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So the time is now: Where can we point to as the real areas of progress in the fight against cancer?

Cancer's high political profile and the commitment of the scientific community have produced real gains against cancer incidence and related mortality. US cancer death rates among men have decreased by more than one-fifth since 1990, largely due to advances in the treatment of lung, prostate, and colorectal cancers. Mortality among females has also dropped, but less rapidly, with the major gains concentrated in cancers of the breast and colon.

Bombs Away with Chemistry

A continuing trend in the treatment of cancer is disabling tumor growth through toxic, undifferentiated interventions such as chemotherapy (antineoplastics).

Cancer therapies of the 20th century were largely a product of serendipity. In the 1940s during World War II came the discovery of alkylating agents (agents that damage DNA). Unrelated research found that US naval personnel exposed to nitrogen mustard gas evidenced major bone marrow suppression upon autopsy. It was hypothesized that this agent "targeted" certain types of cells whose nature it was to rapidly divide, and that this could potentially be useful to suppress malignant cells. Mechlorethamine thus became the first chemical agent to be approved by the FDA, in 1949.

Using a more rational method, Sidney Farber, known as the father of modern chemotherapy, studied the effects of folic acid on leukemic cell growth. Finding that folic acid stimulated these cancerous cells, he administered anti-folates to children with acute lymphoblastic leukemia and was able to induce remissions. His report on the findings in The New England Journal of Medicine was criticized; however, nearly a decade later, in 1956, administration of methotrexate led to the first cure of a metastatic cancer, choriocarcinoma.

Farber's work was important for other reasons. Scientific questions over his counterintuitive approach exemplify the intensity of debate among cancer specialists that continues to this day. In a field where access to a hypothesized "right" treatment can mean the difference between life and death, ethical concerns are equally as important as scientific judgment. Risk is a calculation that will always be factored in the basic bottom line of drug discovery—how long, and at what cost, can we commercialize a treatment so that its benefits reach patients? Balancing this equation is hardest in those with cancer.

As more chemotherapy agents came to market, combination chemotherapy was investigated and created a major breakthrough in cancer therapy. Administering multiple drugs with varying mechanisms of action makes it more difficult for the tumor to develop resistance. In addition, combining agents with individual efficacy and differing toxicity profiles may produce a synergistic effect and allow greater tolerability of the drug.

This in turn prompted changes in the approach used by investigators for drug therapy in the conduct of clinical trials and subsequently in clinical practice. For example, to prove single-agent activity, a logical trial would compare Drug A versus Placebo. If significant improvement is seen, then Drug A could be compared against the combination of Drug A + B. The following step is typically Drug A + B versus A + C. As demonstrated, the process became more complex, often with more than one study required.