Research and Policy Paradigms Must Consider Patients' Assessments of Relevant Goals and Outcomes

Maurie Markman, MD
Published: Tuesday, Dec 02, 2014
Maurie Markman, MD

Maurie Markman, MD

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

At first glance, the principle appears to be as quintessential as mom and apple pie. Of course what patients with cancer perceive as relevant clinical outcomes, and how these outcomes are assessed, is important in the provision of routine care and in the arena of clinical trials. In addition, the perspective of the patient with cancer must be considered in the determination of public policy.

Similarly, there would likely be no real debate regarding the fundamental role individual patients must play in decisions to be made related to the care they are to receive. Further, it would be reasonable to conclude that optimal physician/patient communication demands full disclosure of the risks versus benefits of therapeutic interventions and open discussion by oncologists with their patients to ensure the medical team understands the individual patient’s perspectives on available options.

Unfortunately, it would be difficult to draw the same conclusions regarding the role of the patient’s perspective in the definition of meaningful outcomes in oncology clinical trials that might ultimately change the management paradigm in any given clinical setting or in defining critically important policy issues.

In fact, the primary endpoint in most evidence-based phase III randomized studies in the oncology arena is an objectively measured survival outcome such as overall or, increasingly, progression-free survival. While one would never argue against the proposition that improving cancer- specific survival is an important goal of antineoplastic strategies, one must question whether it is appropriate to categorically state that this is the sole legitimate aim of treatment for an individual patient with cancer. Indeed, formal drug approval of antineoplastic agents in the United States uncommonly acknowledges the favorable impact of a given therapy on specific cancer-related symptoms.1

Nevertheless, subjective assessments of patient perceptions of the impact of therapy are generally considered solely within the category of an evaluation of adverse events (AEs); for example, symptoms of fatigue, neuropathy, emesis, diarrhea, hearing loss, etc. Further, direct inquiries of patient perceptions about their experiences during or following treatment are far more likely to be seen in the context of an evaluation of the tolerability of a given strategy (eg, long-term AEs of pelvic radiotherapy for endometrial cancer 2) rather than as an indication of the overall magnitude of its clinical benefit.

So, the question to be asked is as follows: is this the only appropriate use of patient-reported outcome assessments within the context of clinical trials, including studies employed to achieve regulatory approval?

Patient Perceptions of Symptomatic Clinical Benefit

Consider, for example, the provocative efforts of a group of gynecologic cancer investigators focused on designing a tool to carefully and objectively evaluate the impact of systemic chemotherapy on the symptom burden in women with advanced ovarian cancer.3 Among a group of 126 patients treated with cytotoxic therapy for platinum-resistant ovarian cancer, the researchers noted the (unfortunately expected) quite low (8.5%) RECIST- based objective response rate.4

As might have been anticipated in this patient population, more than 99% of patients in this analysis were symptomatic (pain [44%], fatigue [37%], abdominal bloating [32%]) at treatment initiation. And to emphasize the magnitude of the illness in this group of individuals, approximately 70% of the population reported the presence of a minimum of nine specific symptoms. The treatment regimen was associated with toxicity and less than one-half of the population received more than two cycles of chemotherapy as a result of disease progression or unacceptable AEs.

However, of the patients who were symptomatic at treatment initiation, and who achieved a response or who experienced stable disease such that they were able to continue the therapeutic regimen for a minimum of three to four cycles, almost half (48%) reported improvement in their symptoms. Further, 40% of the population was believed by their oncologists to have achieved an apparently meaningful degree of clinical benefit after their initial two cycles of treatment.

Therefore, the critical issue to be addressed is how the relatively favorable physician and patient assessment of symptomatic clinical benefit should be viewed in the setting of a clearly relatively unfavorable objective response rate. If this analysis had been undertaken in the context of a prospective clinical trial, would it be appropriate to simply state that the regimen is inactive and of no clinical utility?


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