Rebecca A. Snyder, MD, MPH

The invited discussant of the Alliance A21501 findings, Rebecca A. Snyder, MD, MPH, Assistant Professor of Surgical Oncology at the Brody School of Medicine at East Carolina University, Greenville, described the overall survival associated with modified FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) as “impressive” in a patient population treated across multiple centers. She further said the findings represent “an important benchmark for future investigation.”

Alliance A021501 evaluated the benefit of radiotherapy when used preoperatively with modified FOLFIRINOX. The radiotherapy was primarily stereotactic body radiation therapy (SBRT), based on the rationale that a short course of radiation would allow for targeted delivery of a higher radiation dose, including a boost to the tumor vessel interface over a short period. This would minimize the time the patient spends off systemic therapy and maximize the likelihood of margin sterilization, she explained.

Interpreting the Results

“It’s surprising that the radiation therapy arm closed early. We can speculate that perhaps the tumor was harder to dissect after radiotherapy, or there was peritumoral infiltration. Perhaps the periadventitial plane along the [superior mesenteric artery] could have become more fibrotic and difficult to dissect after SBRT, or fiducial placement may have led to more peritumoral infiltration,” she suggested.

The higher pathologic complete response rates in the radiotherapy arm were not surprising, she said, consistent with improvements in pathologic parameters shown in other trials. She also thought the resection rates were noteworthy, especially given the involvement of multiple centers and the very high–risk population with advanced disease.

As Dr. Snyder noted, survival benefits have not been shown for chemoradiation in the adjuvant setting, though not all these studies have included adjuvant systemic chemotherapy and therefore “are difficult to apply to current practice.” The current RTOG 0848 trial is evaluating adjuvant gemcitabine or gemcitabine plus erlotinib with and without chemoradiotherapy in 322 patients, and the results are pending, she said.

In the neoadjuvant setting to date, PREOPANC is the only randomized controlled trial to evaluate neoadjuvant chemotherapy (gemcitabine) plus radiation therapy.¹ The results in 246 patients showed that although secondary endpoints were improved, the primary endpoint of median overall survival was not: 16.0 months with chemoradiotherapy and 14.3 months with upfront surgery (hazard ratio = 0.78; P = .096), she noted.

Study Implications and Limitations

Putting this study in context with the others, Dr. Snyder commented: “Based on multiple studies in both the adjuvant and neoadjuvant settings, including the Alliance trial, there are no convincing randomized data that radiotherapy prolongs survival in any population of unselected patients with pancreatic cancer.”

The caveat is that the current findings mainly pertain to SBRT, and findings for conventional radiation plus modified FOLFIRINOX may differ, “though that seems unlikely,” she maintained. “It does not mean there is no role for radiotherapy here, but it’s not efficacious in the borderline pancreatic cancer neoadjuvant setting.”

Radiation therapy might also have a role in treating “specific subsets” of high-risk patients, added Dr. Snyder. She suggested that trials of such approaches should focus on “patient-centered endpoints” such as symptomatic local recurrence rates, rather than overall survival alone. Some of these questions may be answered by two ongoing trials:

• PREOPANC-2, which is randomly assigning 368 patients with resectable/borderline resectable disease to eight cycles of preoperative FOLFIRINOX or gemcitabine-based chemoradiotherapy (36 Gy) plus adjuvant gemcitabine
• PANDAS/PRODIGE44, which is randomly assigning 90 patients with borderline resectable tumors to preoperative modified FOLFIRINOX with or without capecitabine-based chemoradiotherapy (50.4 Gy) followed by surgery plus adjuvant gemcitabine or 5-FU and leucovorin. 

DISCLOSURE: Dr. Snyder reported no conflicts of interest.

REFERENCE

1. Versteijne E, Suker M, Groothuis K, et al: Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: Results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol 38:1763-1773, 2020.