Learning to Navigate the Neoadjuvant and Adjuvant Paradigms in Pancreatic Cancer

Tanios Bekaii-Saab, MD

Neoadjuvant chemotherapy could become a standard approach for patients with resectable pancreatic cancer, with data suggesting that adjuvant regimens also have a place in the paradigm, said Tanios Bekaii-Saab, MD, a medical oncologist at Mayo Clinic.

Bekaii-Saab explained that patients with borderline resectable, resectable, and locally advanced nonmetastatic pancreatic cancer should receive neoadjuvant chemotherapy, as it enables a cleaner surgery and increases R0 resection rates.

Regarding adjuvant therapy, the phase III ESPAC-4 study demonstrated that the combination of capecitabine and gemcitabine had a 5-year overall survival (OS) rate of 29% compared with 16% with gemcitabine alone for patients with pancreatic cancer whose tumors were surgically removed.¹ The median OS was 28 months with the combination versus 25.5 months with gemcitabine alone, representing an 18% reduction in the risk of death (HR, 0.82; 95% CI, 0.68-0.98; P = .032).

Moreover, findings presented at the 2018 ASCO Annual Meeting showed that adjuvant modified FOLFIRINOX (mFOLFIRINOX) is safe and significantly improved disease-free survival (DFS), metastasis-free survival, and OS versus gemcitabine in patients with resected pancreatic cancer.²

The median OS was nearly 20 months longer with mFOLFIRINOX than with gemcitabine: 54.4 versus 35.0 months, which represents a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median DFS was 8.8 months longer with mFOLFIRINOX than with gemcitabine.

OncLive: Please provide an overview of your presentation on pancreatic cancer.

How should physicians better incorporate chemotherapy into treatment?

Does radiation therapy have a defined role in treatment?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Bekaii-Saab discussed neoadjuvant and adjuvant strategies in treating patients with early-stage pancreatic cancer.Bekaii-Saab: The subject I discussed [focused on] understanding the landscape of adjuvant versus neoadjuvant therapy in pancreas cancer. We know that about 10% to 15% of patients will present with advanced nonmetastatic pancreas cancer in the adjuvant setting. These patients have either resectable, borderline resectable, or locally advanced nonmetastatic disease. Most, if not all, of those patients whose tumors are clearly resectable will ultimately end up in surgery. About half of patients with borderline resectable [tumors will go to surgery], and about 10% to 15% of patients with locally advanced disease will go to surgery.For adjuvant therapy, we have data for patients with resectable disease. Based on the ESPAC-4 study, we know that chemotherapy in the form of capecitabine and gemcitabine should be our standard. In the United States, we should probably use lower doses of capecitabine than used in the ESPAC-4 trial by the Europeans because of the history of capecitabine in this country versus in Europe.Radiation does not have a defined role yet. There are studies that have reported positive findings, negative findings, and in between. At this point in time, radiation does not seem to have a role, although it is still being explored in the adjuvant setting. Patients with very clear resectable disease go to adjuvant therapy. Borderline resectable and locally advanced disease certainly necessitate neoadjuvant therapy, typically in the form of chemotherapy.

For some selected patients, radiation is used to facilitate surgery. Some patients with borderline disease may not need radiation. Most patients with locally advanced disease will not need radiation, because they will never make it to surgery. Surgery determines the need for radiation, and the surgeon helps with that decision. We have studies that are looking at the role of radiation. It has been very disappointing in locally advanced disease, but we're seeing some activity in borderline resectable cancer.

Are more patients receiving neoadjuvant treatment than before?

Then, the question becomes whether we can move adjuvant therapy to neoadjuvant therapy for patients with resectable disease. At Mayo Clinic, that has become the preferred way to treat resectable disease. Essentially, patients with borderline resectable, resectable, and locally advanced cancer get neoadjuvant chemotherapy first and perhaps radiation for borderline resectable disease. Very few patients with locally advanced disease get radiation, and only those patients on study with clearly resectable disease get radiation. Off study, I do not think it matters as much.At this point in time, our landscape has moved from adjuvant therapy for resectable disease to neoadjuvant therapy for all advanced nonmetastatic cancer to facilitate surgical resection. There are advantages for patients with resectable disease in neoadjuvant therapy versus adjuvant therapy. First, we test the biology of the disease. We only cure 10% of all patients who receive surgery. We know that without selection, 90% of patients end up coming back with metastatic disease, so we need to better select patients. Sometimes chemotherapy will better inform us about this.

About 10% to 20% of patients who undergo resection are so sick after their surgery that they will never have the benefit to see chemotherapy. It's better to give it upfront. There are other advantages, as well. You get a cleaner surgery, increased R0 resection rate, and you can clean up some of the lymph nodes. All of these [elements] may improve the likelihood of survival.

However, 10% to 15% of patients with resectable disease may not make it to surgery because they will progress through. When we look at all the numbers combined, it is clear that patients who undergo neoadjuvant therapy and get to surgery have a much higher survival, historically, than those with resectable disease.

The only reason for that is a result of selecting patients who are more likely to succeed from surgical resection. When we put them in a head-to-head comparison in studies, they are about the same. There's no difference between the 2 groups. When we look at large patient population studies, there seems to be an advantage. I don't think that the advantage is because of the exposure as much as the selection. Right now, we favor neoadjuvant therapy for all patients with advanced nonmetastatic disease.

References

1. Neoptolemos JP, Palmer D, Ghaneh P, et al. ESPAC-4: a multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine and capecitabine versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol. 2016;34(18). doi: 10.1200/JCO.2016.34.18_suppl.LBA4006. 2. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group.
2. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4001. meetinglibrary.asco.org/record/159164/abstract.