Preliminary Phase I Evaluation of Bleomycin,a New Antitumor Antibiotic

Abstract

Bleomycin (BLM), a new antitumor antibiotic isolated in Japan from cultures of Streptomyces Verticillus, was administered by single intravenous injections to patients with different types of lymphomas and miscellaneous solid tumors for phase I evaluation. 85 out of the 110 patients included in the study were suitable for the evaluation of acute and delayed toxicity, while 93 patients were evaluable to detect the therapeutic effects of the drug. The average age of the patients was 54 years (range 7–83). 16 patients were untreated and 77 had received one or more courses of radiotherapy and/or chemotherapy. During this trial different doses and schedules were employed (table 2): A) 30 mg/m² × 2/week × 4 weeks; B) 30 mg/m²/day × 8 days; C) 15 mg/m²/day × 8 days. After a month interval all 3 courses were repeated; D) 15 mg/m²/day × 5 days to be repeated twice after 3 weeks interval. Maintenance therapy consisted of 15–30 mg/m²/week. To diminish the febrile reaction, a suppository of indometacin (100 mg) was given 30–60 minutes prior to drug administration. The incidence of toxic manifestations, irrespective of dose and schedule, was as follows (fig. 4): sclerotic changes of the skin of hands (80%), fever (67%), alopecia (61 %), skin hyperpigmentation (60 %), stomatitis (48 %), gastrointestinal disturbances (20%) and pulmonary symptoms (19%). No definite signs of marrow toxicity nor significant changes in the blood chemistry attributable to the drug were observed. Symptoms and signs of pulmonary toxicity, appearing 1–4 weeks after the last dose were: rhonchi, rales and pleural friction rubs, in some cases associated with fever and dyspnea. The chest X-ray showed evidence of interstitial lesions (in early phases most marked at the costophrenic angle) which may become widespread with a bronchopneumonia-like appearance (fig. 5 and 6). No clearcut radiological signs of pulmonary fibrosis were observed (patients were not followed for a period longer than 5 months). If BLM is stopped in time and carticosteroids are given in association to antibiotics, both clinical and radiological findings may disappear completely (fig. 7). Of the 7 patients studied post mortem, 6 revealed lesions attributable to drug toxicity (alveolar collapse with edema, histiocytic proliferation, hyaline membranes, alveolar and interstitial fibrosis (fig. 8–11). In 7 patients pulmonary toxicity was suspected only on clinical grounds, in 2 cases the radiological aspect of the lungs was suggestive of interstitial lesions without concomitant physical findings, in 9 cases a good correlation between clinical and radiological diagnosis was observed and, finally, in 6 patients the pulmonary fibrosis was detected on histological examination (table 3). In the 17 patients in whom the diagnosis of pulmonary toxicity was documented either radiologically or histologically, the average age was 56,5 years (7–78 years) and the mean total dose, producing toxicity was 230 mg/m² (range 60–480). Practically, all these patients prior to the treatment had different grades of chronic pulmonary lesions (emphysema, fibrosis post RT or tuberculosis, silicosis in 1 case). It is difficult to estimate in what proportion BLM could have contributed to the cause of death, since most patients dying during treatment had also lung metastases. However, at least in 1 case in whom postmortem examination did not disclose lymphosarcoma cells (complete remission), the cause of death could be related to drug administration (total 225 mg/m²) since extensive pulmonary fibrosis was seen on histological examination (table 4). Table 5 shows the incidence of side-effects after the first course of BLM. No significant differences were observed among cases treated with 4 different schedules, and the first sign of toxicity appeared in all groups after the 4th–6th dose irrespective of the dose and schedule. Regressions in different types of tumors were observed during this phase I study (table 6). The overall regression rate was 69 % (24 % greater than 50 % and 5% complete). The therapeutic response was prompt but usually short-lived (average 4–6 weeks). No cross-resistance with radiotherapy nor with some of the conventional agents was observed. The most responsive tumors were carcinomas of head and neck, carcinomas of esophagus (fig. 17) and malignant lymphomas (fig. 16). One 7-year-old boy with acute lymphosarcoma cell leukemia had a complete remission and autopsy revealed no signs of neoplastic disease. In 2/3 patients with CLL a moderate decrease in the volume of hepato-splenomegaly was observed without significant fall in the WBC. The minimal toxic dose was 45–60 mg/m² in malignant lymphomas and 60–120 mg/m² in the other solid tumors. BLM appears to be a potent new growth-inhibiting compound specific for epidermoid carcinomas and devoid of bone marrow toxicity. The optimal dose schedule as well as the real incidence and course of pulmonary toxicity should be more clearly defined in future studies.