A phase II study of dihydroxyanthracenedione (DHAD, mitoxantrone, NSC 301739) in advanced malignant melanoma.

The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of Dihydroxyanthracenedione (DHAD, Mitoxantrone, NSC 301739) in 28 patients with advanced malignant melanoma, none of whom had received prior cytotoxic chemotherapy. 27 of 28 patients were ECOG performance status 0 or 1. Mitoxantrone was administered at a dose of 12 mg/M2 as a 30-45 minute intravenous infusion repeated every 3 weeks as toxicity and response permitted. Dose limiting toxicity was myelosuppression. No cardiotoxicity was encountered in this study. In this optimal group of patients, only one partial response to Mitoxantrone was observed. At this dose and schedule, Mitoxantrone has no clinically worthwhile activity against malignant melanomas.

A randomized comparison of cyclophosphamide, Adriamycin, and 5-fluorouracil with triethylenethiophosphoramide and methotrexate, both as sequential and as fixed rotational treatment in patients with advanced ovarian cancer.

The combinations of triethylenethiophosphoramide and methotrexate (TM) and cyclophosphamide, Adriamycin (doxorubicin), and 5-fluorouracil (CAF) were compared, both as sequential and fixed rotational treatments for advanced ovarian cancer, with L-phenylalanine mustard (L-PAM). Treatment with CAF produced a higher response rate (25% complete responses plus 31% partial responses) than treatment with L-PAM (15% complete responses plus 18% partial responses). A fixed rotation of TM and CAF resulted in longer survival (median of 15 months and 75th percentile of 27 months) than sequential treatment with TM initially, followed by CAF upon failure (median of 12 months and 75th percentile of 22 months). The fixed rotation of TM and CAF also increased progression-free survival (median of 12 months and 75th percentile of 24 months) over that achieved by initial treatment with TM (median of 6 months and 75th percentile of 15 months) or L-PAM (median of 9 months and 75th percentile of 21 months). Most patients (96%) on the fixed rotation were treated with both TM and CAF. Fewer patients (62%) on the sequential schedule with TM actually received both combination regimens, and even fewer patients (37%) beginning on CAF ever crossed over to TM. Patient age of 50 years or younger was a favorable prognostic factor for response, survival, and time to first treatment failure (progression-free survival). Disease Stage IIIA or IIIB, surgery including a bilateral salpingo-oophorectomy plus hysterectomy, and treatment within 6 months of initial diagnosis were favorable predictors for both survival and time to first treatment failure. Ambulatory performance status and well-differentiated disease were favorable prognostic factors for survival. Patients with unevaluable disease failed later than those with evaluable disease who, in turn, failed later than patients with measurable disease.

Phase II trial of piperazinedione (NSC 135758) in the treatment of advanced or recurrent carcinoma of the ovary. A Gynecologic Oncology Group study.

Thirty-eight patients with advanced or recurrent epithelial ovarian cancer no longer amenable to management with surgery, radiotherapy, or chemotherapy with known activity were given piperazinedione 9 mg/m2 intravenously every 3 weeks. Of the 31 patients evaluable for response, only one achieved a partial response of disease (3%), while there were no complete responses. Fourteen (45%) experienced progression of disease less than 1 month after starting therapy. Adverse effects consisted primarily of myelosuppression (81%), nausea and vomiting (32%), and azotemia (29%) with three patients (10%) having life-threatening thrombocytopenia. While adverse effects were tolerated, the drug at the dose and schedule tested has only minimal activity at best and should not be considered for further trials in epithelial ovarian cancer.

A Phase II study of Bruceantin (NSC-165, 563) in advanced malignant melanoma.

The Eastern Cooperative Oncology Group (ECOG) conducted a Phase II trial of Bruceantin in malignant melanoma. Twenty-two patients, thirteen without prior cytotoxic chemotherapy, were entered. All patients were evaluable for response and toxicity. Dose limiting toxicity was found to be hypotension during Bruceantin infusion. Other prominent side effects were nausea, vomiting, anorexia, fever, chills, and weakness. Only minor hematologic toxicity was encountered. Two partial responses, both in previously treated patients were observed (response rate -9%). Bruceantin has only limited activity against malignant melanoma and is unlikely to contribute to systemic therapy of this disease, either as a single agent or in combinations of cytotoxic drugs.

Phase II study of Baker's antifol (triazinate, TZT, NSC 139, 105) in advanced carcinoma of the ovary. A Gynecologic Oncology Group study.

Twenty-nine patients with advanced ovarian carcinoma were entered into a Gynecologic Group Phase II study of Baker's Antifol. Of these, 26 were eligible for evaluation of toxicity and 25 for evaluation of response. The evaluable patients constituted an unusually favorable group for a Phase II study in a chemotherapy-sensitive tumor; although all have received prior chemotherapy, eight had had treatment with only a single alkylating agent and the median performance status of the study population was two (ambulatory, capable of self-care). No complete responses were seen. Two patients had regression of abdominal tumor masses sufficient to qualify as partial responders (PR 8%). Dose-limiting toxicity, as expected, was found to be gastrointestinal. Significant mucositis and dermatitis were also observed. No episodes of hypotension during infusion occurred with a 60-120 min time of administration. Baker's antifol has only limited activity against ovarian carcinoma previously treated with chemotherapy and is not likely to contribute to improved therapy, either as a single agent or in combination.

Phase II study of m-AMSA in advances malignant melanoma.

A phase II study of methanesulfonamide, N-(4-(9 acridinylamino)-3-methoxyphenyl)-(m-AMSA) was undertaken by the Eastern Cooperative Oncology Group. Thirty-five evaluable patients were studied, 18 of whom had had no prior therapy and eight of whom had been treated only one cytotoxic drug. Thirty-one of these patients were ECOG performance status 2 or better. The dose of m-AMSA employed in this study was 40 mg/M2 as an I.V. infusion over 20 minutes daily for 3 days, repeated every 3 weeks. Leukopenia was found to be dose-limiting; thrombocytopenia and anemia were also observed. Other prominent toxicities included anorexia, nausea, and vomiting. No cardiovascular toxicity was observed in this study, but none of the patients had received prior anthracycline therapy. Only one partial response of measurable disease was observed, all other patients had progressive disease on m-AMSA therapy. No significant clinical activity of m-AMSA against malignant melanoma was demonstrated in this very favorable group of patients.

Hexamethylmelamine and cisplatin in advanced ovarian cancer after failure of alkylating-agent therapy.

Thirty-eight women with advanced ovarian cancer resistant to alkylating-agent chemotherapy were treated with a combination of hexamethylmelamine and cisplatin. Hematologic toxicity was severe or life-threatening in seven of 13 patients treated with cisplatin at a dose of 100 mg/m2 but was acceptable in 25 patients treated at 75 mg/m2. Thirty-four percent of the combined group developed peripheral neuropathy and only 8% of those treated at 75 mg/m2 developed transient azotemia. Nine complete responses and 12 partial remissions were noted among 38 patients treated, with no obvious advantage for the higher dose of cisplatin. The median duration of remission was 8 months and the overall median survival was 9 months. The response rate of 55% is approximately twice that reported with either agent given alone in similar patient populations and is equal to or better than that reported for more complicated regimens containing these drugs together with other, less active drugs.

Phase II study of Baker's antifol (triazinate, TZT, NSC-139,105) in advanced squamous cell carcinoma of cervix.

Thirty-two evaluable patients with advanced cervical squamous cell carcinoma were treated with Baker's antifol in a phase II study by the Gynecologic Oncology Group (GOG). There were no complete responses and five partial responses for a response rate of 15.6%. Twenty patients remained stable during the course of therapy; seven had progressive disease. The median number of courses to response was four and the median duration of response was 3 months. The dose-limiting toxicity was dermatitis, which occurred in 10 patients. In four, dermatitis was severe with ulceration and/or desquamation. In two, dermatitis was life threatening and may have contributed to death. Half of the patients had mild or moderate GI side effects; in one case it was severe. Very little hematologic toxicity was observed. No cases of respiratory depression or arrest occurred with this regimen. Baker's antifol has some activity against cervical carcinoma and may be of interest for inclusion in studies of combination therapy because of its relative lack of myelotoxicity.

A prospective evaluation of chemohormonal therapy remission maintenance in advanced breast cancer.

From October 1973 to October 1977 the ECOG prospectively evaluated cyclophosphamide, methotrexate, and fluorouracil (CMF) versus CMF plus fluoxymesterone (CMFH) maintenance therapies in responders to 6 months of induction therapy which consisted of either CMF, CMF plus prednisone (CMFP), or adriamycin plus vincristine (AV). Following the maintenance randomization 12% of the patients converted from a PR to a CR status. The median time from randomization to treatment failure was 9.5 months for CMFH and 6.7 months for CMF (p = 0.03). This difference was observed only for partial responders (p = 0.01) and not for complete responders. Patients receiving CMFH tended to maintain higher hemoglobin, leukocyte, and platelet levels, and receive a higher dosage of each of the cytotoxic drugs. The results are taken as evidence that the addition of fluoxymesterone to a maintenance CMF regimen provides a therapeutic advantage. It is hypothesized that this effect is due at least in part to fluoxymesterone associated maintenance of improved marrow function resulting in greater myelosuppressive drug delivery.

Cavitation of pulmonary metastases as a response to chemotherapy.

Several authors have documented the phenomenon of spontaneous cavitation within both primary lung cancers and metastatic pulmonary nodules. Cavitation after treatment, particularly chemotherapy, has not been emphasized. We report on 3 patients who developed radiographic evidence of cavitation of pulmonary metastases as a direct response to system chemotherapy.

Hepatic veno-occlusive disease due to DTIC.

A case of fulminant hepatic failure leading to death in a patient receiving DTIC for metastatic melanoma is presented. Autopsy revealed widespread centrilobular necrosis secondary to a veno-occlusive process. There was no evidence of a similar process in other organs, and common causes of similar pathology were ruled out. It is likely that in this patient the hepatic failure was due to DTIC alone. Similar cases have been reported in patients receiving other chemotherapeutic agents. Physicians using these drugs should be aware of this side-effect of therapy, since it is often fatal.

Second malignancies complicating Hodgkin's disease in remission.

The incidence of second tumours occurring in the course of Hodgkin's disease has been investigated in a series of 452 patients treated with standard chemotherapy or radiotherapy, combination chemotherapy alone, intensive radiotherapy alone, or both intensive radiotherapy and combination chemotherapy administered in sequence. 16 tumours were noted. When analysed according to mode of treatment, 6 cases occurred in a group of 62 patients who received both modalities. When analysed for age, sex, and man-years of follow-up, this group appears to have 14-5 times the risk of developing a second tumour. However, that subgroup which had a complete remission after intensive radiotherapy followed by a relapse of disease, prior to receiving combination chemotherapy, had the highest risk with 18-5 times greater incidence of second tumour than expected. It is noteworthy that, of the 16 second tumours, 2 were acute myeloid leukaemia; in both cases a similar chromosomal abnormality (45 chromosomes, C-group deletion) was noted. The mechanism of oncogenesis may represent a combination of the immunosuppressive effects and cellular effects of those forms of treatment.

American Burkitt's lymphoma: a clinicopathologic study of 30 cases. II. Pathologic correlations.

Thirty cases of malignant lymphoma, undifferentiated, Burkitt's type are reviewed. An older median age and a predominance of presentation in abdominal and pelvic sites rather than in the jaw distinguishes this series of American patients from those reported from endemic regions in Africa. Bone marrow involvement invariably consisted of massive infiltration recognizable in smear, clot and biopsy preparations. Involvement of the central nervous system or bone marrow was always associated with short survival. In all eight long-term survivors lymphoma was apparently confined to a single site at presentation. At autopsy, the most consistent finding was widespread multiorgan involvement without predilection for lymphoreticular structures. The histologic appearance of the tumor changed after chemotherapy, varying from diffuse necrosis within 48 hours of initial therapy to extreme pleomorphism of tumor cells after 9 months of therapy. In one patient, there was almost complete absence of lymphoma at autopsy in an organ site shown clinically to have been extensively involved by tumor prior to treatment. The diagnostic and therapeutic implications of these findings are discussed.

American Burkitt's lymphoma: a clinicopathologic study of 30 cases. I. Clinical factors relating to prolonged survival.

The presenting clinical characteristics and the results of therapy in 30 cases of American Burkitt's lymphoma are described. Five patients presented with localized disease. The abdomen was the most frequent site of involvement (19 cases). Serum lactic dehydrogenase (LDH) levels closely correlated with extent of tumor mass. Of the 22 patients treated with large doses of parenteral cyclophosphamide, complete remission was achieved in 13 (59 per cent). Of these only four have had a relapse, all within 12 months of treatment. The remainder are alive, free of disease and have not received any treatment for up to 80 months or more. The site and volume of tumor mass predicted for prolonged survival. None of the six patients with bone marrow or central nervous system involvement remained tumor-free. A complete remission was achieved in 8 of 9 patients with presenting LDH levels of less than 700 IU/ml and they have remained free of disease, whereas only 4 of 13 patients with LDH levels greater than 700 IU/ml had a complete response and 3 of these had a relapse within 12 months. In six cases, the massive tumor regression following chemotherapy was associated with serious metabolid consequences including hyperkalemia (six cases), hypocalcemia, hyperphosphatemia (one case) and lactic acidosis (one case). There were four sudden deaths in less than 48 hours after chemotherapy; two of these were attributable to hyperkalemia. In all cases therw were large tumor masses and/or elevated serum LDH levels.