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Journal of Clinical Oncology, Vol 24, No 27 (September 20), 2006: pp. 4479-4484 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.0269 Patients' Decision-Making Process Regarding Participation in Phase I Oncology Research
From the Department of Clinical Bioethics, Warren G. Magnuson Clinical Center; Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Colorado Health Outcomes Program, Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO; and the Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, PA Address reprint requests to Manish Agrawal, MD, Department of Clinical Bioethics and National Cancer Institute, Building 10, Room 1C118, 10 Center Dr, Bethesda, MD 20892-1156; e-mail: agrawalm{at}mail.nih.gov
PURPOSE: This study assesses the decision-making process of patients enrolling in phase I oncology studies. PATIENTS AND METHODS: Participants were eligible if they had consented to participate in a phase I cancer study at one of five cancer centers, understood English, and were older than 18 years. Trained interviewers conducted structured in-person interviews. RESULTS: Of the 163 participants, 88% were white, 96% had health insurance, and 51% were college graduates or post graduates. Overall, 81% were aware of hospice, but only 6% had seriously considered hospice for themselves; 84% were aware of palliative care and 10% seriously considered it for themselves; and 7% considered getting no treatment at all. Overall, 75% reported moderate or a lot of pressure to participate in the phase I study because their cancer was growing, whereas 7% reported such pressure from the study investigators and 9% felt such pressure from their families. For 63% of patients, the most important information for decision making was that the phase I drug killed cancer cells; only 12% reported that the adverse effects of the drug(s) was the most useful information. More than 90% of patients said they would still participate in the study even if the experimental drug caused serious adverse effects, including a 10% chance of dying. CONCLUSION: Patients are aware of many alternatives to phase I studies, but do not seriously consider them. Very few experience pressure from family or researchers to participate in research. Their main goal is to fight their cancer, and almost no adverse effect, including death, would dissuade them from enrolling.
Despite substantial improvements in treatments for individual cancers 50% of 550,000 people annually diagnosed with cancer in the United States, still die from it.1 Therefore, research into finding novel therapies for most cancers remains an important national health priority. Phase I oncology trials are a necessary and critical initial step in evaluating new therapeutic agents for cancer, yet they continue to be ethically controversial.2-9 A common ethical concern regarding phase I oncology trials is that patients who participate do not understand the trials' purpose and do not have the information necessary to make an informed decision.3,5,6,9 The implicit claim is that if patients were rational and really understood the purpose of phase I studies and the risks, limited benefits, and their alternatives, most would not participate. There is a concern that patients who participate in phase I oncology studies have a therapeutic misconception.10-12 Unfortunately, the current understanding of patient's decision-making process for enrolling in phase I oncology trials is limited.13-22 First, published studies have addressed factual understanding of trial information and have not adequately considered the subjective appreciation of the information patients bring to their illness and the research study.13,17,19,23 Many of the questions used to assess understanding by participants of phase I oncology trials are posed primarily from an investigator's perspective rather than a patient's.10,14,16,17,24 Thus, prior studies do not adequately evaluate what information patients utilize in their decision making. In addition, prior surveys have not evaluated participants' awareness of their alternatives, what pressures influence their decision making, how they assess potential adverse effects, and other aspects of the experimental regimens.13,17 Further, by delaying the administration of the survey instrument until days or even weeks after signing of the consent, some prior studies evaluate recall of information as opposed to the ethically relevant understanding at the time of decision making.25,26 Finally, most of the studies are small, and all but one were limited to a single institution.14,18,19,27 To address these limitations and expand our understanding of participants' decision making about phase I trials, this multicenter study assesses the actual decision-making process of patients with advanced cancer who participate in phase I oncology studies. Specifically, we assess four areas of the decision-making process: (1) how participants perceive their options and alternatives, (2) what pressures they feel when making their decisions, (3) how they understand the purpose and risk of research, and (4) how they assess the benefits from research.
Patients Participants were eligible if they had just consented to participate in a phase I oncology trial but had not yet received treatment, understood written English, and were older than 18 years. Enrollment occurred at five geographically dispersed sites: (1) National Cancer Institute (Bethesda, MD), (2) Institute for Drug Development of the Cancer Therapy and Research Center (San Antonio, TX), (3) Northwestern Cancer Center (Chicago, IL), (4) The University of Texas M.D. Anderson Cancer Center (Houston, TX), and (5) Fox Chase Cancer Center (Philadelphia, PA). Immediately after they signed consent to participate in the phase I oncology study but before receiving any therapy, patients were asked by the principal investigator or his/her designee to consider participating in this in-person interview. After consenting to the interview, a trained interviewer administered the survey.
Survey Development The final survey instrument consists of 61 questions in eight domains: (1) alternative treatment options, (2) sources of pressure to participate, (3) prognosis, (4) understanding of the specific research protocol, (5) motivations for participation in phase I studies, (6) risk/benefit preferences for treatment for their cancer, (7) information-gathering behavior about phase I oncology studies, and (8) sociodemographic characteristics. Performance status was assessed using the Eastern Cooperative Oncology Group (ECOG) scale.28 Patients were given a list of adverse effects frequently associated with experimental oncology drugs and asked for each one if they would or would not participate in the trial if the study drug they were to receive caused that adverse effect. We asked what type information about the trial was important to them when deciding whether to participate in phase I oncology studies.
Statistical Analyses
Patient Characteristics Of the 163 patients interviewed, 56% were male, 88% white, 80% married with a mean age of 58 years (interquartile range, 46 to 68 years; Table 1). Consistent with prior studies of patients enrolled in phase I oncology trials, the patients had moderate to high socioeconomic status, with 62% having a household income greater than $50,000, 96% having health insurance, and 51% having graduated college or having postgraduate training.10,14,16,17 Almost all (97%) of the enrolled participants had normal physical activity or needed only minimal extra rest during the day (ECOG performance status 0 or 1).
Patients had long experience with cancer and cancer treatments. They had cancer for an average of 4.8 years (interquartile range, 1.3 to 5.7 years) and had received a mean of 3.0 (interquartile range, 1.0 to 4.0) prior chemotherapy regimens (Table 1). These patients had contacted a mean of 3.0 (interquartile range, 1.0 to 4.0) doctors to obtain treatment information before deciding to participate in the phase I oncology trial, and visited a mean of 1.9 (interquartile range, 1.0 to 2.0) medical centers (Table 1).
Knowledge of Alternatives
In the multivariate analyses, only performance status was a significant predictor of awareness of alternatives. Patients with a good performance status were significantly less likely to be aware of hospice (odds ratio [OR] = 0.41; 95% CI, 0.19 to 0.89) and those with a poor performance status were significantly more likely to be aware of symptom management (OR = 2.15; 95% CI, 1.18 to 3.93). Age, education, race, religion, income, insurance status, and prior experience with cancer were not associated with knowledge of alternatives.
Pressure to Participate
In multivariate analyses, only education was a significant predictor of feeling pressure. More-educated research participants were significantly less likely (OR = 0.64; 95% CI, 0.43 to 0.94) to feel pressure from their families to participate in the phase I oncology study.
Understanding the Research Purpose and Risks
No single adverse effect, including a 10% chance of death by the experimental drug, would persuade a majority of the participants not to enroll in the phase I research study (Table 5). Indeed, more than 90% of patients reported that they would still agree to participate in the study if they were told that the experimental drug had the potential of causing complete hair loss, nausea, fatigue, a 20-pound weight gain, required having a bone marrow biopsy, or having to spend a night in the hospital. Only if the phase I drug impaired their ability to think would 24% of the patients not participate in the phase I trial (Table 5). Even a 10% chance of dying as a result of taking the experimental drug would not have dissuaded 90% of the patients from participating in the phase I oncology study.
Understanding the Benefits of Research Patients who enrolled in phase I oncology trials believed that they would personally benefit, and this assessment includes factors other than cure or life prolongation. The patients in this study tended to estimate that they were much more likely to personally benefit from participating in the research study than other participants. Only 3% reported that they personally were very or somewhat unlikely to benefit from participating in the phase I study even though 60% estimated that others were unlikely to benefit—they estimated that in less than half of other participants the cancer would shrink—from participating in the clinical trial. This suggests that patients tend to be therapeutic optimists29 in which the research participant hopes for the best personal outcome rather than be under a therapeutic misconception29 in which the research participant conflates research with clinical care. One reason these patients appear to believe their chance of benefit is so high is that they find benefit from the routines associated with participation in a phase I study, including receiving any type of drug, having frequent tests to assess the status of their cancer, and having regular visits with the oncologist. Overall, 78% reported receiving a moderate amount to a lot of comfort from having diagnostic tests and physician visits at least every 1 to 2 months as part of the phase I oncology study. In addition, 44% reported that participating in the phase I oncology study gave them a sense of control, and 56% said that trying a new chemotherapy drug gave them hope.
This study of patients participating in phase I oncology studies that reveals people who are experienced with the rigors of cancer treatments are well informed about their alternatives, are not dissuaded by serious adverse effects of treatment, and do not feel coercive pressures to enroll. This is not the picture of inexperienced, uninformed, and vulnerable phase I oncology patients commonly portrayed.6,7 It suggests people motivated to fight their cancer at almost any cost.30-32 Participants in phase I oncology studies are neither inexperienced nor uninformed about their alternatives. In this study, the vast majority of participants in phase I oncology studies have experienced cancer chemotherapy and radiation therapy for many years before enrolling in research studies. In search for their current treatment, they have extensively investigated their options, having met with multiple physicians and been assessed at an average of nearly two cancer centers. The vast majority—over 80%—are aware of alternatives, including symptom management, hospice, and even letting the cancer run its course without further treatment, even when these options are not explicitly mentioned in informed consent documents.33 However, palliative care alternatives, including hospice, are not options these individuals seriously consider for themselves. A reasonable conclusion from the data is that one of the reasons palliative care and hospice may not be a serious consideration for patients enrolled in phase I studies is that despite having a terminal diagnosis, they have a relatively good performance status and so they do not feel like they are dying. Importantly, participants do not appear to be vulnerable and coerced into enrolling in the phase I oncology studies. The vast majority of these individuals are white, well educated, with higher incomes, and have the flexibility associated with having health insurance. These are not the characteristics of a population vulnerable to societal pressures or unable to understand information or give voluntary consent. Furthermore, less than 10% report any pressure either from their clinical researchers or their family members. Instead, the pressure they experience is from the inexorable growth of their cancer. Importantly, while this pressure can be psychologically powerful, it is not ethically problematic. Pressure to do something about a growing cancer is not a type of coercion or force that compromises the validity of informed consent.30,34,35 Thus, claims that phase I participants are coerced into enrolling in research are not supported by data. The desire to actively do something to fight their cancer appears to motivate these participants to enroll in phase I oncology trials.25,30 Consequently, the information that they feel is most important to their decisions is whether the experimental drug kills cancer cells, not the details of the research study or the experimental treatment's adverse effects. For these patients, the phase of study, how the drug is administered, how often it is administered, or the financial costs of participating —factors that researchers, bioethicists, and institutional review boards usually consider essential information—are not particularly important to their decision-making process. These participants are well aware of the adverse effects of cancer treatments—especially given their previous experience with chemotherapy—yet information about adverse effects is not particularly influential in their decision making about participation in phase I studies. Nausea, fatigue, a bone marrow biopsy, spending a night in the hospital, even a 10% chance of dying would not deter 90% of patients from enrolling in a phase I research study. These data suggest that the detailed delineation in informed consent forms of the fact that the treatment is part of a research trial, the phase of the research study, the procedures, and the risks are not particularly salient to patients enrolled in phase I studies. This may explain the less-than-perfect recollection of these factors in prior studies about the quality of informed consent in phase I oncology studies.13,17,23 Consistent with their motivation to fight their cancer, these patients receive comfort from frequent diagnostic tests and scheduled visits with their oncologists that assess their disease status, rather than finding such tests and visits burdensome. Finally, these data indicate that participating in a phase I cancer study allows patients to maintain hope.36 Rather than being under a therapeutic misconception, phase I participants appear to be therapeutic optimists.24,25 Only 3% reported that they were personally very or somewhat unlikely to benefit from participating in the phase I study, whereas 60% estimated that other patients were unlikely to have their cancer shrink from participating in the same phase I study. For these patients, an effective method for maintaining hope in the setting of advanced cancer is to engage in an activity that gives them an anticancer treatment, and provides a structured, highly routinized environment.16,30 These patients are therapeutic optimists, which is not ethically problematic but a justifiable coping strategy.24,28 This study has several limitations. It reports on 163 patients from five geographically diverse cancer centers; thus the results may not be generalizable to all participants in phase I oncology studies. However, the sociodemographic characteristics of the patients interviewed in this study are very similar to the characteristics of participants and nonparticipants in phase I oncology studies during the last decade.17,19,25,26,37 This study demonstrates that patients who participate in phase I studies are aware of, but do not seriously consider, other options to the phase I study, and that knowledge of most toxicities would not dissuade them from participating. The information they care the most about is whether the investigational agent can kill cancer cells. Participating in a phase I study is comforting to them and may provide an effective method to deal with a difficult situation. Our data suggest that although patients participate in phase I studies in hope of benefit, it does not necessarily mean they do so with insufficient information to make decisions.
The authors indicated no potential conflicts of interest.
We thank Liz Dean at Research Triangle Institute for assistance in survey development and processing. We thank David Wendler and Eric Kodish for critical reviews of the article. We thank Marty Smith, Eric Rowinsky, and Anthony Tolcher for their assistance in patient accrual.
Supported by the Department of Clinical Bioethics of the National Institutes of Health (NIH) and in part by NIH Grant No. R0182085 (N.J.M.). The ideas and opinions expressed are the authors' own. They do not represent any position of policy of the National Institutes of Health, Public Health Service, or Department of Health and Human Services. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
