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Comparative Study on the Effects of Surgery, Chemotherapy, and Immunotherapy, Alone and in Combination, on Metastases of the 13762 Mammary Adenocarcinoma¹

Department of Immunobiology, Mason Research Institute, Worcester, Massachusetts 01608 [A. E. B., H. J. E., J. H. G.], and Breast Cancer Program, Coordinating Branch, Division of Cancer Biology and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland 20014 [D. J. T.]

The effectiveness of a methanol-soluble fraction of Mycobacterium butyricum (MSF-MB) as a nonspecific immunological adjuvant was tested as a therapeutic modality in various combinations of surgery and chemotherapy in two confirmatory studies using Fischer 344/CRBL female rats bearing the naturally metastasizing, syngeneic 13762 mammary adenocarcinoma. Animals given s.c. tumor grafts and left untreated developed large tumor masses and had a mean survival of 47.8 (S.D., ± 6.9) days. Excision of progressively growing tumors on Day 18 postimplantation prolonged survival to 65.5 ± 8 days, all animals dying from lung and organ metastases. Chemotherapy alone, i.e., treatment of established tumors with the 17ß-estradiol diester of p = [N,N-bis(2-chloroethyl)amino]phenylacetic acid (NSC 112259) at 5 mg/kg/day p.o. for 28 days, induced marked oncolysis and produced 25% cures. Following a short period of remission in the remaining animals and despite continuing chemotherapy, there was regrowth of drug-resistant tumors with a prolongation of survival to 87.3 ± 10.5 days. A short, nonimmunosuppressive, but oncolytic course (10 days) of chemotherapy, either before or after surgery, averaged 75.5% cures against metastases. Chemotherapy that was prolonged for 28 days, whether initiated before or after surgery, was immunosuppressive and reduced cures against metastases to 61%. Surgery followed by a single i.p. injection of 10 mg MSF-MB induced 10 to 20% cures. A 10-day period of chemotherapy either before or after surgery, followed by immunotherapy, was most effective and produced 90 to 100% cures. It would appear that chemotherapy alone was most effective against metastases when administered in a short, nonimmunosuppressive regimen. Thus, when chemotherapy produced a degree of oncolysis and tumor resorption with minimal or no immunosuppression and the primary source of metastases was excised, the possibility of an effective sensitization to tumor antigens was increased and nonspecific stimulation of the immune responses by MSF-MB was able to induce host resistance to cope with the remaining, possibly drug-resistant metastases.

¹ This work was supported by Contract NO1-CB-50006 from Breast Cancer Program Coordinating Branch, Division of Cancer Biology and Diagnosis, National Cancer Institute.

Received 1/30/74. Accepted 3/25/74.

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