Listening to the Patient Voice Adds Value to Cancer Clinical Trials

Michael D. Brundage, MSc, MD, FRCPC; Norah L. Crossnohere, PhD; Jennifer O'Donnell, BScH; Samantha Cruz Rivera, PhD; Roger Wilson, CBE, HonMD, HonLLD; Albert W. Wu, MD, MPH; David Moher, PhD; Derek Kyte, PhD; Bryce B. Reeve, PhD; Alexandra Gilbert, FRCR, PhD; Ronald C. Chen, MD, MPH; Melanie J. Calvert, PhD; Claire Snyder, PhD

Disclosures

J Natl Cancer Inst. 2022;114(10):1323-1332.

Abstract and Introduction

Abstract

Randomized clinical trials are critical for evaluating the safety and efficacy of interventions in oncology and informing regulatory decisions, practice guidelines, and health policy. Patient-reported outcomes (PROs) are increasingly used in randomized trials to reflect the impact of receiving cancer therapies from the patient perspective and can inform evaluations of interventions by providing evidence that cannot be obtained or deduced from clinicians' reports or from other biomedical measures. This commentary focuses on how PROs add value to clinical trials by representing the patient voice. We employed 2 previously published descriptive frameworks (addressing how PROs are used in clinical trials and how PROs have an impact, respectively) and selected 9 clinical trial publications that illustrate the value of PROs according to the framework categories. These include 3 trials where PROs were a primary trial endpoint, 3 trials where PROs as secondary endpoints supported the primary endpoint, and 3 trials where PROs as secondary endpoints contrast the primary endpoint findings in clinically important ways. The 9 examples illustrate that PROs add valuable data to the care and treatment context by informing future patients about how they may feel and function on different treatments and by providing clinicians with evidence to support changes to clinical practice and shared decision making. Beyond the patient and clinician, PROs can enable administrators to consider the cost-effectiveness of implementing new interventions and contribute vital information to policy makers, health technology assessors, and regulators. These examples provide a strong case for the wider implementation of PROs in cancer trials.

Introduction

Randomized clinical trials (RCTs) are critical for evaluating the safety and efficacy of interventions in oncology and thus for informing regulatory decisions, clinical practice guidelines, and health policy. Typically, RCTs evaluate a new intervention against a standard of care for a specific patient population, based on a hypothesis that the new intervention is either superior, equivalent, or not worse (noninferior) than the standard arm by a prespecified clinically relevant margin on the primary study outcome. Patient-reported outcomes (PROs) are commonly included in these RCTs to reflect the impact of receiving cancer therapies from the patient perspective. PROs vary in their content, including symptoms (eg, fatigue, appetite loss, anxiety), psychological well-being, and functional status (eg, physical functioning, sexual functioning, ability to work). PROs are scored based on questionnaires referred to as PRO measures (PROMs), completed directly by the patient, without modification or interpretation by another observer.^[1,2] A PRO may be the primary outcome, or more frequently, secondary outcomes that, for example, assess physical function or tolerability. Importantly, PROs have the potential to inform evaluations of oncological interventions by providing evidence that cannot be obtained or deduced from clinicians' reports or from other biomedical measures (eg, to assess pain, nausea, neuropathy).^[3,4]

PROs are increasingly being included in cancer clinical trials,^[2,5] complementing other clinical assessments including clinician-reported outcomes, observer-reported outcomes, or performance-based outcomes.^[2] Over several decades, the field has benefited from the development of several established PROMs with strong evidence of reliability and validity in a broad range of cancer patient populations. Recent US Food and Drug Administration guidance provides recommendations for the collection and analysis of a core set of PROs for use in cancer clinical trials, including measures of disease-related symptoms, symptomatic adverse events, measures of physical function and role function, and an overall measure of the impact of side effects.^[2,6] Further, the guidance recognizes the need to use specific measures in relevant clinical trials that are fit for purpose for patient populations with specific symptoms and functional domains of interest (for example, xerostomia and swallowing function in patients with head and neck cancers). A fit for purpose measure's properties include the following: it validly and reliably measures concepts important to patients and clinicians and can be communicated in a way that is accurate, interpretable, and not misleading.^[2] There now exist many PROMs of health status, health-related quality of life (HRQOL), and symptom burden that have been rigorously developed and tested to ensure that they address issues relevant to clinicians and patients and that also meet standards for reliability and validity,^[5,7] some of which are available in multiple languages and cultural adaptations. PROs addressing adverse events [such as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) system]^[8] are now available. Beyond measures of symptoms and HRQOL, health utility measures, such as the EQ-5D,^[9] may also be of value for cost-effectiveness analyses and health technology assessments.

But do these PROs add value to the interpretation of RCTs by providing information that can inform clinical and regulatory decision making? This commentary addresses this question with illustrative examples of how PROs have added value beyond that provided by conventional clinical outcome measures such as survival, disease response, and clinician-reported toxicity rates. We undertook this commentary as a key strategic initiative of the Patient-Reported Outcomes Tools: Engaging Users & Stakeholders (PROTEUS) Trials Consortium—a collaboration of 27 international stakeholder organizations that aims to optimize the use of PROs in research studies.^[10] This summary was designed to demonstrate ways in which PROs were key components (as either primary or secondary outcomes) of well-conducted cancer clinical trials.

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Table 1. Summary of illustrative trials: trials with PRO(s) as primary study outcome ^a
Trial name	Setting	Study arms	Sample size primary	Sample size PRO endpoint	PRO measures used	Primary outcome findings	Key PRO findings	Value of PROs	Examples of impact
Trial name	Setting	Study arms	Sample size primary	Sample size PRO endpoint	PRO measures used	Primary outcome findings	Key PRO findings	Value of PROs	Citations	Clinical decision-making or practice guideline inclusion	Policy, regulatory, or other
ALMANAC Mansel et al. (13)	Clinically node-negative breast cancer	Sentinel lymph node biopsy vs standard management of the axillary nodes	1035	816	FACT-B + 4 STAI	Patients reported less shoulder and arm morbidity (eg, lymphedema) with sentinel node approach compared with standard axillary node surgery.	No increase in patient-reported anxiety scores and shorter times to resume normal activities with sentinel node approach.	PROs as primary outcome illustrated the benefits of sentinel node approach beyond objective clinical measures such as wound complications and toxicities. As secondary outcomes, PROs showed no negative impact on patient anxiety rates.	1641	Practice guidelines (14) Patterns of care (15)	Cost-effectiveness (16) Health technology assessment (17,18)
RTOG 9714 Hartsell et al. (19)	Breast or prostate cancer patients with 1–3 sites painful bone metastases	Single fraction of radiotherapy vs 10 fractions over 2 weeks	898	845	FACT BPI	Both single-fraction and 10-fraction regimens were equivalent for pain and narcotic relief at 3 months.	Complete and partial pain and analgesia response rates were not statistically different between arms.	PROs as primary outcome confirmed equivalent rates of symptom relief. As secondary outcomes, PROs illustrated successful reductions in narcotic use and fewer adverse events with a single fraction.	780	Decision making (20) Practice guidelines (21)	Choosing wisely (22) Cost-effectiveness (23)
Temel et al. (24)	Metastatic non-small cell lung cancer	Early palliative care integrated with standard oncologic care or standard oncologic care alone	151	151	FACT-L (including LCS and TOI subscores), HADS, PHQ-9	Overall QOL favored early palliative care integration over standard oncologic care.	Early palliative care patients had less depression.	PROs as primary outcome showed the benefits of early palliative care on overall QOL, as well as secondary benefits in domains such as mental health.	6031	Practice guidelines (25,26)	Cost-effectiveness (27)

^aALMANAC= Axillary Lymphatic Mapping Against Nodal Axillary Clearance; BPI = Brief Pain Inventory; FACT = Functional Assessment of Cancer Therapy (-B = breast; -L = lung; +4 = four additional arm specific items); HADS = Hospital Anxiety and Depression Scale; LCS = Lung Cancer Subscale; PHQ = Patient Health Questionnaire; PRO = Patient-reported outcome; QOL = quality of life; RTOG = Radiation Therapy Oncology Group; STAI = State-Trait Anxiety Inventory; TOI = Trial Outcome Index;.

Table 2. Summary of illustrative trials: trials where PRO findings support the primary outcome(s) ^a
Trial name	Setting	Study arms	Sample size primary	Sample size PRO endpoint	PRO measures used	Primary outcome findings	Key PRO findings	Value of PROs	Examples of impact
Trial name	Setting	Study arms	Sample size primary	Sample size PRO endpoint	PRO measures used	Primary outcome findings	Key PRO findings	Value of PROs	Citations	Clinical decision making or practice guideline inclusion	Policy, regulatory, or other
COMFORT-II Harrison et al. (28,29)	Myelofibrosis patients with splenic enlargement	Ruxolitinib vs best available therapy	219	219	EORTC QLQ-C30; FACT-Lym	Higher proportion of patients met splenic volume reduction endpoints with ruxolitinib vs best available therapy.	Patients receiving ruxolitinib had fewer myelofibrosis-associated symptoms (eg, appetite loss, dyspnea, fatigue, insomnia, and pain).	PROs confirmed that beyond spleen size reduction, the intervention had symptom-domain benefits and functional-domain benefits (eg, superior physical functioning).	1460	Decision making (73,74) Practice guidelines (75)	Cost-effectiveness (76) Drug approval (30,31)
START Trials Haviland et al. (34) Hopwood et al. (33)	Early stage breast cancer	Longer vs shorter radiation schedule post lumpectomy	4451	2208	EORTC QLQ-C30 and protocol- specific radiotherapy items	Local recurrence rates not statistically different between longer vs shorter radiation schedule post lumpectomy.	Patient-rated cosmesis and QOL findings supported shorter fractionation schedule.	PROs confirmed that shorter treatment did not compromise breast-specific outcomes and was superior for skin cosmesis. Late shoulder and arm PROs were independent of radiotherapy schedule.	1126	Decision making (32) Practice guidelines (14,36)	Cost-effectiveness (35)
ProtecT Hamdy et al. (37) Donovan et al. (38)	Clinically localized low-risk prostate cancer	Active surveillance vs radical prostatectomy vs radiotherapy	1643	1643	EPIC-26; EORTC QLQ-C30; others (bowel, bladder, sexual, general QOL domains)	Prostate cancer-specific mortality not statistically significantly different between management options (metastatic progression higher in active monitoring group).	Patterns of severity, recovery, and decline in urinary, bowel, and sexual function domains and associated QOL, differed among the 3 groups.	Active management options were demonstrated to be equivalent for disease-specific outcomes. The differences in PROs for bladder, bowel, and sexual functioning domains were informative for patient-centered decision making.	1618	Clinical guidelines: joint AUA, SUO, ASTRO (39); ASCO (77)	Health technology assessment (78) Cost-effectiveness (41)

^aASCO = American Society of Clinical Oncology; ASTRO = American Society for Radiation Oncology; AUA = American Urological Association; COMFORT = Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment; EORTC QLQ-C30 = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30; EPIC-26 = Expanded Prostate Inventory Cancer Short Form; FACT-Lym = Functional Assessment of Cancer Therapy, lymphoma; PRO = Patient-reported outcome; ProtecT = Prostate Testing for Cancer and Treatment; QOL = quality of life; START = Standardisation of Breast Radiotherapy; SUO = Society of Urologic Oncology.

Table 3. Summary of illustrative trials: trials where PRO findings contrast the primary study outcome(s) ^a
Trial name	Setting	Study arms	Sample size primary	Sample size PRO endpoint	PRO measures used	Primary outcome findings	Key PRO findings	Value of PROs	Examples of Impact
Trial name	Setting	Study arms	Sample size primary	Sample size PRO endpoint	PRO measures used	Primary outcome findings	Key PRO findings	Value of PROs	Citations	Clinical decision making or practice guideline inclusion	Policy, regulatory, or other
ICON7 Oza et al. (42) Stark et al. (43)	Advanced ovarian cancer	Carboplatin paclitaxel vs carboplatin paclitaxel plus bevacizumab	1528	890	EORTC QLQ-OV28 EORTC QLQ-C30 EQ5D utility scores	Prolonged progression-free survival with addition of bevacizumab to carboplatin/paclitaxel; no difference in overall survival.	Global QOL inferior if bevacizumab added.	Quantified the negative impact of the intervention on QOL and informed recommendations against its routine use in some patients.	1949	Decision making (79) Clinical guidelines (46)	Cost-effectiveness (44,45) Health technology assessment (47)
COMPARZ Motzer, McCann, Deen (48)	Metastatic renal-cell carcinoma	Pazopanib vs sunitinib	1110	927	FACIT-F FACT, Kidney Symptom Index, CTSQ, SQLQ	Pazopanib was noninferior for progression-free survival compared with sunitinib.	Pazopanib resulted in better PROs for 11 of 14 domains tested (eg, fatigue, mouth soreness).	PROs illustrated that the intervention resulted in better QOL on most domains despite equivalence in progression-free survival rates.	1553	Decision making (51,80) Clinical guidelines (49,50,52)	Cost-effectiveness (52)
CCTG SR.1 O'Sullivan et al. (54)	Operable soft-tissue sarcoma of the limbs	Pre-operative vs postoperative radiotherapy	190	186	Musculoskeletal Tumor Society rating scale; Toronto extremity salvage score; SF-36	Wound complications favored postoperative radiotherapy.	Shoulder mobility and function favored pre-operative radiotherapy.	PROs demonstrate that postoperative radiotherapy may inhibit functional outcomes despite having benefit for wound complications.	1250	Decision making (55,58) Clinical guidelines (56,57)	Cost-effectiveness (81)

^aCOMPARZ = Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma; CTSQ = Cancer Therapy Satisfaction Questionnaire; EORTC QLQ = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (-C30 = core 30; -OV28 = ovarian 28); EQ5D = EuroQol 5 dimension; FACIT-F = Functional Assessment Chronic Illness Therapy, fatigue; FACT = Functional Assessment of Cancer Therapy; ICON7 = International Collaboration on Ovarian Neoplasms 7; SF-36 = 36 item Short Form Survey; SQLQ = Supplementary Quality of Life Questionnaire; PRO = Patient-reported outcome; QOL = quality of life.

Authors and Disclosures

Michael D. Brundage, MSc, MD, FRCPC^1,*, Norah L. Crossnohere, PhD², Jennifer O'Donnell, BScH¹, Samantha Cruz Rivera, PhD^3–5, Roger Wilson, CBE, HonMD, HonLLD⁶, Albert W. Wu, MD, MPH⁷, David Moher, PhD^8,9, Derek Kyte, PhD^3,10, Bryce B. Reeve, PhD¹¹, Alexandra Gilbert, FRCR, PhD¹², Ronald C. Chen, MD, MPH¹³, Melanie J. Calvert, PhD^3,4,14–16 and Claire Snyder, PhD⁷

¹Queen's University Cancer Research Institute, Cancer Care and Epidemiology, Kingston, ON, Canada; ²Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA; ³Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK; ⁴Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK; ⁵DEMAND (Data-Enabled Medical Technologies and Devices) Hub, University of Birmingham, Birmingham, UK; ⁶NCRI Consumer Forum National Cancer Research Institute, London, UK; ⁷Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA; ⁸Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; ⁹School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; ¹⁰School of Allied Health and Community, University of Worcester, Worcester, UK; ¹¹Center for Health Measurement, Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA; ¹²Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; ¹³Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, USA; ¹⁴National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Birmingham, UK; ¹⁵NIHR Applied Research Collaboration West Midlands, Coventry, UK; and ¹⁶NIHR Surgical Reconstruction and Microbiology Centre, University of Birmingham, Birmingham, UK

*Correspondence to
Michael D. Brundage, MSc, MD, FRCPC, Queen's University Cancer Research Institute, Cancer Care and Epidemiology, 10 Stuart Street Level 2, Kingston, ON K7M4E2, Canada (e-mail: michael.brundage@kingstonhsc.ca).

Disclosures
MB, CS, BBR, AW and MC receive stipend funding as steering committee members from an unrestricted grant from Pfizer in support of PROTEUS, previously supported by an unrestricted grant from Genentech. MC is a National Institute for Health and Care Research (NIHR) Senior Investigator. She receives funding from the NIHR Birmingham Biomedical Research Centre, the NIHR Surgical Reconstruction and Microbiology Research Centre and NIHR Applied Research Collaboration West Midlands at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Health Data Research UK, Innovate UK, Macmillan Cancer Support, UCB UKRI and GSK. MC has received personal fees from Astellas, Aparito Ltd, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK and the Patient-Centered Outcomes Research Institute (PCORI) outside the submitted work. In addition, MC reports that a family member owns shares in GSK. CS has received consulting fees from Janssen via Health Outcomes Solutions.
RCC, who is a JNCI Deputy Editor and co-author on this commentary, was not involved in the editorial review or decision to publish this manuscript.

Author contributions
MB: Conceptualization, Writing—original draft, review and editing. NC: Data curation; project management. JOD: Data curation; project management. SCR: Conceptualization, data curation; writing review and editing. RW: Lay author; patient perspective; writing review and editing. AW, DM, DK, BBR, AG, RC, MC: Conceptualization; writing review and editing. CS: Funding acquisition; conceptualization; writing review and editing.