Robert M. O'Bryan

Phase II evaluation of adriamycin in human neoplasia

Four hundred and seventy‐two patients with disseminated neoplasia were treated with two or more doses of adriamycin. The initial dose for “good risk” patients was 75 mg/m2 every 3 weeks, and for “poor risk” patients was 60 mg/m2 every 3 weeks. Objective remissions were seen in 118/472 patients, with best results noted in lymphomas (21/48), sarcomas (21/64), and carcinoma of the breast (16/50). Eighty‐nine per cent of remissions occurred within three courses. Hematopoietic toxic effects were seen in 73% of patients; nausea, vomiting, and/or stomatitis were observed in 43%. Changes in electrocardiograms were seen in 42/472 patients after cumulative doses of adriamycin ranging from 45 mg/m2 to 600+mg/m2. Irreversible congestive heart failure occurred in two patients after cumulative doses of 555 mg/m2 and 825 mg/m2, respectively. It is concluded that adriamycin is an active agent, most remissions occur promptly, and significant cardiotoxic reactions appear to be cumulative.

Dose response evaluation of adriamycin in human neoplasia.

Because patients treated with 60–90 mg/m2 every three to four weeks reach cardiotoxic doses of 550 mg/m2 within 36 weeks, prolonged treatment with Adriamycin is limited. The purpose of this study was to determine whether lower doses could be given over longer periods without loss of efficacy. Good risk patients treated with 75, 60, or 45 mg/m2 had remission rates of 25, 27, and 19%; poor risk patients treated with 50 and 25 mg/m2 had remission rates of 16 and 12% respectively. Although a dose response was identified, there were no statistically significant differences in remission rates, durations of remission, or toxicities in the dose schedules studied. Irreversible congestive heart failure occurred in five patients with cumulative doses of 240–390 mg/m2. Unless rapid remission induction is urgent, we recommend 60 mg/m2 X four doses and measurement of myocardial function if treatment is to continue.

Phase II study of Cisplatin in recurrent astrocytomas in adults: A Southwest Oncology Group Study

SummaryThirty-one evaluable adults with recurrent astrocytomas were treated with Cisplatin 35 Mg/ M2 I.V. daily for three days every 3–4 weeks. All patients had previously been irradiated and most had previously received chemotherapy. Approximately half had poor performance status. Two patients experienced complete remissions and two additional patients experienced partial remissions. Three patients stabilized. Gastrointestinal toxicity was generally mild. Further studies are planned of Cisplatin in combination with other agents.

Randomized trial of 5-fluorouracil and mitomycin C with or without streptozotocin for advanced pancreatic cancer. A Southwest oncology group study†

A prospective randomized trial comparing streptozotocin, mitomycin C, and 5‐FU (SMF) with mitomycin C and 5‐FU (MF) in patients with advanced pancreatic cancer was performed. In patients with measurable disease the response rates were 34% (19/56) to SMF, and 8% (5/60) to MF (P = 0.009). Median survivals were similar, however, 18 versus 17 weeks (P = 0.356). Median survival of patients responding to chemotherapy was 33 weeks, and for nonresponders it was 17 weeks (P = 0.002). In patients with nonmeasurable disease, median survivals were 21 weeks (SMF) and 18 weeks (MF) (P = 0.797). Patients surviving ⩾48 weeks, however, appeared to be increased in the SMF arm (14 patients) compared to the MF (7 patients). Toxicity was moderate for both regimens, with SMF having greater gastrointestinal and renal toxicity. Chemotherapy with SMF appears to produce objective responses in patients with pancreatic cancer, but does not improve survival compared to MF.

5 FU infusion with mitomycin‐C vs. 5 FU infusion with methyl‐CCNU in the treatment of advanced upper gastrointestinal cancer. A Southwest oncology group study

A randomized trial was conducted by the Southwest Oncology Group (SWOG) in advanced carcinoma of the stomach and pancreas. Patients were assigned to receive monthly 5‐fluorouracil 96‐hour continuous infusions with either bolus mitomycin‐C or oral methyl‐CCNU. Mitomycin‐C and methyl‐CCNU were administered every eight weeks. The 5 FU‐mitomycin combination produced a 14% and 22% response rate in disseminated stomach and pancreatic carcinoma, respectively. The combination of infusion 5 FU and methyl‐CCNU achieved responses in 9% and 5% of stomach and pancreatic tumors, respectively. There was ho significant difference in survival between limbs for either tumor. Median survival in gastric carcinoma on the 5 FU‐mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU‐methyl‐CCNU arm. In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl‐CCNU program. Leukopenia was greater for the first course on the mitomycin limb. Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors. Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms.

5FU infusion with mitomycin‐C versus 5FU infusion with methyl‐CCNU in the treatment of advanced colon cancer. A southwest oncology group study

The Southwest Oncology Group (SWOG) in a randomized trial evaluated 5FU infusions in combination with either Mitomycin‐C or Methyl‐CCNU in patients with disseminated large bowel cancer. A response rate of 18% was noted on the 5FU‐Mitomycin limb as compared to 16% on the Methyl‐CCNU arm (p = .39). Median survival for all treated patients was 43 weeks on both arms. Myelosuppression was found to be more significant on the Mitomycin‐C arm. Regression analysis demonstrated that performance status, sex, and primary site were significant pretreatment characteristics for predicting survival. The response rates associated with this burdensome method of 5FU administration in combination with either Mitomycin‐C or Methyl‐CCNU appear to offer little advantage over bolus 5FU alone.

Southwest Oncology Group study of mitoxantrone for treatment of patients with advanced adenoid cystic carcinoma of the head and neck

SummaryTwenty-two patients are evaluable for response in a Phase II trial of Mitoxantrone for advanced squamous cell carcinoma of the head and neck. One patient had a partial response, one an improvement and twenty had progressive disease. The major toxicities were leukopenia and thrombocytopenia. There was no significant antitumor activity of Mitoxantrone in this group of patients with head and neck cancer, most of whom were previously treated with radiation and chemotherapy.

Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer. A Southwest Oncology Group Study

Small cell lung cancer patients who failed primary systemic therapy or who failed after response were randomly assigned to salvage treatment with etoposide (VP‐16) and cisplatin (CDDP) or bis‐chloroethylnitrosourea, thiotepa, vincristine, and cyclophosphamide (BTOC). Good risk patients were those who had tolerated prior chemotherapy well, those who had not had prior radiation therapy, and those who were 65 years of age or younger. Patients with a history of poor tolerance, prior radiation therapy, or those who were older than 65 years of age were classified as poor risk. Forty‐five patients were randomized to the BTOC regimen and 58 to the VP‐16/CDDP regimen. The overall remission rate was 13% (13 of 103 patients). Good risk patients treated with the BTOC regimen had a remission rate of 27% (three of 11 patients), which was the same rate as patients treated with the VP‐16/CDDP regimen (three of 11 patients). Poor risk patients had remission rates of 9% (three of 34 patients) with the BTOC regimen and 9% (four of 47 patients) with the VP‐16/CDDP regimen. The median survival time from the start of therapy was 16 weeks for all patients. BTOC good risk patients had a median survival time of 10 weeks, as compared with 14 weeks for poor risk patients. VP‐16/CDDP good risk patients had a median survival time of 35 weeks, as compared with 12 weeks for poor risk patients. Although based on small numbers, the advantage in survival time for good risk patients treated with VP‐16/CDDP over those treated with BTOC is statistically significant. Prior exposure to VP‐16 did not influence the outcome of patients treated with VP‐16/CDDP. Both regimens produced moderate toxicity, but were generally well tolerated. It was concluded that VP‐16/CDDP may be a useful salvage treatment for good risk patients, despite its limited remission rate. Also, it was found that BTOC has no value for patients in this setting and that neither regimen helps patients who are poor risk.

Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study

Over a 24‐month period, the Southwest Oncology Group (SWOG) conducted a randomized prospective chemotherapeutic trial in 158 patients with advanced prostatic cancer. Patients were initially randomized to receive either a combination of Adriamycin and cyclophosphamide (AC) or a single agent, hydroxyurea (H), and then crossed over to the other treatment on failure. Of the 137 evaluable patients, 43 (31%) had classically measurable metastatic disease in the lymph nodes, skin, chest, or liver. Focusing their efforts on this subset of patients with measurable disease, the authors of this report found the combination AC to have a superior response rate to the single agent, hydroxyurea. Objective response to AC was seen in 6 of 19 (32%) and in only one of 24 (4%) patients randomized to hydroxyurea (P = 0.06, Fishers exact test). However, in the larger group of 137 evaluable patients, a survival advantage was not seen for those individuals treated with AC. Failure to demonstrate a survival advantage for an objectively superior drug combination would suggest the need for more active phase II agents in this disease.

Phase II study of aziridinylbenzoquinone (AZQ) in patients with central nervous system malignancies: a Southwest Oncology Group study

SummaryAZQ, an alkylating agent with lipophilic characteristics allowing CNS penetration was studied in patients with primary CNS malignancies refractory to surgical and radiotherapeutic modalities. Responses were evaluated by three criteria: neurologic examination, performance status and CT scan of the brain. Improvement in all three parameters with stable or decreasing doses of decadron was required for a partial response. Thirty-six poor risk (prior chematherapy) patients with Grades III and IV astrocytomas were treated with 30 mg/m2. Three patients had a partial response (14, 17, 60 weeks duration). Two patients had mixed responses (worsening of one disease parameter with improvement in another), four had stable disease and one patient had improvement in neurologic parameters with a stable CT scan. Twenty-six patients had increasing disease. Fifteen good risk patients (no prior chemotherapy) with recurrent grades III and IV astrocytomas were treated at a dose of 40 mg/m2 intravenously every three weeks. There were no objective responses in this group of patients. Three patients with nonastrocytomas were treated and no responses observed. The drug was well tolerated. Myelosuppression in the form of leukopenia and thrombocytopenia was the major toxicity. Myelosuppression required dose reductions in eight patients and discontinuation of therapy due to repeated treatment delays in two patients. AZQ at doses of 30 and 40 mg/m2 given on an intermittent bolus schedule is inactive in patients with Grades III and IV recurrent astrocytoma.