Rationale for adjuvant chemotherapy

Surgery or radiation therapy fails to cure clinically evident human cancer, in the main, if the disease is systemic (has metastasized) when first recognized, because neither modality can effectively remove or kill distant and/or unrecognized metastases. Starting drug treatment of a tumor when it is first clinically recognized, or when it re-presents following noncurative surgical or radiological treatment, fails to cure over 90% of cancer in man because the body burden of tumor cells exceeds the tumor cell kill potential of nearly all of the most effective drugs or drug combinations against most tumors. The indicated approach to improving cure rates under these circumstances is to use chemotherapy as an adjuvant to effective (life-prolonging) but noncurative surgical and/or radiological treatment. Surgical adjuvant chemotherapy of carcinoma of the breast and osteogenic sarcoma has already been shown to increase the disease-free interval over that obtained with surgery alone, and the probability of having achieved significant increases in long-term cure rates is high. Laboratory studies with transplantable metastatic lung, breast, and colon carcinomas and melanotic melanoma, and with a spontaneous breast carcinoma of mice, all of which are uniformly fatal if untreated, have shown that: 1) the incidence of metastatic disease is directly related to tumor mass, 2) surgical cure rates drop as tumor mass at surgery increases, 3) grossly evident primary tumors are generally not curable by drug treatment, and 4) surgical adjuvant chemotherapy increases the long-term cure rates with all of these tumors and significantly increases the life span of treatment failures. Effective surgical adjuvant chemotherapy is both dose-responsive and related to the body burden of metastatic tumor at time of drug treatment. The effectiveness of surgical adjuvant chemotherapy decreases 1) as the tumor staging is advanced prior to surgery, 2) as the interval from surgery to start of effective chemotherapy is increased, and 3) as the drug doses are reduced. Additionally, and of critical importance to treatment planning, some drugs that are marginally effective or ineffective against the presurgical total body burden of tumor cells are curative in some to all mice with metastatic disease if given shortly after surgical removal of the primary tumor.