Andrew, a 15-year-old boy, was diagnosed with acute lymphocytic leukemia. He underwent standard chemotherapy treatments and a bone-marrow transplant, none of which produced remission. No other standard therapies were available for Andrew to try. Dr. Wilson, Andrew’s oncologist, knew of a phase I trial of an experimental oncology therapy going on at the hospital where Andrew was being treated. Participants in these types of trials have end-stage cancer and often a prognosis of months to live, criteria that Andrew fit. Phase I trials test the safety of the experimental agent and determine the dosage that will be used in later-phase trials.
Dr. Wilson knew that phase I trials did not aim for efficacy and did not demonstrate very favorable response rates for outcomes such as tumor shrinkage. Yet he felt he should inform Andrew and his family about this study, giving them the option to decide whether or not Andrew would participate. He was concerned that, in presenting this option to them, they may think that he was advocating for Andrew’s participation.
This case raises a number of difficult ethical issues, in both the clinical and philosophical realms. Owing to their complexity, a thorough analysis is impossible in a short commentary; so we will highlight the most salient questions in the hopes that this piece will serve as a springboard for further discussion.
One must begin with some background information about Andrew’s condition. Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia, accounting for upwards of 30 percent of all pediatric cancers . Due in no small part to participation of children and their families in organized clinical trials over the last 30 years, it is now a readily treatable disease in the majority of cases, with cure rates averaging roughly 80 percent . Nonetheless, relapse following therapy for ALL remains the second leading cause of cancer deaths in children. Unlike most adults with cancer, the majority of children with cancer are enrolled in a clinical trial. Clearly, clinical research involving pediatric malignancies is of paramount importance. Children enrolled in so-called therapeutic trials derive direct benefits from their participation, ranging from the Hawthorne effect, to positive effects of the experimental therapy [3-6]. Moreover, the clinical research enterprise bestows a social good that benefits future patients.
Andrew appears never to have been in remission, which portends a dismal prognosis. While myeloablation with stem-cell transplant may offer some possibility for long-term survival, patients must be in remission for the best chance of success. At this point, having failed first- and second-line therapies, options for Andrew’s care include palliation or participation in another clinical trial (if he is eligible), but neither of these is curative. It is a common misconception that therapeutic clinical trials always seek a cure, so we must be careful to clearly distinguish between different types. In this case, Dr. Wilson feels obligated to inform Andrew about a phase I trial. This is a very specific subtype of clinical trial and is quite different from the multicenter cooperative studies that led to today’s improved cure rates for ALL. Rather, the purpose of a phase I study is “to evaluate [a drug’s] safety and identify side effects” . Hence, there can be no reasonable expectation of any direct benefit to a participant.
Unfortunately, it seems that the mere suggestion of a phase I trial as an option lends credence to, or generates a false hope for, a cure or some form of beneficial outcome, especially if it is offered by the treating physician. Dr. Wilson knows (or should know) that such studies aim to collect data regarding safety, pharmacokinetics, and other in vivo drug properties, but these details are easily misconstrued by patients and families, regardless of a physician’s intentions . Some have termed this false hope for cure the “therapeutic misconception” [9, 10]. In this setting, a phase I study may be viewed as a last-ditch effort for a cure, and can be difficult to refuse when presented as an option. Compared to palliation, which is often perceived by families as “giving up hope,” participation in the trial feels like a way to keep fighting. But properly understood, a phase I study stands to yield no such benefit to the subject, and thus cannot rightfully be thought of as a reasonable choice in the quest for a treatment.
The therapeutic misconception presents Dr. Wilson with a difficult dilemma, inasmuch as it may conflict with other physician duties, including the Hippocratic requirement to “do no harm,” and its unwritten prescriptive corollary to “do good” for individual patients. It is particularly problematic if a phase I study is pursued at the expense of palliation, or if the study medication hurts the child. One might argue that the bioethical principle of beneficence mandates a “duty to palliate” whenever there is no remaining hope for a cure. Since a phase I study presents no such hope, it might be considered tragic for Andrew to participate in this trial instead of just going home, spending quality time with family and friends, and living out his remaining weeks on his own terms with the help of a home hospice or similar program.
Insofar as this study provides no reasonable expectation for cure, there can be no legitimate duty to inform a patient or family about the phase I study. One might even argue that raising such a study as an option contributes to the fostering of false hope and inappropriate delay of rightful palliation. The simple act of an oncologist’s presenting a study as an option commonly leads to the presumption that it will benefit the patient. Yet for phase I studies, there can be no reasonable expectation of any direct benefit to the patient, regardless of how promising a new drug or technology might seem. There are too many variables and risks to assume any chance of benefit, and most certainly not a chance of cure. Not surprisingly, pediatric oncologists are conflicted and confused about the nature and role of phase I studies .
Unfortunately, even the process of phase I studies can be misleading with CT scans, blood counts, and bone-marrow biopsies often being part of the protocols. If one has no expectation of a tumor response, why should these measurements be a part of the study? Yet these tests further facilitate unrealistic expectations from participants and confuse families. So if participation delays palliation, one must wonder whether presenting the study as an option is ethical in itself. It would seem that the only ethically reasonable option, then, is to allow participation in phase I studies onlywhen rightful and appropriate palliation is also provided and when participants and families fully understand the aims of the trial. This is quite a tall order, to say the least.
On the other hand, if doctors did not enroll their (and others’) patients in phase I trials—be they children or adults—we would never be able to gather the vital information about new drugs and treatments that fuels the advance of medicine. Thus, there may be a social duty, if you will, for doctors to offer patients the option of participation in these trials (and for patients to volunteer), even when there is no expectation of individual benefit. While outside the scope of this commentary, this point raises the complex questions of the proper role and societal obligations of oncologists in the clinical research enterprise. Less obvious is the fact that, if the patient-doctor relationship remains intact, any recommendation for treatment or care of a condition must be viewed as both potentially beneficial by (and for) the patient and endorsed by the doctor. Therein lie the major dilemmas which remain unresolved.
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These are phase III clinical trials open to patients with primary, previously untreated disease. Often, they are a randomized, controlled design in which the experimental therapy is compared with the standard of care.
Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect.” J Clin Epidemiol. 2001;54(3):217-224.
Roethlisberger FH, Dickson WJ. Management and the Worker: An Account of a Research Program Conducted by the Western Electric Company, Hawthorne Works, Chicago. Cambridge, Massachusetts: Harvard University Press; 1939.
The Hawthorne effect is the poorly understood phenomenon whereby patients enrolled in clinical trials do clinically better than those with comparable disease who are not enrolled in the trial. It was originally described in the setting of behavioral research from the early 20th century.
NIH & Clinical Research. How does clinical research work? 2008. http://clinicalresearch.nih.gov/how.html. Accessed Jan 15, 2009.
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- Kimmelman J, Palmour N. Therapeutic optimism in the consent forms of phase 1 gene transfer trials: an empirical analysis. J Med Ethics. 2005;31(4):209-214.
- Glannon W. Phase I oncology trials: why the therapeutic misconception will not go away. J Med Ethics. 2006;32(5):252-255.
- Estlin EJ, Cotterill S, Pratt CB, Pearson AD, Bernstein M. Phase I trials in pediatric oncology: perceptions of pediatricians from the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group. J Clin Oncol. 2000;18(9):1900-1905.