Barriers to Pancreatic Cancer Clinical Trials Enrollment
Michael S. Lee, MD, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
Shubham Pant, MD, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
Pancreatic cancer is the third leading cause of cancer mortality in the United States, causing an estimated 47,050 deaths in the year 2020, and had the lowest 5-year relative survival of any cancer type diagnosed in 2009-2015, at only 9% 1. More aggressive first-line and second-line systemic therapy regimens have proven to improve survival in metastatic pancreatic cancer2-4, but median survival is still shy of 1 year 2. In light of this limited prognosis, consensus guidelines from ASCO and NCCN recommend that patients be informed about and/or managed in clinical trials5,6. However, only 4.16% of patients with pancreatic cancer ultimately enrolled in clinical trials in 2014, while enrollment to existing trials is noted to be unacceptably slow7. Galvin and colleagues further highlight potential barriers to enrollment of pancreatic cancer patients in early phase clinical trials. Their study highlights several barriers to enrollment of pancreatic cancer patients to both phase 1 and later phase clinical trials.
Several domains of barriers to enrollment in clinical trials have been previously described, including structural, clinical, physician, and patient barriers 8,9. The study by Galvin and colleagues specifically sought to identify clinical patient barriers, as the patient population studied was only patients who were already seen and established in the clinic and who were being considered for clinical trials. However, prior studies showed that structural barriers, such as trial availability at a given institution for a given disease or stage, and clinical barriers were the most common barriers to enrollment in trials. A recent meta-analysis and systematic review across cancer types performed by Unger and colleagues showed 55.6% of patients did not have a clinical trial available at their institution8. Thus, to increase enrollment of pancreatic cancer patients to clinical trials, alleviating structural barriers is necessary, and arguably will yield a greater increase in enrollment. These factors are particularly relevant in the era of precision medicine. While biomarker-selected therapy shows promise in pancreatic cancer10, newer trial designs are needed to maximize enrollment in these rarer cohorts. Ongoing multi-arm trials in pancreatic cancer, such as Precision-Panc11 in the United Kingdom or Precision Promise in the U.S. (NCT04229004), provide a framework for both biomarker-directed and biomarker-agnostic trial arms to optimize trial enrollment.
Clinical barriers to enrollment, such as failure to meet eligibility criteria, are the second most common barrier to enrollment in oncology clinical trials, with 21.5% of patients in the meta-analysis by Unger and colleagues proving ineligible for specific clinical trials8. Clinical barriers in pancreatic cancer are particularly highlighted by the study by Galvin and colleagues. While patients included in the study were deemed to be qualified to enroll in a phase 1 study, 19.2% of the patients who did not enroll in a clinical trial died or transitioned to hospice, and another 15.4% had decline in functional status or disease progression. This underscores the rapid pace of progression and clinical deterioration in patients with uncontrolled, refractory pancreatic cancer. For example, in the NAPOLI-1 trial, the difference between median progression-free survival and median overall survival was roughly 2-3 months in all arms, suggesting a post-progression survival of 3 months or less 4. Consequently, patients with refractory pancreatic cancer typically have only a limited duration of time in which they maintain an ECOG performance status of 0-1, as typically required for enrollment in a therapeutic clinical trial. This is further exacerbated by many trials that exclude patients with low body-mass index or hypoalbuminemia. While patient selection for clinical trials must prioritize patient safety and produce results that are interpretable, overly stringent eligibility criteria also limit patient enrollment and potential generalizability of trial results to the real-world population of patients, and ASCO and the FDA are emphasizing careful evaluation of eligibility criteria to avoid overly restrictive criteria12. Additionally, wash-out periods of no therapy prior to starting on trial treatment should not be excessively long; we feel that in trials enrolling refractory pancreatic cancer patients, the wash-out period should optimally be less than 28 days. Many trials also include an inclusion criterion specifying a minimum life expectancy. However, this criterion is inherently subjective, and indeed oncologists in routine clinical practice typically overestimate patients’ life expectancy by a median of 4.4 months when patients actually had 0-3 months to live13. Given rapid clinical deterioration in pancreatic cancer, patients understandably are less likely to enroll in clinical trials if they are concerned about prolonged wait times for a trial, as Galvin and colleagues identified. Novel phase 1 trial designs may positively impact wait times for patients for trial slots. While many of these clinical barriers are intrinsic to the natural history and prognosis of advanced pancreatic cancer, clinical trials must be designed considering these potential clinical barriers.
Finally, a range of patient barriers to enrollment affect patient’s decisions to enroll in clinical trials. Galvin and colleagues highlight a number of patient barriers, including concerns about time commitment and fear of side effects. The American Cancer Society Cancer Action Network has issued several recommendations for overcoming barriers to patient enrollment incorporating multiple domains of barriers14. While these recommendations are applicable across all cancer types, given the challenges noted in enrollment in pancreatic cancer patients, it is particularly important to address these barriers and ensure that eligibility criteria are modernized to avoid unnecessarily restricting enrollment and allow for timely enrollment onto appropriate clinical trials before clinical deterioration.
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