Chemotherapy drugs are most effective when given in combination (combination chemotherapy). The rationale for combination chemotherapy is to use drugs that work by different mechanisms of action, thereby decreasing the likelihood that resistant cancer cells will develop. When drugs with different effects are combined, each drug can be used at its optimal dose, without intolerable side effects.

For some cancers, the best approach is a combination of surgery, radiation therapy, and chemotherapy. Surgery or radiation therapy treats cancer that is confined locally, while chemotherapy also kills the cancer cells that have spread to distant sites. Sometimes radiation therapy or chemotherapy is given before surgery to shrink a tumor, thereby improving the opportunity for complete surgical removal.

Radiation therapy and low-dose chemotherapy after surgery help to destroy any remaining cancer cells. The stage of the cancer often determines whether single therapy or a combination is needed. For example, early-stage breast cancer may be treated with surgery alone or surgery combined with radiation therapy, chemotherapy, or with all three treatments, depending on the size of the tumor and the risk of recurrence. Locally advanced breast cancer is usually treated with chemotherapy, radiation therapy, and surgery.

Sometimes combination chemotherapy is used not to cure but to reduce symptoms and prolong life. Combination chemotherapy can be useful for people with advanced cancers that are not suitable for radiation therapy or surgical treatment (for example, those with unresectable non-small cell lung cancer, esophageal cancer, or bladder cancer).[