Risks and Benefits of Phase I Oncology Studies

The risks and benefits of Phase I oncology studies have been primarily derived from meta-analyses looking at response rates and mortality.57,58 The two largest published meta-analy-ses of Phase I studies report on trials conducted between 1970 and 1987; they reveal response rates of approximately 5% and mortality of 0.5% (Table 9.4).57,58 Although there have been a few other meta-analyses, they are limited by including only single-institution studies, evaluating only a few trials, and not evaluating trials published in the past decade (Table 9.4).59-63 Consequently, neither the newer compounds currently being evaluated, such as antibodies, vaccines, immuno-toxins, and antiangiogenesis factors, nor improved supportive care measures are reflected in the commonly cited response rate of 5%. More recent data suggest that the response rates may be higher. A recent meta-analysis of 477 Phase I studies sponsored by the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute between 1991 and 2002, including 10,867 participants, reported a response rate of 4% for trials with one investigational agent but an overall response rate of 12.2% for all types of Phase I trials, including those escalating doses of proven therapies.64 In addition, another meta-analysis looking at all studies published in 2002, reports an overall response rate of 18%.65 With the exception of a few agents such as cis-platinum for testicular cancer and imatinib mesylate for chronic myeloid leukemia, which produced a complete hematologic response rate of 98%, of which 96% lasted beyond 1 year, there are few data on the impact of Phase I oncology studies on other clinical parameters of benefit such as overall survival or symptom control.66-68

In regard to risks, the published meta-analyses report a mortality of 0.5% and the more recent meta-analyses report a slightly higher mortality of 0.7% to 1.3%.57,58,64,65 Besides traditional risks such as mortality, toxicity, and survival, non-medical risks are raised as risks that should be factored in the risk-benefit ratio; these include frequent blood draws, radio-logic evaluations, physician visits, and biopsies, all of which require a substantial commitment of time and resources from the patients and their families. However, it is unknown whether such factors adversely affect outcomes and quality of life of Phase I research participants. Similarly, there is a concern that nausea, vomiting, and other debilitating side effects are common; however, their overall frequency, severity, and impact on quality of life have been poorly documented. The few data that do exist on the quality of life effect suggest that despite the time commitment and side effects, participating in Phase I oncology studies may actually improve patients' quality of life compared with the alternative of receiving supportive care.69-74

This result seems paradoxical. The improvement in quality of life of cancer patients in Phase I trials may be due to receiving psychologic benefit from participating in Phase I studies.49 For some participants, the routine and regular physician contacts reduce psychologic distress during a time of great uncertainty. For others, it may allow them to exercise their willpower in a situation they did not choose.45,75 In addition, some also receive comfort from knowing they are helping future patients with cancer.28,75,76 More clinical data besides response rates and mortality are needed to fully characterize the risks and benefits of participating in Phase I oncology studies.

Besides obtaining a more complete picture of the risk-benefit ratio of Phase I oncology trials, there are several other research challenges. What criteria should we use to define a favorable risk-benefit ratio for Phase I oncology

TABLE 9.4. Response rates and death rates of Phase I oncology trials.
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