following variables were evaluated: age, sex, ethnic group, tumor histology and primary site, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels at diagnosis, treatment regimen, and the histologic response to treatment. Three variables showed significant correlation with prognosis: i) histologic response to preoperative treatment. Disease-free survival (DFS) was 89% in patients with grade III-IV histologic response after a median follow-up (MFU) of 64 months, 67% in patients with grade II after an MFU of 64 months, the patients with grade I response died within 15 months (p<0.0001); ii) treatment regimen. DFS was 83% after an MFU of 42 months, 62% after an MFU of 82 months, and 30% after an MFU of 177 months in patients treated by the 90's, 80's, and 70's protocols, respectively (p<0.05); iii) corrected ALP (cALP) levels at diagnosis. DFS was 78% after an MFU of 88 months in patients with cALP levels <200, and 32% after an MFU of 56 months in patients with cALP levels >200 (p=0.01). Low ALP levels, good histologic response to preoperative chemotherapy, and the new therapeutic regimen correlated with good prognosis in patients with osteosarcoma.

Topics: Adolescent; Alkaline Phosphatase; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Cohort Studies; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Extremities; Female; Humans; Israel; L-Lactate Dehydrogenase; Leucovorin; Life Tables; Male; Methotrexate; Neoplasm Proteins; Neoplasm Staging; Osteosarcoma; Preoperative Care; Prognosis; Retrospective Studies; Risk Factors; Salvage Therapy; Survival Analysis; Treatment Outcome; Vincristine

Methotrexate is commonly used in the treatment of rheumatoid arthritis. An osteopathy has been described in children treated with methotrexate for leukaemia, consisting of bone pain, osteoporosis and fractures. Animals given short-term high-dose and long-term low-dose methotrexate have both reduced bone formation and increased resorption on histomorphometry. As patients with rheumatic diseases have numerous risk factors for osteoporosis, possible additional risk from low-dose methotrexate is of relevance to the rheumatologist. To investigate further the mechanism of osteoporosis in animals and man, in vitro studies were carried out on an osteoblast cell line, using concentrations found in patients with rheumatic disease. UMR 106 rat osteoblast-like osteosarcoma cells were incubated with methotrexate, and also with sulphasalazine, an anti-rheumatic drug with no known effect on bone, for comparison. A dose-dependent toxic effect of methotrexate on the cell line was observed using concentrations found in patients with rheumatic disease. This was not observed with sulphasalazine. The reduced bone formation observed in animals and man may be due to a direct effect of methotrexate on the osteoblast.

Topics: Alkaline Phosphatase; Animals; Antirheumatic Agents; Bone Neoplasms; Cell Count; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Leucovorin; Methotrexate; Osteosarcoma; Rats; Sulfapyridine; Sulfasalazine; Tumor Cells, Cultured; Vitamin D

This is a retrospective review of five children with post-irradiation bone sarcoma (PIS). Age at PIS onset ranged between 10 and 17 years (median 11). They were treated with a chemotherapy regimen, similar to that in use for primary osteogenic sarcoma, consisting of vincristine and high-dose methotrexate alternated with cisplatinum and ifosfamide, given for 12 months.. In all children chemotherapy induced a complete clinical remission. Four of them were alive in continuous complete remission at 1, 2, 4, and 12 years from the diagnosis of bone sarcoma. One girl recurred 3 years from PIS diagnosis and was salvaged by repeating the same chemotherapy program: she remained alive in second complete remission 8 years from relapse.. In spite of an intensive treatment previously given for the primary tumor, this drug schedule proved to be feasible and short-term side effects were manageable. Chemotherapy alone, using an intensive regimen effective for primary osteogenic sarcoma, may be an adequate therapy for childhood post-irradiation sarcoma.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Female; Humans; Ifosfamide; Leucovorin; Male; Methotrexate; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Remission Induction; Retrospective Studies; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Survivors; Vincristine

For previously treated advanced breast cancer, there is no standard second-line therapy. Combination chemotherapy with mitoxantrone, high-dose 5-fluorouracil (5-FU) and leucovorin (MFL regimen) had been reported as an effective and well tolerated regimen. From October 1993 to November 1995, we treated 13 patients with previously chemotherapy-treated metastatic breast cancer by mitoxantrone, 12 mg/m2, on day 1 and continuous infusion of 5-FU, 3000 mg/m2, together with leucovorin, 300 mg/m2, for 48 h from day 1 to 2. Each course of chemotherapy was given every 4 weeks. Most of these patients had more than two metastatic sites, with lung metastasis predominant. Seven patients had been treated with anthracycline. Seven patients had previously received radiotherapy and seven had received hormone therapy. Median number of courses of MFL regimen given was six and the median cumulative dose of mitoxantrone was 68.35 mg/m2. One patient had complete response, seven had stable disease, none had partial response and five had progressive disease. The overall objective response rate was 7.6%. The median follow-up period was 14 months. Median survival was 16 months. Median progression-free survival was 5 months. A complete responder had relapse-free survival up to 17 months. Major toxicities were cardiotoxicity and leukopenia. Eight patients were dead in the last follow-up; two of them died of treatment-related toxicity. The MFL regimen achieves little palliative benefit and induces severe toxicity at a fairly high rate. Administration of this regimen to breast cancer patients who have been treated by chemotherapy and those with impaired heart function requires careful attention.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Leukopenia; Lung Neoplasms; Middle Aged; Mitoxantrone; Palliative Care; Prognosis; Survival Analysis

Nasopharyngeal carcinoma is a common cancer in South East Asia. In the early stages, radiotherapy alone may achieve sustained control, but once metastasis occurs, it becomes an incurable disease with limited survival time. We report a case of nasopharyngeal carcinoma, initial stage T4N0M0, diagnosed in 1985 in a patient aged 36 years who received 70 Gy radiotherapy to the head and neck region. In 1988, relapse occurred with multiple lung metastases. The patient received many chemotherapy regimens with a very good response, including near complete remission with the first treatment regimen of cisplatin, 5-fluorouracil and leucovorin for lung metastases, and with the fifth chemotherapy regimen of ifosfamide as a single agent. After ifosfamide treatment, there was residual fibrotic change in the lung and complete disappearance, lasting for almost a year, of the liver and bone lesions. The patient eventually died in July 1995 due to progressive disease. Prolonged survival after mainly thoracic metastasis is possible in patients with nasopharyngeal carcinoma, especially if the tumor is chemo-responsive.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Humans; Ifosfamide; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Nasopharyngeal Neoplasms; Survivors

Cutaneous metastases of gestational trophoblastic disease are extremely uncommon. A patient with metastatic, poor prognosis disease and a large metastatic lesion on her left fifth digit is presented. The clinical course and complete response to EMACO chemotherapy are outlined. The presence of metastatic disease in a reproductive-age woman requires consideration of gestational trophoblastic disease in the differential diagnosis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Dactinomycin; Diagnosis, Differential; Doxorubicin; Etoposide; Female; Fingers; Humans; Leucovorin; Methotrexate; Pregnancy; Pregnancy Complications, Neoplastic; Trophoblastic Neoplasms; Uterine Neoplasms; Vincristine

Topics: Adolescent; Age Factors; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Cyclophosphamide; Doxorubicin; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate; Osteosarcoma; Platinum; Time Factors

Temporary neurologic abnormalities were observed in one out of 23 patients undergoing chemotherapy with high-dose methotrexate (HD-MTX) for osteogenic sarcoma. This patient developed sequential symptoms including alternative hemiparesis, dysarthria and altered consciousness 5 days after the second course of HD-MTX (8 gm/m2 by 6 h continuous infusion) with leucovorin rescue. Laboratory evaluations disclosed normal electrolytes, hemograms and non-toxic serum MTX levels at the onset of the symptoms. Computed tomography of the brain was normal but electroencephalography showed focal theta and delta slow waves over the right temporal-parietal-occipital area. The neurological symptoms resolved completely within 72 h.

Topics: Adolescent; Bone Neoplasms; Dose-Response Relationship, Drug; Humans; Leucovorin; Male; Methotrexate; Nervous System Diseases; Osteosarcoma

Between January 1981 and June 1993, 137 children and adolescents were each treated at the Institut Gustave Roussy for an initially nonmetastatic osteosarcoma of the extremities. We report the retrospective analysis of 42 cases of recurrence that occurred in this population.. The median interval between the diagnosis of the primary osteosarcoma and the first recurrence was 21 months (range, 5 to 60). The site of the first recurrence was limited to the lung in 20 patients, the bone in seven patients, was local in six patients, and was confined to soft tissue in one patient. In eight patients, the first recurrence affected multiple sites. Subsequent recurrences often involved unusual or multiple sites. Management of recurrences included surgery and/or various regimens of second-line chemotherapy, and in one case involved high-dose chemotherapy followed by autologous bone marrow transplantation. Overall survival and event-free survival were, respectively, 36% and 27% at 36 months. At present, 13 patients are alive without evidence of disease. Response of the primary tumor to preoperative chemotherapy, the time between the diagnosis and the first recurrence, and the number of metastatic lesions did not correlate with survival. The survival rate is better in patients with a local or a pulmonary first recurrence.. The most important prognostic indicator at first recurrence seems to be the possible complete resection of disease. Patients not amenable to surgery and patients with a second or a third recurrence have a poor prognosis. The potential benefit of more aggressive treatments such as high-dose chemotherapy and autologous bone marrow transplantation should be investigated for these patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Ifosfamide; Leucovorin; Male; Methotrexate; Neoplasm Recurrence, Local; Osteosarcoma; Prognosis; Retrospective Studies; Survival Rate; Treatment Outcome; Vindesine

The authors evaluated a high-intensity inpatient regimen using augmented but subtransplantation doses of multiple agents in patients with metastatic breast cancer. Two high-dose courses were given in an attempt to improve the efficacy of high-dose regimens using a single course.. Forty women received treatment between October 1988 and October 1991. The median age was 38 years (range, 24-56 years). Twenty-five patients were receiving their first chemotherapy for metastatic disease; 15 patients had received one or more prior regimens. The patients received two courses of chemotherapy, which consisted of the following: cyclophosphamide 1500 mg/m2 intravenously (i.v.) on days 1 and 2; doxorubicin 45 mg/m2 i.v. on days 1 and 2; cisplatin 20 mg/m2 i.v. on days 1, 2, 3, 8, 9, and 10; 5-fluorouracil 1000 mg/m2 on days 8, 9, and 10 (continuous infusion); methotrexate 100 mg/m2 i.v. on days 15 and 22; leucovorin 15 mg/m2 i.v. or by mouth for four doses beginning 24 hours after methotrexate. Etoposide 400 mg/m2 i.v. on days 1, 2, and 3 was substituted for doxorubicin in 14 patients who had received prior doxorubicin.. Twenty-nine of 40 patients (73%) had objective response to therapy, with 10 (25%) complete responses. Four patients who obtained a complete response remain disease-free at 14, 21, 28, and 32 months, respectively; all of these patients received this regimen as first-line therapy for metastatic disease. Myelosuppression was severe, with median durations of leukocytes less than 1000/microliters and platelets less than 50,000/microliters of 15 days (range, 7-48 days) and 13 days (range, 3-49 days), respectively. Moderate or severe mucositis occurred in 56 of 68 courses. Four patients (10%) had treatment-related deaths.. This regimen produced high overall response and complete response rates compared with standard regimens. However, only 15% of patients who received this therapy as first-line treatment for metastatic breast cancer remain disease-free, and median response duration was shorter than that reported using high-dose therapy with bone marrow support. Toxicity with this regimen was greater than anticipated, although myelosuppression and stomatitis would be reduced by the use of cytokines. This regimen does not improve results achieved with standard therapy sufficiently to justify its toxicity and expense.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Fluorouracil; Follow-Up Studies; Hemorrhage; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Methotrexate; Middle Aged; Neutropenia; Remission Induction; Survival Rate; Thrombocytopenia

Topics: Actuarial Analysis; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Clinical Protocols; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Follow-Up Studies; Humans; Ifosfamide; Leucovorin; Methotrexate; Middle Aged; Osteosarcoma; Pilot Projects; Remission Induction; Salvage Therapy; Treatment Outcome; Vincristine

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Humans; Leucovorin; Life Tables; Male; Methotrexate; Osteosarcoma; Survival Rate; Treatment Outcome; Victoria; Vincristine

The mechanism of the transient encephalopathy induced by high dose systemic administration of methotrexate (HDMTX) is unknown. Metabolic and vascular hypothesis have been formulated but convincing evidence is lacking. We report the first case of vascular disturbances (thinness of cortical arteries on angiography, reversible fall down of cerebral flow and increase of carotid resistance) in a young Algerian patient treated for an osteogenic osteosarcoma. This observation might lead to the exploration by non invasive and easily repeatable techniques of the cerebral vascular dynamic in patients submitted to HDMTX and thus contributed to the elucidation of the mechanism and to the prevention of these neurological side effect.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cerebral Arteries; Cerebrovascular Circulation; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Methotrexate; Osteosarcoma; Seizures; Syndrome

Ninety-three cases of primary malignant bone tumors of the limbs were treated for 651 times with preoperative and postoperative HD-MTX-CFR regimen. A number of toxic side reactions appeared, most of which were those of the digestive tract. The side reactions treated symptomatically subsided uneventfully All cases were followed up for 5-7 years, 36 patients died and 57 survived with a 5-year survival rate of 61.3%. A new method to limb salvage was used in 44 cases: the bone segment with tumor was amputated, and replanted back after inactivation with alcohol excision. The five-year survival rate was 63.6%. The excellent results of treatment gave the patients new hope dispelling the misgivings of becoming disabled.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Doxorubicin; Female; Femoral Neoplasms; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Osteosarcoma; Tibia

Studies in which high-dose methotrexate (HDMTX) is used for the treatment of osteosarcoma have utilized commercial formulations of d,l-leucovorin (leucovorin calcium) for rescue from potential methotrexate (MTX) toxicity. These formulations are racemic mixtures containing equal amounts of d and l isomers of leucovorin. All of the available data indicate that the l isomer is the pharmacologically active diastereomer. A clinical study was conducted to determine if l-leucovorin was as safe and efficacious as d,l-leucovorin in the rescue of patients with osteosarcoma who were treated with HDMTX (12.5 g/m2 over 6 h). Because d,l-leucovorin consists of equal proportions of d and l isomers, l-leucovorin was administered at half the usual dose of d,l-leucovorin. In patients with delayed methotrexate excretion, l-leucovorin doses were escalated from 7.5 to 50 mg every 3 h until the MTX level was 0.3 mumol/l or less. Due to the low incidence of osteosarcoma, a control group of patients previously treated with d,l-leucovorin was utilized for comparison. Efficacy of l-leucovorin was determined by its ability to prevent HDMTX-associated toxicity. Demographic and clinical toxicity data from three patients who received 22 courses of MTX rescued with l-leucovorin were compared with data from six patients who had received 42 MTX courses rescued with d,l-leucovorin. Some liver function abnormalities and leukocyte elevations were found in both groups and were attributed to MTX administration. No clinical toxicity attributable to l-leucovorin was observed. l-Leucovorin in half the d,l-leucovorin dose was (equally) effective as a rescue treatment.

Topics: Adolescent; Bone Neoplasms; Child; Drug Administration Schedule; Humans; Kidney Function Tests; Leucovorin; Leukocyte Count; Liver Function Tests; Methotrexate; Osteosarcoma; Retrospective Studies; Stereoisomerism

The disposition of many drugs in obesity is altered, although little is known of the effect of obesity on the pharmacokinetics of anti-cancer drugs. In this report the authors describe the pharmacokinetics of high-dose methotrexate in an obese woman (184% ideal body weight) with osteosarcoma. For this patient, both the volume of distribution at steady-state (0.398 l/kg) and systemic clearance (0.0956 l/h/kg) of methotrexate were increased compared with values observed in adult patients with osteosarcoma. The terminal elimination half-life (9.29 hours) of methotrexate was similar to other reported values in adult patients, thus indicating that increases in methotrexate volume of distribution and clearance may offset each other in obesity. Based on the experience gained from this patient, the authors suggest that renal function and methotrexate serum concentrations should be monitored in obese patients receiving high-dose methotrexate with leucovorin rescue.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Half-Life; Humans; Leucovorin; Methotrexate; Obesity; Osteosarcoma; Tibia; Vincristine

Topics: Bone Neoplasms; Drug Administration Schedule; Drug Therapy, Combination; History, 20th Century; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Osteosarcoma

Sixty times of high dose methotrexate (MTX) with citrovorum factor rescue (HDMTX-CF) therapy were applied for 15 patients with osteosarcoma. The serum level of MTX was measured at every 24 hr. by FPIA (Fluorescence Polarization Immuno Assay) method and blood analysis was performed at the same time. Fourtysix parameters were measured in each HDMTX-CF therapy and examined by multiple parameter statistical analyses by a personal computer. In the results, the number of performed chemotherapy, rescue time, serum GOT and creatinine level at 24 hr. were the most relative factors for the change of serum MTX level.

Topics: Adolescent; Adult; Aspartate Aminotransferases; Bone Neoplasms; Child; Child, Preschool; Creatinine; Female; Humans; Kidney; Leucovorin; Liver; Male; Methotrexate; Multivariate Analysis; Osteosarcoma; Regression Analysis

Topics: Bone Neoplasms; Humans; Leucovorin; Methotrexate; Soft Tissue Neoplasms

The interim results of the use of high-dose methotrexate with leucovorin rescue for the treatment of 26 patients with osteogenic sarcoma are discussed. Preoperative chemotherapy was followed by marked regression of primary tumor in one out of seven patients with localized disease. In that group, metastasis-free period lasted 2, 3, 10+, 12, 17+ and 24+ months. Response was observed in two out of 19 (10.6%) cases of metastases. Toxic side-effects were moderate and were mainly nausea (38.5% of patients), vomiting (26.9%), elevation of serum transaminase levels (38.5%) and fever (30.7% of cases).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Drug Evaluation; Female; Femoral Neoplasms; Humans; Humerus; Leucovorin; Lung Neoplasms; Male; Methotrexate; Osteosarcoma; Preoperative Care; Tibia

A report is presented on 5 cases of pneumothorax which occurred during chemotherapy in patients suffering from osteogenic sarcoma of the extremities. None of them presented radiographically detectable substitutive pulmonary lesions. It was hypothesised that the origin of pneumothorax was the necrosis produced by agents of a pulmonary micrometastasis.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Doxorubicin; Extremities; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Osteosarcoma; Pneumothorax; Time Factors; Vincristine

Three adolescents and one child with osteosarcoma were studied during multiple courses of high-dose methotrexate, citrovorum factor rescue (HDMTX-CFR), with one adolescent treated intermittently over a period of 6 years. Plasma phenylalanine (Phe) and tyrosine (Tyr) were measured immediately before the infusion of MTX and then daily until serum MTX fell below 10(-7) M. At 24 hours, all showed marked increases in Phe and in the Phe/Tyr ratio. This suggests inhibition of dihydropteridine reductase (DHPR) which, in association with hepatic Phe hydroxylase, controls plasma concentrations of Phe. Inhibition of this enzyme system is not relieved by CFR. In the adolescent patients, although MTX levels in plasma declined steadily, Phe concentrations, which fell between 24 and 48 hours, rose to a new peak at 4-7 days. Possible reasons for this secondary increase are discussed. The patient with the longest exposure to HDMTX showed an increase in pretreatment Phe/Tyr ratios with time, suggesting damage to liver parenchymal cells not indicated by standard tests of liver function. Evaluation of plasma Phe during the course of HDMTX-CFR may permit assessment of intracellular concentrations of MTX or its metabolites in the liver without interference by CFR.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Combined Modality Therapy; Female; Humans; Leg; Leucovorin; Male; Methotrexate; Osteosarcoma; Phenylalanine; Time Factors; Tyrosine

At the Orthopaedic University Hospital Vienna, neoadjuvant chemotherapy with high-dose methotrexate (MTX) has been applied since 1975 in patients with osteosarcoma. Since 1977 the hospital has been a participant in the Cooperative German-Austrian Study on Osteosarcoma (COSS, 77, 80, 82, 85, 86). Therapeutic results and incidence of side effects are reviewed at regular intervals. Over a 2-year period (1/86 to 12/87), a total of 1999 g MTX were given to 15 patients in 102 therapeutic cycles. In patients treated with MTX in our hospital, only minor intolerance phenomena occurred, owing to careful leucovorin monitoring. Intoxications of up to grade III (modified WHO-score) have been seen in only a few patients. The management of the administration of leucovorin (leucovorin calcium, calcium folinate, INN; citrovorum factor) which is directly dependent on the serum level of MTX, is exactly shown in the discussion.

Topics: Adult; Blood Cell Count; Bone Neoplasms; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Doxorubicin; Humans; Leucovorin; Methotrexate; Sarcoma

There are still some controversy on the role of adjuvant chemotherapy in the treatment of osteogenic sarcoma, and no relevant report has been published in Chinese medical literature. In this paper 15 patients with osteogenic sarcoma treated from March 1982 to March 1986 by high dose MTX with citrovorum factor rescue after surgery are reported. Another 15 patients treated by surgical amputation alone during the same period served for comparison. The sex, age and site of the tumor in the two groups were comparable. In the treated group, MTX 0.7-1.4 g/m2, averaged 0.92 g/m2 were given intravenously, followed by citrovorum factor rescue, once a month for 2-12 injections. 12 patients (80%) in this group were given more than 4 injections. All patients tolerated the treatment well and no death was ascribed to the treatment. The patients were followed for 7-48 months, in the HD-MTX treated group, 1 patient was lost in the follow up, 9 died and 5 were still alive (35.7%). In the comparison group, 2 were lost, 11 died and only 2 were still alive (15.4%). The 2 year survival rate for the treated group was 57.1% and 30.8% for the comparison group (P greater than 0.05). The authors suggest that the dose of MTX be increased and combined with other cytostatic drugs like doxorubicin and cisplatin when necessary for better results. Adjuvant chemotherapy has definite value in the treatment of osteogenic sarcoma if adequate dose and protocols are used. However, the best adjuvant chemotherapy program for Chinese patients still remains to be studied.

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Child; Combined Modality Therapy; Female; Femoral Neoplasms; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Postoperative Care; Retrospective Studies; Tibia

Twenty patients with osteosarcoma and pathologic fractures were treated with a chemotherapeutic regimen consisting of cis-diamminedichloroplatinum-II (CDP), Adriamycin (ADR) (doxorubicin) and high-dose methotrexate with citrovorum factor "rescue" (MTX-CF). Before the introduction of the regimen, the primary tumor in two patients was treated by immediate amputation and in 13 with preoperative intra-arterial CDP. Among these 13 patients, responses (healing) were observed in 11 (one required the addition of radiation therapy). In three patients, the responses were so dramatic that, at their request, surgery was deferred and treatment exclusively with chemotherapy was instituted. Based on this experience, treatment exclusively with chemotherapy was also administered to an additional five patients who were admitted without pathologic fractures. In the course of such treatment, pathologic fractures also developed; notwithstanding, chemotherapy was maintained and healing also occurred. One of the 20 patients had pulmonary metastases at diagnosis; these were resected after treatment and pathologic examination revealed no evidence of viable tumor. The remaining 19 patients were free of pulmonary metastases but these later developed in seven patients. These data were compared to a historical control series in which 16 of 21 patients with pathologic fractures developed pulmonary metastases. Three of the chemotherapy treated patients died of nonosteosarcoma related causes (leukemia, generalized varicella, and a metabolic complication). Overall, survival was improved in the chemotherapy treated patients as compared to the historical control series: 10 of 20 versus 6 of 21, respectively. Pathologic fractures in osteosarcoma may heal under treatment with chemotherapy, which also has a favorable impact on the eradication of pulmonary metastases and survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Doxorubicin; Fractures, Spontaneous; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma

During the use of a therapeutic regimen of high-dose methotrexate (HD-MTX) with leucovorin rescue in two cases of osteogenic sarcoma and malignant lymphoma without central nervous system (CNS) involvement, serial EEG monitoring before and after MTX infusion was performed with special reference to occipital basic activity. The EEGs were analyzed as to the power average spectrum using an ATAC-450 (NIHON KOHDEN). At 48 hours after the initiation of MTX, there was a transient but statistically significant slowing, such as a drop in the dominant frequency and a decrease in the alpha/theta ratio. Complete recovery of EEG changes occurred within one week. No clinical symptoms suggestive of CNS impairment were noted in either case. These data suggest that EEG alterations might be a reflection of subclinical CNS impairment. Therefore, serial EEGs might be a good early indicator for the detection of leukoencephalopathy in high-risk patients.

Topics: Bone Neoplasms; Child; Child, Preschool; Electroencephalography; Female; Humans; Infusions, Intravenous; Leucovorin; Lymphoma; Male; Methotrexate; Osteosarcoma

The primary site of the metastasis of osteosarcoma is the lung. More than 90% of patients have died of pulmonary metastasis in one to two years. Control of osteosarcoma depend upon the prevention of its pulmonary metastasis. The introduction of chemotherapy consisting mainly of Adriamycin, high-dose methotrexate with Leucovorin rescue and Cisplatinum, dramatically improved the prognosis of osteosarcoma. In the past, when systemic chemotherapy was not available, the five-year survival rate was around 19%. In patients who receive chemotherapy with the current combination of chemotherapeutic agents (ADM, HD-MTX, VCR, CPM, CDDP), the incidence of pulmonary metastasis was low, and the five-year survival rate increased to 65%. In patients who receive chemotherapy, pulmonary metastasis may be either delayed, with a single metastasis appearing after termination of treatment (late isolated type), or early and multiple, emerging in reaction to treatment (early multiple type). It is generally accepted that post-operative chemotherapy can inhibit pulmonary micro metastasis and prove to be of great significance in improving the survival rate of patients with osteosarcoma of extremities and achieve limb salvage operation. On the other hand, effective control of the side effects of drug administration such as nausea, vomiting, alopecia, cardio (ADM) and renal (CDDP) toxicity and bone marrow suppression, is a problem that must be solved as soon as possible.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Doxorubicin; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Osteosarcoma; Postoperative Care

Chemotherapeutical treatment with high dose methotrexate (HD-MTX) of osteogenic sarcoma has been performed at the Orthopaedic University Clinic of Vienna since 1975. In accordance with the cooperative study for osteosarcoma (Coss) which has been in use in Germany and Austria since 1977, HD-MTX has been used in larger quantity beside other cytostatic drugs. The total of 4259 g MTX has been applied to 36 patients who were suffering from malignant bone tumors. We report about the toxicity and compatibility of MTX. Within 231 cycles of treatment in 8 cases a high toxicity (grade IV after modified WHO-Score) was found. One patient died in consequence of the chemotherapy by fungal infection.

Topics: Bone Neoplasms; Humans; Leucovorin; Methotrexate; Osteosarcoma

Since the inception of adjuvant chemotherapy for osteogenic sarcoma (OS), 25 patients were treated for telangiectatic osteogenic sarcoma (TOS) from 1973 through 1980. This represented 12% of all patients with primary OS of an extremity seen during this time period. Tumors that demonstrated only focal areas of TOS with areas of other subtypes were designated not as TOS but as "mixed" subtypes of OS. In the 25 patients with pure TOS, surgery included 18 amputations and seven resections for the primary tumor. Ten patients were treated on the first chemotherapy protocol (T-4) including high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR), Adriamycin (ADR), and cyclophosphamide (CYC). Of those 10 patients, five have been free of disease for seven to ten years from the time of diagnosis. Nine patients were treated on the second protocol (T-7) including HDMTX with CFR, ADR, and the combination bleomycin, cyclophosphamide, and dactinomycin (BCD). Six of those nine patients are disease-free survivors 63 to 88 months (median, 63 months) from diagnosis. Six were treated on the third chemotherapy protocol (T-10) including HDMTX with CFR, ADR, BCD, and the substitution of cisplatinum for those not having a complete response to preoperative chemotherapy with HDMTX. All six of the latter are disease-free survivors 42 to 56 months (median, 49 months) from the start of treatment. Toxicity included two HDMTX-related drug deaths in patients started on treatment prior to 1977. Of the entire group, 17/25 (68%) have remained free of disease at a mean follow-up time of over five and one-half years. This study demonstrates that TOS is responsive to chemotherapy and is potentially curable. Some prior reports of the uniformly poor prognosis of this variant of OS should not discourage attempts of curative therapy by chemotherapy and surgery.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma

Ten patients with non-Hodgkin's lymphoma primarily affecting the orbital region were evaluated at Michael Reese Hospital and Medical Center, Chicago, between 1976 and 1983. Diagnoses were based on the histopathologic classification systems of the Working Formulation of the Non-Hodgkin's Lymphomas and Rappoport. Sequential staging procedures performed at the time of diagnosis included liver-spleen scans, Technecium-99 bone scans, gallium 67 scans, computerized axial tomograms of the orbit and abdomen, bone marrow examination and cerebral spinal fluid analyses. Adverse prognostic factors included the following: orbital bone erosions, Stage IV disease, and large cell or mixed cell, diffuse histologic features. The type of histopathologic findings combined with the results of sequential staging procedures is useful in identifying those patients who would benefit most from systemic chemotherapy.

Topics: Actuarial Analysis; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Neoplasms; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Humans; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Neoplasm Staging; Orbital Neoplasms; Prednisone; Prognosis; Radionuclide Imaging; Vincristine

"Neo-adjuvant therapy" with preoperative high-dose methotrexate (HD-MTX) and CF rescue therapy was investigated in four children with osteogenic sarcoma. Immediately after the diagnosis of osteogenic sarcoma from biopsy, the patients were treated with three to five courses of weekly HD-MTX (300 mg/kg) with CF rescue. Three patients had en bloc tumor resection and one patient underwent disarticulation of the hip joint after the pre-operative HD-MTX. The effect of HD-MTX was evaluated on the basis of pathological changes between the specimen of the primary tumor taken at biopsy and that during surgery. Two out of four patients showed marked tumor cell reduction (greater than 50%) of the specimen upon surgery. Two patients who responded to the preoperative HD-MTX were further treated with HD-MTX on a post-operative adjuvant therapy basis for 18 months. Both of these patients survived with no evidence of disease for 35.6+ and 20.9+ months. Two patients who responded poorly to HD-MTX were treated with a multi-drug postoperative adjuvant therapy including cis-platinum, adriamycin, cyclophosphamide, actinomycin D, and bleomycin. One patient had a solitary lung metastasis at 12.2 months after amputation. Wedge resection of the metastatic tumor was performed and adjuvant therapy with cis-platimum has been given for 20 months. He has remained with no evidence of disease for more than 30 months. Another patient has been receiving multi-drug neo-adjuvant therapy without any evidence of disease for 11.9 months after surgery. These data suggest that neo-adjuvant chemotherapy based on the response to preoperative HD-MTX is more useful for increasing the cure rate of childhood osteogenic sarcoma.

Topics: Adjuvants, Immunologic; Adolescent; Bone Neoplasms; Child; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Pilot Projects; Preoperative Care

Experimental chemotherapy using high-dose methotrexate (MTX) with citrovorum factor (CF) was performed on ddN strain mice bearing 89Sr-induced osteosarcoma and the antitumor efficacy was analyzed through autoradiography ([3H]thymidine). The administration was done using sustained infusion via the tail vein using our own device to maintain certain elevated blood levels of the drugs. As the first experiment, MTX was administered to 4 different groups of mice with dose levels of 250, 500, 1,000, 2,000 mg/kg for 6 hours followed by CF 200 mg/kg for 24 hours. It was found that the blood levels of MTX were maintained at 10(-4) M by the dosage of 500 mg/kg, but no higher levels were achieved by increasing dosage. Tissue such as the small intestine and the bone marrow recovered from the toxicity of MTX in about 1 week after the dosage of 500 mg/kg. In tumors, on the other hand, the tissue showed a gradual recovery with time, but the uptake of [3H]thymidine by the tissue was not restored to the pretreatment level. When the antitumor efficacy of a single dosage of 1,000 mg/kg and 2 dosages of 500 mg/kg each with 1 week interval were compared, the latter was definitely more effective. It was, therefore, concluded that the administration of the drugs should be done repeatedly with optimum doses of MTX and CF rather than with ultrahigh doses of MTX and CF all at once.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Injections, Intraperitoneal; Injections, Intravenous; Leucovorin; Male; Methotrexate; Mice; Mice, Inbred Strains; Neoplasms, Radiation-Induced; Osteosarcoma; Strontium Radioisotopes

Seven patients have been treated for malignant fibrous histiocytoma (MFH) of bone since the end of 1977. One patient received no chemotherapy, and one did not complete attempted chemotherapy. Both died, 7 and 51 months after diagnosis, respectively. The remaining five patients completed chemotherapy. Two first underwent a primary amputation, whereas the other three received primary chemotherapy with histologic evaluation of the effect. These patients showed a complete remission. The five patients who completed chemotherapy are all still alive, without indications of metastases or local recurrence. Although the number of cases is small, a 25- to 58-months (mean, 45) survival, in five patients treated either with chemotherapy alone or chemotherapy and surgery, is surprisingly good in view of previous experience with this tumor. In some of these patients, the authors were able to document an absence of any viable tumor following chemotherapy.

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Doxorubicin; Female; Femoral Neoplasms; Follow-Up Studies; Histiocytoma, Benign Fibrous; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Tibia; Vincristine

High-dose methotrexate with citrovorum factor "rescue" (MTX-CF) produced an apparent complete response of the primary tumor in three patients with osteosarcoma. The response was sustained with MTX-CF, intra-arterial cis-diamminedichloroplatinum II (CDP) and Adriamycin (doxorubicin) for 18 months. Treatment was then electively discontinued. Local recurrence occurred in two patients, 6 and 4 months later, respectively. MTX-CF was reinstated and a complete response was again achieved in one patient. This has been maintained for 15+ months with MTX-CF and intra-arterial CDP administered for 13 of the 15+ months. Reinduction with MTX-CF failed in the second relapsed patient but an apparent remission was again achieved with radiation and intra-arterial CDP. This has been maintained with intravenous CDP, cyclophosphamide and phenylalanine mustard for 14+ months. A complete response in the primary tumor was still present in the nonrelapsed patient, 42 months from diagnosis. All patients have remained free of pulmonary metastases, 40+ to 42+ months from diagnosis.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Femoral Neoplasms; Follow-Up Studies; Humans; Ilium; Infusions, Intra-Arterial; Leucovorin; Male; Methotrexate; Neoplasm Recurrence, Local; Osteosarcoma; Tibia

Temporary neurologic abnormalities were detected in 9 of 60 patients undergoing treatment with high-dose methotrexate and citrovorum factor rescue (MTX-CF) for osteosarcoma. The incidence of abnormalities and abnormalities themselves were more severe than previously reported. This was attributed to an increased dose and more frequent administration of MTX-CF. In view of the transient nature of the abnormalities, a biochemical cause is implicated, and the mechanisms by which it may occur are discussed.

Topics: Bone Neoplasms; Child; Female; Humans; Leucovorin; Male; Methotrexate; Nervous System Diseases; Osteosarcoma

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Follow-Up Studies; Humans; Leucovorin; Male; Methods; Methotrexate; Osteosarcoma; Vincristine

Twenty-six evaluable patients with advanced soft tissue and bony sarcomas refractory to chemotherapy were treated with vincristine plus high-dose methotrexate and leucovorin rescue. A 14% response rate was observed among 14 patients presenting with refractory soft tissue sarcomas. No responses were observed among 12 patients with bony sarcoma. Toxic reaction with nausea, vomiting, nephrotoxicity, and myelosuppression was manageable. While this study did demonstrate activity of this regimen in doxorubicin-refractory patients, the duration of the responses was relatively brief. Thus, the clinical utility of such a regimen is questionable.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Sarcoma; Vincristine

Malignant fibrous histiocytoma (MFH) is a pleomorphic sarcoma that is uncommon in children. It most frequently arises from the soft tissues; however, it has been recently established that primary bone MFH also exists. Surgical resection or amputation is the cornerstone of treatment for MFH of bone. But, with this modality of therapy alone the majority of patients develop either distant metastases or local recurrence. This study reports on three adolescent girls with MFH of bone who were successfully treated with radical resection and 18 months of adjuvant chemotherapy with vincristine, high dose methotrexate, Citrovorum Factor rescue, and Adriamycin. All three patients remain disease-free for a follow-up period of 42-48 months. The current regimen was well tolerated. Morbidity was minimal, with no patient developing any significant drug-related complications. The adjuvant chemotherapy regimen described appears to be effective in prolonging survival in patients with MFH of bone and appears to warrant further study in additional patients.

Topics: Adolescent; Antineoplastic Agents; Bone Neoplasms; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Histiocytoma, Benign Fibrous; Humans; Infant; Leucovorin; Methotrexate; Prognosis; Vincristine

Five patients with evaluable malignant fibrous histiocytoma (MFH) of bone (three with primary tumor and two with primary tumor and metastatic disease) were treated with preoperative chemotherapy including high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) as is used for patients with osteogenic sarcoma. All five patients demonstrated a clinical response to chemotherapy. Three of four patients who underwent surgery had complete responses and one patient had greater than 90% tumor necrosis as documented by histologic examination of the resected primary tumor. All four patients who underwent surgery following preoperative chemotherapy are surviving free of disease from one to six years from the start of treatment; chemotherapy was discontinued after six to 11 months in these patients. The median disease-free survival time is 31.5 months. This study demonstrates the effectiveness of chemotherapy in MFH of bone, and in particular the effectiveness of HDMTX with CFR which caused measurable responses in all patients while receiving this therapy as a single agent.

Topics: Adolescent; Adult; Bone Neoplasms; Drug Therapy, Combination; Female; Follow-Up Studies; Histiocytoma, Benign Fibrous; Humans; Leucovorin; Male; Methotrexate; Neoplasm Metastasis

9 patients with osteosarcoma were treated with a total of 122 infusions of high-dose methotrexate (MTX; 140-350 mg/kg) followed by leucovorin rescue. Plasma kinetics of MTX and 7-hydroxymethotrexate (7-OH-MTX) has been routinely monitored. Due to inadequate hydration and alkalinization, 1 of the 122 high-dose MTX infusions was followed by delayed disappearance of MTX and 7-OH-MTX from plasma with subsequent development of severe mucositis. Serious hepatotoxicity repeatedly developed in another patient with inconspicuous MTX kinetics. The benefit of monotherapy with high-dose MTX for adjuvant treatment of osteosarcoma remains questionable, since 6 of 8 patients with primary osteosarcoma developed pulmonary metastases within 4-12 months (median 5 months), 2 have been disease-free and alive for 25 and 53 months.

Topics: Adolescent; Adult; Bone Neoplasms; Chemical and Drug Induced Liver Injury; Female; Humans; Kinetics; Leucovorin; Male; Methotrexate; Middle Aged; Mucous Membrane; Osteosarcoma

Since October 1973, 185 patients 21 years of age or younger with primary osteogenic sarcoma of an extremity were treated with adjuvant chemotherapy. Twenty-five of the first fifty-two patients (48%) have remained free of disease for a median of 7 years. In the next chemotherapy protocol most patients had chemotherapy prior to amputation or resection, during which time the dose of high-dose methotrexate was escalated in many patients to that needed to shrink the primary tumor. For a median of 4 years 43 of 54 patients (80%) have remained free of disease. In the current protocol, the response of the primary tumor to chemotherapy with high-dose methotrexate was used to select postoperative adjuvant chemotherapy for the patient. With the latter approach 73 of 79 patients (92%) have remained continuously free of disease for a median of 2 years. This experience demonstrates the value of chemotherapy in increasing the cure rate in osteogenic sarcoma and that the response to preoperative chemotherapy can help select postoperative chemotherapy to produce an even higher potential cure rate for osteogenic sarcoma.

Topics: Adolescent; Adult; Antineoplastic Agents; Bone Neoplasms; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Osteosarcoma; Preoperative Care; Radiography; Time Factors

Since June 1978, 57 patients with primary osteogenic sarcoma of an extremity were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR), Adriamycin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) given for 4-16 weeks prior to definitive surgery. Histologic examination of the resected primary tumor determined the effect of preoperative chemotherapy with many primary tumors showing greater than 90% tumor necrosis attributable to preoperative chemotherapy. All patients having this favorable effect of chemotherapy on the primary tumor were continued on the same chemotherapy regimen postoperatively (regimen B). However, in those patients not having a good effect of preoperative chemotherapy on the primary tumor, HDMTX with CFR was subsequently deleted from their postoperative chemotherapy and they were placed on a regimen containing cisplatinum at the dose of 120mg/M2 with mannitol diuresis combined with Adriamycin in addition to BCD (regimen A). In the current study, 35 of the 57 patients did not demonstrate a good effect of chemotherapy on the primary tumor and were assigned to regimen A postoperatively. Of these 35 patients, 32 (91%) have remained continuously free of recurrent or metastatic disease from 6-34 months following the start of therapy. Among the 22 remaining patients having a good histologic response and treated with regimen B postoperatively, there has been only one relapse in a patient who had a local recurrence in the area of an inadequately resected primary tumor three months after the cessation of chemotherapy. Thus, 53 of 57 patients (93%) are continuously with no evidence of recurrent or metastatic disease from 6-35 months (median, 20 months) from the start of treatment. This study demonstrates the value of thorough histologic examination in predicting survival in responding patients and in helping identify patients whose disease-free survival rate can be substantially increased if they are given alternative postoperative adjuvant chemotherapy after failing to have a good response to preoperative chemotherapy. This individualized chemotherapeutic strategy has yielded the highest disease-free survival rate reported to date for osteogenic sarcoma.

Topics: Antineoplastic Agents; Bleomycin; Bone Neoplasms; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Osteosarcoma; Prognosis; Time Factors

Of 41 consecutive patients with newly diagnosed osteogenic sarcoma admitted to the Children's Orthopedic Hospital and Medical Center in Seattle, Washington, between 1952 and 1977, 19 treated before 1973 did not receive adjunctive chemotherapy (histological group) whereas after 1972 22 have been so treated (chemotherapy group). Chemotherapy consisted primarily of high doses of methotrexate and adriamycin for 16 months after surgical treatment. Patients in the historical group have been observed for a minimum of nine years (six patients) or until death (13 patients). The 13 surviving patients in the chemotherapy group have been followed for a minimum of three years (median five years) and all 12 disease-free patients have been off therapy for between one and a half and five and a half years (median three years). Overall, the chemotherapy group has had a significant increase in both survival (p = 0.03) and disease-free survival (P = 0.02) compared to the historical group. In 35 patients with localised disease at diagnosis, the three-year disease-free survival and the three-year survival rates were 18 per cent and 41 per cent respectively in the historical group, and 67 per cent and 78 per cent (life table estimates) respectively in the chemotherapy group. With adjunctive chemotherapy only one of the seven patients developing pulmonary metastases did so later than nine months after diagnosis. The superior results in the chemotherapy group could not be accounted for by differences in age, sex, presence of metastases at diagnosis, histopathology, location of primary tumour, type of initial or subsequent surgical treatment, or the use of standard or computerised lung tomography. Although the use of historical controls in this study does not exclude other changes as contributing to the observed improvement in outcome, our data support the contention that adjunctive chemotherapy improves both the disease-free survival and the overall survival of patients with osteosarcoma and rarely delays the onset of recurrent or metastatic disease.

Topics: Adolescent; Adult; Age Factors; Bone Neoplasms; Child; Child, Preschool; Doxorubicin; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Sex Factors; Vincristine

Sixty-three patients with osteogenic sarcoma of the long bones, all of whom were treated with chemotherapy, demonstrated striking and unusual radiographic changes. Patients with a "good" radiographic response (48%) showed the most dramatic changes, including medullary sclerosis, prominent periosteal new bone formation, and disappearance of the soft-tissue mass; and these findings correlated well with the histological grading of the surgical specimens. Radiographic evaluation of patients receiving chemotherapy for osteogenic sarcoma is a valuable method of assessing response.

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Leg; Leucovorin; Male; Methotrexate; Osteosarcoma; Radiography

From 1975 through 1979, 25 patients with osteosarcoma received therapy with vincristine, high-dose methotrexate, citrovorum factor, and Adriamycin. Five patients had metastases prior to receiving chemotherapy, and 11 of the remaining 20 nonmetastatic patients received preoperative or preirradiation chemotherapy. Chemotherapy caused objective tumor regression in 1 of 5 patients with metastases and 1 of 11 with measurable primaries. All five patients with metastatic disease died 7-16 months from diagnosis. Of the 20 nonmetastatic patients, 4 did not have primary amputations: all died. Of 16 patients with primary amputations, 6 are alive relapse-free 24-86 months from diagnosis, and 10 are dead. The actuarial survival of 36% is not statistically different from that of historical control groups or from that of concurrent control groups treated with surgery alone. However, because most adjuvant chemotherapy studies have involved few patients, 36% survival is not statistically different from the 50-70+% survival reported in previous studies. Our data fail to demonstrate that the adjuvant chemotherapy has improved the survival rate of children with osteosarcoma. We support a randomized, controlled comparison of adjuvant chemotherapy and aggressive surgical resection.

Topics: Actuarial Analysis; Adolescent; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Child; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma

A 13-year-old girl was treated surgically for a giant-cell tumor of bone originating in the talus and for a recurrence in the distal tibia. She later developed liver and lung metastases and was treated for two years, five months with a combination of vincristine, doxorubicin, cyclophosphamide and actinomycin-D, and thereafter with high-dose methotrexate/vincristine with citrovorum factor rescue. A good response was obtained and the patient is without evidence of disease 12 months after a salvage thoracotomy for residual disease in the left lung. Aspects of this singular case are discussed.

Topics: Adolescent; Antineoplastic Agents; Bone Neoplasms; Drug Therapy, Combination; Female; Giant Cell Tumors; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Methotrexate; Talus; Tibia; Vincristine

We have measured phenylalanine and tyrosine in the plasma of patients with osteogenic sarcoma undergoing chemotherapy with high-dose methotrexate (HDMTX) citrovorum factor rescue (CFR). During 14 treatments in six different patients, the phenylalanine to tyrosine ratio (PHE/TYR) at 21 to 38 hours was elevated over pretreatment levels. The observed increase in plasma phenylalanine is attributed to inhibition by MTX of the phenylalanine hydroxylase system of the liver, which is not folate-dependent and thus is not corrected by administration of CV. A post-infusion increase in PHE/TYR of 571% after 22 hours in one patient and of 410% after 30 hours in another were associated with marked MTX toxicity. The greatest increase in PHE/TYR seen in a patient who did not experience toxicity was was 249% in 21 hours. Thus, in this group of patients, there appears to be a correlation between evidence of clinical MTX toxicity and the magnitude of the percentage increase in PHE/TYR in the plasma, which indicates inhibition of a liver enzyme and thus reflects the intracellular concentration of MTX.

Topics: Adolescent; Bone Neoplasms; Child; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Phenylalanine; Time Factors; Tyrosine

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Economics; Femoral Neoplasms; Humans; Humerus; Leucovorin; Methotrexate; Osteosarcoma; Prognosis; Tibia

Primary systemic chemotherapy and delayed surgery, if it is surgically feasible with preservation of the limb, has produced better results in osteogenic sarcomas than primary surgery with loss of time due to the postoperative therapy free interval. Histologic examination of the resected tumor determines the effect of preoperative chemotherapy and identifies patients at high risk. These patients not having a favorable effect on preoperative chemotherapy can be placed on an alternative postoperative regimen before relapsing clinically. These earlier changes of chemotherapeutic strategy in patients with histologically proven ineffective chemotherapy has yielded further improvement in treatment results in patients with osteogenic sarcomas with a 93% disease free survival (median 20 months) to date using an individualized taylored treatment approach at the Memorial Sloan Kettering Cancer Center/New York. Now that effective chemotherapy is available for many other malignant tumors this model of "neo-adjuvant" chemotherapy could also serve as a model for the treatment of other highly malignant tumours.

Topics: Amputation, Surgical; Bone Neoplasms; Female; Humans; Humerus; Leucovorin; Methotrexate; Osteosarcoma; Preoperative Care; Prognosis

Topics: Amputation, Surgical; BCG Vaccine; Bone Neoplasms; Doxorubicin; Follow-Up Studies; Humans; Leucovorin; Methotrexate; Osteosarcoma

Topics: Bone Neoplasms; Cyclophosphamide; Doxorubicin; Humans; Leucovorin; Melphalan; Methotrexate; Osteosarcoma; Vincristine

Tissue concentrations of methotrexate (MTX) in osteosarcomas were examined with special reference to their histologic findings. Primary tumors in five cases and metastatic tumors in two cases were removed at 6-18 days after MTX administration. The concentrations of MTX in osteosarcoma tissues were higher than those in normal tissues and serum, ranging from 15.0 to 168 ng/g. Necrotic portions of the tumor lesion were less in MTX concentration than cellular portions. As the cellularity increased, the tumor tissue showed higher MTX concentration. Tissue concentrations of MTX in nude mice with transplanted osteosarcoma from human were also studied after the high-dose 3H-MTX infusion. MTX total, which contains dihydrofolate reductase-bound MTX, free MTX and its metabolites, decreased gradually with time in the tumor tissues. The concentrations of MTX total in tumor were proportional to the administrated dose and the clearances of MTX were prolonged according to the dose-increase of MTX. Tissue concentrations of MTX total in the lung, kidney and liver were higher than that in tumor itself at 192 hours after the injection. The value for MTX total includes some MTX active fraction which can inhibit the activity of dihydrofolate reductase. Tissue concentrations of MTX active also increased dose-dependently. The proportions of MTX active to MTX total in tumors decreased with the increment of the MTX dose, and the same findings were observed in the kidney and liver.

Topics: Adolescent; Adult; Animals; Bone Neoplasms; Child; Female; Humans; Leucovorin; Male; Methotrexate; Mice; Mice, Nude; Osteosarcoma; Tissue Distribution

Topics: Adolescent; Adult; Bone Neoplasms; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Postoperative Care

23 patients with osteogenic sarcoma were observed during 142 6-hour high-dose infusions of methotrexate (MTX, 3,000--8,200 mg/m2). Calcium leukovorin was given by intravenous injection at 3-hour intervals beginning 2 h after the completion of each MTX infusion with extension of the intervals to 6 h following the first day of rescue. All patients also received continuous intravenous infusions of alkalinized fluids for the entire duration of leukovorin rescue. No larger doses of leukovorin were given to any patient. Three of the 142 MTX infusions resulted in mild cytotoxic side effects. Plasma MTX clearance ranged from 90 to 600 ml/min among the 62 infusions where plasma clearance could be accurately calculated. The 3 patients with mild toxicity had low drug clearance, but others with similar low MTX clearance experienced no apparent toxic effects beyond the expected transient nausea.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Female; Humans; Leucovorin; Leukocyte Count; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Osteosarcoma

From 1972 to 1979, high-dose methotrexate (HDMTX) and 3 adjuvant regimens were used at the Sidney Farber Cancer Institute and Children's Hospital Medical Center. In the first regiment, HDMTX was used alone; the second, HDMTX and adriamycin, and the third, weekly courses of HDMTX and combination. Actuarial disease-free survival achieved with these regimens in patient with local control of the primary lesion varied from 42 to 75% at 3 years. This compared favorably with historical control patients, of whom 50% were free of disease at 6 months and only 20% at 12 months. Among 41 patients with established pulmonary metastases, 14 were alive and free of disease from more than 4 to over 60 months. The most efficacious method of administering HDMTX was a weekly schedule which produced an overall response rate of 48% in the treatment of pulmonary metastases and primary tumor in patients previously not exposed to HDMTX. Urinary alkalinization was not a standard procedure, and investigations failed to demonstrate any significant effect of alkalinization on HDMTX pharmacokinetics.

Topics: Antineoplastic Agents; Bone Neoplasms; Child; Doxorubicin; Humans; Kinetics; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma; Vincristine

Forty-three patients, ranging in age from 7 to 30 years (median age, 17 yr), with primary osteogenic sarcoma (OS), confirmed by biopsies and with no evidence of metastatic disease at the time of diagnosis, received T-7 chemotherapy for an average of 4 months before surgery, including high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR) (median, 7 courses), and 1 course each of bleomycin, cyclophosphamide, and dactinomycin, and adriamycin. At the time of definitive surgery, the surgical specimen showed a good histologic response to chemotherapy (grade III or IV response) in 29 (67%) of 43 patients and a poor histologic response (grade I or II response) in 14 (33%) of 43 patients. Among those who responded well, no patient relapsed, as all received a complete course of preoperative and postoperative chemotherapy for more than 5 to over 28 months after the initiation of treatment (medium, 13 mo). Among those who responded poorly, 6 of 14 patients relapsed with pulmonary metastases (a thoracotomy was beneficial to 1), 4 of 6 patients are alive with disease, and 1 patient died of progressive disease. On retrospective analysis, we observed that good and poor responders did not differ in the distribution of sex, age, race, primary site of disease, or histologic subtype of OS. An elevated alkaline phosphatase level that returned to normal under preoperative chemotherapy indicated a good response. Neither the 24-, 48-, and 72-hour serum MTX levels nor the fluid intake and urinary output during 3 days that followed HDMTX with CFR correlated significantly with tumor response. Based on our studies with this form of therapy, we concluded that the response of OS to preoperative chemotherapy is of prognostic value.

Topics: Adolescent; Adult; Antineoplastic Agents; Bone Neoplasms; Child; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Preoperative Care; Prognosis; Retrospective Studies

Topics: Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Doxorubicin; Drug Therapy, Combination; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma; Probability; Time Factors; Vincristine

Topics: Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Humans; Immunization; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma

Review of the reported use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CF) for treatment of primary and metastatic osteosarcoma indicates the rarity of responses in clinical situations other than treatment of the primary tumor or isolated pulmonary metastases with doses of 7.5 g/m2 or greater delivered on a weekly basis for 4 to 6 weeks. Adjuvant chemotherapy using HDMTX-CF at triweekly intervals has led to 2-year disease-free survival rates that are inferior to those obtained with combinations of agents including HDMTX-CF Adriamycin (Adria), with or without vincristine, cyclophosphamide, phenylalanine mustard, bleomycin, and dactinomycin. We concluded that although HDMTX-CF has a role in the treatment of primary and metastatic osteosarcoma, its use in combination with other active agents offers greater potential advantage to affected patients.

Topics: Antineoplastic Agents; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Osteosarcoma; Prognosis; Vincristine

Topics: Adolescent; Adult; Bone Neoplasms; Child; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Osteosarcoma

9 HDMTX infusions with 30 to 55 g MTX and leucovorin rescue were given to 3 patients with multifocal osteosarcoma. Resistance to standard MTX infusions with up to 12 g/m2 body surface in 4 hours indicated the administration of these higher doses (27 g/m2 body surface on average) over a shorter period of time (160 min on average). MTX input was controlled by the increase in plasma MTX levels which were determined by EMIT enzyme assay within a few minutes of sampling. The plasma MTX levels were found to be up to 10 times (average 4 times) higher than those achieved by the standard infusion. All infusions proved to be relatively well tolerated in all 3 cases, although, thrice after 36 hours an increased leucovorin rescue had to be made for 12 hours, because of delayed renal methotrexate excretion; the usual leucovorin rescue (15 mg every 6 hours) was given for an average of five days. No therapeutic effects were seen either clinically, radiologically, or histologically. The resistance to HDMTX in these three patients could not be broken by HDMTX PLRD infusions.

Topics: Adolescent; Bone Neoplasms; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunoenzyme Techniques; Leucovorin; Male; Methotrexate; Osteosarcoma; Prognosis

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

Seven patients with bone or soft tissue sarcomas but without metastatic CNS disease developed a chronic leukoencephalopathy after high-dose (8000-15,000 mg/m2) iv methotrexate (MTX) chemotherapy with leucovorin (LV) rescue. Approximately 12 MTX-LV treatments were administered over a 3-7 month period. None of the patients had cranial irradiation. The syndrome usually began several months after the initiation of chemotherapy with subtle personality changes followed by a progressive dementia, focal seizures, pseudobulbar palsy, spastic quadriparesis, and stupor. Computerized tomographic scans revealed diffuse white matter hypodensity in five patients and atropic changes in five patients. Serum MTX concentrations were elevated in four of six patients prior to several MTX-LV treatments, suggesting that MTX persisted in tissues for a long time. Abnormally high levels of MTX were detected in the cerebrospinal fluid of all four patients several days after an MTX-LV treatment, at a time when their encephalopathy was most severe. Pathologic brain material was obtained from three patients and revealed a spectrum of abnormalities. The syndrome observed in our patients clinically resembles the one described in children with acute lymphatic leukemia who received cranial irradiation and large cumulative amounts of low-dose (12-20 mg/m2) systemic MTX without LV.

Topics: Adolescent; Adult; Bone Neoplasms; Brain; Child; Female; Humans; Leucovorin; Leukoencephalopathy, Progressive Multifocal; Male; Methotrexate; Soft Tissue Neoplasms; Tomography, X-Ray Computed

Topics: Adolescent; Adult; Bone Neoplasms; Doxorubicin; Humans; Leucovorin; Methotrexate; Osteosarcoma; Prognosis

From 1973--1975, 31 patients with biopsied primary osteogenic sarcoma were treated with preoperative chemotherapy followed by surgical ablation of the primary tumor. Surgery was delayed in order to obtain a custom-fitted prosthetic bone implant in an attempt to avoid amputation. Preoperative chemotherapy included high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (T-5 protocol) and was administered for 3 months preoperatively and continued with the inclusion of cyclophosphamide for approximately 5 months postoperatively. At a follow-up period of 30--52 months, 23 of 31 patients (75%) are surviving (21 of 23 with no evidence of disease). Histologic examination of primary tumor removed at surgery revealed varying degrees of tumor destruction (from very little effect to no evidence of viable tumor) attributable to the effect of chemotherapy. The 21 patients that are disease-free survivors had a more complete effect of preoperative chemotherapy on the primary tumor. Some patients achieving favorable effects upon the primary tumor did so only after the dose of HDMTX was escalated to greater than the starting dose of 8 g/m2. Preoperative chemotherapy for all patients with osteogenic sarcoma would seem to offer the following advantages: 1) Evaluation of the effect of HDMTX with CFR on the primary tumor with escalation of the dose of HDMTX until a clinical response is observed, thus defining the dose of HDMTX effective in that patient, to be continued postoperatively as adjuvant therapy; 2) The early use of systemic therapy to eradicate distant microfoci of disease that will eventually kill the patient if not adequately treated by effective chemotherapy; 3) Allow more time for postoperative healing without the need to start adjuvant chemotherapy immediately; and 4) Provide the surgeon time to plan resection surgery. To date, 20 additional patients with biopsy proven osteogenic sarcoma have been treated with more aggressive preoperative chemotherapy (T-7) for approximately 2 1/2 months prior to definitive surgery (resection or amputation). Doses of HDMTX were escalated where necessary and good clinical responses were obtained in 19 of 20 patients. In the majority of patients, no evidence of viable tumor was found on histologic examination of the surgically removed primary tumor. All 20 patients are surviving free of active disease at this brief follow-up period of 4--20 months.

Topics: Adolescent; Adult; Antineoplastic Agents; Bleomycin; Bone Neoplasms; Brain; Child; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methotrexate; Osteosarcoma; Time Factors; Vincristine

In 22 patients with osteogenic sarcoma, treated with 103 high-dose methotrexate infusions (6-8.5 g/m2 in 4-6 h) plasma methotrexate levels were measured with a specific and rapid radioimmunoassay. Nontoxic infusions were associated with methotrexate concentrations below 8.0 X 10(-6) mol/l at 24 h, 8.0 X 10(-7) mol/l at 48 h and 4.25 X 10(-7)/mol/1 at 72 h. All patients with 48 h methotrexate levels above 1 X 10-6 mol/l manifested severe toxicity with myelosuppression and stomatitis due to delayed methotrexate excretion. Rise of serum creatinine was not reliable to predict oxicity. Determination of 48- and 72-h methotrexate concentrations proved to be a valuable method for identifying patients at high risk for toxic side effects. Additional citrovorum factor may thus be given in time.

Topics: Adolescent; Adult; Bone Marrow; Bone Neoplasms; Child; Creatinine; Humans; Leucovorin; Methotrexate; Osteosarcoma; Radioimmunoassay; Stomatitis

The occurrence of overall toxicity was analyzed for 43 patients with osteosarcoma who received 349 high-dosage courses of methotrexate (HD-MTX) with citrovorum factor (Leukovorin) "rescue" (CF). The dosages of HD-MTX ranged from 50 to 350 mg/kg. Overall toxicity was assessed on the basis of five manifestations of toxicity: stomatitis, dermatitis, myelosuppression, liver dysfunction, and kidney function abnormalities. The great majority (91.4%) of the infusions were well tolerated, but 8.6% were associated with moderate or severe toxicity. Stomatitis and serum glutamic-oxaloacetic transaminase (SGOT) changes were the most frequent postinfusion findings. Three patients died from causes related to MTX toxicity. Dose, age, sex, and number of prior infusions were investigated by logistic regression analysis for prognostic effect on frequency of moderate to severe overall toxicity. Age and number of prior infusions had significant (P less than 0.06) effects on overall toxicity. Patients older than 15 years with greater than 10 prior infusions constituted the "high risk" group with a risk of moderate to severe toxicity 6.3 times that of the younger patients with fewer than 10 infusions.

Topics: Adolescent; Age Factors; Bone Marrow; Bone Neoplasms; Child; Dermatitis; Drug Administration Schedule; Female; Humans; Kidney; Leucovorin; Leukopenia; Liver; Male; Methotrexate; Osteosarcoma; Sex Factors; Stomatitis; Thrombocytopenia; Vincristine

Topics: Bone Neoplasms; Drug Therapy, Combination; Half-Life; Humans; Kinetics; Leucovorin; Methotrexate; Osteosarcoma; Risk; Time Factors

Topics: Adolescent; Amputation, Surgical; Bleomycin; Bone Neoplasms; Child; Cyclophosphamide; Dactinomycin; Dose-Response Relationship, Drug; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Preoperative Care; Prostheses and Implants; Radiography; Vincristine

Topics: Bone Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasms; Osteosarcoma; Vincristine

DNA metabolism in bone marrow cells was measured under high-dose Methotrexate/Leucovorin adjuvant chemotherapy of a patient with primary amputation of his right leg because of osteogenic sarcoma. The biochemical data showed that there was no rescue effect of Leucovorin after 200 mg/kg Methotrexate. Corresponding to this "biochemical failure" of the rescue effect the patient died from the complications of a long and very severe bone marrow suppression. To improve the safety of this therapeutic regimen the intravenous injection and in some cases a higher dose of Leucovorin is recommended.

Topics: Bone Marrow; Bone Neoplasms; DNA; Humans; Leucovorin; Methotrexate; Osteosarcoma

Topics: Amputation, Surgical; Bone Neoplasms; Doxorubicin; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Vincristine

The occurrence of pulmonary metastases in patients suffering from primary classic osteogenic sarcoma is compared among two groups of patients treated according to different protocols at Groote Schuur Hospital. A group of 28 patients treated by radiation and delayed amputation (before the end of 1974) is compared with 12 patients managed by immediate ablation and adjuvant chemotherapy with vincristine, high-dose methotrexate and leucovorin rescue, and adriamycin (after 1974). The incidence of pulmonary metastases at 12 months was significantly lower in the latter group.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Doxorubicin; Extremities; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

An unusual neurological syndrome occurred in 4 of 158 patients treated for osteogenic sarcoma with combination chemotherapy. There was an abrupt onset of focal cerebral deficits approximately ten days after chemotherapy with vincristine and high-dose methotrexate plus citrovorum factor rescue. The syndrome was short lived and always occurred early in the course of treatment. Prolonged neurological deficits remained in 2 patients. When similar chemotherapy was reinstituted in the 4 patients, no further neurological complications ensued. Possible causes include a leukoencephalopathy related to methotrexate or an embolic cerebral vasculopathy related to necrotic tumor microemboli emanating from the lungs.

Topics: Adolescent; Adult; Bone Neoplasms; Brain Diseases; Drug Therapy, Combination; Female; Femoral Neoplasms; Humans; Humerus; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Pelvic Bones; Syndrome; Vincristine

Five dogs with ostoegenic sarcoma were treated by surgical removal of the primary tumor and by adjuvant chemotherapy. Methotrexate at dosages of 3 to 6 g/m2 was used with leucovorin rescue. All dogs tolerated E g of methotrexate/m2 of body surface, but granulocytopenia precluded escalation beyond this dosage in 4 dogs. The rate and time of appearance of pulmonary metastases were not altered by treatment, with all dogs developing metastases at a median time of 4 months after amputation.

Topics: Animals; Bone Neoplasms; Dog Diseases; Dogs; Female; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma

Twenty patients with osteogenic sarcoma of the distal portion of the femur and the proximal portion of the tibia received chemotherapy (vincristine sulfate, methotrexate with leucovorin calcium rescue, [citrovorum factor; folinade calcium], and doxorubicin hydrochloride [Adriamycin]), followed by radical en bloc resection and prosthetic bone replacement. Histologic examination of surgical specimens obtained after chemotherapy showed variable degrees of tumor destruction and, in some cases, massive tumor necrosis, attesting to the profound effects of vigorous chemotherapy. This new therapeutic regimen, when feasible, may prove to be the treatment of choice in osteogenic sarcoma.

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Child; Drug Therapy, Combination; Female; Femoral Neoplasms; Humans; Leucovorin; Male; Methotrexate; Necrosis; Osteocytes; Osteosarcoma; Tibia; Vincristine

Vincristine-high-dose methotrexate-citrovorum factor (VCR-MTX-CF) was administered preoperatively at weekly intervals to eight patients, four with primary tumors and four with pulmonary metastases. These patients had not received prior VCR-MTX-CF treatment. A similar treatment program was administered to five patients with pulmonary metastases who had received prior VCR-MTX-CF. Among the eight patients who had not received prior VCR-MTX-CF, complete responses were obtained in three with primary tumors (this was followed by surgical excision) and two with pulmonary metastases. Partial responses occurred in two additional patients. Partial responses were also obtained in two patients who had received VCR-MTX-CF. Chemotherapy and surgery in one patient with an extremity lesion resulted in preservation of the limb and useful function. The major toxicity was anorexia and weight loss. Other side effects included stomatitis, myelosuppression, hepatitis and transient renal impairment. The weekly program was highly effective when compared to responses obtained with the tri-weekly schedule utilized in previous studies.

Topics: Bone Neoplasms; Drug Administration Schedule; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Remission, Spontaneous; Vincristine

Results of treatment for osteosarcoma of the extremity have been poor with metastases usually causing death within 2 years following diagnosis. Because of the great risk of development of metastases, 20 patients have received adjuvant chemotherapy with Adriamycin, cyclophosphamide and high-dose methotrexate-leucovorin rescue for up to 12 months following amputation for osteosarcoma. Sixteen of these patients are surviving; 11 are free of evident tumor from 6 to 34 months following amputation. Five patients were found to have pulmonary metastases while receiving chemotherapy and three patients developed metastases following completion of chemotherapy. One patient died following her third treatment with high-dose methotrexate-leucorovin rescue. Other toxicity included nausea, vomiting, mucosal ulcerations, infections, hematologic abnormalities, changes in kidney and liver functions tests, and minor coagulation abnormalities. The natural history of osteosarcoma may have been modified by the use of these agents for periods exceeding the median time to predicted detection of pulmonary metastases. Microscopic metastases of some patients were eradicated by this adjuvant chemotherapy. For patients who developed metastases, these metastases were delayed in their time of detection and in their number at the time of detection.

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Bone Neoplasms; Child; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Extremities; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma

Surgical extirpation of the primary tumor has traditionally been utilized as initial treatment for sarcomas in children. The present report, however, demonstrates that sarcomas are optimally treated by means of a coordianted multidisciplinary approach. The latter offers the potential for achieving improved survival and preservation of organs and limbs, particularly for structures of the head and neck, for extremities, and in the genitourinary system.

Topics: Adolescent; Age Factors; Antineoplastic Agents; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Leucovorin; Lymphatic Metastasis; Male; Methods; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Vincristine

Four white women who developed osteosarcoma during pregnancy were referred for treatment, 2 prior to delivery and development of metastases, and 2 after delivery and development of metastases. After amputation, these patients received combination chemotherapy with either vincristine-cyclophosphamide or adriamycin-cyclophosphamide followed by high-dose methotrexate with leucovorin rescue. Two patients survived, 1 tumor-free and 1 with bony and soft tissue metastases. Management of pregnant patients with osteosarcoma should include the use of adjuvant systemic chemotherapy to prevent detectable metastases. This treatment should follow amputation or resection and early termination of pregnancy.

Topics: Abortion, Induced; Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Extremities; Female; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Pregnancy; Pregnancy Complications; Vincristine

Fifty patients with metastatic breast cancer were treated with 8-day courses of vincristine (1 mg iv, Day 1), adriamycin (50 mg/m2 iv, Day 1), cyclophosphamide (100 mg/m2 orally, Days 1-8), methotrexate (200 mg iv by 3-hour infusion, Day 8), and citrovorum factor rescue (15 mg in 12, 18, and 24 hours after methotrexate, Day 8) at 3-4-week intervals. Forty-two patients had previously received treatment with hormones and 17 patients had received chemotherapy. Fifteen patients achieved a complete remission (CR) and 24 patients a partial remission (PR). There was a significant correlation between the response and the number of metastatic organs (0.01 less than P less than 0.02). The response rate was roughly uniform irrespective of the organ predominantly involved (0.2 less than P less than 0.3). The remission duration was significantly longer for the patients with CR compared with that for the patients with PR (0.001 less than P less than 0.01). The patients who achieved CRs and PRs survived significantly longer than the patients with no change and progressive disease (P less than 0.001). The toxic effects of the treatment were acceptable and no drug-related deaths occurred.

Topics: Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Remission, Spontaneous; Vincristine

Disseminated malignant disease should be approached with the intention of curing the patient. This requires a multidisciplinary approach. Essential to the successful application of multidisciplinary treatment is the administration of effective chemotherapy, which may achieve reduction in both microscopic disease and overt tumour. In Ewing's sarcoma, the latter should be treated also by irradiation. Limited areas of bulk tumour that have failed to respond or have responded only partially may be removed surgically. Chemotherapy and radiation therapy should be used extensively for palliation; surgery may be required occasionally for control of pain. The decision to treat palliatively should be reached only after patients have received multidisciplinary consultation.

Topics: Bone Neoplasms; Child; Cyclophosphamide; Dactinomycin; Doxorubicin; Humans; Leucovorin; Methotrexate; Osteosarcoma; Sarcoma, Ewing; Vincristine

The evolution of treatment for osteogenic sarcoma at the Memorial Sloan-Kettering Cancer Center is reviewed. The possible control of micrometastases by chemotherapy and the excision of macrometastases at single or multiple thoracotomies by the thoracic surgeon have added greatly to the salvage rate of this tumour. Intensive chemotherapy has made possible en bloc resection of bones involved by tumour, with preservation of the limb. Despite advances, however, amputation or en bloc resection is still necessary to control the primary tumour.

Topics: Adult; Amputation, Surgical; Bone Neoplasms; Child; Chondrosarcoma; Fibrosarcoma; Humans; Leucovorin; Methotrexate; Osteosarcoma; Sarcoma, Ewing

Topics: Age Factors; Bone Neoplasms; Chondrosarcoma; Cyclophosphamide; Dactinomycin; Doxorubicin; Humans; Leucovorin; Osteosarcoma; Sarcoma, Ewing; Vincristine

Topics: Adolescent; Adult; Bicarbonates; Bone Neoplasms; Child; Female; Humans; Infusions, Parenteral; Leucovorin; Male; Methotrexate; Middle Aged; Osteosarcoma; Sodium; Solutions; Water

The cyclic chemotherapy scheme OS I/75 was tried in 6 patients with newly diagnosed osteosarcoma and in 3 patients with secondary metastases. The treatment consists of high dose methotrexate, followed by citrovorum-factor rescue, doxorubicine (Adriblastin) and cyclophosphamide (Endoxan). All 6 primary patients are in a continuous remission of 6+ to 21+ months (median 12+ months). The length of remission in the patients with metastases is 5.5+ and 8+ months. The haematological side effects led to an average prolongation of the cycle by 11 days in a planned cycle duration of 42 days. However, they were readily manageable. Among the other side effects two cases of Adriblastin myocardiopathy are remarkable which became apparent after methotrexate and ifosfamide. In order to improve possibilities for treatment regional centralisation of patient care and interdisciplinary and supraregional cooperation of treatment centres are necessary. A prospective treatment programme has been developed for the Federal Republic of Germany and Austria.

Topics: Adolescent; Age Factors; Bone Neoplasms; Child; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Methods; Methotrexate; Osteosarcoma; Time Factors

Two patients with osteogenic sarcoma of the proximal tibia were treated pre-operatively with intensive chemotherapy with high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (ADR). One patient died before surgery. The other underwent en bloc resection of the primary tumor with prosthetic replacement of the involved tibia, following by adjuvant chemotherapy consisting of HDMTX with CFR and ADR, but died of metastases. Complete control of the primary or metastatic tumor was not achieved. It is emphasised that intensive multiple drug chemotherapy should be administered with extreme caution. The histologic findings are carefully analysed in relation to objective tumor response and toxic chemotherapy effects.

Topics: Adolescent; Antineoplastic Agents; Bone Neoplasms; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Tibia

We have reviewed the literature and described experience in treating Ewing's sarcoma and osteosarcoma before and during the era of intensive systemic chemotherapy. Local control of Ewing's sarcoma may relate to increasing doses of radiation, especially when intensive chemotherapy is administered also. Problems of radiation enhancement by chemotherapy have caused us to reconsider time-dose and volume parameters in treating these patients. The role of radiation in osteogenic sarcoma is limited to patients with inoperable lesions and metastases.

Topics: Bone Neoplasms; Child; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Therapy, Combination; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Radiation Tolerance; Radiotherapy Dosage; Radiotherapy, High-Energy; Sarcoma, Ewing; Vincristine

The development and application of the VCR-MTX-CF regimens for the treatment of osteogenic sarcoma have changed the biological behavior of the tumor. Recent results strongly project major advances for the future. Although the major effect of chemotherapy resides in the eradication of micrometastases, its application for treatment of the primary tumor may also be considered. However, careful experimental design and follow-up periods for several years will be required to determine the optimum approaches. For example, it is possible that the interaction between weekly VCR-MTX-CF and radiation therapy may assume increasing importance. Thus, with the effective application of VRC-MTX-CF, the management of osteogenic sarcoma has evolved into a multidisciplinary approach and future advances will be based on the collective judgement of specialists from many fields.

Topics: Bone Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Osteosarcoma; Prognosis; Vincristine

In clinical studies performed during 111 infusions of high dose methotrexate (MTX) we have evolved a clinical and laboratory protocol which permits such therapy without prohibitive risk to the patient. The plasma MTX data obtained indicate that pharmacokinetic disposition is dose related during these infusions and that such data are useful in identifying patients at risk from serious toxicity.

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Drug Therapy, Combination; Humans; Leucovorin; Melanoma; Methotrexate; Middle Aged; Neoplasms; Sarcoma; Soft Tissue Neoplasms

Topics: Bone Neoplasms; Child; Dacarbazine; Doxorubicin; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Vincristine

Using a co-ordinated multidisciplinary approach with surgery, radiation therapy, and chemotherapy, 14 out of 21 patients with metastases from osteogenic sarcoma were rendered free of disease for over two to over 18 months. Most patients had pulmonary metastases, two had bony metastases, and one had metastases in the iliac nodes. As part of this multidisciplinary approach weekly high-dose methotrexate was given and caused tumour regression in seven out of 15 patients. After all clinical evidence of disease had been removed high-dose methotrexate was administered every two to three weeks as maintenance treatment. To assess the efficacy of treatment the results were compared with those in a historical control group of 82 consecutive patients who developed pulmonary or other metastases. The results in the study group were significantly better. This experience may be similar to that in Wilms's tumour, where actinomycin D has increased the cure rate when administered as adjuvant therapy after treatment of localised or overt metastatic disease.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Doxorubicin; Female; Humans; Leucovorin; Lung Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Radiotherapy Dosage; Vincristine

Based on our prior experience in treating children with metastatic osteogenic sarcoma, a multidrug regimen was developed. Nine children with evaluable osteogenic sarcoma were treated with vincristine 1.5 mg/m2 on day 1, highdose methotrexate 200-300 mg/kg i.v. on day 2, with p.o. citrovorum factor "rescue" 9 mg every 6 hours x 12, followed in 2 weeks by cyclophosphamide 40 mg/kg i.v., then 2 weeks later Adriamycin 1.5 mg/kg/day x 2; in 2 weeks cyclophosphamide was repeated. After a 2-week rest, the 56-day cycle was repeated for a total period of 1 year. Oropharyngeal mucositis was the most frequent severe manifestation of gastrointestinal toxicity. Hematologic depression was mild to severe. Nine patients with clinically evaluable osteogenic sarcoma and no previous chemotherapeutic treatment were treated with this regimen. One patient had only a transient shrinkage in tumor mass, and one patient had no progression of multiple pulmonary and bone metastases for 16 months while on therapy. Of the remaining seven patients, all had clinically significant responses with tumor regression demonstrated for from 5 to 20+ months. Four of these patients (three presenting with primary tumor and pulmonary metastases) demonstrated regression of their primary tumor. In an attempt to increase the cure rate in osteogenic sarcoma, chemotherapy that has proven to be effective against metastatic osteogenic sarcoma should now be employed as prophylactic therapy, after amputation, at cancer treatment centers where it can be safely and effectively administered.

Topics: Adolescent; Bone Neoplasms; Child; Cyclophosphamide; Digestive System; Doxorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Leucovorin; Male; Methotrexate; Mouth Mucosa; Mucous Membrane; Neoplasm Metastasis; Osteosarcoma; Vincristine

Topics: Bone Neoplasms; Child; Humans; Leucovorin; Methotrexate; Neoplasm Metastasis; Osteosarcoma

The survival times in a control series of 145 cases of osteogenic sarcoma without pulmonary resections including records of pulmonary nodules and surgical wedge excisions, suggest that pulmonary resection is a noteworthy adjunct treatment. The 5-year survival of patients subjected to repeated pulmonary surgery is known for 22 patients who were under the age of 21. Where aggressive pulmonary resections were performed, i.e., repeated thoracotomies, and multiple wedge resections of nodules, a 5-year survival rate of 31 per cent (after date of primary amputation) is noted and compared to a previous study of 145 cases, 121 of which had untreated pulmonary metastases, and at 5 years, only 2 per cent of these patients with metastases were still alive. Lung wedge resection survivals are highly significant statistically although survival with residual disease must be considered in part at least, due to aggressive chemotherapy (i.e., high dose methotrexate with citrovorum rescue in combination with other drugs).

Topics: Bone Neoplasms; Humans; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma

Topics: Adolescent; Age Factors; Alkaline Phosphatase; Aspartate Aminotransferases; Bone Neoplasms; Child; Doxorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Hematopoietic System; Humans; Leucovorin; Male; Methotrexate; Mucous Membrane; Nausea; Neoplasm Metastasis; Osteosarcoma

Topics: Adolescent; Adult; Bone Marrow; Bone Neoplasms; Child; Dose-Response Relationship, Drug; Humans; Kidney; Leucovorin; Lung Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Radiotherapy Dosage; Skin; Stomatitis