Randomized controlled trials have long been considered the gold standard of clinical research, forming the foundation of treatment guidelines in oncology and beyond. We also know that participation in a clinical trial is often associated with better outcomes, in part due to the restrictive eligibility criteria used to standardize the study population and reduce the risk of bias and confounding.1 However, balance is needed when formulating these criteria, both to maintain the integrity of the trial design and to ensure the trial is applicable to patients in routine practice.
In this issue, Kobayashi et al.2 report the results of their assessment of patient eligibility in the Adjuvant S-1 for Cholangiocarcinoma Trial (ASCOT) JCOG-1202.3 Specifically, the authors direct their attention to understanding why potentially eligible patients were not enrolled in this trial in Japan. They administered a prospective survey to oncology providers to examine and provide commentary on the barriers to enrollment. The survey was conducted every 6 months over a 30-month period, resulting in five completed assessments at each of the 36 participating institutions. The lead investigator from each center was asked to select from a standardized list to best describe the reason for ineligibility among patients who had not been enrolled in ASCOT. Kobayashi et al.2 report that of the more than 2000 patients with biliary tract cancers resected in Japan during the trial enrollment period, 81.5% of patients were deemed ineligible for the ASCOT trial. The authors highlight the predominant reasons for trial ineligibility, including patient refusal (20%), pathologic stage (15%), age ≥ 81 years (12%), and prolonged postoperative complications (11%), among others.2 All of these reasons impact the potential pace of trial accrual and thereby the applicability of the results in a contemporaneous time period. Furthermore, with less than 20% of potentially eligible patients enrolled, the authors rightly raise the question as to the generalizability of the trial results to the patient population seen in routine clinical practice. Of these predominant factors limiting enrollment, we believe that our surgical oncology community plays a critical role in understanding the reasons for patient refusal and increasing our efforts to limit postoperative complications.
Data from the Commission on Cancer demonstrates that only 6.3% of all patients with cancer in the USA enroll in a clinical trial.4 Patient “refusal”—a commonly reported reason for non-enrollment—can be influenced by the patient’s reluctance toward randomization, fear of side effects, an implicit bias on the part of the providers, and the anticipated or actual financial toxicity of trial enrollment.5,6 A better understanding of the reasons for “refusal” is paramount to developing our approach to educating patients and providers regarding the goals of the trial, and to proactively address common misconceptions that may impede participation. As surgical oncologists, we can improve enrollment by having a working knowledge of trials for which our patients may be eligible, along with engaging patient navigators early in the clinical evaluation process. Within our multidisciplinary teams, we can help frame the risk–benefit ratio for our patients, for providers within our own institution, and for referring providers through outreach efforts.
Addressing the financial toxicity experienced by patients enrolling in a clinical trial is multifactorial, spanning from concerns regarding insurance coverage to challenges of traveling to the treating institution. Left unaddressed, this results in a cohort of patients with disproportionately higher socioeconomic status enrolling in clinical trials compared with the general population,7 thereby limiting the generalizability of the trial results. A potential solution is once again to seek the engagement of patient navigators to help patients access and utilize financial assistance programs.8 In a pilot study by Nipp et al.9 that established a financial assistance program to cover trial related expenses, the authors found the intervention was associated with increased trial accrual, ultimately enrolling a population of patients not typically participating in clinical trials due to a higher risk of financial burden. These data have stimulated a policy statement from the American Society of Clinical Oncology to proactively address the financial burden as a barrier to clinical trial enrollment, including transparency of out-of-pocket costs and the development of financial assistance programs to help offset these expenses.10
For patients being evaluated for adjuvant trials, eligibility criteria often include the ability to initiate adjuvant chemotherapy within a specific time frame following resection. The 11% of patients reported by Kobayashi et al. who were deemed ineligible due to prolonged postoperative complications are of particular relevance to our practice as surgical oncologists.2 We have seen that performance status, comorbidities, and surgical morbidity prevent up to 30% of patients from initiating adjuvant treatments following complex oncologic resections.11 Minimizing the impact of postoperative complications on potential trial enrollment requires our oncology teams to optimize patient performance preoperatively, as well as to continue to refine our perioperative protocols. As treatment algorithms for many solid cancers evolve from adjuvant to perioperative, and potentially to total neoadjuvant strategies, there will need to be ongoing work to minimize the impact of perioperative complications. Our efforts in preoperative rehabilitation and in refining perioperative recovery pathways are essential to mitigating the impact of postoperative complications on patient eligibility for adjuvant trials.
The study by Kobayashi et al. ultimately highlights two critical questions: How do we increase access to clinical trials and investigational treatments? How do we refine eligibility criteria and trial design so the findings are applicable to a broader population of patients? While there is bound to be overlap in the answers to these questions, the list of things to consider is daunting and yet imperative to address:
Redesigning clinical trials to be patient-centered and reduce financial burden
Liberalizing eligibility criteria where possible
Increasing the participation of community oncology settings
Increasing the odds of randomization to the experimental arm within the bounds of equipoise and statistical design
Engaging active community outreach to improve trust with patients and providers regarding clinical trial enrollment and eligibility
However, as demonstrated by Kobayashi et al.2, the most impactful first step we may be able to take at this time is simply to study the eligibility barriers to enrollment in our existing trials.
The authors are to be commended for their great foresight in the prospective collection of survey data to better understand barriers to trial enrollment, especially in a spectrum of diseases as challenging as biliary tract cancers. We hope to see similar analyses become standard and reported for all randomized trials as part of continued improvement and quality control in clinical trials. We believe reviewing and reporting patient eligibility assessments are essential to our efforts in the oncology community to maximize trial enrollment and the generalizability of results. Should an assessment of patient ineligibility at each center become a mandatory part of randomized clinical trial protocols? Ultimately, this may be the only way to confront our assumptions and remove barriers to maximize the potential for all eligible patients to enroll in clinical trials. We urge surgeons to examine the patient eligibility patterns in perioperative trials within their own institutions as a starting point to address these barriers. Only through our active participation in the design of perioperative clinical trials can we ensure the relevance of the results to the greatest number of our patients.
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The authors declare no conflicts of interest.
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Sood, D., Mayo, S.C. Understanding Barriers to Enrollment in Adjuvant Clinical Trials: Insights into Patient Eligibility Criteria from the Adjuvant S-1 for Cholangiocarcinoma Trial (JCOG1202, ASCOT). Ann Surg Oncol 30, 6967–6969 (2023). https://doi.org/10.1245/s10434-023-14272-y