For more than three decades, the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) has engaged in clinical trial research that includes direct reporting from patients regarding their symptoms and quality of life. Patient-reported outcomes (PRO) research has led to many discoveries that have influenced current research priorities and the way the Group designs its trials.

PROs are health outcomes directly reported by the patient without interpretation by a clinician or anyone else. By incorporating PROs into select phase 2 and phase 3 trials, ECOG-ACRIN ensures that researchers consider patient experiences during the trial alongside the clinical outcomes included in that trial. Also, having PROs in a trial provides critical data on drug efficacy and tolerability to better inform the interpretation of the trial results.

Below, we highlight just a few of the advancements ECOG-ACRIN has contributed to the field of PRO research.

Characterization of Fatigue

A prime example is E2810, a study of adjuvant sorafenib or sunitinib versus placebo in early-stage renal cell cancer (RCC). This trial followed the successful introduction of tyrosine kinase inhibitors (TKIs) in advanced RCC. Although this trial found that adjuvant TKI therapy was not more effective than placebo, measuring fatigue using both the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and the Patient-Reported Outcomes Measurement Information System-Fatigue (PROMIS Fatigue) measures allowed us to characterize fatigue associated with these agents vis-à-vis a placebo control (Zhao et al, 2018). Additionally, it enabled evidence-based estimates of meaningful change in patient-reported fatigue on both measures, helping ECOG-ACRIN statisticians plan for future studies where fatigue is a key trial endpoint.

More Accurate Estimation of Toxicity Burden

In another example, a comparison of adjuvant platinum-based chemotherapy versus capecitabine for treating patients with triple-negative breast cancer (trial EA1131) found that patient-reported side effects assessed early in the trial using the NCCN Functional Assessment of Cancer Therapy Breast Cancer Symptom Index (NFBSI-16) were worse in the capecitabine arm, despite clinician-rated toxicity showing no difference (Smith et al, 2024). This finding contributed to a growing body of literature indicating that clinician-reported adverse event rates often underestimate the impact of treatment toxicity on patients.

Recognizing this, the National Cancer Institute (NCI) recently funded a multi-group consortium that aimed to better understand treatment tolerability, especially from the patient perspective. ECOG-ACRIN participated in this consortium under a cooperative agreement entitled EVOLV: Analysis of ECOG-ACRIN adverse event data to optimize strategies for the longitudinal assessment of tolerability in the context of evolving cancer treatment paradigms. It resulted in a series of published manuscripts on the powerful predictive value of even a simple question about side effect bother. This question, known as FACT GP5, is a five-point patient rating of the degree of side effect bother, ranging from “not at all” to “very much” bothered.

Medical journals have published several ECOG-ACRIN papers on the utility of FACT GP5  for predicting treatment withdrawal, dose reduction, and other downstream clinical events (Wagner et al, 2018; O’Connell et al, 2024; Peipert et al, 2024).  In addition, the US Food and Drug Administration (FDA) has pointed to this simple question as a useful way to gain an overall patient-centered understanding of what is often a complex combination of side effects from one treatment versus another.

In fact, two recent FDA-approved oncology drugs (involisib for HER2-negative metastatic breast cancer and selpercatinib for locally advanced or metastatic non-small cell lung cancer) included tolerability label claims assessed by PROs, further signaling FDA’s interest in hearing and incorporating the patient voice. Selpercatinib has FACT GP5 in the label and involisib has the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in the label. These are both measures the ECOG-ACRIN PRO Advisory Group supports when advising on measure selection during protocol development.

Novel Measures of Patients’ Experiences with Treatment

ECOG-ACRIN contributed extensively to the understanding of treatment tolerability and has been shaped by it as well. The Group has been focusing increasingly on the patient’s experience of treatment, including the use of PRO-CTCAE and the FACIT item libraries to capture patient side effects as well as treatment benefits.

This focus is especially critical in the modern era of immunotherapy, where ECOG-ACRIN has contributed to the development and application of novel measures. Beginning with the original FACT-Biologic Response Modifier scale, developed with the Melanoma Committee years ago (McLouth et al, 2023), it was reported that ipilimumab 3 mg/kg was considerably better tolerated than interferon as adjuvant therapy for melanoma. More recently, PRO researchers at ECOG-ACRIN have contributed newer measures of immune therapy toxicity, ranging from the effects of checkpoint modulators to CAR T-cell therapy (Webster et al, 2020; Gudenkauf et al, 2025).

In conclusion, the examples above illustrate the value of PROs in enhancing the relevance of clinical trials, as well as the contributions of the members of ECOG-ACRIN’s PRO Working Group, led by John (Devin) Peipert, PhD. Expert advisors are available as a resource to guide ECOG-ACRIN investigators on how best to include PRO measures and endpoints in selected phase 2 and phase 3 trials through the PRO Advisory Group. 

If you are interested in learning more about PROs in clinical trials, becoming a PRO advisor, or receiving insights on a trial you are developing, please contact your protocol development associate or send an email directly to the PRO Working Group team.

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References

Zhao F, Cella D, Manola J, DiPaola RS, Wagner LI, Haas NSB. Fatigue among patients with renal cell carcinoma receiving adjuvant sunitinib or sorafenib: patient-reported outcomes of ECOG-ACRIN E2805 trial. Support Care Cancer. 2018 Jun;26(6):1889-1895. doi: 10.1007/s00520-017-4027-7. Epub 2017 Dec 23. PMID: 29274030; PMCID: PMC5924580.

Smith KL, Zhao F, Mayer IA, Tevaarwerk AJ, Garcia SF, Arteaga CL, Symmans WF, Park BH, Burnette BL, Makower DF, Block M, Morley KA, Jani CR, Mescher C, Dewani SJ, Brown-Glaberman U, Flaum LE, Mayer EL, Sikov WM, Rodler ET, DeMichele AM, Sparano JA, Wolff AC, Miller KD, Wagner LI. Adjuvant platinum versus capecitabine for residual, invasive, triple-negative breast cancer: Patient-reported outcomes in ECOG-ACRIN EA1131. Cancer. 2024 May 15;130(10):1747-1757. doi: 10.1002/cncr.35187. Epub 2024 Jan 18. PMID: 38236702; PMCID: PMC11078225.

Wagner LI, Zhao F, Goss PE, Chapman JW, Shepherd LE, Whelan TJ, Mattar BI, Bufill JA, Schultz WC, LaFrancis IE, Nagargoje GG, Vemuri R, Nikcevich DA, Sledge GW, Cella D. Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03). Breast Cancer Res Treat. 2018 Jun;169(3):537-548. doi: 10.1007/s10549-018-4713-2. Epub 2018 Feb 17. PMID: 29455298; PMCID: PMC6092930.

O'Connell NS, Zhao F, Lee JW, Ip EH, Peipert JD, Graham N, Smith ML, Gareen IF, Carlos RC, Obeng-Gyasi S, Sparano JA, Shanafelt TD, Thomas ML, Cella D, Wagner LI, Gray R. Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial. J Clin Oncol. 2024 Jan 20;42(3):266-272. doi: 10.1200/JCO.23.00377. Epub 2023 Oct 6. PMID: 37801678; PMCID: PMC10824381.

Peipert JD, Zhao F, Lee JW, Shen SE, Ip E, O'Connell N, Carlos RC, Graham N, Smith ML, Gareen IF, Raper PJ, Weiss M, Kumar SK, Rajkumar SV, Cella D, Gray R, Wagner LI. Patient-Reported Adverse Events and Early Treatment Discontinuation Among Patients with Multiple Myeloma. JAMA Netw Open. 2024 Mar4;7(3):e243854. doi: 10.1001/jamanetworkopen.2024.3854. PMID: 38536173; PMCID: PMC10973895.

McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. doi: 10.1007/s11136-022-03226-8. Epub 2022 Aug 27. PMID: 36029412; PMCID: PMC9839512.

Webster KA, O'Connor ML, Hansen AR, Kircher S, Jim HSL, Dicker AP, Janda M, Ala-Leppilampi K, Bingham CO 3rd, Feliciano J, Lynn Henry N, Steffen McLouth LE, Cella D. Development of a Functional Assessment of Chronic Illness Therapy item library and primary symptom list for the assessment of patient-reported adverse events associated with immune checkpoint modulators. J Cancer Metastasis Treat. 2020;6:8. doi: 10.20517/2394-4722.2019.38. Epub 2020 Mar 13. PMID: 34790879; PMCID: PMC8594877.

Gudenkauf LM, Tometich DB, Hoogland AI, Kirtane K, Small BJ, Barata A, Gonzalez BD, Chung CH, Khushalani NI, Cella D, Webster KA, Dicker AP, Jim HSL. Validation of the Functional Assessment of Cancer Therapy – Immune Checkpoint Modulator Symptom Index (FACT-ICM SI-17) to facilitate implementation for research and clinical care. Annual Meeting and Scientific Sessions of the Society of Behavioral Medicine, San Francisco, CA. 2025, March. (Poster)