Clinical trials in older patients with cancer – typical challenges, possible solutions, and a paradigm of study design in breast cancer
DOI:
https://doi.org/10.2340/1651-226X.2023.40365Keywords:
Barriers to recruitment, breast cancer, clinical trials, elderly, older patientsAbstract
Background and purpose: While the prevalence of older breast cancer patients is rapidly increasing, these patients are greatly underrepresented in clinical trials. We discuss barriers to recruitment of older patients to clinical trials and propose solutions on how to mitigate these challenges and design optimal clinical trials through the paradigm of IMPORTANT trial.
Patients and methods: This is a narrative review of the current literature evaluating barriers to including older breast cancer patients in clinical trials and how mitigating strategies can be implemented in a pragmatic clinical trial.
Results: The recognized barriers can be roughly divided into trial design-related (e.g. the adoption of strict inclusion criteria, the lack of pre-specified age-specific analysis), patient-related (e.g. lack of knowledge, valuation of the quality-of-life instead of survival, transportation issues), or physician-related (e.g. concern for toxicity). Several strategies to mitigate barriers have been identified and should be considered when designing a clinical trial dedicated to older patients with cancer. The pragmatic, de-centralized IMPORTANT trial focusing on dose optimization of CDK4/6 -inhibitors in older breast cancer patients is a paradigm of a study design where different mitigating strategies have been adopted.
Interpretation: Because of the existing barriers, older adults in clinical trials are considerably healthier than the average older patients treated in clinical practice. Thus, the study results cannot be generalized to the older population seen in daily clinical practice. Broader inclusion/exclusion criteria, offering telehealth visits, and inclusion of patient-reported, instead of physician-reported outcomes may increase older patient participation in clinical trials.
Downloads
References
Biganzoli L, Battisti NML, Wildiers H, McCartney A, Colloca G, Kunkler IH, et al. Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG). Lancet Oncol. 2021;22:e327-40.
https://doi.org/10.1016/S1470-2045(20)30741-5 DOI: https://doi.org/10.1016/S1470-2045(20)30741-5
Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol Biomarkers Prev. 2017;26:809-15.
https://doi.org/10.1158/1055-9965.EPI-16-0889 DOI: https://doi.org/10.1158/1055-9965.EPI-16-0889
DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Sauer AG, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438-51.
https://doi.org/10.3322/caac.21583 DOI: https://doi.org/10.3322/caac.21583
Eaker S, Dickman PW, Bergkvist L, Holmberg L; Uppsala/Orebro Breast Cancer Group. Differences in management of older women influence breast cancer survival: results from a population-based database in Sweden. PLoS Med. 2006;3:e25-8.
https://doi.org/10.1371/journal.pmed.0030025 DOI: https://doi.org/10.1371/journal.pmed.0030025
Karihtala P, Jääskeläinen A, Roininen N, Jukkola A. Real-world, single-centre prospective data of age at breast cancer onset: focus on survival and reproductive history. BMJ Open. 2021;11:e041706.
https://doi.org/10.1136/bmjopen-2020-041706 DOI: https://doi.org/10.1136/bmjopen-2020-041706
van de Water W, Markopoulos C, van de Velde CJH, Seynaeve C, Hasenburg A, Rea D, et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA. 2012;307:590-7.
https://doi.org/10.1001/jama.2012.84 DOI: https://doi.org/10.1001/jama.2012.84
Hurria A, Levit LA, Dale W, Mohile SG, Muss HB, Fehrenbacher L, et al. Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol. 2015;33:3826-33.
https://doi.org/10.1200/JCO.2015.63.0319 DOI: https://doi.org/10.1200/JCO.2015.63.0319
Sedrak MS, Freedman RA, Cohen HJ, Muss HB, Jatoi A, Klepin HD, et al. Older adult participation in cancer clinical trials: a systematic review of barriers and interventions. CA Cancer J Clin. 2021;71:78-92.
https://doi.org/10.3322/caac.21638 DOI: https://doi.org/10.3322/caac.21638
Freedman RA, Foster JC, Seisler DK, Lafky JM, Muss HB, Cohen HJ, et al. Accrual of older patients with breast cancer to alliance systemic therapy trials over time: Protocol A151527. J Clin Oncol. 2017;35:421-31.
https://doi.org/10.1200/JCO.2016.69.4182 DOI: https://doi.org/10.1200/JCO.2016.69.4182
Singh H, Kanapuru B, Smith C, Fashoyin-Aje LA, Myers A, Kim G, et al. DA analysis of enrollment of older adults in clinical trials for cancer drug registration: a 10-year experience by the U.S. Food and Drug Administration. J Clin Oncol. 2017;35:15_suppl:10009.
https://doi.org/10.1200/JCO.2017.35.15_suppl.10009 DOI: https://doi.org/10.1200/JCO.2017.35.15_suppl.10009
Nightingale G, Schwartz R, Kachur E, Dixon BN, Cote C, Barlow A, et al. Clinical pharmacology of oncology agents in older adults: a comprehensive review of how chronologic and functional age can influence treatment-related effects. J Geriatr Oncol. 2019;10:4-30.
https://doi.org/10.1016/j.jgo.2018.06.008 DOI: https://doi.org/10.1016/j.jgo.2018.06.008
Hwang IG, Kwon M, Kim JW, Kim SH, Lee Y-G, Kim JY, et al. Prevalence and predictive factors for upfront dose reduction of the first cycle of first-line chemotherapy in older adults with metastatic solid cancer: Korean Cancer Study Group (KCSG) multicenter study. Cancers. 2021;13:331.
https://doi.org/10.3390/cancers13020331 DOI: https://doi.org/10.3390/cancers13020331
Bumanlag IM, Jaoude JA, Rooney MK, Taniguchi CM, Ludmir EB. Exclusion of older adults from cancer clinical trials: review of the literature and future recommendations. Semin Radiat Oncol. 2022;32:125-34.
https://doi.org/10.1016/j.semradonc.2021.11.003 DOI: https://doi.org/10.1016/j.semradonc.2021.11.003
Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol. 2011;29:1290-6.
https://doi.org/10.1200/JCO.2010.30.6985 DOI: https://doi.org/10.1200/JCO.2010.30.6985
Dale W, Klepin HD, Williams GR, Alibhai SMH, Bergerot C, Brintzenhofeszoc K, et al. Practical assessment and management of vulnerabilities in older patients receiving systemic cancer therapy: ASCO guideline update. J Clin Oncol. 2023;41:4293-312.
https://doi.org/10.1200/JCO.23.00933 DOI: https://doi.org/10.1200/JCO.23.00933
Korc-Grodzicki B, Holmes HM, Shahrokni A. Geriatric assessment for oncologists. Cancer Biol Med. 2015;12:261-74.
Le Saux O, Falandry C, Gan HK, You B, Freyer G, Péron J. Changes in the use of comprehensive geriatric assessment in clinical trials for older patients with cancer over time. Oncologist. 2019;24:1089-94.
https://doi.org/10.1634/theoncologist.2018-0493 DOI: https://doi.org/10.1634/theoncologist.2018-0493
Javid SH, Unger JM, Gralow JR, Moinpour CM, Wozniak AJ, Goodwin JW, et al. A prospective analysis of the influence of older age on physician and patient decision-making when considering enrollment in breast cancer clinical trials (SWOG S0316). Oncologist. 2012;17:1180-90.
https://doi.org/10.1634/theoncologist.2011-0384 DOI: https://doi.org/10.1634/theoncologist.2011-0384
Kornblith AB, Kemeny M, Peterson BL, Wheeler J, Crawford J, Bartlett N, et al. Survey of oncologists' perceptions of barriers to accrual of older patients with breast carcinoma to clinical trials. Cancer. 2002;95:989-96.
https://doi.org/10.1002/cncr.10792 DOI: https://doi.org/10.1002/cncr.10792
Townsley CA, Chan KK, Pond GR, Marquez C, Siu LL, Straus SE. Understanding the attitudes of the elderly towards enrolment into cancer clinical trials. BMC Cancer. 2006;6:34.
https://doi.org/10.1186/1471-2407-6-34 DOI: https://doi.org/10.1186/1471-2407-6-34
Freedman RA, Dockter TJ, Lafky JM, Hurria A, Muss HJ, Cohen HJ, et al. Promoting accrual of older patients with cancer to clinical trials: an Alliance for Clinical Trials in Oncology member survey (A171602). Oncologist. 2018;23:1016-23.
https://doi.org/10.1634/theoncologist.2018-0033 DOI: https://doi.org/10.1634/theoncologist.2018-0033
Sedrak MS, Mohile SG, Sun V, Sun CL, Chen BT, Li D, et al. Barriers to clinical trial enrollment of older adults with cancer: a qualitative study of the perceptions of community and academic oncologists. J Geriatr Oncol. 2020;11:327-34.
https://doi.org/10.1016/j.jgo.2019.07.017 DOI: https://doi.org/10.1016/j.jgo.2019.07.017
Hsu T. Educational initiatives in geriatric oncology 2013-who, why, and how? J Geriatr Oncol. 2016;7:390-6.
https://doi.org/10.1016/j.jgo.2016.07.013 DOI: https://doi.org/10.1016/j.jgo.2016.07.013
Kimmick G. Clinical trial accrual in older cancer patients: the most important steps are the first ones. J Geriatr Oncol. 2016;7:158-61.
https://doi.org/10.1016/j.jgo.2016.03.006 DOI: https://doi.org/10.1016/j.jgo.2016.03.006
Abi Jaoude J, Kouzy R, Mainwaring W, Lin TA, Miller AB, Jethanandani A, et al. Performance status restriction in phase III cancer clinical trials. J Natl Compr Canc Netw. 2020;18:1322-6.
https://doi.org/10.6004/jnccn.2020.7578 DOI: https://doi.org/10.6004/jnccn.2020.7578
Lewis JH, Kilgore ML, Goldman DP, Trimble EL, Kaplan R, Montello MJ, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003;21:1383-9.
https://doi.org/10.1200/JCO.2003.08.010 DOI: https://doi.org/10.1200/JCO.2003.08.010
Lichtman SM, Harvey RD, Smit MAD, Rahman A, Thompson MA, Roach N, et al. Modernizing clinical trial eligibility criteria: recommendations of the american society of clinical oncology-friends of cancer research organ dysfunction, prior or concurrent malignancy, and comorbidities working group. J. Clin. Oncol. 2017;35:3753-9.
https://doi.org/10.1200/JCO.2017.74.4102 DOI: https://doi.org/10.1200/JCO.2017.74.4102
Liu J, Gutierrez E, Tiwari A, Padam S, Li D, Dale W, et al. Strategies to improve participation of older adults in cancer research. J Clin Med. 2020;9:1571.
https://doi.org/10.3390/jcm9051571 DOI: https://doi.org/10.3390/jcm9051571
McCleary NJ, Hubbard J, Mahoney MR, Meyerhardt JA, Sargent D, Venook A, et al. Challenges of conducting a prospective clinical trial for older patients: lessons learned from NCCTG N0949 (Alliance). J Geriatr Oncol. 2018;9:24-31.
https://doi.org/10.1016/j.jgo.2017.08.005 DOI: https://doi.org/10.1016/j.jgo.2017.08.005
BrintzenhofeSzoc K, Krok-Schoen JL, Canin B, Parker I, MacKenzie AR, Koll T, et al. The underreporting of phase III chemo-therapeutic clinical trial data of older patients with cancer: a systematic review. J Geriatr Oncol. 2020;11:369-79.
https://doi.org/10.1016/j.jgo.2019.12.007 DOI: https://doi.org/10.1016/j.jgo.2019.12.007
Howie LJ, Singh H, Bloomquist E, Wedam S, Amiri-Kordestani L, Tang S, et al. Outcomes of older women with hormone receptor-positive, human epidermal growth factor receptor-negative metastatic breast cancer treated with a CDK4/6 inhibitor and an aromatase inhibitor: an FDA pooled analysis. J Clin Oncol. 2019;37:3475-83.
https://doi.org/10.1200/JCO.18.02217 DOI: https://doi.org/10.1200/JCO.18.02217
Hamaker ME, Seynaeve C, Nortier JWR, Wymenga M, Maartense E, Boven E, et al. Slow accrual of elderly patients with metastatic breast cancer in the Dutch multicentre OMEGA study. Breast. 2013;22:556-9.
https://doi.org/10.1016/j.breast.2012.12.010 DOI: https://doi.org/10.1016/j.breast.2012.12.010
Ayodele O, Akhtar M, Konenko A, Keegan N, Calacsan F, Duggan L, et al. Comparing attitudes of younger and older patients towards cancer clinical trials. J Geriatr Oncol. 2016;7:162-8.
https://doi.org/10.1016/j.jgo.2016.03.005 DOI: https://doi.org/10.1016/j.jgo.2016.03.005
Hoogland AI, Mansfield J, Lafranchise EA, Bulls HW, Johnstone PA, Jim HSL. eHealth literacy in older adults with cancer. J Geriatr Oncol. 2020;11:1020-2.
https://doi.org/10.1016/j.jgo.2019.12.015 DOI: https://doi.org/10.1016/j.jgo.2019.12.015
Mohile SG, Hurria A, Cohen HJ, Rowland JH, Leach CR, Arora NK, et al. Improving the quality of survivorship for older adults with cancer. Cancer. 2016;122:2459-568.
https://doi.org/10.1002/cncr.30053 DOI: https://doi.org/10.1002/cncr.30053
Kemeny MM, Peterson BL, Kornblith AB, Muss HB, Wheeler J, Levine E, et al. Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol. 2003;21:2268-75.
https://doi.org/10.1200/JCO.2003.09.124 DOI: https://doi.org/10.1200/JCO.2003.09.124
Lackman M, Vickers MM, Hsu T. Physician-reported reasons for non-enrollment of older adults in cancer clinical trials. J Geriatr Oncol. 2020;11:31-6.
https://doi.org/10.1016/j.jgo.2019.01.019 DOI: https://doi.org/10.1016/j.jgo.2019.01.019
Moore DH, Kauderer JT, Bell J, Curtin JP, Van Le L. An assessment of age and other factors influencing protocol versus alternative treatments for patients with epithelial ovarian cancer referred to member institutions: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;94:368-74.
https://doi.org/10.1016/j.ygyno.2004.05.033 DOI: https://doi.org/10.1016/j.ygyno.2004.05.033
Parks RM, Holmes HM, Cheung KL. Current challenges faced by cancer clinical trials in addressing the problem of under-representation of older adults: a narrative review. Oncol Ther. 2021;9:55-67.
https://doi.org/10.1007/s40487-021-00140-w DOI: https://doi.org/10.1007/s40487-021-00140-w
Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123-33.
https://doi.org/10.1016/j.ejca.2018.05.017 DOI: https://doi.org/10.1016/j.ejca.2018.05.017
Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, et al. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018;167:659-69.
https://doi.org/10.1007/s10549-017-4523-y DOI: https://doi.org/10.1007/s10549-017-4523-y
Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36:2465-72.
https://doi.org/10.1200/JCO.2018.78.9909 DOI: https://doi.org/10.1200/JCO.2018.78.9909
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929-40.
https://doi.org/10.1056/NEJMoa1813904 DOI: https://doi.org/10.1056/NEJMoa1813904
Goetz MP, Okera M, Wildiers H, Campone M, Grischke EM, Manso L, et al. Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. Breast Cancer Res Treat. 2021;186:417-28.
https://doi.org/10.1007/s10549-020-06029-y DOI: https://doi.org/10.1007/s10549-020-06029-y
Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387:9-20.
https://doi.org/10.1056/NEJMoa2203690 DOI: https://doi.org/10.1056/NEJMoa2203690
Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for breast cancer. N Engl J Med. 2022;386:1143-54.
https://doi.org/10.1056/NEJMoa2115022 DOI: https://doi.org/10.1056/NEJMoa2115022
André F, Hee Park Y, Kim SB, Takano T, Im SA, Borges G, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;401:1773-85.
https://doi.org/10.1016/S0140-6736(23)00725-0 DOI: https://doi.org/10.1016/S0140-6736(23)00725-0
Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.
https://doi.org/10.1056/NEJMoa1914609 DOI: https://doi.org/10.1056/NEJMoa1914609
Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and Nab-Paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379:2108-21.
https://doi.org/10.1056/NEJMoa1809615 DOI: https://doi.org/10.1056/NEJMoa1809615
Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-28. DOI: https://doi.org/10.1200/JCO.2020.38.15_suppl.1000
https://doi.org/10.1016/S0140-6736(20)32531-9 DOI: https://doi.org/10.1016/S0140-6736(20)32531-9
Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab Govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384:1529-41.
https://doi.org/10.1056/NEJMoa2028485 DOI: https://doi.org/10.1056/NEJMoa2028485
Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-33.
https://doi.org/10.1056/NEJMoa1706450 DOI: https://doi.org/10.1056/NEJMoa1706450
Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753-63.
https://doi.org/10.1056/NEJMoa1802905 DOI: https://doi.org/10.1056/NEJMoa1802905
Baldini C, Charton E, Schultz E, Auroy L, Italiano A, Robert M, et al. Access to early-phase clinical trials in older patients with cancer in France: the EGALICAN-2 study. ESMO Open. 2022;7:100468.
https://doi.org/10.1016/j.esmoop.2022.100468 DOI: https://doi.org/10.1016/j.esmoop.2022.100468
Izmailova ES, Wagner JA, Perakslis ED. Wearable devices in clinical trials: hype and hypothesis. Clin Pharmacol Ther. 2018;104:42-52.
https://doi.org/10.1002/cpt.966 DOI: https://doi.org/10.1002/cpt.966
Chodankar D, Raval TK, Jeyaraj J. The role of remote data capture, wearables, and digital biomarkers in decentralized clinical trials. Perspect Clin Res. 2024;15:38-41.
https://doi.org/10.4103/picr.picr_219_22 DOI: https://doi.org/10.4103/picr.picr_219_22
Wildiers H, Mauer M, Pallis A, Hurria A, Mohile SG, Luciani A, et al. End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer - Alliance for Clinical Trials in Oncology - International Society Of Geriatric Oncology position article. J Clin Oncol. 2013;31:3711-8.
https://doi.org/10.1200/JCO.2013.49.6125 DOI: https://doi.org/10.1200/JCO.2013.49.6125
Fanaroff AC, Li S, Webb LE, Miller V, Navar AM, Peterson ED, et al. An observational study of the association of video- versus text-based informed consent with multicenter trial enrollment: lessons from the PALM Study (Patient and Provider Assessment of Lipid Management). Circ Cardiovasc Qual Outcomes. 2018;11:e004675.
https://doi.org/10.1161/CIRCOUTCOMES.118.004675 DOI: https://doi.org/10.1161/CIRCOUTCOMES.118.004675
Adams DV, Long S, Fleury ME. Association of remote technology use and other decentralization tools with patient likelihood to enroll in cancer clinical trials. JAMA Netw Open. 2022 Jul 1;5:e2220053.
https://doi.org/10.1001/jamanetworkopen.2022.20053 DOI: https://doi.org/10.1001/jamanetworkopen.2022.20053
Oakley-Girvan I. The powerful impact of caregivers on clinical trials. Appl Clin Trials. 2022;31:2.
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2023 Peeter Karihtala, Aglaia Schiza, Elena Fountzilas, Jürgen Geisler, Icro Meattini, Emanuela Risi, Laura Biganzoli, Antonios Valchis
This work is licensed under a Creative Commons Attribution 4.0 International License.
