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During World War II, naval personnel who were exposed to mustard gas during military action were found to have toxic changes in the bone marrow cells that develop into blood cells. During that same period, the US Army was studying a number of chemicals related to mustard gas to develop more effective agents for war and also develop protective measures. In the course of that work, a compound called nitrogen mustard was studied and found to work against a cancer of the lymph nodes called lymphoma. This agent served as the model for a long series of similar but more effective agents (called alkylating agents) that killed rapidly growing cancer cells by damaging their DNA.

Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that aminopterin, a compound related to the vitamin folic acid, produced remissions in children with acute leukemia. Aminopterin blocked a critical chemical reaction needed for DNA replication. That drug was the predecessor of methotrexate, a cancer treatment drug used commonly today. Since then, other researchers discovered drugs that block different functions in cell growth and replication. The era of chemotherapy had begun.

Metastatic cancer was first cured in 1956 when methotrexate was used to treat a rare tumor called choriocarcinoma. Over the years, chemotherapy drugs (chemo) have successfully treated many people with cancer. Long-term remissions and even cures of many patients with Hodgkin disease and childhood ALL (acute lymphoblastic leukemia) treated with chemo were first reported during the 1960s. Cures of testicular cancer were seen during the next decade. Many other cancers can be controlled with chemo for long periods of time, even if they are not cured. Today, several approaches are available to improve the activity and reduce the side effects of chemo. These include:

• New drugs, new combinations of drugs, and new delivery techniques
• Novel approaches that target drugs more specifically at the cancer cells (such as liposomal therapy and monoclonal antibody therapy) to produce fewer side effects
• Drugs to reduce side effects, like colony-stimulating factors, chemoprotective agents (such as dexrazoxane and amifostine), and anti-emetics (to reduce nausea and vomiting)
• Agents that overcome multi-drug resistance (when the cancer doesn’t respond to the usual treatment drugs)

Early in the 20th century, only cancers small and localized enough to be completely removed by surgery were curable. Later, radiation was used after surgery to control small tumor growths that were not surgically removed. Finally, chemotherapy was added to destroy small tumor growths that had spread beyond the reach of the surgeon and radiotherapist. Chemo used after surgery to destroy any remaining cancer cells in the body is called adjuvant therapy. Adjuvant therapy was tested first in breast cancer and found to be effective. It was later used in colon cancer, testicular cancer, and others.

A major discovery was the advantage of using multiple chemotherapy drugs (known as combination chemotherapy) over single agents. Some types of very fast-growing leukemia and lymphoma (tumors involving the cells of the bone marrow and lymph nodes, respectively) responded very well to combination chemo, and clinical trials led to gradual improvement of the drug combinations used. Many of these tumors can be cured today by appropriate combination chemotherapy.

The approach to patient treatment has become more scientific with the introduction of clinical trials on a wide basis throughout the world. Clinical trials compare new treatments to standard treatments and contribute to a better understanding of treatment benefits and risks. They are used to test theories about cancer learned in the basic science laboratory and also test ideas drawn from the clinical observations on cancer patients. They are necessary for continued progress.