Doctors Debate: Is Radiotherapy Still an Essential Component of Neoadjuvant Therapy for Resectable Pancreatic Cancer?

Susan Tsai, MD, MSH

In the neoadjuvant setting, physicians treating resectable pancreatic cancer have more treatment options than ever before. Recently, however, the routine use of radiotherapy has been called into question, leading to a debate at the5^thAnnualSchool of Gastrointestinal Oncology™ (SOGO^®), hosted by Physicians’ Education Resource, LLC^®.

Susan Tsai, MD, MSH, an Associate Professor at the Medical College of Wisconsin in Milwaukee, argued in favor of neoadjuvant strategies for treating pancreatic cancer that routinely use radiotherapy. Her opponent, Michael Choti, MD, MBA, chief of surgery at Banner MD Anderson Cancer Center in Phoenix, Arizona, who argued against the use of always using radiotherapy in the in resectable patient, rather favoring neoadjuvant chemotherapy in all patients prior to surgical treatment, and only using radiation therapy selectively for borderline and locally advanced tumors.¹

Radiotherapy is Essential for Treatment of Pancreatic Cancer in the Neoadjuvant Setting

Tsai held that radiotherapy is a necessary part of neoadjuvant treatment due to its proven efficacy as treatment for nodal disease and its ability to limit or resolve perineural invasion, which has a high incidence rate in pancreatic cancer. Chemotherapy also has an important place in the neoadjuvant setting, Tsai said.

“The community as a whole is moving toward neoadjuvant therapy. [Part of the controversy is because] the current National Comprehensive Cancer Network [NCCN] guidelines²mention borderline resectable pancreas cancer but are less firm on resectable pancreas cancer,” Tsai said. “Even the earliest stage resectable disease should be managed with neoadjuvant therapy. The only question is what the neoadjuvant therapy should consist of.”

Tsai first reviewed data on the surgery-first approach for pancreatic cancer and revealed evidence that the margin positivity rate following surgery was higher than what would be considered acceptable in other cancers, with rates as high as 40% to 60%.

In the phase III ESPAC-4 trail, Robert P. Jones, PhD, and colleagues sought to define the patterns of recurrence after resection surgery and adjuvant chemotherapy by randomizing patients to either gemcitabine or gemcitabine plus capecitabine. A total of 730 patients were included in the study. At a median follow-up of 43.2 months (95% CI, 39.7-45.5 months), the overall survival (OS) from time of surgery was 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine monotherapy and 30.2 months (95% CI, 25.8-33.5 months) with the gemcitabine/capecitabine (HR, 0.81; 95% CI, 0.68-0.98;P  = .03).³

The results of the secondary analysis showed that gemcitabine plus capecitabine led to a 21% reduction of death following recurrence versus monotherapy (HR, 0.79; 95% CI, 0.64-0.98;P=.03). Also, the hazard model of ESPAC-4 showed that a positive resection margin was associated with poorer overall survival (HR, 1.39; 95% CI, 1.106-1.744;P=.005). The same was true for distant metastases with N2 nodal involvement.

The conclusion drawn from these data that supported Tsai’s argument was patients with up front resection of pancreatic cancer are at high risk for R1 and N1/2 disease.

Tsai noted that in ESPAC-4, the positive margin status following resection was around 60%.

Tsai argued that patients with resectable pancreatic cancer who are treated with chemotherapy following surgery, regardless of the regimen, are at higher risk of developing R1 and N1/2 disease, further supporting her argument in favor of neoadjuvant approaches.

Tsai’s argument was further supported with results from the intention-to-treat population in the PRODIGE study.

In a clinical trial organized by the Canadian Cancer Trials Group and the Unicancer-GI—PRODIGE Group, fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) demonstrated an improvement in overall survival compared with gemcitabine as adjuvant treatment for patients with resectable pancreatic cancer.⁴In this study, the locoregional recurrence rate was 13.4% in the FOLFIRINOX arm and 17.9% in the gemcitabine arm.

During her presentation, Tsai stated that local-only recurrence is seen in about 20% of patients, meaning more effective local control with the addition of neoadjuvant radiotherapy could be a potentially curative therapy for patients who recur with local-only disease.

Finally, Tsai argued that the benefit of neoadjuvant chemoradiation has been demonstrated in the recently published PREOPANC trial. This landmark randomized clinical trial compared neoadjuvant gemcitabine-based chemoradiation versus immediate surgery and adjuvant chemotherapy for patients with localized pancreatic cancer. Those patients who received neoadjuvant chemoradiation experienced a 44% reduction in local recurrence rates (HR: 0.56; 95%CI: 038-0.83;P=.003).⁵

For the optimal sequencing of neoadjuvant therapy, however, questions remain.

“Although we have consensus that neoadjuvant therapy is the best treatment sequencing strategy, we lack consensus on the endpoints of treatment and whether neoadjuvant treatment strategies should be based on time or patient response.”

Radiotherapy Is not Essential for Treatment of Pancreatic Cancer in the Neoadjuvant Setting

Michael Choti, MD, MBA

Despite acknowledging Tsai’s perspective, Choti argued that radiotherapy should not routinely be used as part of the neoadjuvant therapy of resectable pancreatic cancer, but rather only used selectively in borderline or locally advanced tumors where the risk for positive resection margins are higher.

“Pancreatic cancer is a difficult problem, but we’re making significant strides. The mainstay of treatment is to diagnose the cancer and determine if it is operable or not. Unfortunately, about 50% patients at the time of diagnosis are inoperable because the cancer has alreadymetastasized. Another 15-20% present with unresectable locally advanced disease, where the tumor is encasing a vital arteries and veins in the region. The remaining patients may be operative candidates with a potential for a curative-intent approach. These can be either initially resectable, where the tumor is away from the blood vessels, or borderline resectable where it abuts these structures. This is why it is critical when evaluating a patient with newly diagnosed pancreas cancer that high quality CT or MR scan is done and that the case is reviewed and discussed within an experienced multidisciplinary team.

For the roughly 15% of patients with pancreatic cancer whose tumors are initially resectable, Choti said there are still challenges related to the aggressive nature of the disease and a high probability of recurrence. As a result, surgery is always combined with additional therapy, given either before or after surgery

Choti said that in the past the debate had been over whether up front surgery or neoadjuvant therapy, by either radiation or chemotherapy, is the preferred approach in resectable pancreatic cancer. Choti feels that this is no longer as controversial, advocating neoadjuvant chemotherapy for all patients, eben those who appear clearly resectable. While both Choti and Tsai agree that neoadjuvant therapy is but the way to go, they disagree on the type of neoadjuvant therapy that should be administered.

Choti argued that for borderline resectable pancreatic cancer, particularly when involving the arteries, it is sensible to consider adding radiation. However, when the tumor is resectable, this should be treated with chemotherapy alone, restaged, and followed by surgery is responsive or stable. He noted that routine radiation had been advocated in the past primarily because older regimens of chemotherapy was less effective. More recently, but the effectiveness of chemotherapy regimens such as FOLFIRINOX have changed the management paradigm away from routine radiation therapy. As systemic therapies continue to improve, including possibly targeted and immunotherapies, this trend away from radiation will continue.

The equipoise for this debate was reinforced by the most recent NCCN guidelines (version 1.2020), which states that providers should consider neoadjuvant therapy, particularly in patients who are high risk, but states that there is limited evidence to suggest which neoadjuvant regimens are most beneficial off study. Acceptable regimens include FOLFIRINOX or gemcitabine plus albumin-bound paclitaxel. The NCCN also states that subsequent chemoradiation can sometimes be included.²

Choti challenged some of Tsai’s supporting studies, noting that most were in patients with borderline risk status rather than resectable, and, for the most part, studies presented compared neoadjuvant chemoradiation to upfront surgery rather than to neoadjuvant chemotherapy.

Choti made a strong case for the use of neoadjuvant therapy in the resectable patient but that these reasons align better with the systemic benefit. Specifically, he argued that the benefits of neoadjuvant treatment include:

• early treatment for patients with occult micrometastatic disease at distant sites
• avoiding morbid surgical therapy for those who develop early distant metastases and would derive no benefit from surgery
• increasing the number of patients receiving and completing therapy is greater when given before rather than after surgery, particularly when surgical therapy is a pancreaticoduodenectomy (Whipple operation).
• a period for improving the patient performance status prior to major surgery
• preoperative therapy can shrink the tumor, potentially improving the margin negative (R0) resection rate.

“While the benefit of neoadjuvant therapy is clear, the only argument for adding radiation therapy to the regimen is to possibly improve the R0 resection rate.” Choti said. “This is why there is a potential role for radiation in borderline or locally advanced disease, where the margin concerns are increased. In resectable tumors where the operation is done by experienced surgeon, margin negative resection can be achieved >90% of the time without radiation.”

In an interview following the debate, Choti also commented on the role of targeted therapies in the treatment of pancreatic cancer. He noted that targeted therapies are currently being used and are showing promise in the setting of more advanced disease. In addition, ongoing research may show promise with immunotherapies as well. In the future, similar to how chemotherapy was moved from the advanced to the neoadjuvant space, he pondered this possibility for the future use of these newer agents.

“If we find actionable mutations or a positive signal of efficacy in patients who aren’t being offered surgical therapy, then it may be possible in the future to offer targeted therapies, even in the neoadjuvant setting,”

The debate left off with an agreement that neoadjuvant therapy is needed to improve upon surgical efforts. Both surgical oncologists were eager to reach a consensus on the type of neoadjuvant therapy that is most helpful and the sequencing of these therapies in pancreatic cancer treatment. The matter remains an area of active research.

References

1. Tsai, S and Choti, M. DEBATE: Radiation therapy is an essential component of neoadjuvant therapy for resectable pancreatic cancer. Presented at:5th AnnualSchool of Gastrointestinal Oncology™, hosted by Physicians’ Education Resource^â, LLC.; March 21, 2020.
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Pancreatic Adenocarcinoma Version 3.2017. NCCN.org. Accessed March 26, 2020. https://bit.ly/33O9G79
3. Jones RP, Psarelli EE, Jackson R, et al. Patterns of recurrence after resection of pancreatic ductal adenocarcinoma: a secondary analysis of the ESPAC-4 randomized adjuvant chemotherapy trial.JAMA Surgery. 2019;154(11):1038-1048. doi: 10.1001/jamasurg.2019.3337
4. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.N Engl J Med. 2018; 379:2395-2406 doi: 10.1056/NEJMoa1809775
5. Verstejine E, Sucker G, 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. doi:10.1200/JCO.19.02274