Maurie Markman, MD, asks who should decide whether it is ethically valid to consider off-label treatment in a patient with a very serious medical illness.
Editor-in-Chief of OncologyLive
Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center
A recent commentary in The New England Journal of Medicine regarding the theoretical use of the FDA-approved antineoplastic bexarotene to treat Alzheimer disease1 based on provocative preclinical data2,3 highlights a complex topic in the management of patients with progressive serious illnesses, including cancer, where no standard therapy of known clinical utility is available.
The matter to be highlighted here is not the critically important question of who should pay for such therapy when considered for off-label use, but rather the even more difficult issue of who should decide whether it is ethically valid to even consider such an approach in a patient with a very serious medical illness.
In their commentary, Lowenthal et al noted that "… the proper exercise of clinical judgment should certainly lead physicians to counsel patients and families that it is premature to prescribe bexarotene for this purpose. Even if patients and families are willing to take the risks for the potential benefit, the physician’s answer should be no." The commentators add, "Recommendations for the situation today should be clear and unequivocal: Bexarotene should not be prescribed before any human tests have been completed."1
But is this statement the only ethically acceptable response to this difficult situation? Is it truly appropriate to unequivocally conclude that it is the physician who should decide and simply answer "no"? What is wrong with an alternative interpretation that it is the patient who has the ultimate authority to decide?
It is critical to note here that there is no intent to suggest physicians should encourage the use of completely unproven therapeutics, or even that it is necessary for a physician to specifically bring up the topic for discussion. Further, if a patient in a desperate clinical situation elects to consider such an option, it is appropriate that any reservations a physician has should be clearly, even forcefully, expressed. After all, a major component of effective physician/patient communication in difficult situations is a willingness to openly and honestly discuss risks and benefits associated with possible medical approaches to disease management.
However, if an individual patient facing a debilitating illness or progressive cancer wishes to consider using an FDA-approved drug for an off-label indication when the approach has a rational basis, such as strong preclinical laboratory support or preliminary evidence of utility in an early-phase clinical trial, and appears to be associated with acceptable risk—or at least a well-known toxicity profile based on prior clinical investigation—by what ethical authority does a physician have the right to answer "no"?
And specifically in the cancer arena, where it has become remarkably common to see reports of novel strategies favorably impacting molecularly defined subsets of cancers in individual patients labeled as having untreatable malignancies, how can we be so smug as to believe we know all the answers?
After all, under that reasoning, was it not rather crazy or ridiculous to even consider giving that initial patient with an advanced therapy-resistant gastrointestinal stromal tumor the drug imatinib simply because there was a theoretical reason to believe that the cancer appeared to possess the same molecular abnormality as seen in chronic myeloid leukemia?4 Or to administer crizotinib based solely on preclinical data to the young man with progressive untreatable lung cancer who was found to have a novel ROS1 mutation?5 Of course, in both cases, major clinically relevant responses were observed. Should the treating oncologist have simply answered "no" when the question of the use of these drugs was raised?
One would hope that the physician community has learned something important from these and other experiences: that our own beliefs regarding how clinical innovation should be undertaken—or what is right for an individual patient— might not always be correct. And in these situations, if the patient has been provided with sufficient information by the physician and others to fully understand the possible risks, including serious side effects that may remain quite undefined, why should it not be that individual who decides whether potential clinical benefit, no matter how uncertain this may be, can justify that risk?