mitoguazone and Esophageal-Neoplasms

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Doxorubicin; Esophageal Neoplasms; Etoposide; Fluorouracil; Humans; Lomustine; Methotrexate; Mitoguazone; Mitomycin; Mitomycins; Neoplasm Metastasis; Postoperative Care; Preoperative Care; Vinblastine; Vindesine

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

Broad phase II trial of methylglyoxal-bi (guanylhydrazone) (MGBG) is under way at the Memorial Sloan-Kettering Cancer Center. Studies in renal cell carcinoma, lymphomas, and non-small-cell lung cancer are completed, and substantial numbers of patients with esophageal and head and neck cancer have been treated. Small numbers of patients with other solid tumors have also been entered into the study. MGBG has significant antineoplastic activity against lymphomas, with 16/40 heavily pretreated patients (40%) having partial remissions (PR) lasting 1 to 8+ months. MGBG has also demonstrated more modest activity in non-small-cell lung cancer, esophageal, and head and neck carcinoma; it appears to have little or no therapeutic value in renal cell cancer. Toxicities have been manageable, and included mild nausea and vomiting, diarrhea, mucositis, and myelosuppression. The dose-limiting toxicity, seen most frequently in those patients with impaired renal function, was lethargy and fatigue. MGBG has demonstrated activity in lymphomas, lung, esophageal, and head and neck cancer. Further trials of this agent are indicated, both alone and in combination.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Clinical Trials as Topic; Drug Evaluation; Esophageal Neoplasms; Female; Guanidines; Head and Neck Neoplasms; Humans; Kidney; Lung Neoplasms; Lymphoma; Male; Middle Aged; Mitoguazone; Skin Diseases; Ulcer

Thirty-six patients with adenocarcinoma or epidermoid carcinoma of the esophagus were entered into a phase II trial evaluating the combination of cisplatin 100 mg/m2 intravenously (IV) day 2, vinblastine 1.6 mg/m2 IV days 1 to 4, and mitoguazone (MGBG) 500 mg/m2 IV days 1 and 8. Twenty-nine patients (group A) were newly diagnosed with local-regional disease only and were candidates for transhiatal esophagectomy (THE). These patients received two courses of chemotherapy at 3-week intervals prior to surgery. Response was assessed by measuring changes in the primary tumor length and depth on serial biphasic contrast esophagrams and comparing this result with tumor measurements obtained from the surgical specimen. Complete (CR) and partial responders (PR) received three additional postoperative cycles. Seven patients had recurrent or metastatic disease (group B) and were treated every 4 weeks until disease progression. Of 34 patients evaluable for response, there was one pathologically confirmed CR and 15 PRs (47%). This consisted of 12 of 27 (44%) group A patients (seven of 11 epidermoid, five of 16 adenocarcinoma) and four of seven (57%) group B patients (two of four epidermoid, two of three adenocarcinoma). Toxicity included leukopenia in one third of treatment courses and thrombocytopenia in 21%. Nausea and vomiting occurred in 60% of patients, diarrhea in 18%, transient nephrotoxicity in 18%, peripheral neuropathy in 12%, and ototoxicity in 3%. Twenty-five group A patients underwent resection. Four chemotherapy nonresponders (NR) and one PR had known disease left at surgery; all others (80%) had gross total removal of their disease. The median survival time (MST) of the 29 group A patients was 14 months, with 21% alive at 36 months. The MST of group A chemotherapy responders was 15 months compared with 9 months for NRs (P = .032). Initial sites of recurrence in 14 patients were local-regional in six, distant only in six, both local-regional and distant in two. This regimen, administered in maximally tolerated doses, was active in epidermoid and adenocarcinoma histologies, recurrent disease and newly diagnosed patients. However, nearly all responses were PRs and the MST of resected patients was similar to a prior series of patients treated with esophagectomy alone. Observations from this pilot trial and those of others have led to a follow-up study, in progress, evaluating intensive preoperative chemotherapy and concurrent radiation therapy (RT).

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Evaluation; Esophageal Neoplasms; Humans; Mitoguazone; Vinblastine

Forty patients with locally extensive or metastatic squamous cell carcinoma of the esophagus were registered onto a phase II trial employing cisplatin, vinblastine, and mitoguazone. Of 36 eligible patients, four (11%) had partial responses. None had received prior chemotherapy or radiation therapy. Toxicity was mild to moderate and consisted mostly of nausea and vomiting. The activity of this regimen at the doses and schedule used was minimal. More aggressive use of therapy should be considered for further trials.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Evaluation; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Mitoguazone; Vinblastine

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Mitoguazone; Pancreatic Neoplasms; Stomach Neoplasms

Forty-two patients with epidermoid carcinoma of the esophagus were treated with the three-drug combination of cisplatin, vindesine, and mitoguazone (DVM). Twenty patients had locoregional disease and 22 had extensive disease. Of 39 patients evaluable for response, 16 (41%) had complete or partial remission (95% confidence limits, 26%-56%). Of 14 patients with locoregional disease treated prior to surgery, 12 (86%) had resectable disease. There was one death associated with surgery (7.1%). Six of these 14 patients remain alive and free of disease. The median duration of remission for patients with extensive disease was 3 months (range, 2-8). As was the case for an earlier study involving cisplatin, vindesine, and bleomycin, the dose-limiting toxic effect for DVM was leukopenia (median wbc count nadir, 1800/mm3). No clinical evidence of pulmonary toxicity was seen. DVM had moderate activity in esophageal cancer, with acceptable toxicity. Although the risks of pulmonary damage were decreased, the substitution of mitoguazone for bleomycin did not improve the major dose-limiting toxicity of myelosuppression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Esophageal Neoplasms; Female; Humans; Leukopenia; Male; Middle Aged; Mitoguazone; Neoplasm Metastasis; Vindesine

Eighteen patients with measurable or evaluable lesions from squamous cancer of the esophagus received a regimen combining four active agents on an outpatient basis. Nine of 14 evaluable patients (64%, or 50% of 18 patients entered) responded: four of five with previously untreated regional disease and five of nine with recurrent or metastatic disease. Median duration of response in the latter group was 5 months (longest response, 13). Treatment was well-tolerated in all patients but one, who developed signs of severe methotrexate toxicity and died of sepsis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Creatinine; Esophageal Neoplasms; Female; Hemoglobins; Humans; Leukocyte Count; Male; Methotrexate; Middle Aged; Mitoguazone; Platelet Count; Vomiting

Twenty-four patients with epidermoid carcinoma of the esophagus have been treated, in a phase II trial, with methyl-GAG using a weekly schedule. Eighteen patients had received prior chemotherapy with cisplatin-containing combinations. Of 23 evaluable patients, four (17%) had partial remissions, each lasting 2 months. All patients had received prior chemotherapy. Toxic effects were manageable and included mild nausea and vomiting, mucositis, and fatigue. Using this schedule, methyl-GAG had modest activity in esophageal cancer, with acceptable toxicity. Its role in combination chemotherapy remains to be defined.

Topics: Aged; Carcinoma, Squamous Cell; Drug Evaluation; Esophageal Neoplasms; Female; Guanidines; Humans; Male; Middle Aged; Mitoguazone

Topics: Adult; Cobalt Radioisotopes; Esophageal Neoplasms; Female; Guanidines; Heart; Heart Function Tests; Humans; Male; Middle Aged; Mitoguazone; Radioisotope Teletherapy