The James Ewing lecture. The relationship between tumor mass and resistance to chemotherapy. Implications for surgical adjuvant treatment of cancer.

Tumor mass negatively influences the outcome of surgery and radiotherapy by its influence on invasiveness and the propensity to metastasize before local treatment is applied. Tumor mass negatively affects the outcome of cancer chemotherapy in a manner quite different from the way in which it does surgery or radiotherapy. Cancer chemotherapy fails because cells develop resistance to anticancer drugs. Conceptually, there are two types of resistance both of which are mass related: temporary resistance (due to pharmacologic sanctuaries or altered cell kinetics) or permanent resistance (mutant lines developing specific and permanent resistance to one or more cancer drugs). Based on somatic mutation theory, it now appears that resistant mutants arise spontaneously early in the natural history of cancers, and the likelihood of a resistant line developing appears closely related to cell number, such that one or more resistant lines are likely present before most human malignancies become clinically evident. The development of permanent resistance more precisely accounts for the invariable inverse relationship between cell number and curability by drugs and the greater effectiveness of combination chemotherapy over single agents. New information on common pathways of drug resistance appear exploitable using tools available today or on the horizon. Treatment of bacterial infections, particularly tuberculosis, now truly appears to be a paradigm for cancer chemotherapy.