Gynecologic Oncology 140 (2016) 191–192

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Incorporating Patient Perspectives and Priorities into Clinical Trial Design

Despite advances in therapy for ovarian cancer over the past 20 years, overall gains in life expectancy have been modest. In the search for more efficient strategies to identify effective treatments to prolong life, surrogate clinical trial endpoints, such as progression-free survival (PFS), have been proposed to circumvent the extended follow-up and cost associated with the gold standard endpoint, overall survival (OS). While the discussion regarding the pros and cons of trial endpoints other than overall survival have been vigorously debated, the debate has seldom included the voices of ovarian cancer survivors themselves. Such perspectives may move the dialogue forward in redefining basic definitions of trial success and failure. In this spirit, the study authors sought to better understand how patients define clinically meaningful outcomes in terms of both treatment toxicities and expectations for cure. In this issue of Gynecologic Oncology, Minion et al. found that when presented with hypothetical treatment choices of varying toxicities, patients consistently preferred treatment that offered the possibility of a cure over treatments that did not offer a cure but engendered minimal side effects [1]. If cure was not possible, patients indicated that a meaningful extension to overall survival should constitute at minimum 5-6 months. When presented with the option of a treatment with a gain of 3-4 months in overall survival and minimal side effects versus another treatment with a gain of 5-6 months in overall survival but 3 times the rate of neurotoxicity, more than twice the number of patients chose the more toxic treatment. This willingness to tolerate a greater level of toxicities in return for an increased chance of cure and/or survival was further borne out when patients were asked to rate their tolerance for common toxicities (infection, fatigue, pain, sexual dysfunction) within varying contexts for expectation of cure. Finally, when asked to rank the importance of cure and living longer without cure in relation to reduced side effects, patients overwhelmingly ranked cure and increased survival without cure over reduced toxicities and lowered treatment cost. This preference profile was unaltered by recurrence status. These results represent an important first step in incorporating patient perspectives into the ongoing discussion of surrogate trial endpoints and their validity. The study findings illustrate the respondents’ will to survive, even at the cost of increased neurotoxicities and lower quality of life. The authors make note of the mismatch in patient expectations for gains in OS versus the typical gain that is currently found. (As already implied, a gain of 5-6 months survival represents a worthy goal for future studies). However, it is striking that when presented with a choice of extended OS with high rates of toxicity or extended PFS with minimal toxicity, over one-third of respondents opted for neither treatment. It is unclear whether fewer patients would have chosen “neither” if options with more specific attributes had been presented. Future studies incorporating patient preferences could use conjoint analysis

http://dx.doi.org/10.1016/j.ygyno.2016.01.014 0090-8258/© 2015 Published by Elsevier Inc.

to characterize patient preferences and subgroup preferences, with a wider array of hypothetical scenarios. Furthermore, ensuring that hypothetical treatment choices are presented in a realistic manner (including explicit options for palliative care or no further treatment) will be important to confirm the endpoints and parameters of greatest priority to survivors. An acknowledged risk of adopting PFS as a primary endpoint is the possibility that new treatments could receive regulatory approval without demonstrating improvement in OS. The findings of this study validate this concern and suggest that trials not specifically focused on significantly prolonging life are not aligned with patients’ preferences. On the other hand, patient preferences are dynamic over the course of illness, as indicated by the well-known “response shift” phenomenon in quality of life research. Indeed, in this study respondents currently receiving therapy were more likely than those off therapy to accept a hypothetical treatment that prolonged disease stability without increasing OS. Thus, understanding the context in which treatment preferences are elicited is an important consideration for future research. One implicit assumption of this study and similar investigations is that patients’ expressed values and preferences for treatment are predictive of their eventual treatment decisions (including, presumably, the decision to participate in a clinical trial). Research on medical decision-making paints a more complex picture. For instance, experimental work highlights biases favoring action (e.g., accepting treatment) and avoidance of undesired outcomes even when the expected consequences of the decision are unfavorable or are in contrast to stated preferences [2,3]. Although decision aids have been proposed to help patients align treatment decisions more closely with their values and preferences, cognitive biases are likely to persist and shape treatment decisions in predictable ways. In conclusion, we acknowledge the importance of including survivors in the conversation on strategies to make the treatment development process more nimble and efficient. Concurrently, we call for further research on survivors’ perspectives to be informed by theories of medical decision-making and health behavior. For instance, how the probable outcomes of a given treatment are framed and presented to patients can have a marked influence on treatment decisions [4]. Therefore, it seems appropriate to consider principles for development of decision aids, such as the Ottawa framework [5], when constructing surveys of patient preferences for treatment. The results of rigorously constructed surveys should be triangulated with data on survivors’ treatment seeking and engagement in real-world clinical settings, and apparent gaps or inconsistencies between these two sources of information should be explored. The study by Minion and colleagues is an important first step toward more patient-centered treatment development in ovarian cancer.

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A. Bradford, E. Shinn / Gynecologic Oncology 140 (2016) 191–192

References [1] L.E. Minion, R.L. Coleman, R.D. Alvarez, et al., Endpoints in clinical trials: What do patients consider important? A survey of the Ovarian Cancer National Alliance, Gynecol. Oncol. 140 (2) (2016) 193–198 (in this issue). [2] A. Fagerlin, B.J. Zikmund-Fisher, P.A. Ubel, Cure me even if it kills me: preferences for invasive cancer treatment, Med. Decis. Making 25 (6) (2005) 619. [3] L.D. Scherer, M. de Vries, B.J. Zikmund-Fisher, H.O. Witteman, A. Fagerlin, Trust in deliberation: the consequences of deliberative decision strategies for medical decisions, Health Psychol. 34 (11) (2015) 1090–1099. [4] R. Matsuyama, S. Reddy, T.J. Smith, Why do patients choose chemotherapy near the end of life? A review of the perspective of those facing death from cancer, J. Clin. Oncol. 24 (21) (2006) 3490–3496. [5] Ottawa Hospital Research Institute, Development methods for Ottawa Patient Decision AidsAccessed January 8, 2016. Available at: https://decisionaid.ohri.ca/ methods.htm.

Andrea Bradford⁎ Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, P.O. Box 301439 – Unit 1362, Houston, TX 77230-1439 Corresponding author. E-mail address: [email protected] Eileen Shinn Department of Behavioral Science, University of Texas MD Anderson Cancer Center, P.O. Box 301439 – Unit 1330, Houston, TX 77230-1439 E-mail address: [email protected] 9 January 2016

Incorporating Patient Perspectives and Priorities into Clinical Trial Design.

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