Neoadjuvant FOLFIRINOX chemotherapy followed by selective chemoradiation therapy (CRT) may be the best clinical practice for patients with borderline resectable pancreatic cancer, at least in selected patients, according to the participants in a debate on the role of radiation therapy in this patient population at the 2022 Great Debates & Updates in Gastrointestinal Malignancies.
"There is a role for radiation in borderline resectable pancreatic cancer, but it might not be the role you're thinking. [It] has evolved to more of a selective role, but definitely there's a role for radiation therapy. With the emergence of more modern chemotherapy, [it] has a role, but CRT also has a role," said Christopher Crane, MD, Radiation Oncologist at Memorial Sloan Kettering Cancer Center.
Borderline resectable pancreatic cancer is an incredibly heterogeneous disease, ranging from those with minimal vein involvement to extensive arterial involvement. Those with extensive involvement may not be able to go to surgery, Crane explained.
"Optimally, we use neoadjuvant standard CRT for those at high risk for positive margin. There's an emerging role for use of ablative radiation therapy-double the standard dose to 100 Gy biologically effective dose-for those who do not have surgery in the neoadjuvant setting. Also, CRT has a role for ablating locoregional recurrences," he said.
Crane provided a rationale for pre-operative therapy in pancreatic cancer. "This gives us time to observe disease biology and avoid futile surgery for those who progress on chemotherapy. We can select the most fit patients for surgery who can tolerate it the best and, therefore, minimize complications and maximize compliance of adjuvant therapy. In the post-op setting, probably half of patients are not good candidates for timely use of neoadjuvant chemotherapy."
The FOLFIRINOX regimen was established in the metastatic setting for pancreatic cancer and quickly became used in the neoadjuvant setting. "In single-arm studies, the margin positivity was reduced from 30 percent to 10 percent, and the locoregional recurrence rate is lower as well," said Crane.
Four randomized controlled trials have validated the pre-operative rationale in high-risk patients, leading to fewer futile surgeries and more R0 resections. "Next, we need trials with neoadjuvant FOLFIRINOX to see if we can achieve similar results by randomizing palliative therapy versus neoadjuvant therapy followed by surgery," he stated.
"So far, there are no clear negative trials in gemcitabine-based CRT. No Phase III trials show positive results with neoadjuvant chemotherapy. FOLFIRINOX is a reasonable modern standard, but selective use of CRT can be used in the patients at highest risk with positive margins. Ablative radiation has a role to play for isolated locoregional recurrence."
Crane concluded: "Borderline resectable pancreatic cancer is heterogeneous. FOLFIRINOX should be included in therapy and radiation therapy individualized. Every patient may not need radiation. I concede that. We are evolving to the highest risk end of the spectrum for those with positive margins or those who have isolated locoregional recurrence or who may not be able to undergo surgery."
Another View on Radiation
In a counter argument, Efrat Dotan, MD, Chief of the Division of Gastrointestinal Medical Oncology at Fox Chase Cancer Center, stated: "There is no approved role for this approach. Dr. Crane showed some data in support of radiation therapy. But one of the biggest challenges is the great variability between types of radiation used, chemotherapy used, radiation sensitizers, dose of radiation, and how patients are treated around radiation therapy."
She noted that a meta-analysis of four earlier trials evaluating the benefit of CRT showed no improvement in survival. More recently, the Phase III PREOPANC study of preoperative CRT examined surgery followed by gemcitabine plus cisplatin (GC) versus GC plus radiation, more gemcitabine, surgery, and adjuvant GC (J Clin Oncol 2020; doi: 10.1200/JCO.19.02274). She noted that this is not the chemotherapy recommended today for adjuvant therapy and 45 percent of patients had borderline resectable tumors.
The results show disease-free survival (DFS) improved, with some improvement in local control. However, overall survival (OS) was not statistically significant. DFS for those with metastatic disease also showed no significant improvement.
"Pancreatic cancer is a systemic disease," Dotan stated. "Systemic chemotherapy is highly important. It leads to a higher rate of RO resection and some improvement in survival, but it's not clear if radiation benefits patients in terms of making them more resectable in this setting."
The Alliance A021501 trial for borderline resectable pancreatic cancer patients compared neoadjuvant FOLFIRINOX alone versus FOLFIRINOX plus stereotactic body radiation therapy (SBRT), followed by surgery and adjuvant therapy (J Clin Oncol 2021; doi: 10.1200/JCO.2021.39.3_suppl.377). The addition of SBRT did not lead to better R0 resection, and showed no significant improvement in survival, with 66.4 percent 18-month OS with FOLIFIRINOX and 47.3 percent 18-month OS with FOLFIRINOX followed by radiation therapy. Also, there was a higher rate of postoperative adverse events with radiation therapy (64%) versus chemotherapy alone (57%), she explained.
"Large prospective trials have tried to define a role for radiation therapy. There are no data to date to show OS improvement with addition of radiation therapy," Dotan noted. "I argue data are limited, with various methods used for radiation and various chemotherapy backbones. It's hard to draw a definitive conclusion that radiation therapy is effective or beneficial until we have more trials that are uniform in approach and we have a better understanding of the right radiation therapy and the right population for this approach."
Mark L. Fuerst is a contributing writer.