Faculty Bibliography

Data on the antitumour activity and toxicity of epirubicin in the treatment of 18 hepatoma carcinoma patients and 16 pancreatic carcinoma patients are presented. Two methods of administration were used: 6-hour infusion subsequently changed to bolus administration. Median total dosage with the pancreatic carcinoma patient was 165 mg/m 2; for the hepatoma carcinoma patients, some managed to accept 110 mg/m 2 and some 135 mg/m 2. Gastro-intestinal toxicity in both hepatoma and pancreatic patients was relatively mild. Only one patient suffered significant mucositis; mild to moderate alopecia occurred in a significant number of patients. There were four cases of infection, one serious; there were cases of cardiac toxicity. The limiting toxicity was myelosuppression. In the 18 previously untreated patients with hepatoma carcinoma, three (17%) showed some response to epirubicin. Four patients with stable disease showed a median overall survival of only 12 weeks. In the 16 pancreatic carcinoma patients, nine of whom had been treated previously, two (19%) showed some response to epirubicin. Three objective responders survived for 12, 14 and 20 weeks respectively. The median survival in the group was less than three months. It is suggested that further trial of epirubicin in multidrug combinations or in multimodality regimens is warranted

Forty-four patients with non-small cell carcinoma of the lung were treated every 3 weeks with vinblastine (4 mg/m2/day iv X 2) and cisplatin (20 mg/m2/day iv X 3). Of the 28 patients with metastatic disease, eight (29%; 90% confidence interval of true response, 17%-47%) achieved objective response, for a median duration of 27 weeks. Median survival in this group was 47 and 28 weeks for responders and nonresponders, respectively. Of the 16 patients with advanced regional disease, 11 (69%; 90% confidence interval of true response, 49%-86%) achieved objective response. Thirteen of these patients received consolidation radiotherapy (4500 cGy/25 fractions/5 weeks), with a boost of 1000 cGy/5 fractions/1 week in those patients who achieved response. In the three patients who did not receive radiotherapy, two died during the induction phase, one from grade 4 leukopenia and sepsis and the second from unrelated factors. The third patient had systemic progression of disease during induction chemotherapy. Six patients experienced overall improvement in their chemotherapy response from the radiotherapy. Two patients who did not respond to the chemotherapy achieved partial response with irradiation. Four patients who had partial response to the chemotherapy achieved complete response with irradiation, and seven patients had no further change in their degree of response to irradiation. The overall median survival of this group was 81 weeks. Maintenance chemotherapy was not given. After radiotherapy, the site of first failure was outside the radiation field in nine of 13 patients (69%). Hematologic toxicity was dose-limiting. Other toxic effects that were not dose-limiting included nephrotoxicity, neurotoxicity, and acute nausea and vomiting. In the patients with advanced regional disease, there was no increase in the radiation toxicity attributable to the chemotherapy. We conclude that: (a) this dose schedule of vinblastine and cisplatin has reproducible activity in non-small cell carcinoma of the lung; (b) the response and median survival of patients with advanced regional disease are superior to those of patients with metastatic disease; and (c) in patients with advanced regional disease, treatment with chemotherapy followed by radiotherapy yielded an overall response rate of 81% (90% confidence interval of true response, 60%-93%) and improved survival compared to a similar group of patients studied by others receiving radiotherapy alone. We recommend further testing of this concept

The bisdioxopiperazine (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane (ICRF 187) abrogates doxorubicin cardiotoxicity in every mammalian species tested, but its effect on doxorubicin antitumor activity remains poorly understood. In order to better define the anthracycline-bisdioxopiperazine interaction, the ability of murine sarcoma S180 cells to form colonies in soft agar and their capability to proliferate in microtiter wells were assayed after exposure to drug at varying doses and schedules. Incubation of cell suspensions for 1 h with doxorubicin, 0.1 microgram/ml, with or without (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, 80 micrograms/ml, produces additive cytotoxicity for the combination. Prolonged incubation (24 h) with the same drugs produces synergistic cytotoxic and antiproliferative effects at 1- and 2-log order reductions in dose. These studies indicate that the antineoplastic activity of the single agents doxorubicin and (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane is enhanced when the drugs are used in combination, and that this phenomenon is highly dose and schedule dependent.