David L. Ahmann

Randomized Clinical Trial of Diethylstilbestrol versus Tamoxifen in Postmenopausal Women with Advanced Breast Cancer

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of bilateral oophorectomy with that of tamoxifen at a dose of 10 mg twice daily in premenopausal women with metastatic breast cancer, and to examine the efficacy of each as a crossover treatment. Initial treatment responses were seen in ten of 27 patients (37%) treated with oophorectomy and seven of 26 patients (27%) treated with tamoxifen. The difference was not statistically significant. Crossover responses were seen in five of 15 patients (33%) treated with oophorectomy, including three responses in ten prior tamoxifen nonresponders; and two of 18 patients (11%) treated with tamoxifen. Time to progression distributions were not significantly different during initial treatment, and no significant differences in survival were noted. Thus, there was no overall disadvantage to the use of tamoxifen as opposed to oophorectomy as initial hormonal therapy, and a failure to respond to tamoxifen did not preclude a response to subsequent oophorectomy. Exploratory data analysis within subsets indicated consistent differential treatment effects in the visceral dominant patients. Of the 16 such patients treated with oophorectomy, eight (50%) experienced objective responses but there were no responses in the 14 patients treated with tamoxifen. In the nine visceral dominant crossover patients who had not responded to initial tamoxifen, three (33%) subsequently responded to oophorectomy. Time to progression distributions within the visceral dominant subset appeared to be better for the patients treated initially with oophorectomy. However, one must be very cautious in drawing conclusions from exploratory subset analyses, especially with the small sample size. Further studies would be required to test any hypothesis of differential organ site responsiveness.

Phase II study of recombinant leukocyte A interferon (rIFN-αA) in disseminated malignant melanoma

Thirty‐one patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN‐αA), 50 × 106 units/m2 three times weekly for a planned treatment duration of 3 months. Seven objective regressions (23%), which ranged in duration from 3 to 11.2+ months, were observed. Forty‐two percent of 12 patients who were fully active (Eastern Cooperative Oncology Group [ECOG] performance score, 0) responded compared to 11% of 19 patients with impairment of performance status (ECOG, 1–3). Prior chemotherapy did not influence response rate. For all patients the median time to progression and of survival was 2 months and 6 months, respectively. Four patients had partial regressions in soft tissue (3, 4.6 months), pulmonary (7 months), and prostatic lesions (3 months). The latter was biopsy‐proven and assessed by serial computerized tomography (CT) scans. Three had complete regressions of soft tissue disease (2 patients, 6.4 and 10+ months each), and liver involvement (11.2+ months). The major toxicities were moderate to severe fatigue (87%), anorexia (58%), and confusion (23%). Performance score deteriorated in 84% of patients during the time they were receiving rIFN‐αA. Among the 13 patients whose tumors did not progress for at least 12 weeks, 7 required dose reductions or termination of treatment due to toxicities. Hematologic and hepatic toxicity was transient and of little clinical significance. The study indicates that rIFN‐αA has some antitumor activity accompanied by difficult side effects in patients with disseminated malignant melanoma.

Biological markers in breast carcinoma. I. Incidence of abnormalities of CEA, HCG, three polyamines, and three minor nucleosides

Patients with breast carcinoma were screened for abnormal concentrations of CEA, HCG, putrescine, spermidine, spermine, pseudouridine, N2, N2‐dimethylguanosine, and 1‐methylinosine. Abnormal polyamine levels occurred in less than 15% of the patients. Among the nucleosides, N2, N2‐dimethylguanosine was the most frequently abnormal, occurring in 57% of the patients with metastatic disease. CEA levels were abnormal in 30% of postoperative N+ patients and 74% of patients with metastatic disease, while HCG elevations were found in 45% and 50%, respectively. All the patients with one or more marker abnormalities could be detected by measuring only CEA, N2, N2‐dimethylguanosine, and HCG. Among these three tests, a singular marker abnormality occurred in 35.8% of the patients, and all three tests were abnormal in 21.8% of the patients. The performance of these three tests in each patient revealed one or more abnormalities in 97% of the patients with metastatic disease, and 67% of the postoperative N+ patients.

A comparative evaluation of marketed analgesic drugs.

Abstract In a double-blind crossover study of marketed drugs given by the oral route to relieve pain, aspirin (650 mg) was superior to all agents tested. Mefenamic acid (250 mg), pentazocine (50 mg), acetaminophen (650 mg), phenacetin (650 mg) and codeine (65 mg) also showed a significant advantage over a placebo. Propoxyphene (65 mg), ethoheptazine (75 mg) and promazine (25 mg) gave no significant evidence of therapeutic activity; and each of these agents was significantly inferior to aspirin in analgesic effect. Pentazocine (50 mg) produced sufficient gastrointestinal and Central-nervous-system side effects to make this agent of dubious value for ambulatory patients. All other drugs tested in this single dose study did not produce significantly greater side effects than a placebo.

The urinary excretion of nucleosides of ribonucleic acid by patients with advanced cancer.

By means of a sensitive and specific method utilizing gas‐liquid chromatography, the excretion levels for three nucleosides, degradation minor base products of ribonucleic acid, primarily transfer ribonucleic acid, were determined in 24–hour urine specimens from over 200 patients with solid tumor malignancies. These nucleosides were N2, N2‐dimethylguanosine, 1–methylinosine, and pseudouridine. When compared to normal control values, elevated levels of these compounds were found for patients in each of several tumor types studied. Increases in pseudouridine excretion suggest increased tumor transfer ribonucleic acid turnover; in addition, for the methylated nucleosides, higher than normal values may reflect enhanced transfer ribonucleic acid methylase activity of the neoplastic cells.

Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients

SummaryCyclophosphamide pharmacolinetics have been studied in 16 female patients with advanced breast cancer. The group included 7 patients who were >20%, ≤30% over ideal body weight and 5 patients who were >30% over ideal body weight. Cyclophosphamide plasma elimination half-lives ranged between 152 and 984 min (mean 457 min), the apparent volume of distribution between 19.1 and 62.31 (mean 36.11), and plasma clearance between 25.9 and 166.6 ml/min (mean 69.5 ml/min). There was a significant positive correlation (r=0.624,P=0.010) between body weight and plasma elimination half-life, and a significant negative correlation between body weight and cyclophosphamide clearance when normalized to body surface area (r=0.578,P=0.019) or normalized to ideal body weight (r=0.531,P=0.0345). the apparent volume of distribution did not correlate with body weight. The results show that cyclophosphamide disposition is altered in patients with increased body weight.

Complete responses and long-term survivals after systemic chemotherapy for patients with advanced malignant melanoma.

Five hundred three patients with advanced malignant melanoma were exposed to a number of clinical investigative chemotherapeutic regimens between 1971 and 1984 in an effort to assess the clinical activity of these regimens in this disease. Of the 503 patients participating in the studies, ten patients experienced a complete response. However, only three of these patients survived more than 5 years. Of this group of 503 patients, seven additional patients who did not experience a complete response survived more than five years. Of the ten patients surviving more than 5 years, two had immediate progression after institution of investigative regimens, whereas five remained stable for brief periods of time before progressive metastatic disease. Three patients experienced a complete response. It appeared that systemic therapeutic interventions in these trials were conspicuously ineffective for this large group of patients. A few long‐term survivors attest to the capricious nature of this neoplasm and its association with likely spontaneous regressions. Although these long‐term survivors did survive after institution of systemic chemotherapy, it is likely that this survival was related temporally, but perhaps not causally, to the institution of treatment.

Phase II study of low-dose recombinant leukocyte A interferon in disseminated malignant melanoma.

Thirty patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN-alpha A), 12 X 10(6) U/m2, three times weekly for a planned treatment duration of three months. This dose was selected in view of our prior phase II data indicating that 50 X 10(6) U/m2 three times weekly produced excessive toxicity. In this current trial we observed three objective partial regressions (20%) among the 15 better-risk patients (performance score 0, 1, and no prior chemotherapy) with times to disease progression of 1.9, 9.6, and 12.9+ months. There were also three regressions (one complete and two partial) among the 15 poor-risk patients (performance score 2, 3, or prior chemotherapy) with progression times of 3, 3.2, and 9.6+ months. For all patients, the median survival time was 4.2 months. One half of the patients were observed to have progressive disease within one month of commencing treatment. Responding metastatic lesions were limited to soft tissue, although one patient also had a partial response of a lung nodule. The most substantial toxicities were moderate-to-severe myalgias (27%), nausea (33%), anorexia (47%), and fatigue (50%). Among the 22 patients with weight loss, the median was 2.3 kg (range, 0.6 to 8.4 kg). Hematologic and hepatic toxicity was transient and of little clinical significance. Our study indicates that rIFN-alpha A in the dose and schedule that we used is clinically tolerable and has antitumor activity in malignant melanoma. The response rate was similar to results observed in our previous study of a higher dose regimen.

A preliminary assessment of factors associated with recurrent disease in a surgical adjuvant clinical trial for patients with breast cancer with special emphasis on the aggressiveness of therapy

Two HUNDRED NINETY-THREE PATIENTS were randomly assigned to three treatment regimens following mastectomy for operable but prognostically unfavorable breast cancer: L-PAM, CFP, or CFP with radiation therapy. For premenopausal patients an increased risk of recurrence was associated with the presence of unfavorable local signs, large number of lymph nodes involved, greater body weight, younger age, and L-PAM treatment. For the postmenopausal patients only three factors were associated with an increased risk of recurrent disease: large tumor size, large number of lymph nodes involved, and inner/central location of the primary lesion. Specifically, the treatment employed has shown no effect. Of particular importance is the fact that for neither group of patients does our experience presently demonstrate clear association of recurrent disease with the level of drug dose administered. Furthermore, evidence suggests that although patients who experience little or no myelosuppression have significantly worse disease-free intervals than patients who experience moderate or severe myelosuppression, there is no benefit for severe myelosuppression over moderate, myelosuppression.