Patient-reported outcomes are measures used in clinical trials to capture aspects of a patient’s health condition, reported directly by the patient, without introduction of bias from third parties. They are distinct from the physical toxicities reported by clinicians1 and are collected using a standardized instrument or questionnaire at different time points to monitor patient well-being and other health markers. These measures have gained traction in recent years due to a growing interest in patient-centered care, including quality of life. Various types of patient-reported outcomes are used, ranging from tools to assess physical symptoms and functions; psychological and social well-being; cognitive functioning; and the more commonly used comprehensive measure, health-related quality of life.2
Aakash Desai, MBBS, MPH
Talal Hilal, MD
Health-related quality of life is a subjective assessment of the impact of disease and treatment on a patient’s well-being (eg, functional status, symptom burden, and patient experience). It is especially relevant in cancer, where quality of life may be more meaningful to patients than longevity.
Several studies have suggested that incorporation of patient-reported outcomes in routine oncologic care improves patient outcomes, quality of life, and patient satisfaction.3 For example, a meta-analysis of 30 randomized clinical trials between 1986 and 2004 showed that health-related quality of life is prognostic of survival in patients with cancer.4 Patient-reported outcomes (most commonly health-related quality of life) were shown to be an independent predictor of overall survival and, in some cases, treatment response.5 Benefits also include increased physician-patient communication and increased symptom management.6 Recognizing the importance of health-related quality of life by the U.S. Food and Drug Administration (FDA) as a clinically relevant measure for cancer therapy approvals has led to its incorporation in various trials. Overall, this has led to an increase in the use of patient-reported outcomes from 14% to 27% in clinical trials between 2004 and 2013.7
With the increasing use of patient-reported outcomes in clinical trials, this commentary aims to explain concepts related to these measures that are geared toward general oncologists to aid in their understanding of general discussions of the topic.
Validated and Nonvalidated Patient-Reported Outcomes
Many patient-reported outcomes tools exist, but only a few have been validated. An example of commonly used and validated health-related quality-of-life tools include the National Institute of Health’s (NIH) Patient-Reported Outcome Measurement Information System (PROMIS) tool, which can be applied across various diseases.8 Its application in cancer led to the first FDA approval based on this type of measure in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I (COMFORT) trial. Validated tools that are specific to cancer include the European Organisation for Research and Treatment Quality-of-Life Core Questionnaire (EORTC QOL-C30), the Functional Assessment of Cancer Therapy–General (FACT-G), and the 36-item short-form health survey (SF-36).9-12 These tools have the capability to measure patient-reported benefit indicative of tumor response to therapy (eg, physical symptoms and limitations, social aspects, and psychological well-being).
Nonvalidated tools are sometimes easier to administer and complete but are best used as adjuncts to a primary endpoint (eg, progression-free survival) rather than as primary endpoints themselves. This is because the significance of the results acquired by a nonvalidated tool is unclear, and their value to patients has not been fully explored.
Challenges With Patient-Reported Outcomes
There are multiple aspects to patient-reported outcomes that present challenges, including choosing the right measure, experience in administering these measures to trial participants,13 choosing the right mode of administration, and ensuring full reporting of data from these measures. Beyond that, challenges for the consumer of research and the practicing clinician include accurate interpretation of patient-reported outcomes data.
First, like survival or disease progression endpoints in cancer trials, the methodology in analyzing patient-reported outcomes data should be determined a priori and included in the protocol and the manuscript. These statistical methods should be able to comment on the handling of missing data, which is a common phenomenon in clinical trials. This lack of clear reporting of methods increases bias in trials reporting such data, with more than half of the patient-reported outcomes content in trials often missing.14
Second, patient-reported outcomes tools vary in scale, measurement, and interpretation, making it difficult for patients and physicians alike to reach conclusions when evaluating results from these measures in clinical trials. Metrics can indicate a favorable result with higher values, whereas some indicate a favorable result with lower values. This can lead to a lack of patient or clinician acceptance and may limit its utility.
Third, the determination of appropriate clinical time points to assess clinically meaningful changes in health-related quality of life can be difficult. The use of unstandardized methods for longitudinal data analysis and missing data from patient dropouts further add complexity.15 To address this, a statistical approach focusing on the time until definitive deterioration has been utilized to produce meaningful longitudinal health-related quality-of-life results, which are easily interpretable.16
Patient-Reported Outcomes and Value-Based Care
Value-based care focuses on providing quality care in a cost-effective manner. On a conceptual level, patient-reported outcomes such as health-related quality of life address the patient experience in the value equation. Without them, value is judged by assessing survival outcomes alone, which does not shed light on the patient’s well-being. Furthermore, guidelines consistently incorporate survival outcome (and surrogate outcome) data in their recommendations, whereas the incorporation of patient preferences and patient-reported outcomes is inconsistent, largely due to lack of measuring and reporting.
For example, the poly (ADP ribose) polymerase inhibitor olaparib was shown to improve global health-related quality of life (using the EORTC QLQ-C30) across all patients with metastatic, HER2-negative, BRCA-associated breast cancer. Although it did not show a significant overall survival advantage over chemotherapy, some may argue that the improvement in health-related quality of life, coupled with an advantage in a surrogate endpoint (ie, progression-free survival), may be sufficient to prefer this agent over chemotherapy.17
“Patient-centered care is often overshadowed by other aspects of quality, such as efficacy and safety.”— Aakash Desai, MBBS, MPH, and Talal Hilal, MD
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Furthermore, despite the approval of anticancer drugs by the FDA on the basis of single-arm trials with a response rate endpoint, longitudinal patient-reported outcomes are rarely implemented in early clinical trials. Despite the development of a patient-reported outcomes version of the Common Terminology Criteria for Adverse Events,18 only a few phase I studies used health-related quality of life as an endpoint. Among studies with it as an endpoint, the methodology of its measurement and statistical analysis were found to be heterogeneous.19 It is currently unclear why this disparity between the uses of health-related quality of life exists among different phase trials. Thus, patient-centered care is often overshadowed by other aspects of quality, such as efficacy and safety.
Potential Solutions
Recently, an international consortium proposed standardized methods for analyzing and reporting of patient-reported outcomes in randomized cancer clinical trials.20 Areas of priority included identifying appropriate statistical methods for analysis, standardizing terminology related to missing data, and managing missing data. This may be a step in the right direction in an effort to validate patient-reported outcomes results for regulatory approval.
An increased awareness among practicing oncologists of the importance of health-related quality of life for patients is paramount. For patient-reported outcomes to become impactful for clinical decisions, oncologists will need to take into consideration one drug’s impact on health-related quality of life over another. This will only happen when health-related quality of life is universally reported in clinical trials and is easily interpretable. Whether this consortium and other protocols that aim to improve reporting will actually impact clinicians on a day-to-day basis remains to be seen.
As of now, patient-reported outcomes measurement in clinical trials is an area of evolution. However, the ultimate goal of bringing the patient’s voice into regulatory decisions for anticancer drug approvals may soon be realized.
Dr. Desai is currently a resident in the Department of Medicine at the University of Connecticut Health Center, Farmington. He will be pursuing a fellowship in Hematology/Oncology at Mayo Clinic, Rochester, Minnesota, starting later this year. Dr. Hilal is Assistant Professor of Medicine at the University of Mississippi Medical Center Cancer Center and Research Institute, Jackson.
DISCLOSURE: Drs. Desai and Hilal reported no conflicts of interest.
Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO or The ASCO Post.
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