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

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?

Patient Perceptions of Antineoplastic Therapy AEs

It is also necessary to inquire whether the traditional view of patient input into the toxicity profile of antineoplastic therapy and the currently accepted standard toxicity scale adequately capture the magnitude of patient concerns or even the relative weight patients place on avoiding specific AEs. Further, there is solid evidence that reporting of short-term antineoplastic drug AEs observed in clinical trials and reported in the peer-reviewed literature may fail rather substantially to capture the true magnitude of the longterm consequences of particular toxicities (eg, peripheral neuropathy⁵).

One might suggest that prospective patients be routinely surveyed regarding their preferences for the absence of development and the acceptable severity of various AEs initially observed in early studies when a new anticancer agent or combination chemotherapy strategy enters into later-stage clinical trials (phase IB, II, and III) to be certain that the patient-stated concerns for specific toxicities are appropriately considered. The use of Web- based surveys to obtain this information from a sufficiently large group of individuals to assure meaningful input may be an attractive strategy to accomplish this worthy goal.⁶

Finally, it is relevant to note here the frequent and most unfortunate total disconnect between standard toxicity scales routinely employed in cancer clinical trials, as well as study results published in the peer-reviewed oncology literature, and the real world impact of therapy on a patient’s quality of life. As observed in one analysis, so- called low-severity AEs may not even be included in many published reports of the AE profile of an antineoplastic strategy.7

The potentially serious inappropriateness of the current approach to drug evaluation can be seen in the setting of chronic oral therapy being employed in an increasing number of cancers. Consider, for example, an oral drug regimen taken once a day that produces low-level (grade 1) nausea that lasts for at least several hours after each daily dose, or grade 1 mouth sores that never quite heal, or grade 1 diarrhea or peripheral neuropathy that persists for as long as the patient remains on the agent. Or perhaps a patient may experience several of these “low level” AEs when taking the medication.

Just how adherent do we really anticipate patients will be in regularly taking this antineoplastic agent, despite its documented favorable impact on the natural history of a given cancer? Despite considerable efforts to optimize patient-reported assessments of the toxicity of therapy, the current utility of such approaches remains questionable.8 However, the importance of efforts to enhance the value of the patient perspective cannot be overstated.

The Patient’s Perspective Versus the Medical Expert or Governmental Official on Public Policy Decisions

Existing evidence strongly suggests that patients with cancer and the public in general may have substantially different perspectives on the potential benefits of more aggressive therapy for advanced cancer;⁹ the relative value versus the cost of treatment of metastatic disease;¹⁰ or even the relative value of specific benefit options that might be considered within a fixed health-related funding structure,¹¹ compared with so-called medical experts or governmental policymakers.

Similarly, it is a highly debatable question whether it is appropriate to suggest that “cancer experts” are capable of defining the most meaningful clinical outcomes or the value of therapy on behalf of all patients with cancer. Yet, this is precisely how some believe such determinations should be made.

Consider, for example, a recent summary of an Institute of Medicine workshop entitled “Delivering Affordable Cancer Care in the 21st Century,” which certainly correctly noted that, “too often, new agents are approved based on extremely modest improvements in outcome.”¹² Unfortunately, in the very next sentence in this report the authors rather remarkably and inappropriately conclude: ^12:“Although the patient has every reason to want every measure of benefit, it should be the role of expert panels and patient advocates to determine what value a new innovation represents.”

Really? And how exactly is an expert panel or several patient advocates going to assess for an individual patient with cancer faced with this life-threatening illness the subjective and highly personal balance between the potential benefits versus the possible risks and overall impact of a given therapy on that specific individual’s quality of life?

Unfortunately, such thinking has the potential to result in policy decisions that are rather irrational and potentially harmful to patients, as recently seen when a hand-picked group of medical experts recommended to the FDA that the drug regulatory agency not approve the novel antineoplastic agent olaparib in the management of recurrent ovarian cancer,¹³ despite overwhelming evidence of its potential clinical utility in a select group of individuals with this malignancy.¹⁴

Somehow these experts believed it was appropriate that they have the authority to determine how all patients with ovarian cancer should view the utility of this agent, based on the expert panel’s opinions of the risks versus benefits of the approach, rather than permitting individual patients to make their own determination.

Is this really how we want cancer medicine to be practiced in this country?

References

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