[CANCER RESEARCH (SUPPL.) 42, 774S-781 s, February 1982] 0008-5472/82/0042-0000$02.00 Controlled Clinical Trials of Nutritional Intervention as an Adjunct to Chemotherapy, with a Comment on Nutrition and Drug Resistance1 Arthur S. Levine, Murray F. Brennan, Avner Ramu, Richard I. Fisher, Philip A. Pizzo, and Daniel L. Glaubiger Pediatrie Oncology [A. S. L, A. P.. P A. P., D. L. G.J. Surgery [M. F. B.]. and Medicine [P. I. F.] Branches, National Cancer Institute NIH Bethesda Maryland 20205 Abstract Nutritional intervention in the cancer patient [e.g., total par- enteral nutrition (TPN)] might improve durable survival because of increased tolerance to aggressive tumor therapy. To deter mine whether this assumption is correct, 42 patients with diffuse histiocytic lymphoma were induced with prednisone, high-dose methotrexate, Adriamycin, cyclophosphamide, and VP-16 (ProMACE). Nitrogen mustard-vincristine-procarbazine- prednisone (MOPP) consolidation was then used, followed by late intensification with ProMACE. Patients were selected ran domly to receive adjuvant TPN or a standard diet during ProMACE-MOPP treatment. While TPN patients had a greater median weight gain than did control patients, lean body mass and degree of myelosuppression did not differ between the 2 groups; drug tolerance was not improved as a consequence of TPN. There was no significant difference in tumor response or survival between TPN and control patients, whether or not the patients were initially malnourished. In a second trial, 32 young patients with metastatic or other poor-prognosis sarcomas were randomly allocated to receive TPN or a standard diet as an adjunct to one very intensive course of combination chemo therapy or chemotherapy plus total body irradiation; autolo- gous marrow transplantation was used with certain regimens. TPN patients experienced a greater weight gain than did con trols but remained in a negative nitrogen balance. Response rates and median durable survival did not differ between the two groups. In both trials, the maximum nutritional support permitted by currently available technology was offered. Thus, the limiting factor may not be nutritional status but rather the intrinsic biology of the tumors and the limitations of their response to current therapy. In in vitro studies of the possible influence of nutrition on cancer treatment, we have compared sublines of P388 murine leukemia cells which are sensitive or resistant to Adriamycin. The difference in drug sensitivity correlated with differences in lipid composition, with more intracellular lipid, and with greater membrane rigidity in the resistant cells. Resistant cells have a relatively poor transport of drug into the cell; moreover, intra cellular Adriamycin is sequestered in lipid depots away from DNA. These results suggest one possible relationship between nutritional phenomena and drug sensitivity. Introduction The most compelling question to be posed in studies of nutritional intervention in the patient with cancer is whether such intervention will yield a significantly improved durable survival. Controlled clinical trials of TPN2 may serve as a paradigm in addressing this question (1). It is evident that certain basic assumptions underlie treatment regimens which use TPN (2). The tumor and/or its therapy, whether surgery, chemotherapy, or radiotherapy, must induce some variant of malnutrition. Also, the malnutrition must in fact be reversible by a manipulation such as TPN. Moreover, it should be demon strable that, if nutritional defects are corrected, tolerance to cancer therapy will improve; i.e., either the dose or dose rate (or both) of the cancer treatment can be increased. To establish the ultimate utility of TPN (or any supportive care maneuver), this increase in the maximum tolerable dose or dose rate of the tumor therapy should promote an increased tumor response with respect to an increased remission rate and/or a longer remission duration. Finally, this improved tumor response should yield a significant improvement in durable survival. In essence, these assumptions reflect the notion that there are at least some tumors, at some point in their natural histories, that demonstrate a relatively linear dose-response relationship. One of the reasons for failing to achieve effective tumoricidal doses or dose rates on this linear plot would be failure to correct a nutritional deficiency (3). It is this notion which trials of nutri tional intervention in cancer patients must address directly, as in all trials of supportive care maneuvers (9). However, the failure to achieve long-term tumor control with sophisticated supportive care technologies is more likely to be due to the lack of an effective tumoricidal treatment than to our inability to provide effective supportive care (10). Moreover, it must be noted that, in some studies involving animal tumor models, a change in nutritional status has favored the tumor rather than the host (15). In this regard, Goldie and Goldman (8) have proposed that drug resistance may relate to the spontaneous rate of somatic mutation within tumor cells. If an improvement in nutrition were to enhance the proliferative rate of the tumor, this increased rate might reflect an increase in the rate at which somatic mutation occurs, favoring drug resistance. Thus, meaningful clinical trials of TPN in young cancer patients require that the tumor be responsive (i.e., at the maximum achievable dose and/or dose rate, a significant number of tumor regressions must ensue); moreover, this dose or dose rate must not be achievable unless nutritional defects are corrected. In essence, the responsive tumor is not permit ted to respond mainly because of the nutritional status of the host (4). It is evident that controlled clinical trials of TPN in young cancer patients must therefore be stratified with respect to the type of tumor being studied, since tumors are differen tially responsive to various treatments. Tumor stage and other ' Presented at the Pediatrie Cancer and Nutrition Workshop, December 11 and 12, 1980, Bethesda, Md. 2 The abbreviations used are: TPN, total parenteral nutrition; NCI, National Cancer Institute; MOPP, nitrogen mustard-vincristine-procarbazine-prednisone; ProMACE, prednisone-methotrexate-Adriamycin-cyclophosphamide-VP-16; DTIC, dimethyl-triazeno imidazole carboxamide. 774s CANCER RESEARCH VOL. 42 Research. on December 4, 2021. © 1982 American Association for Cancer cancerres.aacrjournals.org Downloaded from