Neoadjuvant mFOLFIRINOX Produces Favorable OS Results Without Radiation in Borderline Resectable Pancreatic Cancer

Neoadjuvant mFOLFIRINOX induced favorable overall survival (OS) results for patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) when administered prior to pancreatectomy, according to findings from the phase 2 A021501 trial (NCT02839343). However, the trial could not clearly demonstrate that neoadjuvant mFOLFIRINOX followed by hypofractionated radiation therapy was similarly effective.

At a median follow-up of 42.9 months (95% CI, 39.7-43.4), the Kaplan-Meier–estimated 18-month survival rate was 66.7% (95% CI, 56.1%-79.4%) for patients assigned to mFOLFIRINOX, which is a regimen comprised of oxaliplatin at 85 mg/m², irinotecan at 180 mg/m², leucovorin at 400 mg/m2, and fluorouracil at 2400 mg/m². That survival rate was noted to exceed the preselected historical control of 50%.

For patients who received mFOLFIRINOX along with radiotherapy, the Kaplan-Meier–estimated 18-month survival rate was 47.3% (95% CI, 35.8%-62.5%). Investigators closed the radiation arm at the interim futility analysis because statistical requirements to conclude efficacy were not met.

In an interview with OncLive^®, lead investigator Matthew H. G. Katz, MD, CMQ, FACS, FASCO, chair of surgical oncology at the University of Texas MD Anderson Cancer Center, expressed disappointment that the radiation arm closed early.

“My interpretation of existing data, and the data provided by this trial is pretty clear: I do not believe that the routine use of radiation therapy is indicated for any anatomic stage of localized pancreatic cancer” Katz said. “I do believe that there is a role for radiation therapy in selected patients with localized pancreatic cancer. The problem is we just have not figured out precisely who those patients are. I have heard that this is the end of radiation therapy. I think that is a gross overstatement. We just have to figure out who benefits.”

Patients with borderline resectable PADC have tumors that involve major abdominal blood vessels. However, surgery is difficult and not all patients benefit from the procedure. Furthermore, the cancer often recurs shortly after surgery if patients do not receive neoadjuvant therapy, which can include chemotherapy and possibly radiation treatment.

Although investigators have conducted multiple studies to determine the optimal treatment regimen in this setting, the use of radiation in the neoadjuvant setting remains controversial. Investigators conducting A021501 sought to assess the efficacy of neoadjuvant treatment with and without radiotherapy.

This study was not designed to directly compare chemotherapy with chemotherapy and radiotherapy in the neoadjuvant setting, and the role of radiation therapy in this setting remains undefined. Future studies will have to determine whether certain patients can benefit from neoadjuvant radiation and to identify who those patients are.

Investigators enrolled 70 patients to the mFOLFIRINOX arm and 56 to the mFOLFIRINOX/radiation arm at 50 sites across the United States. Those in the mFOLFIRINOX arm received 8 cycles of treatment. Patients assigned to radiation received 7 cycles of mFOLFIRINOX plus 33 Gy to 40 Gy of stereotactic body radiation therapy in 5 fractions (n = 35) or 25 Gy of hypofractionated image-guided radiation therapy in 5 fractions (n = 5).

Among the first 30 evaluable patients enrolled to each arm, 17 in the chemotherapy arm and 10 in the combination arm had undergone complete resection with negative margins. This led investigators to close the combination arm and proceed to full enrollment in the chemotherapy arm.

Thirty-eight patients in the chemotherapy arm and 28 patients in the chemotherapy and radiation arm underwent surgery on protocol. Thirty-two patients in the chemotherapy arm and 19 in the radiation arm received pancreatectomy. Among those who underwent pancreatectomy, 88% in the chemotherapy arm and 74% in the radiation arm had complete resection with negative margins.

Follow-up continued every 4 months after the end of treatment until 24 months post registration or documented progression, whichever occurred first. Thereafter, investigators collected survival information every 6 months for 5 years post registration.

The primary end point of the trial was 18-month OS rate, which was defined as the number of patients who were alive at 18 months after randomization divided by the total number of evaluable patients in each arm. Secondary end points included event-free survival (EFS), surgery with R2 resection, recurrent disease following surgery, any-cause death, R0 resection rate, pathologic complete response rate, and rate of adverse effects.

The median OS reported in patients within the mFOLFIRINOX arm was 29.8 months (95% CI, 21.1-36.6) compared with 17.1 months (95% CI, 12.8-24.4) in those who were in the radiation arm. The median EFS was 15.0 months (95% CI, 11.2-21.9) vs 10.2 months (95% CI, 6.7-17.3) in favor of the mFOLFIRINOX arm.

Katz noted that the prospective, multicenter trial enrolled patients at sites all over the United States. “When you think about that in that context, I think that the data are really impressive,” Katz said. “30 months of OS for a group of patients who were selected only by their anatomically advanced disease and who were operated on in centers across the United States is really impressive.”

Reference

Katz MHG, Shi Q, Meyers J, et al. Efficacy of preoperative mFOLFIRINOX vs mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable adenocarcinoma of the pancreas: the A021501 phase 2 randomized clinical trial. JAMA Oncol. Published online July 14, 2022. doi:10.1001/jamaoncol.2022.2319