As predicted by studies in animal models, drugs were most effective when used in patients with tumours of smaller volume. Another important strategy developed from this — if the tumour burden could be reduced first by surgery, then chemotherapy may be able to clear away any remaining malignant cells, even if it would not have been potent enough to destroy the tumor in its entirety. This approach was termed "adjuvant therapy".
Emil Frei first demonstrated this effect — high doses of methotrexate prevented recurrence of osteosarcoma following surgical removal of the primary tumour. 5-fluorouracil, which inhibits thymidylate synthase, was later shown to improve survival when used as an adjuvant to surgery in treating patients with colon cancer. Similarly, the landmark trials of Bernard Fisher, chair of the National Surgical Adjuvant Breast and Bowel Project, and of Gianni Bonadonna, working in the Istituto Nazionale Tumori di Milano, Italy, proved that adjuvant chemotherapy after complete surgical resection of breast tumours significantly extended survival — particularly in more advanced cancer.