Take care when discussing phase I trial options

Will cancer patients develop false hopes from participation?

The Ethics Group provides discussions on questions of ethics and professionalism in medical practice. Readers are encouraged to submit questions and comments to [email protected], or to Ethics Group, AMA, 515 N. State St., Chicago, IL 60654. Opinions in Ethics Forum reflect the views of the authors and do not constitute official policy of the AMA. Posted Aug. 17, 2009.

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A 45-year-old man with pancreatic cancer has undergone radiation, surgery and multiple rounds of chemotherapy, and returns to discuss the results of a follow-up computed tomography scan, which suggests progression of disease. There are no remaining curative-intent therapies, nor are there any data about other reasonable palliative therapies. Should you discuss phase I trials as an option?

Reply: Phase I trials are an essential yet often misunderstood component of modern clinical research, especially in the realm of oncology. This topic continues to spark controversy for two important reasons: the frequent exhaustion of the few standard treatment options available for many patients with advanced cancers, and several common yet fundamental misconceptions about phase I trials and their goals. Due to the lack of expected benefit to the immediate participant, and the trials' controversial nature, an oncologist who decides not to raise the possibility of phase I studies with some patients has not violated professional obligations or ethics. In fact, discussing phase I trials with every patient may have unintended negative consequences for some, particularly if their decision comes at the expense of more intensive palliation or even a hospice referral.

Despite numerous advances over the past several decades, some cancers remain incurable today, especially when diagnosed at an advanced stage. Owing to this unfortunate reality, patients and physicians frequently come to a point where few promising options in traditional therapies, such as surgery, radiation and chemotherapeutics, remain, and those that do are soon exhausted when a disease continues to progress despite proven treatments. It is in this setting that phase I trials often arise as a point of discussion. In such situations, the potential for misunderstanding is enormous.

Phase I studies represent a special subtype of clinical research, each of which has its own unique characteristics and limits. The National Institutes of Health defines a phase I trial as a study whose "purpose is to evaluate [a drug's] safety and identify side effects," and one wherein "researchers test an experimental drug or treatment in a small group of people for the first time." It is these characteristics that create difficulties in deciding to offer participation in -- or even broaching discussions about -- a phase I study to a patient, much less the feasibility of obtaining truly informed consent in light of common misconceptions that are highlighted in the literature on this topic.

Still, phase I studies are vital components of the clinical research engine, both historically and currently. Were it not for such experimentation, highly promising therapies such as Gleevec, which revolutionized the treatment of chronic myelogenous leukemia, might not exist. In that study, promising results were almost immediately obvious, but most phase I trials bear little resemblance to this famous example. Less frequently discussed is the real potential for harm, and the lack of any reasonable expectation of direct benefits to the participant in the vast majority of phase I trials (less than 5%, per published data). These considerations create a dilemma for oncologists, especially those involved in clinical research, as they strive to keep the best interests of the patient in mind while working toward improving therapies for future patients and discovering eventual cures for even the most devastating diagnoses.

Perhaps the most serious aspect of this dilemma involves what is termed the "therapeutic misconception." This refers to the likelihood that patients who opt for participation in phase I research will overestimate the chance of direct benefit conferred by taking part in the study or misunderstand the goals of the trial, which are entirely research-based. In phase I trials, patients may receive medications with hypothesized therapeutic potential whose proper dose and potential side effects are not well-known. Even if a drug shows great therapeutic promise in animal models, its behavior and metabolism might be so fundamentally different in humans that it could cause significant harm or be of no benefit whatsoever. For this and many other reasons, most investigational drugs never make it to market. It can be challenging for patients to perceive the difference between the research aims of phase I studies, which focus on toxicity and safety, and the more clinically oriented aims of phase III studies, which might be more in line with their personal goals of improving symptoms, hoping for a tumor response or "maintaining hope for a cure." These goals, while ultimately shared by a patient and oncologist, cannot be reasonably expected to be fulfilled through participation in a typical phase I trial. Though we hope that all novel therapeutics will be as promising as Gleevec, they rarely are. Published estimates of tumor response in phase I trials hover around 5%, with a real risk of harm, and an estimated mortality of about 0.5%.

Though such concerns might seem theoretical and minor, they are supported by a small but growing body of studies that demonstrates the prevalence of patient misconceptions about phase I trials, a recent example of which describes these in upwards of 20% to 30% of participants. Some of these involve subtleties of understanding, such as the level of quantitative literacy that patients have, whereas others consist of frank misconstruals of research goals. For example, a smaller study found that 85% of patients opted for a phase I study out of hope for a therapeutic benefit. While the numbers vary from study to study, misconceptions among participants abound. Given these patient responses, there is clearly cause for concern.

One must wonder then whether the discussion of this "option" represents an implicit endorsement by an oncologist that it might be of some benefit to the patient. Even if this is not stated directly, and the objectives of a study are spelled out clearly in spoken word and written consent forms, patients still often get the wrong idea. Survey research suggests that some patients pursue phase I studies to fulfill a perceived need to "try everything." In such cases, the mere discussion of a trial as an option seemingly handcuffs this type of patient to participating and might make such a person resistant to hospice referral, which might have occurred had a phase I study not been raised as an "option." After all, when one is still hoping for "the cure," it can be difficult to be accepting of a more palliative approach.

For this reason, the therapeutic misconception continues to pose significant ethical concerns with regard to informed consent. After all, if one misunderstands the goals of a clinical trial (and data suggest that at least a sizeable minority still do), it would seem that consent is hardly "informed" in all cases. This seems to be the most common objection to phase I trials and the consent process that is raised in the literature. Still, some data suggest that most participants hope for a treatment response even while knowing that a study drug is unlikely to yield this benefit. In these cases, it would seem that consent is valid. One might wonder then, is there really any significant harm in this type of patient participating in a phase I trial? Perhaps not, at first glance, but, at what other costs does participation occur?

What patients may be giving up when they enroll in a phase I trial is of more serious concern. Many patients are effectively excluded from hospice or other palliative care programs because of participation in a clinical trial. The reasons for this are no doubt myriad and complex, and, although data about the ultimate origins of the problem are few, it clearly persists, despite the finding that both clinical trialists and hospice directors, when surveyed, do not object to dual enrollment.

Considering these difficulties, it seems clear that oncologists should be under no obligation to discuss phase I trials with their patients. Indeed, there are reasons to think that, with at least some patients, doing so might cause harm, as it stands to delay a more proven, beneficial intervention: palliation. Palliation, by contrast, is something I argue that physicians indeed are obligated to discuss, offer and provide. Whether palliation occurs via hospice or through a non-hospice palliative care program, or even via consultation in a palliative medicine clinic, great strides can be made in symptom management and quality of life in these venues.

Although phase I trials are a critical component of the clinical research engine that drives innovation and fuels the development of future cures, they remain problematic in some cases, and sometimes stand at odds with patients receiving the palliation they rightfully deserve when they have an advanced malignancy.

Thomas W. LeBlanc, MD, fellow in hematology and medical oncology, Duke University Medical Center, Durham, N.C.

The Ethics Group provides discussions on questions of ethics and professionalism in medical practice. Readers are encouraged to submit questions and comments to [email protected], or to Ethics Group, AMA, 515 N. State St., Chicago, IL 60654. Opinions in Ethics Forum reflect the views of the authors and do not constitute official policy of the AMA.

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