Consortium Organization

Principal Investagator(s): Ethan Basch, M.D., M.Sc.; Amylou Dueck, Ph.D.
Institution(s): University of North Carolina, Chapel Hill; Mayo Clinic-AZ

Project Title: Analyzing and Interpreting PRO-CTCAE with CTCAE and Other Clinical Data to Characterize Drug Tolerability

Ethan Basch, M.D.

Amylou Dueck, Ph.D. 

Team

• Gita Thanarajasingam, M.D. (Site PI: Mayo Clinic-Rochester)
• Lauren Rogak, M.A. (Site PI: Memorial Sloan Kettering Cancer Center)
• Gina Mazza, Ph.D. (Mayo Clinic-AZ)
• Blake Langlais, M.S. (Mayo Clinic-AZ)
• Brenda Ginos, M.S. (Mayo Clinic-AZ)
• Allison Deal, M.S. (UNC-Chapel Hill)
• Molly Voss (Mayo Clinic-AZ)
• Carolyn Mead-Harvey, M.S. (Mayo Clinic-AZ)
• Paul Novotny, M.S. (Mayo Clinic-Rochester)
• Brie Noble (Mayo Clinic-AZ)
• Minji Lee, Ph.D. (Mayo Clinic-Rochester)
• Bellinda King-Kallmanis, Ph.D. (Lungevity)
• Bryce Reeve, Ph.D. (Duke University)
• Annissa Ulbrich, M.B.A. (Mayo Clinic-Rochester)

Research Area

The Basch/Dueck team are at the forefront of patient-reported outcomes—they are the team behind the development and validation of the PRO-CTCAE item library. Along with a multi-disciplinary team across academic institutions, community cancer centers, the NCI, NIH and FDA, they have been at the helm of the evolution of patient-reported outcomes within oncology.

Research areas include development of standardized interpretable and clinically useful metrics of tolerability, including approaches to missing data, statistical analysis and graphical representations. Examples include: baseline adjustment, composite grading, summary measures, imputation strategies and longitudinal bar charts.

Methods and Approaches

• Baseline adjustment
• Composite scoring
• Summary metrics
• Imputation strategies
• Longitudinal bar charts

Resources and Tools

Publications

1. Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, Mendoza TR, Hay J, Atkinson TM, Abernethy AP, Bruner DW, Cleeland CS, Sloan JA, Chilukuri R, Baumgartner P, Denicoff A, St Germain D, O'Mara AM, Chen A, Kelaghan J, Bennett AV, Sit L, Rogak L, Barz A, Paul DB, Schrag D. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 2014 Sep 29;106(9):dju244. doi: 10.1093/jnci/dju244. PMID: 25265940; PMCID: PMC4200059.
2. Hay JL, Atkinson TM, Reeve BB, Mitchell SA, Mendoza TR, Willis G, Minasian LM, Clauser SB, Denicoff A, O'Mara A, Chen A, Bennett AV, Paul DB, Gagne J, Rogak L, Sit L, Viswanath V, Schrag D, Basch E; NCI PRO-CTCAE Study Group. Cognitive interviewing of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Qual Life Res. 2014 Feb;23(1):257-69. doi: 10.1007/s11136-013-0470-1. Epub 2013 Jul 20. PMID: 23868457; PMCID: PMC3896507.
3. Dueck AC, Mendoza TR, Mitchell SA, Reeve BB, Castro KM, Rogak LJ, Atkinson TM, Bennett AV, Denicoff AM, O'Mara AM, Li Y, Clauser SB, Bryant DM, Bearden JD 3rd, Gillis TA, Harness JK, Siegel RD, Paul DB, Cleeland CS, Schrag D, Sloan JA, Abernethy AP, Bruner DW, Minasian LM, Basch E; National Cancer Institute PRO-CTCAE Study Group. Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. 2015 Nov;1(8):1051-9. doi: 10.1001/jamaoncol.2015.2639. Erratum in: JAMA Oncol. 2016 Jan;2(1):146. PMID: 26270597; PMCID: PMC4857599.
4. Bennett AV, Dueck AC, Mitchell SA, Mendoza TR, Reeve BB, Atkinson TM, Castro KM, Denicoff A, Rogak LJ, Harness JK, Bearden JD, Bryant D, Siegel RD, Schrag D, Basch E; National Cancer Institute PRO-CTCAE Study Group. Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Health Qual Life Outcomes. 2016 Feb 19;14:24. doi: 10.1186/s12955-016-0426-6. PMID: 26892667; PMCID: PMC4759776.
5. Basch E, Rogak LJ, Dueck AC. Methods for Implementing and Reporting Patient-reported Outcome (PRO) Measures of Symptomatic Adverse Events in Cancer Clinical Trials. Clin Ther. 2016 Apr;38(4):821-30. doi: 10.1016/j.clinthera.2016.03.011. Epub 2016 Apr 2. PMID: 27045992; PMCID: PMC4851916.
6. Basch E, Dueck AC. Patient-reported outcome measurement in drug discovery: a tool to improve accuracy and completeness of efficacy and safety data. Expert Opin Drug Discov. 2016 Aug;11(8):753-8. doi: 10.1080/17460441.2016.1193148. Epub 2016 Jun 16. PMID: 27310432.
7. Arnold B, Mitchell SA, Lent L, Mendoza TR, Rogak LJ, Barragán NM, Willis G, Medina M, Lechner S, Penedo FJ, Harness JK, Basch EM. PRO-CTCAE Spanish Translation and Linguistic Validation Study Group. Linguistic validation of the Spanish version of the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Support Care Cancer. 2016 Jul;24(7):2843-51. doi: 10.1007/s00520-015-3062-5. Epub 2016 Feb 2. PMID: 26838022.
8. Mendoza TR, Dueck AC, Bennett AV, Mitchell SA, Reeve BB, Atkinson TM, Li Y, Castro KM, Denicoff A, Rogak LJ, Piekarz RL, Cleeland CS, Sloan JA, Schrag D, Basch E. Evaluation of different recall periods for the US National Cancer Institute's PRO-CTCAE. Clin Trials. 2017 Jun;14(3):255-263. doi: 10.1177/1740774517698645. Epub 2017 Mar 20. PMID: 28545337; PMCID: PMC5448293.
9. Basch E, Pugh SL, Dueck AC, Mitchell SA, Berk L, Fogh S, Rogak LJ, Gatewood M, Reeve BB, Mendoza TR, O'Mara AM, Denicoff AM, Minasian LM, Bennett AV, Setser A, Schrag D, Roof K, Moore JK, Gergel T, Stephans K, Rimner A, DeNittis A, Bruner DW. Feasibility of Patient Reporting of Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):409-418. doi: 10.1016/j.ijrobp.2017.02.002. Epub 2017 Feb 10. PMID: 28463161; PMCID: PMC5557037.
10. Reeve BB, Mitchell SA, Dueck AC, Basch E, Cella D, Reilly CM, Minasian LM, Denicoff AM, O'Mara AM, Fisch MJ, Chauhan C, Aaronson NK, Coens C, Bruner DW. Recommended patient-reported core set of symptoms to measure in adult cancer treatment trials. J Natl Cancer Inst. 2014 Jul 8;106(7):dju129. doi: 10.1093/jnci/dju129. PMID: 25006191; PMCID: PMC4110472.
11. Atkinson TM, Hay JL, Dueck AC, Mitchell SA, Mendoza TR, Rogak LJ, Minasian LM, Basch E. What Do "None," "Mild," "Moderate," "Severe," and "Very Severe" Mean to Patients With Cancer? Content Validity of PRO-CTCAE™ Response Scales. J Pain Symptom Manage. 2018 Mar;55(3):e3-e6. doi: 10.1016/j.jpainsymman.2017.10.024. Epub 2017 Nov 10. PMID: 29129739; PMCID: PMC6317851.
12. Schoen MW, Basch E, Hudson LL, Chung AE, Mendoza TR, Mitchell SA, St Germain D, Baumgartner P, Sit L, Rogak LJ, Shouery M, Shalley E, Reeve BB, Fawzy MR, Bhavsar NA, Cleeland C, Schrag D, Dueck AC, Abernethy AP. Software for Administering the National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events: Usability Study. JMIR Hum Factors. 2018 Jul 16;5(3):e10070. doi: 10.2196/10070. PMID: 30012546; PMCID: PMC6066634.
13. Basch E, Dueck AC, Rogak LJ, Mitchell SA, Minasian LM, Denicoff AM, Wind JK, Shaw MC, Heon N, Shi Q, Ginos B, Nelson GD, Meyers JP, Chang GJ, Mamon HJ, Weiser MR, Kolevska T, Reeve BB, Bruner DW, Schrag D. Feasibility of Implementing the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in a Multicenter Trial: NCCTG N1048. J Clin Oncol. 2018 Sep 11;36(31):JCO2018788620. doi: 10.1200/JCO.2018.78.8620. Epub ahead of print. PMID: 30204536; PMCID: PMC6209091.
14. Chung AE, Shoenbill K, Mitchell SA, Dueck AC, Schrag D, Bruner DW, Minasian LM, St Germain D, O'Mara AM, Baumgartner P, Rogak LJ, Abernethy AP, Griffin AC, Basch EM. Patient free text reporting of symptomatic adverse events in cancer clinical research using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Am Med Inform Assoc. 2019 Apr 1;26(4):276-285. doi: 10.1093/jamia/ocy169. PMID: 30840079; PMCID: PMC6402312.
15. Basch EM, Scholz M, de Bono JS, Vogelzang N, de Souza P, Marx G, Vaishampayan U, George S, Schwarz JK, Antonarakis ES, O'Sullivan JM, Kalebasty AR, Chi KN, Dreicer R, Hutson TE, Dueck AC, Bennett AV, Dayan E, Mangeshkar M, Holland J, Weitzman AL, Scher HI. Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint. Eur Urol. 2019 Jun;75(6):929-937. doi: 10.1016/j.eururo.2018.11.033. Epub 2018 Dec 4. PMID: 30528222; PMCID: PMC6876845.
16. Atkinson TM, Reeve BB, Dueck AC, Bennett AV, Mendoza TR, Rogak LJ, Basch E, Li Y. Application of a Bayesian graded response model to characterize areas of disagreement between clinician and patient grading of symptomatic adverse events. J Patient Rep Outcomes. 2018 Dec 4;2(1):56. doi: 10.1186/s41687-018-0086-x. PMID: 30515599; PMCID: PMC6279753.
17. Gounder MM, Mahoney MR, Van Tine BA, Ravi V, Attia S, Deshpande HA, Gupta AA, Milhem MM, Conry RM, Movva S, Pishvaian MJ, Riedel RF, Sabagh T, Tap WD, Horvat N, Basch E, Schwartz LH, Maki RG, Agaram NP, Lefkowitz RA, Mazaheri Y, Yamashita R, Wright JJ, Dueck AC, Schwartz GK. Sorafenib for Advanced and Refractory Desmoid Tumors. N Engl J Med. 2018 Dec 20;379(25):2417-2428. doi: 10.1056/NEJMoa1805052. PMID: 30575484; PMCID: PMC6447029.
18. Reeve BB, Mitchell SA, Dueck AC, Basch E, Cella D, Reilly CM, Minasian LM, Denicoff AM, O'Mara AM, Fisch MJ, Chauhan C, Aaronson NK, Coens C, Bruner DW. Recommended patient-reported core set of symptoms to measure in adult cancer treatment trials. J Natl Cancer Inst. 2014 Jul 8;106(7):dju129. doi: 10.1093/jnci/dju129. PMID: 25006191; PMCID: PMC4110472.
19. Thanarajasingam G, Atherton PJ, Novotny PJ, Loprinzi CL, Sloan JA, Grothey A. Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254. Lancet Oncol. 2016 May;17(5):663-70. doi: 10.1016/S1470-2045(16)00038-3. Epub 2016 Apr 12. PMID: 27083333; PMCID: PMC4910515.
20. Thanarajasingam G, Minasian LM, Baron F, Cavalli F, De Claro RA, Dueck AC, El-Galaly TC, Everest N, Geissler J, Gisselbrecht C, Gribben J, Horowitz M, Ivy SP, Jacobson CA, Keating A, Kluetz PG, Krauss A, Kwong YL, Little RF, Mahon FX, Matasar MJ, Mateos MV, McCullough K, Miller RS, Mohty M, Moreau P, Morton LM, Nagai S, Rule S, Sloan J, Sonneveld P, Thompson CA, Tzogani K, van Leeuwen FE, Velikova G, Villa D, Wingard JR, Wintrich S, Seymour JF, Habermann TM. Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol. 2018 Nov;5(11):e563-e598. doi: 10.1016/S2352-3026(18)30051-6. Epub 2018 Jun 18. Erratum in: Lancet Haematol. 2019 Mar;6(3):e121. PMID: 29907552; PMCID: PMC6261436.
21. Dueck AC, Scher HI, Bennett AV, Mazza GL, Thanarajasingam G, Schwab G, Weitzman AL, Rogak LJ, Basch E. Assessment of Adverse Events From the Patient Perspective in a Phase 3 Metastatic Castration-Resistant Prostate Cancer Clinical Trial. JAMA Oncol. 2020 Feb 1;6(2):e193332. doi: 10.1001/jamaoncol.2019.3332. Epub 2020 Feb 13. PMID: 31556911; PMCID: PMC6764147.
22. Atkinson TM, Dueck AC, Satele DV, Thanarajasingam G, Lafky JM, Sloan JA, Basch E. Clinician vs Patient Reporting of Baseline and Postbaseline Symptoms for Adverse Event Assessment in Cancer Clinical Trials. JAMA Oncol. 2020 Mar 1;6(3):437-439. doi: 10.1001/jamaoncol.2019.5566. PMID: 31876902; PMCID: PMC6990818.
23. Thanarajasingam G, Leonard JP, Witzig TE, Habermann TM, Blum KA, Bartlett NL, Flowers CR, Pitcher BN, Jung SH, Atherton PJ, Tan A, Novotny PJ, Dueck AC. Longitudinal Toxicity over Time (ToxT) analysis to evaluate tolerability: a case study of lenalidomide in the CALGB 50401 (Alliance) trial. Lancet Haematol. 2020 Jun;7(6):e490-e497. doi: 10.1016/S2352-3026(20)30067-3. PMID: 32470440; PMCID: PMC7457391.
24. Basch E, Mody GN, Dueck AC. Electronic Patient-Reported Outcomes as Digital Therapeutics to Improve Cancer Outcomes. JCO Oncol Pract. 2020 Sep;16(9):541-542. doi: 10.1200/OP.20.00264. Epub 2020 Jun 2. PMID: 32484724.
25. Basch E, Stover AM, Schrag D, Chung A, Jansen J, Henson S, Carr P, Ginos B, Deal A, Spears PA, Jonsson M, Bennett AV, Mody G, Thanarajasingam G, Rogak LJ, Reeve BB, Snyder C, Kottschade LA, Charlot M, Weiss A, Bruner D, Dueck AC. Clinical Utility and User Perceptions of a Digital System for Electronic Patient-Reported Symptom Monitoring During Routine Cancer Care: Findings From the PRO-TECT Trial. JCO Clin Cancer Inform. 2020 Oct;4:947-957. doi: 10.1200/CCI.20.00081. PMID: 33112661; PMCID: PMC7768331.
26. Basch E, Becker C, Rogak LJ, Schrag D, Reeve BB, Spears P, Smith ML, Gounder MM, Mahoney MR, Schwartz GK, Bennett AV, Mendoza TR, Cleeland CS, Sloan JA, Bruner DW, Schwab G, Atkinson TM, Thanarajasingam G, Bertagnolli MM, Dueck AC. Composite grading algorithm for the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Clin Trials. 2021 Feb;18(1):104-114. doi: 10.1177/1740774520975120. Epub 2020 Dec 1. PMID: 33258687; PMCID: PMC7878323.

Principal Investigator(s): Robert Gray, Ph.D.; Lynne Wagner, Ph.D.
Institution(s): Dana-Farber Cancer Institute; Wake Forest School of Medicine

Project Title: Analysis of ECOG-ACRIN Adverse Event Data to Optimize Strategies for the Longitudinal Assessment of Tolerability in the Context of Evolving Cancer Treatment Paradigms (EVOLV)

Robert Gray, Ph.D.

Lynne Wagner, Ph.D.

Team

• David Cella, Ph.D. (Northwestern University)
• Devin Peipert, Ph.D. (Northwestern University)
• Edward Ip, Ph.D. (Wake Forest)
• Fengmin Zhao, Ph.D. (Harvard University)
• Ilana Gareen, Ph.D., M.P.H. (Brown University)
• Joseph Sparano, M.D. (Montefiore)
• Ju-Whei Lee, M.S. (Harvard University)
• Mary Lou Smith, J.D., M.B.A. (Patient advocate)
• Nate O’Connell, Ph.D. (Wake Forest)
• Noah Graham, M.S. (Harvard University)
• Pamela Raper, B.S.N., R.N. (Wake Forest)
• Ruth Carlos, M.D. (University of Michigan)
• Samilia Obeng-Gyasi, M.D., M.P.H. (OSU)
• Santiago Saldana (Wake Forest)
• Shu-En Shen, M.D. (Northwestern University)

Research Area

The EVOLV/ECOG-ACRIN team proposes to deliver sophisticated and standardized methods for assessing, monitoring, analyzing, and reporting adverse events (AEs) experienced by individuals undergoing cancer treatment. These methods will harness the potential of the patient-reported outcomes version of the NCI Common Terminology Criteria for Adverse Events (PRO-CTCAE) to provide previously unavailable patient perspectives on the tolerability of treatments – including targeted agents, immunotherapies, and others evolving treatments for which the type, severity, timing, and trajectory of adverse events is less known. Such information will help providers better identify and support patients at risk for treatment discontinuation, dose reductions, and treatment delays.

Specifically, this study aims to:

• Perform longitudinal analyses of CTCAE and PRO-CTCAE data from trials conducted within the ECOG-ACRIN Cancer Research Group, using traditional and innovative strategies to examine AE trajectories and to produce a new reporting standard that reflects severity and fluctuations over time;
• Examine PRO-CTCAE and CTCAE predictors of treatment adherence and discontinuation; and 
• Validate the broader predictive value of GP5, a single item from the Functional Assessment of Cancer Therapy- General (FACT-G) shown to predict early treatment discontinuation among women with breast cancer taking aromatase inhibitors.

The study will also explore two novel measurement models for PRO-CTCAE scores and CTCAE grades: a phenotypic model including co-occurrence of symptoms and a cumulative burden index (CBI) for characterizing the quantity of burden accumulated by patients over time. Analyses will include demographic factors and insurance status to identify potential disparities. This research is significant in improving methods for analyzing and interpreting adverse event data that can lead to a more accurate and precise understanding of patients' experiences with cancer treatment – including newly emerging treatment regimens. The development of an effective approach to identifying patients who are experiencing – or who are at risk of experiencing – treatment tolerability issues could trigger improved AE management and maximize treatment outcomes.

Publications

1. Wagner LI, Zhao F, Goss PE, et al. 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;169(3):537-548. doi:10.1007/s10549-018-4713-2
2. Pearman TP, Beaumont JL, Mroczek D, O'Connor M, Cella D. Validity and usefulness of a single-item measure of patient-reported bother from side effects of cancer therapy. Cancer. 2018;124(5):991-997. doi:10.1002/cncr.31133
3. Dueck AC, Mendoza TR, Mitchell SA, et al. Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. Nov 2015;1(8):1051-1059. doi: 1010.1001/jamaoncol.2015.2639.
4. Basch E, Pugh SL, Dueck AC, et al. Feasibility of Patient Reporting of Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial. Int J Radiat Oncol Biol Phys. Jun 1 2017;98(2):409-418. doi: 410.1016/j.ijrobp.2017.1002.1002. Epub 2017 Feb 2010.

Meeting Abstracts

1. Zhao F, Peipert JD, Lee J, Hong F, Ip E, Gareen IF, O'Connell N, Carlos RC, Mayer IA, Miller KD, Partridge AH, Shanafelt TD, Stewart K, Tarhini A, Thomas M, Weiss M, Sparano JA, Cella D, Gray RJ, Wagner LI. Predictive value of bother by side effects of treatment prior to protocol therapy for early treatment discontinuation in clinical trials. Proceedings from the American Society of Clinical Oncology, e19132.
2. Peipert JD, Zhao F, Lee J, Hong F, Ip E, Gareen IF, O'Connell NS, Carlos RC, Stewart K, Weiss M, Sparano JA, Cella D, Gray RJ, Wagner LI. Increase in side effect bother was associated with early treatment discontinuation in a clinical trial among multiple myeloma patients. Proceedings from the American Society of Clinical Oncology, Abstract e19136f.
3. Peipert JD, Zhao F, Lee J, Hong F, Ip E, Gareen IF, Carlos RC, Mayer IA, Miller KD, Partridge AH, Shanafelt TD, Stewart K, Tarhini A, Thomas M, Weiss M, Cella D, Gray RJ, Wagner LI. 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. Proceedings from the International Society for Quality of Life Research
4. Obeng-Gyasi S, Graham N, Kumar S, Lee JW, Cella D, Zhao F, Ip E, O'Connell N, Hong F, Peipert J, Gareen I, Gray R, Wagner LI, Carlos R. Association between allostatic load, symptom burden and mortality in E1A11 trial for myeloma. Proceedings from the American Society of Clinical Oncology, Abstract 12102.

Seminal previous work that brought the team to the Consortia

1. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides criteria for the standard classification of AEs. A patient-reported outcomes version of the CTCAE items (“PRO-CTCAE”) were developed to improve upon the precision and validity of symptomatic AE reporting and have been increasingly incorporated in therapeutic trials. Strategies to incorporate PRO-CTCAE scores into treatment decision-making hold great potential to understand and improve tolerability.
2. The Functional Assessment of Cancer Therapy-General (FACT-G) includes an item assessing tolerability (Item GP5). Prior research identified the GP5 as a powerful predictor of early treatment discontinuation among women with breast cancer taking an aromatase inhibitor (AI) and found GP5 was correlated with clinician-rated AEs. The item GP5 could enhance our understanding of tolerability and may serve as a powerful predictor of tolerability-related disruption.
3. The ECOG-ACRIN Cancer Research Group (E-A) leads two clinical trials which include PRO-CTCAE items (E2112 and EA6134). Several additional E-A trials evaluate new treatment strategies that include targeted therapy or immunotherapy and incorporate PRO endpoints, including the FACT-GP5 item (e.g., E1912, E1A06, E1A11). We proposed innovative analysis of E-A clinical trial data to advance our understanding of tolerability.

Prinicipal Investigator(s): Supriya Mohile, M.D., M.S.
Institution(s): University of Rochester Medical Center

Project Title:  Understanding Treatment Tolerability in Older Patients with Cancer

Supriya Mohile, M.D., M.S.

Team

• Beverly Canin
• Ben Chapman Ph.D. (University of Rochester)
• Eva Culakova, Ph.D. (University of Rochester)
• William Dale, M.D. Ph.D. (City of Hope)
• Paul Duberstein, Ph.D. (Rutgers)
• Richard Dunne, M.D. (University of Rochester)
• Marie Flannery, Ph.D., RN (University of Rochester)
• Charles Kamen, Ph.D. (University of Rochester)
• Mostafa Mohamed, M.D. (University of Rochester)
• Supriya Mohile, M.D. (University of Rochester)
• Gary Morrow, M.S., Ph.D. (University of Rochester)
• Luke Peppone, Ph.D. (University of Rochester)
• Erika Ramsdale, M.D. (University of Rochester)
• Rachael Tylock, M.S. (University of Rochester)
• Meg Wells (University of Rochester)
• Martin Zand, M.D., Ph.D. (University of Rochester)

Research Area

To evaluate whether items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) are associated with tolerability of treatment for advanced cancer in older patients with age-related conditions (i.e., disability, comorbidity, and geriatric syndromes). In collaboration with the U01 consortium, we will:

1. develop and compare the trajectories of PRO-CTCAE scores and clinician-rated CTCAE grades 2-5 in older patients with age-related conditions;
2. evaluate associations between PRO-CTCAE scores and clinician-rated CTCAE grades with clinical tolerability metrics;
3. evaluate associations between PRO-CTCAE scores and clinician-rated CTCAE grades with PRO endpoints (e.g., function, QoL, satisfaction); and
4. validate a model that identifies older patients with age-related conditions who are at high risk for poor tolerability from treatment for advanced cancer. Developed with stakeholders, our operational definition of tolerability is novel; it includes both clinical outcomes and PRO endpoints.

Methods and Approaches

• Apply established statistical methodology related to analysis of patient reported and/or clinical outcomes such as measurement theory, repeated measures mixed effect modeling, or Cox regression modeling together with recently emerging machine learning methods, and work on novel methods to better operationalize data to inform treatment tolerability in older adults with advanced cancer.
• Use Sankey Flow Diagrams to visualize PRO-CTCAE trajectory
• Perform prediction modeling (e.g. LASSO regression modeling, boosting algorithm, tree classification) to refine existing models and build new risk stratification tools
• Apply the cumulative index methodology to PRO-CTCAE items extending this method to developing a cumulative symptomatic toxicity score.

Publications

1. Mohamed MR, Ramsdale E, Loh KP, Xu H, Patil A, Gilmore N, Obrecht S, Wells M, Nightingale G, Juba KM, Faller B, Onitilo A, Bradley T, Culakova E, Holmes H, Mohile SG. Association of Polypharmacy and Potentially Inappropriate Medications With Physical Functional Impairments in Older Adults With Cancer. J Natl Compr Canc Netw. 2021 Jan 22;:1-8. doi: 10.6004/jnccn.2020.7628. [Epub ahead of print] PubMed PMID: 33482631; NIHMSID:NIHMS1666465.
2. Pandya C, Magnuson A, Flannery M, Zittel J, Duberstein P, Loh KP, Ramsdale E, Gilmore N, Dale W, Mohile SG. Association Between Symptom Burden and Physical Function in Older Patients with Cancer. J Am Geriatr Soc. 2019 May;67(5):998-1004. doi: 10.1111/jgs.15864. Epub 2019 Mar 8. PubMed PMID: 30848838; PubMed Central PMCID: PMC7851835.
3. Flannery MA, Culakova E, Canin BE, Peppone L, Ramsdale E, Mohile SG.J Clin Oncol. 2021 May 27:JCO2100195. doi: 10.1200/JCO.21.00195. Understanding Treatment Tolerability in Older Adults With Cancer. Online ahead of print. PMID: 34043433
4. Culakova, E., Mohamed M, Flannery M, Patil A, Obrecht S, Xu H, Carpenter K, Jonnalagadda S, Plumb S, Kleckner A, Loh KP, Gewandter J, Kleckner I, Mohile S. Patient-reported numbness and tingling augments Common Terminology Criteria for Adverse Events (CTCAE) to detect chemotherapy-induced peripheral neuropathy (CIPN) in older adults with advanced cancer undergoing systemic treatment (Submitted) International Society of Geriatric Oncology,Geneva, Nov 14-19, 2019.
5. Culakova, E., Mohile S, Peppone L, Ramsdale E, Maggiore R, Patil A, Xu H, Obrecht S, Mohamed M, Jonnalagadda S , Canin B, Flannery M. Patient-reported symptom burden and association of geriatric assessment (GA) impairments with the symptom burden in older adults with advanced cancer receiving systemic treatment. International Society of Geriatric Oncology,Geneva, Nov 14-19, 2019.
6. Culakova E, Peppone L, Flannery M, Xu H, Ramsdale E, Patil A, Canin B, Mohile S.G. Relationships between aging-related conditions and treatment tolerability in older adults with advanced cancer. International Society for Quality of Life Research, Virtual Presentation due to COVID-19, Oct 19th-23rd, 2020
7. Xu H, Mohile SG, Flannery M, Peppone L, Mohamed M, Ramsdale E, Patil A, Jonnalagadda S, Jamieson L, Vogel V, Katato K, Culakova E . Using machine learning to identify older adults at high risk for adverse outcomes by Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) scores. ASCO Quality Care, 2020
8. Flannery M, Culakova E, Zhang Z, Zhang Y, Mohile SG. Patient Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE): Free-Text Symptom Responses in Older Adults with Advanced Cancer. Podium Presentation at: State of the Science (SOS) Congress on Nursing Research, to be held September 17-18, 2020 (Virtual due to COVID-19).
9. Culakova E, Mohile S, Xu H, Patil A, Plumb S, Mohamed M, Pan Z, Meng S, Gilmore N, Wells M, Ritterman R, Loh K, Magnuson A, Ramsdale E, Peppone L, Flannery M. Effects of a Geriatric Assessment (GA) Intervention on Symptomatic Toxicity Burden Reported by Older Adults with Advanced Cancer During Treatment; American Society of Clinical Oncology, 2020
10. Mohile SG, Mohamed M, Culakova E, Xu H, Loh KP, Magnuson A, Flannery M, Ramsdale E, Dunne R, Gilmore N, Obrecht S, Patil A, Plumb S, Lowenstein L, Janelsins M, Mustian K, Hopkins J, Gaur R, Berenberg J, Dale W. A Geriatric Assessment (GA) Intervention to Reduce Toxicity in Older Patients with Advanced Cancer: A University of Rochester NCI Community Oncology Research Program (NCORP) Cluster Randomized Controlled Trial (CRCT). American Society of Clinical Oncology, 2020
11. Flannery MA, Culakova E, Canin BE, Peppone L, Ramsdale E, Mohile SG.J Clin Oncol. 2021 May 27:JCO2100195. doi: 10.1200/JCO.21.00195. Understanding Treatment Tolerability in Older Adults With Cancer. Online ahead of print.PMID: 34043433
    https://ascopost.com/videos/2020-asco-quality-care-symposium/marie-flannery-and-eva-culakova-on-managing-symptoms-in-older-adults-with-advanced-cancer/

Principal Investigator(s): Patricia Ganz, M.D.; Mourad Tighiouart, Ph.D.; Andre Rogatko, Ph.D. (emeritus)
Institution(s): Cedars-Sinai Medical Center; University of California Los Angeles; Cedars-Sinai Medical Center

Project Title: Advancing Analysis and Interpretation of Adverse Events and PROs in Cancer Clinical Trials

Patricia Ganz, M.D.

Mourad Tighiouart, Ph.D.

Andre Rogatko, Ph.D.
(emeritus)

Team

• Marcio Diniz, Ph.D. (Cedars-Sinai Medical Center)
• Gillian Gresham, Ph.D. (Cedars-Sinai Medical Center)
• Zahra Razaee, Ph.D. (Cedars-Sinai Medical Center)
• Sungjin Kim, M.S. (Cedars-Sinai Medical Center)
• Michael Luu, M.P.H. (Cedars-Sinai Medical Center)
• Mahendra Yatawara, M.B.A. (Cedars-Sinai Medical Center)
• Shao-Chi G Huang, B.S. (Cedars-Sinai Medical Center)
• Ron D. Hays, Ph.D. (University of California at Los Angeles)
• N. Lynn Henry, M.D., Ph.D. (University of Michigan)
• Steven Piantadosi, M.D., Ph.D. (Brigham and Woman’s Hospital)
• Gregory Yothers, Ph.D. (NRG Oncology)
• Hanna Bandos, Ph.D. (NRG Oncology)
• Reena Cecchini, Ph.D. (NRG Oncology)

Research Area

Our research focuses on developing new methods to analyze and summarize toxicity data. The data comes from several therapeutics and cancer types from past and ongoing NSABP/NRG clinical trials, with an emphasis on the impact of host factors (e.g., age, gender, performance status, baseline PRO assessments) on toxicity and treatment discontinuation. Specifically, we are focusing on developing and validating the toxicity index to summarize CTCAE and PRO-CTCAE toxicity data from clinical trials. We are also exploring novel approaches for data visualization and graphical presentation and development of research and patient-facing tools.

Methods and Approaches

• Development and validation of summary/scoring methods
• Integration of patient risk factors into models
• Correspondence analysis
• Visualization methods
• Predictive modeling and simulation studies

Publications

1. Calsavara VF, Diniz MA, Tighiouart M, Ganz PA, Henry NL, Hays RD, Yothers G, Rogatko A. Simulation Study Comparing Analytical Methods for Single Item Longitudinal Patient-Reported Outcomes Data. Quality of Life Research (submitted)
2. Diniz MA, Gresham G, Kim S, Luu M, Henry NL, Tighiouart M, Yothers G, Ganz P, Rogatko A. Visualizing adverse events using correspondence analysis. 2021. BMC Med Res Methodol 21, 244
3. Hays R, Ganz PA, Spritzer KL, Rogatko A. Applying the Toxicity Index to Patient-Reported Symptom Data: An Example Using the EORTC Colorectal Cancer-specific Quality of Life Questionnaire. ClinTher. (in press)
4. Henry NL, Kim S, Hays RD, Diniz MA, Luu M, Cecchini RS, Yothers G, Rogatko A, Ganz PA. Toxicity Index, patient-reported outcomes, and early discontinuation of endocrine therapy for breast cancer risk reduction in NRG Oncology/NSABP B-35. J Clin Oncol 39:34, 3800-3812
5. Henry NL, Rogatko A, Ganz PA. 2021. Evaluating the Association of Adverse Events and Patient-Reported Symptoms to Endocrine Therapy Tolerability. J Clin Oncol. 2021 Dec 9:JCO2102387. doi: 10.1200/JCO.21.02387. Epub ahead of print. PMID: 34882498.
6. Langlais B, Mazza GL, Thanarajasingam G, Rogak LJ, Ginos B, Heon N, Scher HI, Schwab G, Ganz PA, Basch E, Dueck AC. Evaluating Treatment Tolerability Using the Toxicity Index With Patient-Reported Outcomes Data. J Pain Symptom Manage 63 (2): 311-320, 2022
7. Ganz PA, Hays RD, Spritzer KL, Rogatko A, Ko CY, Colangelo LH, Arora A, Hopkins JO, Brufsky AM, Yothers G. Health-related Quality of Life Outcomes after Neoadjuvant Chemoradiotherapy for Rectal Cancer in NRG Oncology/NSABP R-04. Cancer
8. Ganz P, Kim S, Diniz M, Luu M, Gresham G, Henry NL, Hays R, Yothers G, Cecchini R, Piantadosi S, Tighiouart M. Measuring the tolerability of cancer therapy: incorporating host factors as moderators of toxicity and outcomes. In Qual Life Res 2020 Oct 1 (Vol. 29, No. Suppl1 1, pp. S12-S12).
9. Gresham G, Diniz MA, Razaee ZS, Luu M, Kim S, Hays RD, Piantadosi S, Tighiouart M, Yothers G, Ganz PA, Rogatko A. Evaluating Treatment Tolerability in Cancer Clinical Trials Using the Toxicity Index. J Natl Cancer Inst. 2020 Dec 14;112(12):1266-1274. doi: 10.1093/jnci/djaa028. PMID: 32091598; PMCID: PMC7735773.
10. Henry NL, Kim S, Hays RD, Diniz MA, Tighiouart M, Gresham G, Luu M, Cecchini RS, Yothers G, Rogatko A, Ganz PA. Toxicity Index, patient-reported outcomes, and persistence of breast cancer chemotherapy-associated side effects in NRG Oncology/NSABP B-30. NPJ Breast Cancer (submitted)
11. Razaee, ZS, Amini, AA, Diniz, MA, Tighiouart, M, Yothers, G, Rogatko, A. On the properties of the toxicity index and its statistical efficiency. Stat Med. 2021; 40: 1535– 1552. https://onlinelibrary.wiley.com/doi/10.1002/sim.8858