Experiences of Patients After Withdrawal From Cancer Clinical Trials | Oncology | JAMA Network Open | JAMA Network
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Table 1.  Sample Characteristics
Sample Characteristics
Table 2.  Patient-Participant–Stated Reason for Withdrawal, With Illustrative Quotations
Patient-Participant–Stated Reason for Withdrawal, With Illustrative Quotations
Table 3.  Themes, Subthemes, and Illustrative Quotations
Themes, Subthemes, and Illustrative Quotations
1.
Ulrich  CM, Knafl  KA, Ratcliffe  SJ,  et al.  Developing a model of the benefits and burdens of research participation in cancer clinical trials.   AJOB Prim Res. 2012;3(2):10-23. doi:10.1080/21507716.2011.653472PubMedGoogle ScholarCrossref
2.
Ulrich  CM, Ratcliffe  SJ, Wallen  GR, Zhou  QP, Knafl  KA, Grady  C.  Cancer clinical trial participants’ assessment of risk and benefit.   AJOB Empir Bioeth. 2016;7(1):8-16. doi:10.1080/23294515.2015.1034381PubMedGoogle ScholarCrossref
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Naylor  M, Keating  SA.  Transitional care.   Am J Nurs. 2008;108(9)(suppl):58-63. doi:10.1097/01.NAJ.0000336420.34946.3a PubMedGoogle ScholarCrossref
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Coleman  EA, Boult  C; American Geriatrics Society Health Care Systems Committee.  Improving the quality of transitional care for persons with complex care needs.   J Am Geriatr Soc. 2003;51(4):556-557. doi:10.1046/j.1532-5415.2003.51186.x PubMedGoogle ScholarCrossref
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Ulrich  CM, Grady  C.  Time for advance care planning discussions during transitions in care in cancer clinical trials.   JAMA Oncol. 2019;5(4):459-460. doi:10.1001/jamaoncol.2018.6872PubMedGoogle ScholarCrossref
6.
Dresser  R.  Silent Partners: Human Subjects and Research Ethics. Oxford University Press; 2017.
7.
Patton  M.  Qualitative Research and Evaluation Methods. Sage; 2015.
8.
Tong  A, Sainsbury  P, Craig  J.  Consolidated Criteria for Reporting Qualitative Research (COREQ): a 32-item checklist for interviews and focus groups.   Int J Qual Health Care. 2007;19(6):349-357. doi:10.1093/intqhc/mzm042 PubMedGoogle ScholarCrossref
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Gubrium  JF, Holstein  JA.  Handbook of Interview Research: Context and Method. Sage; 2002.
10.
Hennink  MM, Kaiser  BN, Marconi  VC.  Code saturation versus meaning saturation: how many interviews are enough?   Qual Health Res. 2017;27(4):591-608. doi:10.1177/1049732316665344 PubMedGoogle ScholarCrossref
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Braun  V, Clarke  V.  Using thematic analysis in psychology.   Qual Res Psychol. 2006;3(2):77-101. doi:10.1191/1478088706qp063oa Google ScholarCrossref
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Hsieh  H-F, Shannon  SE.  Three approaches to qualitative content analysis.   Qual Health Res. 2005;15(9):1277-1288. doi:10.1177/1049732305276687 PubMedGoogle ScholarCrossref
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Naylor  MD, Bowles  KH, McCauley  KM,  et al.  High-value transitional care: translation of research into practice.   J Eval Clin Pract. 2013;19(5):727-733. PubMedGoogle Scholar
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Naylor  M, Berlinger  N.  Transitional care: a priority for health care organizational ethics.   Hastings Cent Rep. 2016;46(1)(suppl):S39-S42. doi:10.1002/hast.631 PubMedGoogle Scholar
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World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle ScholarCrossref
16.
Cho  HL, Danis  M, Grady  C.  Post-trial responsibilities beyond post-trial access.   Lancet. 2018;391(10129):1478-1479. doi:10.1016/S0140-6736(18)30761-X PubMedGoogle ScholarCrossref
17.
The American Cancer Society Action Network. The Costs of Cancer: 2020 edition. Published October 2020. Accessed July 7, 2021. https://www.fightcancer.org/sites/default/files/National%20Documents/Costs-of-Cancer-2020-10222020.pdf
18.
Yabroff  KR, Bradley  C, Shih  YT.  Understanding financial hardship among cancer survivors in the United States: strategies for prevention and mitigation.   J Clin Oncol. 2020;38(4):292-301. doi:10.1200/JCO.19.01564 PubMedGoogle ScholarCrossref
19.
Gilbertson-White  S, Perkhounkova  Y, Saeidzadeh  S, Hein  M, Dahl  R, Simons-Burnett  A.  Understanding symptom burden in patients with advanced cancer living in rural areas.   Oncol Nurs Forum. 2019;46(4):428-441. PubMedGoogle Scholar
20.
Gilbertson-White  S, Aouizerat  BE, Jahan  T, Miaskowski  C.  A review of the literature on multiple symptoms, their predictors, and associated outcomes in patients with advanced cancer.   Palliat Support Care. 2011;9(1):81-102. doi:10.1017/S147895151000057X PubMedGoogle ScholarCrossref
21.
Butt  Z, Rosenbloom  SK, Abernethy  AP,  et al.  Fatigue is the most important symptom for advanced cancer patients who have had chemotherapy.   J Natl Compr Canc Netw. 2008;6(5):448-455. doi:10.6004/jnccn.2008.0036 PubMedGoogle ScholarCrossref
22.
Chung  AE, Shoenbill  K, Mitchell  SA,  et al.  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;26(4):276-285. doi:10.1093/jamia/ocy169 PubMedGoogle ScholarCrossref
23.
Ethier  JL, Paramsothy  T, You  JJ, Fowler  R, Gandhi  S.  Perceived barriers to goals of care discussions with patients with advanced cancer and their families in the ambulatory setting: a multicenter survey of oncologists.   J Palliat Care. 2018;33(3):125-142. doi:10.1177/0825859718762287 PubMedGoogle ScholarCrossref
24.
Ferrell  B, Borneman  T, Williams  AC, Scardina  A, Fischer  P, Smith  TJ.  Integrating palliative care for patients on clinical trials: opportunities for oncology nurses.   Asia Pac J Oncol Nurs. 2020;7(3):243-249. doi:10.4103/apjon.apjon_2_20 PubMedGoogle ScholarCrossref
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Temel  JS, Greer  JA, El-Jawahri  A,  et al.  Effects of early integrated palliative care in patients with lung and GI cancer: a randomized clinical trial.   J Clin Oncol. 2017;35(8):834-841. doi:10.1200/JCO.2016.70.5046 PubMedGoogle ScholarCrossref
26.
LeBlanc  TW.  Hope, phase I trials, and palliative care: so you’re telling me there’s a chance?   J Oncol Pract. 2017;13(10):675-677. doi:10.1200/JOP.2017.026070 PubMedGoogle ScholarCrossref
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Kroenke  CH, Kwan  ML, Neugut  AI,  et al.  Social networks, social support mechanisms, and quality of life after breast cancer diagnosis.   Breast Cancer Res Treat. 2013;139(2):515-527. doi:10.1007/s10549-013-2477-2 PubMedGoogle ScholarCrossref
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Sullivan  DR, Forsberg  CW, Ganzini  L,  et al.  Depression symptom trends and health domains among lung cancer patients in the CanCORS study.   Lung Cancer. 2016;100:102-109. doi:10.1016/j.lungcan.2016.08.008 PubMedGoogle ScholarCrossref
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Ha  EH, Cho  YK.  The mediating effects of self-esteem and optimism on the relationship between quality of life and depressive symptoms of breast cancer patients.   Psychiatry Investig. 2014;11(4):437-445. doi:10.4306/pi.2014.11.4.437 PubMedGoogle ScholarCrossref
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Ho  RT, Fong  TC, Cheung  IK.  Cancer-related fatigue in breast cancer patients: factor mixture models with continuous non-normal distributions.   Qual Life Res. 2014;23(10):2909-2916. doi:10.1007/s11136-014-0731-7 PubMedGoogle ScholarCrossref
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Lawton  J, Blackburn  M, Rankin  D,  et al.  Broadening the debate about post-trial access to medical interventions: a qualitative study of participant experiences at the end of a trial investigating a medical device to support type 1 diabetes self-management.   AJOB Empir Bioeth. 2019;10(2):100-112. doi:10.1080/23294515.2019.1592264PubMedGoogle ScholarCrossref
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Lawton  J, Fox  A, Fox  C, Kinmonth  AL.  Participating in the United Kingdom Prospective Diabetes Study (UKPDS): a qualitative study of patients’ experiences.   Br J Gen Pract. 2003;53(490):394-398.PubMedGoogle Scholar
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Sofaer  N, Thiessen  C, Goold  SD,  et al.  Subjects’ views of obligations to ensure post-trial access to drugs, care and information: qualitative results from the Experiences of Participants in Clinical Trials (EPIC) study.   J Med Ethics. 2009;35(3):183-188. doi:10.1136/jme.2008.024711 PubMedGoogle ScholarCrossref
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Millum  J.  Post-trial access to antiretrovirals: who owes what to whom?   Bioethics. 2011;25(3):145-154. doi:10.1111/j.1467-8519.2009.01736.x PubMedGoogle ScholarCrossref
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    Original Investigation
    Oncology
    August 10, 2021

    Experiences of Patients After Withdrawal From Cancer Clinical Trials

    Author Affiliations
    • 1School of Nursing, University of Pennsylvania, Philadelphia
    • 2Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 3School of Nursing, University of North Carolina, Chapel Hill
    • 4School of Nursing, George Washington University, Washington, DC
    • 5Department of Family and Community Health, Marcella Niehoff School of Nursing, Loyola University Chicago, Chicago, Illinois
    • 6Public Health Sciences, University of Virginia, Charlottesville
    • 7National Institutes of Health Clinical Center, Bethesda, Maryland
    • 8Department of Psychology, University of Massachusetts, Lowell
    • 9Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
    JAMA Netw Open. 2021;4(8):e2120052. doi:10.1001/jamanetworkopen.2021.20052
    Key Points

    Question  What are the experiences of patient-participants when they leave a cancer clinical trial?

    Findings  In this qualitative study in which 20 patients with cancer who withdrew or were withdrawn from clinical trials were interviewed, 5 themes emerged: posttrial prognostic awareness, goals of care discussions, emotional coping, burden of adverse effects, and professional trust and support.

    Meaning  Clinical trial exit is a critical time for engaging patients and families, who have invested their time and hopes in the trial, in meaningful dialogue about posttrial care needs; ongoing research is needed to inform responsible transitions from clinical trials and ensure ethical treatment of patient-participants.

    Abstract

    Importance  Cancer clinical trials (CCTs) provide patients an opportunity to receive experimental drugs, tests, and/or procedures that can lead to remission. For some, a CCT may seem like their only option. Little is known about experiences of patient-participants who withdraw or are withdrawn from CCTs.

    Objective  To examine patient-participants’ experiences during withdrawal from CCTs.

    Design, Setting, and Participants  This qualitative, descriptive study used a semistructured interview designed specifically for it, with open-ended and probing questions. The study took place at a National Cancer Institute–designated comprehensive cancer center affiliated with the University of Pennsylvania. The need for a sample of 20 interviewees was determined by code and meaning saturation (ie, no new themes revealed and identified themes fully elaborated). Interviews were transcribed verbatim and analyzed with a qualitative software program. Data coded with the software were refined into categories reflecting broad themes. A criterion-based sampling approach was used to select a subset of adult patients with cancer who were former CCT participants and who agreed on exit from those CCTs to a later interview about withdrawal experiences. They were contacted one by one by telephone from September 2015 through June 2019 until 20 agreed. Data analysis was completed in October 2020.

    Main Outcomes and Measures  Themes characterizing patient-participants’ perceptions of their withdrawal experiences.

    Results  Respondents’ mean (SD) age was 64.42 (8.49) years; 12 (63.2%) were men. Most respondents were White (18 respondents [94.7%]) and college educated (11 respondents [55.0%]). Cancer stage data were available for 17 participants, 11 of whom (64.7%) had stage IV cancer at CCT enrollment. Thirteen respondents reported withdrawal as a result of disease progression, and 5 withdrew because of adverse effects. Other reasons for withdrawal included acute illness and participant uncertainty about the reason. Analysis of interview data yielded 5 themes: posttrial prognostic awareness, goals of care discussions, emotional coping, burden of adverse effects, and professional trust and support. Subthemes included regrets or hindsight, urgency to start next treatment, and weighing benefits and burdens of treatment. Limited discussions about patient-participants’ immediate posttrial care needs left many feeling that there was no clear path forward.

    Conclusions and Relevance  Patient-participants transitioning from a CCT described feeling intense symptoms and emotions and awareness that their life span was short and options seemed to be limited. Communication that includes attention to posttrial needs is needed throughout the CCT to help patient-participants navigate posttrial steps. Research should focus on components of responsible and ethical CCT transitions, including types and timing of discussions and who should begin these discussions with patient-participants and their families.

    Introduction

    Patients with cancer participate in research trials for many reasons, including hope for remission or cure or a desire to give something back to society.1,2 Participation may be viewed as the only option available. We know little, however, about the experiences of patients with cancer when they withdraw or are withdrawn from cancer clinical trials (CCTs) and confront the possibility of limited life expectancy.

    Transitions occur every day in health care as patients move between clinical units, acute and primary care systems, and various health care practitioners. Transitions are especially vulnerable times for at-risk patients, many of whom are experiencing deteriorating health status and must cope with changes in care delivery. Patients who withdraw or are withdrawn from CCTs represent such a patient group. Transitional care is operationally defined as a time-limited range of services designed to enable at-risk patients to modify their goals and optimize their quality of life.3,4 Such services are essential for high-quality outcomes among patients who withdraw or are withdrawn from CCTs. Transitions can create uncertainty and confusion for patients and families, with the potential for miscommunication, medical errors, and poor outcomes. As Ulrich et al5 have argued, “Patients who complete a CCT may be feeling well but frightened of disease recurrence and unsure of future treatment plans.” When patients are nearing the end of their lives and previous treatments have failed, CCT transitions can be very difficult. Effective transitional care is achieved by providing such patients and their family caregivers with access to a trusted clinician who will ensure continuity of care, prevent avoidable and costly breakdowns in care, and advocate to ensure that patients achieve what matters most to them. Communication processes between patient-participants and practitioners at CCT transitions are not well understood, nor is the association between poorly managed transitions and subsequent patient morbidity.

    The voices of patient-participants who have exited CCTs are often missing from research ethics literature. Dresser6 pointed out that most research ethics reports incorporate perspectives of ethicists, clinicians, and researchers, not those of patients who participate in CCTs. Also missing are family members’ perspectives. There are many gaps in our understanding of patient-participants’ withdrawal from CCTs, including reasons for trial exit, supports received during the transition, and planning for post-CCT next steps and treatment options. Closing these gaps can inform development of evidence-based guidelines for ethical practice and informed decision-making during trial exits. Therefore, the purpose of this qualitative study was to further our understanding of patients’ experiences during and after trial exit by interviewing CCT patient-participants who withdrew or were withdrawn from CCTs.

    Methods
    Sample and Design

    Criterion-based sampling was used to select patient-participant cases meeting a certain criterion (in this case withdrawal from CCTs).7 As such, participants in this study were a subset of 498 adult CCT patient-participants who consented between September 2015 through June 2019 to a sequential mixed-methods parent study of their views about research participation and retention in CCTs at a Northeast urban National Cancer Institute–designated comprehensive cancer center. Patient-participants were aged 18 years or older, with a cancer diagnosis in the following categories: gastrointestinal or genitourinary cancer, hematological or lymphatic malignant disorders, lung cancer, and breast or gynecological cancer. Of the 498 who consented to the parent study, 20 who had withdrawn or been withdrawn from their CCTs and who indicated a willingness to be subsequently interviewed were contacted for a semistructured interview about their withdrawal experiences. Nineteen also completed a baseline survey about their CCT experience. Patient-participants were provided with a nominal incentive ($20) for their participation. Verbal informed consent was obtained from all participants by telephone. This study follows the Consolidated Criteria for Reporting Qualitative Research (COREQ) reporting guideline to promote transparency and quality of the research process.8 The study was approved by the institutional review board at the University of Pennsylvania and the affiliated cancer center.

    Data Collection

    Sociodemographic information was collected as part of the larger study, and an interview script of open-ended questions (semistructured interview) was developed by the research team. Race/ethnicity was self-reported by the patients. Race/ethnicity was assessed in this study because disparities continue to exist in CCT research participation. We used an interview guide that balanced structure with flexibility, and all patient-participants were asked the same open-ended questions and encouraged to discuss their perspectives and experiences related to each question. Probing (follow-up) questions were used to gain further insights and more detailed accounts of experiences.9,10 Interview scheduling was flexible and was based on patient-participants’ preferences. Interviews were conducted by 2 postdoctoral fellows (C.P. and another fellow who is not a coauthor of this article) working with the principal investigator (C.U.), all of whom were academic researchers with a clinical background. All participants were willing to share their perspectives with the research team. When challenging topics or emotions arose, the interviewers used therapeutic communication to support participants. Interviews were audiotaped, transcribed verbatim, uploaded to a secure site, and transferred to NVivo qualitative software version 12 (SQR International). On the basis of our previous qualitative research with a similar study population, we anticipated needing 20 to 25 interviews to identify and fully develop themes. We achieved saturation at 20 interviews when the interviews no longer revealed new themes (code saturation) and identified themes were fully elaborated (meaning saturation).9

    Statistical Analysis

    We used descriptive statistics for demographic and clinical characteristics, including age, sex, education, and cancer type. We used principles of conventional content and thematic analysis to explore patient-participants’ CCT withdrawal experiences.11,12 Transcripts were initially reviewed by team members with qualitative expertise (C.U., K.K., and A.M.F.), who coded phrases, sentences, and paragraphs. The list reflected both preset codes based on interview guide questions (eg, benefits and burdens of CCT participation) and codes inductively derived from the interview transcripts. NVivo was used to code interviews and access data on selected codes. Coded data were reviewed and refined into categories reflecting broader themes characterizing withdrawal experiences (described in the Results). Data analysis was performed using NVivo and Stata SE statistical software version 16 (StataCorp) and was completed in October 2020.

    Results
    Sample Characteristics

    The sample consisted of 20 patient-participants who agreed to be interviewed about their CCT withdrawal; 19 had provided baseline data (Table 1). Respondents’ mean (SD) age was 64.42 (8.49) years. The sample consisted of more men (12 men [63.2%]) than women (7 women [36.8%]); information on sex was missing for 1 respondent. Most respondents were White (18 respondents [94.7%]) and college educated (11 respondents [55.0%]). Cancer stage data were available for 17 participants, 11 of whom (64.7%) had stage IV cancer at CCT enrollment; 10 of 20 participants (50.0%) had stage IV cancer at diagnosis. Thirteen participants reported being withdrawn because of disease progression, 5 were withdrawn because of adverse effects, 1 was withdrawn because of acute illness, and 1 patient-participant was uncertain as to the reason for withdrawal (Table 2).

    Qualitative Themes

    Five major themes emerged: post-CCT prognostic awareness, goals of care discussions, emotional coping, burden of adverse effects, and professional trust and support. In addition, some subthemes were identified, including regrets or hindsight, urgency to start next treatment, hope, the odds of effectiveness or survival, trade-offs, and weighing benefits and burdens of treatment. Transcripts documented patient-participants’ unique cancer journeys, disappointment regarding a failed trial, and examination of personal values after withdrawal. Themes and subthemes are discussed later in the article. Table 3 presents illustrative quotations.

    Post-CCT Prognostic Awareness

    Patient-participants described their CCT withdrawal experience in multiple ways. Many characterized withdrawals as a failure of the trial drug. Others blamed their cancer for growing despite treatment or blamed the CCT’s protocolized nature, pledging allegiance to their oncologist. Others were unclear why they were removed and voiced assumptions about reasons. Finally, some described the decision as jointly made with their oncologist. Several subthemes highlight the range of participants’ post-CCT prognostic awareness, including where the patient is now; regrets, hindsight, and should-haves; and urgency to start the next treatment. At the beginning of each interview, a general “How are you doing?” question was asked. Some participants reported a positive outlook despite treatment failure, others admitted to feeling horrible, and 1 revealed she was in hospice care after the CCT.

    Participants rarely used the medicalized language of withdraw, but instead used verbs such as taken off, removed, or stopped. Some disagreed with the research team’s decision to remove them or stated they had no choice in the decision. After withdrawal, some expressed regret at having enrolled in the trial. Many wondered whether enrollment had been a wise decision because it interfered with living their life. Others speculated there might be another drug that must work better for their type of cancer and regretted not choosing such a medication, instead of enrolling in the CCT.

    For those with a good understanding of advanced-stage cancer, there was a sense of urgency to start the next treatment after CCT withdrawal, which stemmed from the knowledge that their cancer would continue to grow without treatment. Some participants enrolled in the next trial at the same appointment during which they learned they had been withdrawn from the original CCT. Many participants (15 of 20 participants [75.0%]) expressed an unwavering belief that CCTs are the source of breakthrough treatments and wanted to enroll in another trial.

    Goals of Care Discussions

    When reflecting on CCT withdrawal, participants also considered their cancer journey and its emotional roller coaster. These goals of care discussions included reflections around decision-making, living with cancer, other options (or lack thereof), values, advanced care planning, acceptable trade-offs, hopes, the odds of effectiveness or survival, and personhood. More than two-thirds (13 of 19 participants [68.4%]) of patient-participants had an advance directive. Some reflected on their decision to enroll in a CCT as part of their value system, which shaped their care goals. Values shaping care goals included the importance of having more time to pursue life goals, doing any treatment vs no treatment, and living to continue to care for their family or children. Also reflected in comments about care goals were implicit fears. For many (14 of 20 participants [70.0%]), the ultimate fear was death, and they bargained for more time. For them, CCTs represented hope or the key to survival.

    In making a decision based on personal goals, patient-participants weighed the benefits and burdens of enrolling. Some focused on numbers when making decisions. Others considered acceptable states of living or trade-offs (ie, survival time vs pain) when weighing options. Several (7 of 20 participants [35.0%]) valued their personhood and wished to be treated as more than their disease—that is, more than just a number or a trial participant. Feeling valued as a person creates a therapeutic relationship and can support the decision-making process.

    Emotional Coping

    Patient-participants reported intense emotions throughout their journey, starting with the diagnosis. CCT participation and withdrawal generated many emotions: hope, fear, sadness, anxiety, shock, and even happiness. Some described feeling emotionally vulnerable, even naked, as a result of seeing a new oncologist, differences in monitoring procedures, or the uncertainty of it all. Some described certain treatments, including CCTs, as a safety net, which contributed to a sense of hope. After CCT withdrawal, they reported experiencing disappointment and a loss of hope. One said that she feared the unknown and what CCT withdrawal meant for her cancer and her life.

    Participants reported coping with fears and disappointment in various ways. Many (18 of 20 participants [90.0%]) discussed relying on personal and professional supports, including spouses, children, siblings, friends, neighbors, colleagues, medical staff, and others with cancer, to support them following CCT withdrawal. Although some took on the burden of decision-making as solely their own, all expressed support from a social network, which they linked to their emotional coping.

    Burden of Adverse Effects

    Five of 20 patient-participants (25.0%) reported withdrawing from the CCT because they were experiencing unbearable symptoms from the treatment, including fatigue, pain, dyspnea, neuropathy, chills, coughing, diarrhea, hives or rash, blindness, and loss of hearing. Many of these symptoms had a negative effect on their daily lives. When patient-participants and their physicians believed the burden outweighed any benefits, they were removed from the CCT. Others experienced symptoms only at the time of administration of the CCT drug.

    Professional Trust and Support

    When reflecting on their trial withdrawal, patient-participants often discussed their medical practitioner, research team, and/or overall impressions of the research center. Positive reflections focused on the contribution of nursing care to their trial experience, their trust and respect for their oncologist, or the professionalism and caring nature of staff. However, some noted a lack of professionalism among staff. One was disappointed with the impersonal quality of his experiences with the researcher oncologist, compared with a local oncologist with whom he had a closer relationship. Others had mixed feelings toward the medical staff, noting both positive and negative interactions. For example, one expressed disappointment with a physician’s communication about the CCT withdrawal decision while continuing to hold much respect for the researcher.

    Some patient-participants thought the withdrawal decision was dictated by too many fixed rules and rigid protocols. When they were removed because of protocols and drug developer rules, they thought this took away both the physician’s clinical judgment and the individualized, patient-centered care that they deserved.

    Discussion

    To our knowledge, this study is one of the first to focus on understanding the perspectives and experiences of patient-participants when they withdraw voluntarily or involuntarily from CCTs. This understudied area of research requires ethical attention, and our results will help identify what is needed for responsible transitioning of patient-participants from a CCT. We highlight 3 points for discussion. First, patient-participants transitioning out of a CCT described feeling intense symptoms and emotions and awareness that their life span was short and options seemed limited. Indeed, what happens at trial exit is just as important as what happens at entry, as many patient-participants were facing life-limiting illness. Second, limited discussions with patient-participants about their immediate posttrial care needs left many feeling that there was no clear path forward. Third, good communication that deliberatively includes attention to posttrial needs throughout the CCT is needed to help scared and disappointed patient-participants navigate the next steps.

    As patient-participants expressed, having to withdraw from a CCT for whatever reason triggers many emotions, including sadness, fear, and hope for something else, as well as mixed emotions. A care transition is generally described as a transfer between different locations, practitioners, or levels of care.4,13,14 Effective transitions include communication about a care plan that incorporates the patient’s goals and preferences (including advanced care planning) and preparation for next steps. Most of the focus on post-CCT clinical care has been on providing patient-participants with access to any benefits that result from the trial, as affirmed in the Declaration of Helsinki.15 Cho et al16 argued that there is a broader set of posttrial responsibilities that have been overlooked by the research community. Needs related to posttrial care or responsible transitioning of participants are not well understood. After withdrawing from a CCT, patient-participants have a variety of needs, as our findings indicate. They may have a need for advanced care planning or end-of-life discussions or may want to discuss alternative interventions to the investigational drug or entry into another CCT. Many may need access to medical services and other community resources, as well as other supports. CCT patient-participants may experience many financial, emotional, physical, and spiritual hardships that can affect their health outcomes, as our data indicate.17,18 Our patient-participants were at different stages of their cancer trajectory, with some needing discussions of goals of care, some searching for new trials following their withdrawal, and others experiencing adverse effects. Although ineffective care transitions have mostly focused on older adults with chronic illnesses and their costly rehospitalizations, CCT patient-participants also need coordinated transitional care management, because they may need multiple treatments and specialists to support their ongoing health regimen.

    Cho et al16 further argued that, on the basis of the principles of ethical research, every research participant should be offered posttrial care to varying degrees at trial exit. Posttrial care was not evident in our study, as most participants expressed that they had no other options than to participate in the CCT, and some were regretful about participation. In fact, one-half of our patient-participants (10 patients) had stage IV disease at cancer diagnosis, and 11 had stage IV disease by the time they enrolled in their CCT. Although more than two-thirds of our withdrawn patient-participants had an advance directive, we do not know whether there were any discussions or preparation for next steps. It could be that given their stage at diagnosis, goals of care discussions with their oncologist or others had occurred before CCT enrollment. These conversations should be ongoing throughout the trial, and we need more data to understand these types of discussions.

    Patients with cancer experience many different symptoms depending on their type of cancer and treatment course. Indeed, these symptoms can be both physically and emotionally distressing, as our findings indicate. Symptoms such as pain, fatigue, and neuropathies can interfere with day-to-day functioning and outcomes of care.19,20 The patient-participants in our sample described a variety of distressing symptoms, including fatigue and respiratory, neurological, muscular, and gastrointestinal symptoms, consistent with other research.21,22 Given the distress participants were experiencing at CCT exit, it remains unclear whether palliative care consultation was offered at any point during the CCT. Furthermore, most patient-participants were withdrawn because of disease progression; at this stage of advanced cancer, referral to palliative care might be considered late along the cancer journey, but it should still be considered. It is interesting that patient-participants rarely acknowledged that disease progression was the reason for withdrawal. It may have been easier for them to consider reasons other than worsening disease and, therefore, worsening prognosis.

    Patients with cancer may avoid palliative care as they continue to search for a cure or remission.23,24 In our study, this usually meant seeking other CCTs. Delivery of palliative care concurrently with disease-directed therapies should become a standard at cancer institutions, as palliative care consultation has been shown to improve quality of life and emotional states in patients with advanced cancer.25 LeBlanc26 proposed that palliative care specialists be considered part of the cancer team at CCT enrollment, especially for patients in early-phase trials. This approach has the added benefit of providing needed support to discuss goals of care and ongoing concerns throughout the trial.

    Several participants left the CCT because of symptom burden. We do not know whether symptom burden increased at CCT exit because of the stress of withdrawing. Some evidence suggests that the experience of symptom burden may be affected by social, socioeconomic, and supportive factors,27,28 along with perceived stress and optimistic views.29,30 CCT patient-participants are generally very hopeful at trial entry, but hopefulness may wax and wane over the CCT’s course. More research is needed to measure hope over time in relationship to symptom burden at trial exit and beyond.

    Finally, improving communication with the CCT research team is imperative as we help patient-participants transition and assess posttrial care needs. We concur with Lawton et al31 who noted that, “Despite the emphasis placed on treating trial participants in fair and ethical ways, it is noteworthy that these individuals have rarely been consulted about the care and support they feel they need at the end of a trial.” As one of our patient-participants noted, the whole experience was a roller coaster. Members of clinical and research teams should more deliberately discuss what responsible CCT withdrawals should include, types of discussions that are needed, timing of such discussions, and who should begin these discussions with patient-participants and families. The emotional bonds that patient-participants build with their research team are often broken at CCT exit. The transition to new practitioners also needs attention. Some authors have indicated that loss of contact with accustomed practitioners can be a form of emotional harm for patient-participants, who may experience bereavement through this loss.32,33

    Limitations

    Our study was limited in several ways. First, we recruited patients from a single cancer institution in 1 geographical area. Patient-participants may view their withdrawals differently from those at other cancer institutions depending on whether they received support for their symptom burden and posttrial care needs. In addition, their views on what is owed them may differ depending on their trial.34 Second, although we identified some ethical challenges arising at CCT exit, more work is needed to explain these issues from a diverse group of patients with cancer, including the emotional, physical, and cultural influences that might affect posttrial needs. Third, although the sample size was appropriate for qualitative research, we cannot generalize beyond the study sample, and larger quantitative samples may be helpful to test hypotheses and factors associated with CCT withdrawal.

    Conclusions

    Participating in CCTs affords an opportunity for novel and experimental therapies that may extend life and, in some instances, may even cure the disease. CCT participation involves risks that may prove to outweigh benefits. Exiting a CCT represents a type of risk for participants, especially those withdrawn because of disease progression, lack of effect, toxic effects, or symptom burden. They must navigate next steps, including end-of-life care. CCT team members should do all they can to help patients at exit from CCTs, and this requires more dialogue and research from all stakeholders to identify best practices. Understanding the posttrial needs of patients with cancer and their families and what constitutes responsible transitions represents a measure of ethical respect for the many contributions that patients with cancer make to advancing our scientific knowledge and finding treatments that save lives.

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    Article Information

    Accepted for Publication: May 22, 2021.

    Published: August 10, 2021. doi:10.1001/jamanetworkopen.2021.20052

    Correction: This article was corrected on September 3, 2021, to fix an error in the Funding/Support statement.

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Ulrich CM et al. JAMA Network Open.

    Corresponding Author: Connie M. Ulrich, PhD, RN, School of Nursing, University of Pennsylvania, 418 Curie Blvd, Rm 339, Philadelphia, PA 19104 (culrich@nursing.upenn.edu).

    Author Contributions: Dr Ulrich had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Ulrich, Knafl, Zhou, Ratcliffe, Wallen, Richmond, Naylor, Gordon, Grady, Miller.

    Acquisition, analysis, or interpretation of data: Ulrich, Knafl, Foxwell, Zhou, Paidipati, Tiller, Ratcliffe, Richmond, Naylor.

    Drafting of the manuscript: Ulrich, Foxwell, Ratcliffe, Wallen.

    Critical revision of the manuscript for important intellectual content: Ulrich, Knafl, Foxwell, Zhou, Paidipati, Tiller, Ratcliffe, Richmond, Naylor, Gordon, Grady, Miller.

    Statistical analysis: Ratcliffe, Gordon.

    Obtained funding: Ulrich, Zhou, Ratcliffe, Naylor.

    Administrative, technical, or material support: Tiller, Naylor.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: Dr Ulrich is supported in part by grant R01CA196131 from the National Institutes of Health (NIH). Dr Ratcliffe is supported in part by grant R01-NR014865 from the NIH. Ms Foxwell is supported in part by grant T32NR009356 from the NIH and the New Courtland Center for Transitions and Health.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The views expressed are those of the authors and do not necessarily reflect those of the Clinical Center, the National Institutes of Health, or the Department of Health and Human Services.

    Additional Contributions: We thank all the patients who provided data for this project. Lillie Larochelle, BSN (University of Pennsylvania), and Kim Mooney-Doyle, PhD (University of Maryland), assisted with the project and were not compensated beyond their normal salaries.

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