Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second-leading cause of cancer-related deaths in the U.S. by 2030.1 Despite advances in pancreatic cancer therapeutic approaches, improvement in the overall survival (OS) of PDAC patients has lagged behind other gastrointestinal malignancies. While surgical resection remains the cornerstone of treatment, the systemic nature of PDAC warrants a multimodal approach to maximize the therapeutic benefits, mitigate the risk of local and distant recurrence, and improve OS. The crucial role of chemotherapy in the multimodality approach is undisputed, although the optimal treatment sequence and regimen are still under investigation. Despite the lack of randomized data, a paradigm shift has occurred in recent years, with greater consideration of the neoadjuvant approach in the treatment of PDAC. However, uncertainty surrounding the role of radiation therapy (RT) persists, particularly in the neoadjuvant setting.
While surgical resection remains the cornerstone of treatment, the systemic nature of PDAC warrants a multimodal approach to maximize the therapeutic benefits, mitigate the risk of local and distant recurrence, and improve OS.
The rationale for the addition of RT in the neoadjuvant setting is to improve locoregional control by margin sterilization and targeting of regional lymph node basins. Several retrospective studies, systematic reviews, and meta-analyses have supported this approach, but most have failed to translate these pathologic parameters into improved overall survival.2 Randomized multi-institutional trials in locoregional pancreatic cancer have been historically challenging to design, accrue, and successfully complete.3 Moreover, ongoing changes in multi-agent chemotherapy regimens, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and the addition of nab-paclitaxel to gemcitabine (Gem), have outdated the design and results of older clinical trials. As a result, there is a paucity of high-level evidence to define the role of RT in the contemporary neoadjuvant setting.
Results of recent clinical trials
The recently completed ALLIANCE A021501 (Combination Chemotherapy With or Without Hypofractionated Radiation Therapy Before Surgery in Treating Patients With Pancreatic Cancer) was a phase II randomized trial designed to investigate the therapeutic role of hypofractionated RT (stereotactic body radiation therapy [SBRT] or image-guided RT [IGRT]) in patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting.4 It is an important study, as it was the first randomized trial to investigate the clinical value of the addition of RT to neoadjuvant FOLFIRINOX. In this study, patients were randomized to receive modified (m) FOLFIRINOX versus mFOLFIRINOX + hypofractionated RT (SBRT or IGRT), with the primary endpoint of 18-month OS compared with historical control. On interim analysis, the radiation study arm was closed as the result of failure to achieve the prespecified futility cutoff for margin-negative resection rate (n < 11/30).
The 18-month OS rate in the neoadjuvant mFOLFIRINOX arm was 66.4 percent, exceeding the prespecified historical control rate of 50 percent, establishing the use of FOLFIRINOX as a reference preoperative regimen for patients with BRPC. However, study results demonstrated that the addition of hypofractionated RT to mFOLFIRINOX did not improve R0 resection rates or OS compared to historical control (47.3 percent versus 50 percent), suggesting that hypofractionated RT should not routinely be added in the borderline resectable neoadjuvant setting. However, this study does not close the door for conventional chemoradiation, as this regimen was not examined.
Future investigation focused on molecular and multi-omic profiling may provide prognostic information and inform targeted treatment strategies to better select patients likely to benefit from both systemic and locoregional therapies, including radiation.
The recently reported PREOPANC trial was a Dutch phase III trial that compared neoadjuvant chemoradiation with Gem versus upfront surgery followed by adjuvant Gem in patients with both resectable and BRPC. The primary endpoint was OS by intention-to-treat analysis.5 In the RT arm, three courses of Gem were administrated, and RT was combined in the second course (Gem-Gem/RT-Gem).
The long-term results of this trial were presented at the American Society of Clinical Oncology 2021 annual meeting, demonstrating improved OS with preoperative chemoradiation compared with upfront surgery (three- and five-year OS was 27.7 percent and 20.5 percent versus 16.5 percent and 6.5 percent; hazard ratio (HR) 0.73, p = 0.025).6 Preoperative chemoradiation also improved disease-free survival and locoregional failure-free survival. When stratified by resectability, the benefit was observed in patients with BRPC (HR 0.67; p = 0.045).
Although this trial demonstrates safety as well as an OS benefit for chemoradiation, the administered chemotherapy is outdated and is no longer standard of care. Moreover, chemoradiation was administered without induction chemotherapy. Therefore, it is still unclear whether chemoradiation would provide a meaningful oncologic benefit when added to modern chemotherapeutic regimens.
PREOPANC-2 was designed to compare mFOLFIRINOX with the superior arm in the PREOPANC trial (Gem-Gem/RT-Gem).7 Accrual of the trial is complete, and the results are much anticipated. However, the critique still remains that the RT arm was designed to include single-agent Gem, which is no longer the standard of care. PANDAS-PRODIGE 44 (Neoadjuvant mFolfirinox With or Without Preoperative Concomitant Chemoradiotherapy in Patients With Borderline Resectable Pancreatic Carcinoma) is another randomized phase II trial designed to compare mFOLFIRINOX with mFOLFIRINOX + chemoradiation in the preoperative setting. The eagerly awaited results could complement ALLIANCE A021501 and provide further clarification on the role of radiation in the neoadjuvant setting.
In summary, evidence to confirm a survival benefit of RT in the neoadjuvant setting is still lacking. It is conceivable that in a subset of patients with effective systemic control, RT could confer oncologic advantages. Future investigation focused on molecular and multi-omic profiling may provide prognostic information and inform targeted treatment strategies to better select patients likely to benefit from both systemic and locoregional therapies, including radiation.
- Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921.
- Janssen QP, van Dam JL, Kivits IG, et al. Added value of radiotherapy following neoadjuvant FOLFIRINOX for resectable and borderline resectable pancreatic cancer: A systematic review and meta-analysis. Ann Surg Oncol. June 17, 2021 [Epub ahead of print].
- O’Reilly EM, Ferrone C. Neoadjuvant or adjuvant therapy for resectable or borderline resectable pancreatic cancer: Which is preferred? J Clin Oncol. 2020;38(16):1757-1759.
- Katz MHG, Shi Q, Meyers JP, et al. Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. J Clin Oncol. 2021;39(3_suppl):377.
- 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. 2020;38(16):1763-1773.
- Eijck CHJV, Versteijne E, Suker M, et al. Preoperative chemoradiotherapy to improve overall survival in pancreatic cancer: Long-term results of the multicenter randomized phase III PREOPANC trial. J Clin Oncol. 2021;39(15_suppl):4016.
- Janssen QP, van Dam JL, Bonsing BA, et al. Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): Study protocol for a nationwide multicenter randomized controlled trial. BMC Cancer. 2021;21(1):300.