mitoguazone and Carcinoma--Squamous-Cell

Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lung Neoplasms; Mitoguazone; Vinblastine; Vindesine

We designed a protocol to evaluate the possibility of organ preservation in patients with advanced, resectable carcinoma of the head and neck. The regimen consisted of intensive chemotherapy followed by radiation therapy alone for patients with good response to treatment. The end points of the study were response rate, organ preservation, toxicity, and survival.. Forty-two eligible patients with carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses were enrolled. Induction chemotherapy consisted of three cycles of mitoguazone, fluorouracil (5-FU), and high-dose continuous infusion cisplatin. Patients who had a complete response to chemotherapy, or whose tumor was downstaged to T1N1, were treated with definitive radiation therapy, to a total dose of 66 to 73.8 Gy. Patients with residual disease greater than T1N1 underwent surgery and postoperative radiation.. The overall response rate to chemotherapy was 84%, with a 43% complete response rate, and a 68% complete response rate at the primary tumor site. Sixty-nine percent of patients (29 of 42) were initially spared surgery to the primary tumor site, and four of these patients (14%) required neck dissection only, after radiation therapy. These tumor sites included oral cavity, oropharynx, hypopharynx, larynx, and sinuses. Eventually, five of these patients (17%) required salvage surgery and eight patients (28%) had unresectable or metastatic relapses. With a median follow-up duration of 38.5 months, 36% of all patients have had preservation of the primary tumor site and remain disease-free. The median survival duration is 26.8 months. Toxicity was substantial, with a 70% incidence of grade 3 to 4 granulocytopenia and two septic deaths.. Organ preservation without apparent compromise of survival was achieved in patients with selected nonlaryngeal sites of head and neck carcinoma. Larger site-specific trials with less toxic regimens conducted in randomized fashion are required to extend these data.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Staging; Radiotherapy Dosage; Survival Analysis

Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lung Neoplasms; Mitoguazone; Vinblastine; Vindesine

Topics: Adenocarcinoma; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Recurrence, Local

The combination of cisplatin 100 mg/m2 every 3 weeks and mitoguazone 500 mg/m2 every week with dose escalation was administered as a 9-week induction regimen to 27 patients with previously untreated Stage III or IV squamous cell carcinoma of the head and neck. This was followed by full-course radiation therapy for unresectable patients or surgery and postoperative radiation therapy for those with resectable disease. Sixteen patients had bulky unresectable disease, and ten were candidates for curative resection at study entry. Of 26 patients evaluable for response to chemotherapy, there were seven complete responses (CR) (five of six pathologically confirmed) and ten partial responses (PR) (65% CR + PR). Toxicity was generally mild with Grade 3 or 4 nausea and vomiting occurring in 15% and diarrhea in 12%. Nineteen percent of the patients developed transient nephrotoxicity (serum creatinine greater than 2), 62% anemia (hemoglobin decrease greater than 2 g/dl), 23% leukopenia (leukocyte count less than 3500 cells/microliters) and 8% thrombocytopenia (platelets less than 50,000 cells/microliters). Anorexia, fatigue, and weight loss occurred in nearly all patients. The median survival time of all patients was 17.5 months; complete responders, 43 months; partial responders, 16 months; and nonresponders, 9 months (P = 0.0025). In a multivariate analysis of stage, primary site, resectability status, response to chemotherapy, and local treatment (surgery plus radiation versus radiation), complete response was the only statistically significant covariate for survival. In Phase II single agent trials, mitoguazone has been shown to have a 15% response rate in head and neck cancer and cisplatin, a 30% to 40% response rate (less than 10% CR). Thus, our results, both complete and overall response rates, were higher than would be expected from either drug alone. A possible mechanism for this high response rate may be mitoguazone-induced cell synchronization. In vitro studies demonstrate the accumulation of tumor cells exposed to mitoguazone in S- and G2-phases of the cell cycle. These results would support further evaluation of mitoguazone in combination to explore the theoretical potentiation of antitumor effects by sequencing with cycle-specific agents.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Lymphatic Metastasis; Male; Middle Aged; Mitoguazone

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: Adult; Aged; Carcinoma, Squamous Cell; Central Nervous System Diseases; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone

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

Thirty-one patients with unresectable squamous cell carcinoma of the head and neck, 28 with local or distant recurrences following primary surgery and/or radiation and three with distant metastases at diagnosis, were treated with cisplatin and methylglyoxal bis-guanylhydrazone (MGBG). Cisplatin was given at 60 mg/m2 i.v. every 21 days X 3, followed by 80 mg/m2 every 28 days in responding patients. MGBG 500 mg/m2 i.v. was given weekly X 5, then every 14 days. Each dose of MGBG was to be escalated in the absence of toxicity, but in the majority of patients doses greater than 500 mg/m2 resulted in unacceptable toxicity. Gastrointestinal symptoms were the major side effects of this combined treatment. In 28 evaluable patients there were two complete remissions and nine partial remissions. This 39% response rate is not different from that reported with either drug alone. Combined cisplatin and MGBG as administered in this study had no apparent advantage compared to either agent alone in this group of patients.

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

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

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Facial Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Recurrence, Local

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Guanidines; Head and Neck Neoplasms; Humans; Middle Aged; Mitoguazone

We used mitoguazone (500 mg/m2 iv weekly, with 50-mg/m2 escalations weekly as tolerated) to treat 22 patients with squamous cell carcinoma of the head and neck which recurred after initial therapy. Nine of 22 (11%) patients responded: two had complete responses and seven had partial responses. Gastrointestinal toxicity and anemia were commonly seen. We conclude that mitoguazone is active in squamous cell carcinoma of the head and neck and should be incorporated into phase III trials.

Topics: Adult; Aged; Anemia; Carcinoma, Squamous Cell; Drug Evaluation; Gastrointestinal Diseases; Guanidines; Head and Neck Neoplasms; Humans; Middle Aged; Mitoguazone; Prognosis

Methylglyoxal bis-dihydrochloride is a drug that has been available for use in cancer chemotherapy since 1955. In earlier studies, it was used on a daily schedule with resulting severe gastrointestinal toxicity and myelosuppression. To avoid that toxicity, a new weekly schedule has been adopted in several Phase II studies. With the weekly schedule, new types of toxicity have been described and we report four patients who have developed a severe sensory-motor neuropathy with the chemotherapy which appears to be drug-related.

Topics: Aged; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Evaluation; Guanidines; Humans; Lung Neoplasms; Male; Middle Aged; Mitoguazone; Peripheral Nervous System Diseases; Time Factors

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

Thirty-four assessable patients with advanced squamous cell and adenocarcinoma of the lung were treated with weekly MGBG in a phase II trial. Only one partial response, in adenocarcinoma, was observed. Myelosuppression was mild to moderate. Major toxicities consisted of myalgia, myopathy, mucositis, gastrointestinal and pronounced vasculitis in one patient. It would appear that MGBG does not have sufficient antitumor activity to warrant further investigation in advanced squamous cell and adenocarcinoma of the lung.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Evaluation; Female; Guanidines; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Middle Aged; Mitoguazone

Fifty-two patients with metastatic or recurrent non-small-cell lung cancer (NSCLC) were treated, during a phase II trial, with methylglyoxal-bis-(guanylhydrazone) (MGBG). Of the 44 patients who had adequate trials, 4 had partial responses (PR), for an overall 9% PR rate. Response durations ranged from 3 to 5+ months. Prior treatment with chemotherapy may have adversely affected response rate; 15% of previously untreated patients responded, compared to only 4% of previously treated patients. A syndrome of weakness and fatigue was the most serious side effect. Anorexia and weight loss, stomatitis, nausea and vomiting, diarrhea, and peripheral neuropathy were the other toxic effects. We conclude that MGBG has activity in NSCLC, especially in previously untreated patients, and further studies are indicated in that population.

Topics: Adenocarcinoma; Anorexia; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Drug Evaluation; Fatigue; Female; Guanidines; Humans; Lung Neoplasms; Male; Mitoguazone