Faculty Bibliography

Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions

The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study

Fifty-five patients with Stage II (36 patients) or Stage III (19 patients) malignant melanoma confirmed histologically received adjuvant immunotherapy with a polyvalent melanoma antigen vaccine to evaluate toxicity and immunogenicity. There was no toxicity. Antibody and/or cellular immune responses to melanoma were induced more frequently in Stage II (36 patients [69%]) than Stage III (19 patients [53%]) disease. The ability of different immunization schedules, alum, or pretreatment with low-dose cyclophosphamide to potentiate immunogenicity was compared after 2 months of immunization. Immunization biweekly with a fixed intermediate dose of vaccine was more immunogenic than immunization weekly with escalating vaccine doses. Alum increased the intensity of cellular responses slightly, whereas pretreatment with cyclophosphamide augmented both the incidence and intensity of cellular immune responses slightly. However, these changes did not reach statistical significance. There was a reciprocal relationship between the induction of humoral and cellular immune responses. These results show that (1) active immunotherapy with a polyvalent melanoma vaccine is safe in patients with minimal disease, (2) the vaccine augments immunity to melanoma in many, but not all, patients, and (3) several immunization strategies failed to potentiate immunogenicity significantly

Forty-one evaluable patients with localized squamous cell carcinoma of the thoracic esophagus were treated by a course of radiation therapy (3000 cGy in 3 weeks), 5-Fluorouracil (5-FU) and Cis-platinum (Pt). This was followed by an esophagectomy in medically eligible patients who agreed to the procedure and who had no evidence of extrathoracic tumor. If tumor was found in the specimen, an added 2000 cGy of radiation therapy and additional 5-FU and Pt were given. One-year survival was 44%, 2-year survival 15%, and 3-year survival 8%. All 3-year survivors had tumor-free specimens, but one patient with tumor in the thorax and subdiaphragmatic metastasis survived 2 years

Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170-500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2 alpha of 1.6 h and a t1/2 beta of 3.0 h. The mean (+/- SD) residence time, total body clearance, and apparent volume of distribution were 3.5 +/- 0.4 h, 4.4 +/- 0.85 l/h, and 16 +/- 3 l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12-16 h. All of the platinum in 24-h urine was carboplatin, and only 2%-3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r = -0.98). Over a dose range of 300-500 mg/m2, carboplatin exhibited linear, dose-independent pharmacokinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure

Thirty-nine patients with stage III and IV epithelial ovarian cancer who underwent second-look laparotomy (SLL) at New York University Medical Center and 11 eligible patients who did not undergo reexploration were retrospectively studied with follow-up from 24 to 105 months after diagnosis. Sixteen patients (41%) were found to have macroscopic disease, six (15%) microscopic tumor, and 17 (44%) no disease at SLL. Five of 22 patients who received further therapy based on positive SLL findings have remained without clinical evidence of disease 17 to 65 months after SLL. Nine of 17 patients with negative SLL, in whom treatment was stopped, recurred 8 to 52 months after SLL, five in extraperitoneal sites only. Five of 11 patients not undergoing SLL recurred 16 to 39 months after diagnosis, four intraperitoneally. There was no significant difference in survival between the second-look and no second-look groups for the period of study. Clinical trials are needed to determine if SLL influences longer-term survival and if continued treatment is indicated in a high-risk subgroup despite negative SLL. The value of SLL is limited by the efficacy of second line therapy. The role of routine SLL outside an investigational setting is questioned

Fifty-two patients with advanced (stage III and IV) ovarian cancer were treated with a regimen of cisplatin (100 mg/m2 over 5 days) and cyclophosphamide (600 mg/m2/day 4). Treatment was repeated every 3-4 weeks for 6-8 months and followed by second look surgery. The median follow up for this single institution study (1980-1984) is 36 months. The median progression-free survival (projected) is 24 months and the median overall survival (projected) is 37 months in this group of patients with unfavorable pretreatment characteristics: median age: 61, median performance status (ECOG) 2, poorly-differentiated tumors: 60%, extensive residual tumors (greater than 2 cm): 65%. Pretreatment performance status was the only independent predictor for prolonged survival. Pathologically documented complete responses were observed in 23% of all patients and 43% of the patients who underwent second-look surgery (28 patients). Neurotoxicity from this regimen was substantial: it occurred in 65% of cases, was severe in 17% and was often not entirely reversible. The results with this intensive 2-drug cisplatin-containing regimen compare favorably to other more complex regimens in the literature. It is possible that the 'dose intensity' of cis-platinum may be the most important element of current therapeutic regimens in ovarian cancer