Long-term intermittent adjuvant chemotherapy for primary, resected lung cancer.

Adjuvant chemotherapy for lung cancer has previously been unsuccessful in improving the results of pulmonary resections. During a 12 year period, we tested long-term intermittent chemotherapy (LTIC) with mitomycin C and chromomycin A3 adjuvant to resections. LTIC was begun before the operations and the first course was completed postoperatively. Additional courses of 4 weeks each were scheduled at 3 month intervals during the first postoperative year and at 6 month intervals during the next 2 years. LTIC was defined as three or more full courses, and short-term chemotherapy (STC) was defined as a single course of adjuvant treatment. Resections for cancer in 425 patients over a 22 year period included 117 operations during a 10 year control period in which LTIC was not used and 308 during the LTIC test period. Results from adjuvant LTIC in 85 patients were compared with lesser adjuvant chemotherapy in 155 synchronously treated patients who included 77 STC recipients. Further comparison was made between LTIC and asynchronously treated, comparable control subjects. Although there were side effects and occasional deaths from chemotherapy, they did not alter the operative mortality rate. The over-all 5 year survival rate of the adjuvant LTIC patients was 50.9 per cent, as compared to 22.6 per cent in the asynchronous control subjects (p less than 0.01). For patients who were given LTIC adjuvant to palliative resections the 5 year survival rate was 35.6 per cent, as compared to 4.3 per cent for STC patients or 5.2 per cent for asychronous control subjects (p less than 0.01). Strikingly promising results were obtained from adjuvant LTIC in 10 of 33 patients with undifferentiated cancers. We conclude that LTIC prolonged life among lung cancer patients who were not cured by resection alone. Dual-agent LTIC is safe, apparently beneficial, and worthy of further clinical trials in a research setting.

[In vitro experiment on combination effect of chromomycin A3 and amphotericin B (author's transl)].

The combination effect of chromomycin A3 and amphotericin B against HeLa cells and Bacillus subtilis ATCC 6633 by the agar plate diffusion and the serial dilution method was examined. As a result, evident synergistic effect was observed when the HeLa cell was used as the test cell.

Combination chemotherapy for solid tumors using 5-fluorouracil, chromomycin-A, and prednisolone.

Clinical effect of 5-fluorouracil or chromomycin-A3 alone, 5-fluorouracil + chromomycin-A3, and of the first two plus prednisolone on gastrointestinal and other solid tumors was evaluated. Out of 133 cases acceptable for evaluation, the number of responders was as follows: 3 (18.8%) of 6 cases treated with 5-fluorouracil alone, 1 (9.1%) of 11 cases treated with chromomycin-A3 or chromomycin-A3 hemisuccinate, 13 (21.7%) of 60 cases on the two-drug regimen, and 21 (45.7%) of 46 cases on the three-drug regimen. In cases of stomach carcinoma, response rate to the three-drug regimen was 54.2% (13/24), significantly higher than that of other regimens. At least 25% regression in the size of primary tumor was observed in 2 (7.1%) of 28 cases on the two-drug regimen and in 6 (33.3%) of 18 cases on the three-drug regimen. Of 51 cases on the three-drug regimen, steroid diabetes developed in 5 cases, moon face in 4 cases, and gastric ulcer in 1 case. However, toxic effect of these regimens (especially appearance of leucopenia) was less than those of previously tried combined regimens. The duration of response, on an average, was 10.8 weeks in 13 cases on the two-drug regimen and 11.7 weeks in 21 cases on the three-drug regimen. It was concluded from these results that a better response is obtained by the three-drug regimen than other regimens, and that prednisolone in combination, in addition to its favorable effect in improving the general condition of the patients, might enhance the anticancer effect of the drugs used in combination.

Effect of the antitumor antibiotic chromomycin A3 on the humoral immune response in rats.

Chromomycin A3 (250 mug/kg) suppressed the humoral immune response in rats against sheep erythrocytes when administered 48 h or later after antigenic stimulus. The antibiotic at this dose enhanced immunity when given along with or before antigen administration. The natural heterohemagglutinin levels in rabbits and guinea pigs were not affected by the antibiotic (10 mug/kg per day x 7).

Phase I alternate-day dose study of chromomycin A3.

Chromomycin A3 was given to 43 patients with metastatic cancer in order to determine the tolerable dose when the drug was administered on an every-other-day dose schedule for a total of five iv push injections, with the course of therapy being repeated every 4 weeks. At least three patients were entered at each dose level, graduated in 0.1-mg/m2 increments between 0.7 and 1.6 mg/m2. The most common (19 patients) side effect was nausea and/or vomiting, but this was usually mild, lasted for a few hours, and diminished in severity with repeated injections. Skin necrosis due to drug extravasation was a problem early in the study, but was eliminated by injecting the drug through iv tubing. Transient elevations in SGOT and alkaline phosphatase levels were observed, but proved not to be of serious consequence. Renal toxicity proved to be the limiting factor in therapy. However, a dose level of 1.3 mg/m2 was found to be a tolerable level of drug administration in previously untreated patients. Objective tumor responses were noted in four patients (Hodgkin's disease, embryonal rhabdomyosarcoma, adenocarcinoma of the lung, and malignant melanoma).