Patient Quality of Life Endpoints in Oncology Trials, Part I

In this interview we discuss symptom management and quality of life outcomes in cancer clinical trials with Bryce B. Reeve, PhD, associate professor in the department of health policy and management and a member of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and Carol M. Moinpour, PhD, full member of the Fred Hutchinson Cancer Research Center, Public Health Sciences Division.

As cancer treatments improve, and patients live longer and survive their cancer, patient-centered outcomes, control of symptoms, and quality of life both during treatment courses, as well as in the long term, are becoming increasingly more important. In oncology clinical trials, health-related quality of life measurements are being incorporated as secondary and sometimes as primary or co-primary endpoints.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: How have quality of life endpoints evolved as part of clinical trials over the last decade? Are there specific cancer types that are more likely to incorporate these patient-centered endpoints and are there any standardized tools that are used either in the United States or internationally? Professor Reeve, let’s start with you.

[[{"type":"media","view_mode":"media_crop","fid":"18096","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_6030383082894","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1227","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Bryce B. Reeve, PhD","typeof":"foaf:Image"}}]]Prof. Reeve: Thank you very much, it is a pleasure to be on this podcast. You ask a great set of questions. As far as how quality of life endpoints in clinical trials have evolved, we have seen over the past 15 to 20 years a tremendous growth in the incorporation of health-related quality of life endpoints in clinical trials. I can think of at least three sources for why we have seen this incredible growth in use of quality of life endpoints or patient-reported data on quality of life.

The first point is that there have been incredible advances in the medical and technology fields, where we have found that for any particular cancer, there may be two, three, or more different interventions that have relatively equivalent outcomes, when you consider outcomes such as survival. For example, for localized prostate cancer, we know that a radical prostatectomy or radiation treatment have equivalent survival, but each of these interventions may have different toxicity profiles. A prostatectomy could result in sexual dysfunction, as well as urinary dysfunction. With radiation therapy, the patient may experience bowel dysfunction. So the quality of life endpoints have become very important in that aspect, to allow patients the choice between two different treatments with similar survival results, allowing patients to choose the one with a lower impact on their quality of life and functioning.

The second reason I see that there has been a growth in quality of life endpoints is that the field as a whole has moved toward a patient-centered view. This means that while survival and morbidity are still important endpoints in clinical trials, and will always be the primary endpoints typically for treatment trials, we have found that there needs to be a broader focus on how the patient is affected as a whole in terms of the symptoms they experience, their functional impact, and their overall quality of life. I think this shift in the field has been driven by the patient advocacy groups and research organizations, such as the International Society for Quality of Life Research (ISOQOL), an organization focused on quality of life research, most importantly the value of incorporating patient-reported data in research and practice.

Thirdly, I think that another reason for increased utilization of quality of life endpoints in clinical trials is the result of initiatives driven by the US federal government and how it has pushed patient-reported outcomes (PROs) to the forefront. For example, the US Food and Drug Administration (FDA) released a draft guidance document for using PROs for product labeling claims in 2006, and then finalized that document in 2009. I think that guidance document drove both industry and the research field as a whole to include patient-reported outcomes and to recognize that patients are the best source for reporting quality of life data.

In addition, the National Cancer Institute (NCI) has also focused a lot of its mission and research on quality of life as an important endpoint in clinical trials. This includes the NCI’s formation of the Cancer Outcomes Measurement Working Group (COMWG) that published standards for measuring quality of life for different cancer types (Lipscomb, Gotay, Snyder, 2005). In 2006, the NCI hosted a conference on patient-reported outcomes assessment in clinical trials and the recent reorganization of clinical trials networks that led to the formation of the Symptom Management and Quality of Life Steering Committee, again with the focus on integrating patient-centered endpoints in clinical trials. So all three of these factors are why we have seen a tremendous growth in the use of quality of life in clinical trials.

In terms of standardized tools used in the United States or internationally, there have been several standardized quality of life questionnaires used over the past 2 decades. Some commonly used measures include the Functional Assessment of Cancer Therapy (FACT) (Cella et al, 1993), MD Anderson Symptom Inventory (MDASI) (Cleeland et al, 2000), and the European Organization for Research and Treatment of Cancer (EORTC QLQ) (Aaronson et al, 1993). More recently, starting in 2004, the National Institutes of Health (NIH) and the NCI have been developing a more generic, standardized set of quality of life measures called PROMIS, the Patient-Reported Outcomes Measurement Information System (Cella et al, 2007; Reeve et al, 2007), which is developing standardized endpoints to use across different types of cancer and even beyond cancer to other disease settings. Dr. Carol Moinpour is one of the principal investigators on the PROMIS project.

Cancer Network: Professor Moinpour, do you have anything to add?

[[{"type":"media","view_mode":"media_crop","fid":"18093","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_5267301845574","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1226","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Carol M. Moinpour, PhD","typeof":"foaf:Image"}}]]Prof. Moinpour: Building on what Bryce said on the role of the NCI, a number of meetings were held in the 1990s by the NCI to bring the trial researchers together, particularly those researchers in the cooperative groups, to identify important quality of life outcomes that could be included in trials. In the Southwest Oncology Group (SWOG) where I have done most of my work, it was a long struggle to get quality of life outcomes accepted, but they were. The concern was always that if you included a quality of life outcome questionnaire, you could harm accrual to the trial. We never had any evidence that that was the case, however.

An important implementation and quality control milestone was our ability to have the baseline quality of life questionnaire in SWOG trials mandatory, as long as there was a questionnaire in the patient’s language, important in minimizing bias. Over the last 15 years, there has definitely been more support for the importance of these measures, with clinicians recognizing their value.

Cancer Network: Is quality of life related to overall survival and how so? Professor Moinpour, let’s start with you.

Prof. Moinpour: There are two ways to look at this question. One way is whether or not quality of life measures are prognostic for patient survival. That means, do quality of life outcomes add information above and beyond other clinical values and in the absence of treatment? The other question is, do these variables predict the effect of treatment on survival, which would be important in personalized medicine, where ahead of time, by using biomarkers or maybe quality of life data, clinical researchers could identify particular patients who may be more likely to benefit from a particular treatment.

I think right now we have more data examining the prognostic question, and quality of life does appear to be prognostic for patient survival. Jeff Sloan (Sloan et al, 2012) from the Mayo Clinic had a recent paper in the Journal of Clinical Oncology, showing that a single item was prognostic for patient survival, while controlling for other clinical variables.

Cancer Network: Professor Reeve, do you have anything to add?

Prof. Reeve: I agree with what Dr. Moinpour said. There have been a large number of studies that have looked at this issue and have confirmed that health-related quality of life data are independent prognostic indicators for survival. To note, these studies have controlled for typical clinical data, since you control for the type of cancer, the stage of cancer and comorbid conditions, and many other clinical factors, we still see that quality of life is a significant prognostic factor for overall survival.

There have been a few landmark studies, including the one that Dr. Moinpour mentioned about Dr. Sloan’s work. One of the seminal review studies was that of Dr. Carolyn Gotay (Gotay et al, 2008), who looked across 39 clinical trials and found that patient-reported outcomes had prognostic value for overall survival in 36 of the 39 trials. There has also been significant work by EORTC researchers, who pulled data from all of their randomized, controlled trials in Europe and found that overall quality of life, including physical and fatigue factors, is prognostic for overall survival (Quinten et al, 2009). Dr. Angelina Tan (2008), who looked across different clinical trials from the North Central Cancer Treatment Group (NCCTG) and the Mayo Clinic, found again that quality of life is a significant predictor of overall survival.

We think that this has a huge impact on the field, and will be important in terms of implementation of risk prediction tools for use in clinical practice to help guide physicians and patients to make treatment choices that are most appropriate for a particular patient. A colleague of mine, Dr. Paul Han at the University of Maine, has been using quality of life data to derive a clinical tool to help physicians make decisions regarding hospice care, again to help inform whether a patient may benefit from hospice care, when they have less than 6 months to live.

Prof. Moinpour: One thing I would like to add, with respect to prognostic value of quality of life outcomes-most of the studies have used baseline quality of life data that patients provide during the trial. More recently the EORTC quality of life group, the PROBE project that Bryce mentioned, has been looking at change in quality of life (Ediebah et al, 2012). There are more data supporting the prognostic value of baseline quality of life, but there are studies supporting value for the relationship between change in quality of life and survival.

References:

Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–373.

Ahmed S, Berzon RA, Revicki DA, et al. The use of patient-reported outcomes (PRO) within comparative effectiveness research: implications for clinical practice and health care policy. Med Care. 2012;50:1060–1070.

Cella D, Yount S, Rothrock N, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS): progress of an NIH Roadmap cooperative group during its first two years. Med Care. 2007;45(5 suppl 1):S3–S11.

Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11:570–579.

Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer: the M. D. Anderson Symptom Inventory. Cancer. 2000;89:1634–1646. Available here.

Ediebah DE, Coens C, Zikos E, et al. Does change in health-related quality of life (HRQoL) score predict survival? Analysis of a lung cancer RCT. J Clin Oncol. 2012;30(15S): abstract 7607.

Food and Drug Administration, US Department of Health and Human Services. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims; 2009. Available here.

Gotay CC, Kawamoto CT, Bottomley A, Efficace F. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol. 2008;26:1355–1363.

Lipscomb J, Gotay CC, Snyder C. Outcomes assessment in cancer: findings and recommendations of the Cancer Outcomes Measurement Working Group, Chapter 7. New York: Cambridge University Press; 2005.

Quinten C, Coens C, Maser M, et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data from EORTC clinical trials. Lancet Oncol. 2009;10:865–871.

Reeve BB, Hays RD, Bjorner JB, et al. Psychometric evaluation and calibration of health-related quality of life item banks: plans for the Patient-Reported Outcomes Measurement Information System (PROMIS). Med Care. 2007;45(5 suppl 1):S22–S31.

Reeve BB, Wyrwich KW, Wu AW, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013 Jan 4. [Epub ahead of print]

Sloan JA, Zhao X, Novotny PJ, et al. Relationship between deficits in overall quality of life and non–small-cell lung cancer survival. J Clin Oncol. 2012;30:1498–1504.

Tan AD, Novotny PJ, Kaur JS, et al. A patient-level meta-analytic investigation of the prognostic significance of baseline quality of life (QOL) for overall survival (OS) among 3,704 patients participating in 24 North Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. J Clin Oncol. 2008;26(15S): abstract 9515.