Cancer is the leading cause of death among Americans 85 years and younger. According to the American Cancer Society, more than 500,000 Americans died of cancer in 2004.

The good news is that many new anticancer drugs are in development. In order to gain FDA approval, all drugs must go through three levels of testing. Phase 1 trials are conducted in small groups of patients to figure out dosage and reveal any harmful effects. Phase 2 trials determine whether the drug is effective, while Phase 3 trials compare the safety and effectiveness of the drug against conventional treatments.

Phase 1 trials for anticancer drugs usually enroll patients with advanced, progressive cancer that has not responded to available treatments. Although Phase I trials are necessary for the development of new anticancer drugs, they are controversial. Critics contend that Phase 1 trials offer a small chance of benefit, and the potential for serious harm, to a vulnerable group of patients.

Previous studies have reported that only 4% to 6% of patients respond positively in Phase 1 trials, and that approximately 0.5% of patients die from toxic effects of the drug being studied. However, these numbers only reflect trials of individual, mostly chemotherapy drugs, and not trials testing new types of anticancer drugs (such as so-called antiangiogenesis factors, vaccines, and gene therapies), or combinations of drugs.

In a study published in the March 3, 2005 New England Journal of Medicine, researchers found that more patients responded positively to the drugs being studied in Phase 1 trials than had previously been reported, and that the toxicity-related death rate was about the same as previous studies had established. They also found that about one-third of patients’ cancers remained stable following treatment, but that about 14% of study subjects suffered a serious toxic side-effect.

About the Study

The researchers reviewed data from all National Cancer Institute (NCI)-sponsored Phase 1 trials for anticancer drugs that began between 1991 and 2002. They sorted the trials into categories based on what type of drug was being studied (chemotherapy or gene therapy, for example) and then further subdivided the trials based on whether they were testing one or more drugs and whether the trials included any drugs that were already FDA-approved.

The researchers then determined the potentially beneficial effects of the drugs being studied, categorizing the patient responses to the drugs as follows:

Complete response : disappearance of a tumor

Partial response : substantial reduction in tumor size

Stable disease : no reduction or progression of tumor size

Finally, the researchers noted any serious toxic side effects or deaths that resulted from the treatments being studied.

The Findings

The NCI sponsored 460 Phase 1 trials of anticancer drugs that began between 1991 and 2002. These trials included 11,935 study subjects, all of whom were assessed for toxic side effects, and 10,402 of whom were assessed for response to treatment.

When the researchers combined the results of all of the trials, they found that 10.6% of patients had either a complete or partial response (3.1% and 7.5% respectively). An additional 34.1% had stable disease.

The response rate varied substantially based on the type of drug being studied. For example, patients receiving vaccines had an overall response rate (complete or partial response) of 3.0%, while patients in trials of drugs that influence the immune system (also known as immunomodulators) had an overall response rate of 13.6%.

The type of trial also had an effect. Patients in trials studying an individual chemotherapy drug had an overall response rate of 4.4%, but patients in chemotherapy studies involving more than one drug had an overall response rate of 11.7%.

Of the 11,935 study participants, 58 patients (0.49%) died. Of the 58 deaths, 74.1% were enrolled in chemotherapy trials. Patients in chemotherapy trials were also more likely to suffer a serious toxic side effect than patients in trials of other types of drugs, with 17.4% of chemotherapy patients reporting at least one serious toxic side effect.

Of the 460 trials, 25.4% tested a drug that had not been previously tested in humans. These so-called first-in-human trials had an overall response rate of 4.8%, compared to 13.1% for the other trials.

This study was limited by the fact that it only looked at trials sponsored by the National Cancer Institute. Although the NCI is the major sponsor of Phase 1 trials of anticancer drugs in the United States, the decision by the researchers to limit their review to NCI-sponsored studies leaves open the possibility that trials sponsored by pharmaceutical companies, for example, could have response rates that differed from those reported in this study.

How Does This Affect You?

In reviewing all recent NCI-sponsored Phase 1 trials of anticancer drugs, the researchers found a higher overall response rate and a similar toxicity-related death rate compared to previously published, mostly chemotherapy trials. As the review showed, the response rates and rates of death and serious toxic side effects varied greatly based on the type and number of drugs being studied.

An important finding of this study was that about one-third of study participants had stable disease, meaning their tumors did not progress. Because all study subjects had progressive disease going into the trials, treatments that kept tumors from growing should be viewed as beneficial.

Finally, it is worth considering the costs and benefits to study participants that are not routinely measured in Phase 1 trials. On the down side, patients may have been subjected to additional doctor’s visits or unpleasant procedures associated with the treatments being studied. On the other hand, study subjects in these trials may have enjoyed increased energy, reduced pain, increased appetite, weight gain, or other benefits of the drugs that made their participation worthwhile.