Viewpoint
May 20, 2024
Are Patients With Cancer Best Managed in a Clinical Trial?
David I. Shalowitz, Franklin G. Miller
JAMA. 2024;331(24):2077-2078. doi:10.1001/jama.2024.1235
Tremendous improvement in the care of patients with cancer is largely due to the proliferation of well-designed clinical trials leading to therapeutic advances. Additionally, the results of interventional cancer research have facilitated the development of robust, evidence-based guidelines for cancer care, such as those developed by the National Comprehensive Cancer Network (NCCN), which widely serve as benchmarks for high-quality oncology practice. Perhaps as acknowledgment of the ongoing need for data-driven advancement in cancer care, each page of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) features a boxed statement that reads, “NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged” (https://www.nccn.org/guidelines/category_1). This view regarding the superior therapeutic benefit from clinical trial participation may be widespread in the oncology research community.1,2 Despite the critical importance of clinical trials to improving cancer care, we argue that this statement about the management of patients with cancer cannot withstand critical scrutiny. Moreover, it reflects a pervasive, fundamental misunderstanding about the ethics of clinical research and clinical care that may be detrimental to some patients with cancer.
Whenever possible, something should be learned from each patient with cancer, for the benefit of future patients. One important method of generating knowledge is through clinical trials, defined as “research studies in which researchers assign participants to get one or more interventions to test what happens in people” (https://clinicaltrials.gov/study-basics/learn-about-studies). However, the assertion that the “best management of any patient with cancer is in a clinical trial” [emphasis added] is not accurate for the full range of treatment and care of patients with cancer, through diagnosis, treatment, and survivorship, including care at the end of life.
First, the claim that participation in clinical trials is superior to care outside of a trial obscures fundamental differences in these 2 settings. Clinical practice guidelines (of which NCCN Guidelines are a prominent example) are developed to assist clinicians in selecting treatment best tailored to individual patients’ circumstances. Clinical trials, on the other hand, are designed and conducted to produce generalizable knowledge applicable to the care of future patients. Accordingly, patient management in clinical trials is standardized per study protocol, not individualized. Confusion by clinicians and patients of the goals and methods of clinical management during a trial with care off trial, reflects a “therapeutic misconception,” which has been extensively described and associated with failure of adequate informed consent for research.3 In view of the uncertainty required to conduct clinical trials, experimental interventions under investigation may demonstrate inferior outcomes compared with standard care, making it impossible to presuppose that on-trial care is “best.” For some patients, enrollment in a treatment trial may on balance offer a desirable chance of therapeutic benefit4; however, the claim that trial participation offers superior outcomes for cancer patients in all cases is not supported by available data.1,5
Second, clinical trials typically include procedures or interventions for the purpose of testing study hypotheses, which may not provide direct patient benefit. For example, biopsies may put patients at risk of clinical morbidity. Furthermore, clinic visits and other interventions required solely for research purposes consume patients’ and caregivers’ valuable time and may worsen financial consequences of cancer diagnosis through costs associated with travel and associated dependent care, and lost opportunities to generate income.6 Accordingly, investigators and research staff who promote the view that clinical trials offer the best management for any cancer patient may impair informed consent for clinical research by obscuring the differences between research participation and standard clinical care, including the additional risks and burdens patients may take on by enrolling in a clinical trial. Moreover, oncologists’ nonclinical motivations to enroll patients in trials, including academic advancement, health system initiatives, or ties to sponsoring organizations, have the potential to diminish focus on the needs of individual patients in making decisions about clinical trial participation.7
Third, the statement that the best management of any cancer patient is in a clinical trial appears disdainful to clinical oncologists by suggesting that navigating the complex, conflicting evidence base with patients to select cancer treatment that best matches patients’ values, preferences, and disease is less than the best management. Furthermore, in clinical scenarios in which guideline-based care offers a high probability of cure or prolonged survival, clinical trial enrollment may be low priority and offer an unfavorable risk-benefit ratio. The NCCN’s boxed statement is also disrespectful to patients who make informed decisions not to participate in clinical trial by suggesting that they have selected an inferior management option. Consider a randomized trial in which usual care treatment given every 3 weeks is compared with an investigational, weekly treatment regimen. If a patient knows that childcare and work responsibilities will not allow them to visit their oncologist more frequently than every 3 weeks, how can clinical trial enrollment be unquestionably the best management? Patients may choose to altruistically take on additional burdens to contribute to generalizable knowledge, but shared decision-making and informed consent for research are predicated on the fundamental ethical principle that patients are best placed to judge risks and benefits for themselves.
Fourth, espousing the view that the “best management of any patient” is participating in a clinical trial has the potential to exacerbate inequities in cancer care rather than attenuate them. To be sure, increased diversity in clinical trial enrollment has appropriately been highlighted as a marker of improvement in cancer health equity: the applicability of data supporting therapeutics depends on the inclusion of a diverse patient population in trials establishing efficacy. Additionally, some data suggest that sociodemographic inequities existing off trial may be improved when cancer care is provided through trial protocols.8 We agree that cancer health equity should be promoted by improving access to clinical trials. However, if clinical resources in community cancer centers treating vulnerable patient populations were diverted to trial infrastructure, it may become more difficult to provide high-quality care.9 When a trial is not available locally, the burdens of travel for treatment and research interventions fall disproportionately on patients who must travel the furthest. Patients with the least support from caregivers and employers might fare the worst when asked to take on additional health care interactions as part of clinical trial enrollment. Moreover, for some underserved populations, trust in the health care system is already a major barrier to timely cancer prevention and treatment. If oncologists promote enrollment in interventional trials as the best management for any patient with cancer, they may exacerbate gaps in trust with vulnerable populations who are reluctant enough to seek out standard clinical care and even more reluctant to participate in research.10
Finally, many patients may decide to discontinue cancer-specific therapy. Care for these patients encompasses holistic treatment of medical and psychosocial symptoms, including palliative care and hospice, and is classified in the NCCN Guidelines as “best supportive care.” The claim that the best management of any patient with cancer occurs while participating in a clinical trial implies that best supportive care never offers the best option. Consider the case of a 90-year-old patient with inflammatory breast cancer and congestive heart failure who declines chemotherapy recommended by her oncologist. In view of her prognosis, she is encouraged to enroll in hospice. It is difficult to see how participation in a clinical trial is necessarily the best management strategy for her. Although some clinical trials focus on supportive care, patients and caregivers may find trial participation burdensome or intrusive as their focus shifts to quality of life. For these patients, supportive care off trial may well be best.
In sum, the best management for some patients with cancer may be participation in a clinical trial; however, it is problematic to claim that trials offer the best management for any patient with cancer. Consideration of participation in research should be offered whenever appropriate with attention to potential therapeutic benefit, altruistic contribution to biomedical knowledge, and burdens and risks associated with enrollment. Management plans should always be selected through shared decision-making considering patients’ and caregivers’ circumstances, values, and preferences. We therefore call on NCCN and other cancer-focused organizations to revise the narrative that clinical trials offer the best management for any patient with cancer.
