Preoperative Combination Chemotherapy Improves Survival in Pancreatic Cancer Without Addition of Radiotherapy

Article

Favorable overall survival results were shown with preoperative combination chemotherapy in patients with pancreatic cancer.

Patients with borderline resectable pancreatic cancer given adjuvant modified FOLFIRINOX (irinotecan, fluorouracil, folinic acid, and oxaliplatin) were associated with a favorable overall survival (OS) higher than patients on FOLFIRINOX and hypofractionated radiotherapy, according to research published in JAMA Oncology.1

The prospective, multicenter, randomized phase 2 clinical trial (NCT02839343) evaluated 126 patients with 65 patients on the modified FOLFIRINOX alone for a median of 8 (range, 1-8) treatment cycles in arm 1 compared with 55 patients on a median of 7 (range, 1-7) treatment cycles of FOLFIRINOX with 35 patients on additional stereotactic body radiation therapy (SBRT), and 5 patients given hypo-fractionated image-guided radiation therapy (HIGRT) in arm 2.

At a median follow up of 42.9 months (95% CI, 39.7-43.4), results showed that patients in arm 1 had a higher 18-month OS rate at 66.7% (95% CI, 56.1%-79.4%) vs 47.3% (95% CI 35.8%-62.5%) in arm 2. Moreover, the median OS of patients in arm 2 was 17.1 (95% CI, 12.8-24.4) months compared with 29.8 months (95% CI, 21.1-36.6) in arm 1, and 41 of the first 62 evaluable patients were still alive at 18 months.

FOLFIRINOX was split at 85 mg/m2 of oxaliplatin; 180 mg/m2 of irinotecan; 400 mg/m2 of leucovorin; and 2400 mg/m2 of infusional fluorouracil over 46 hours administered every 2 weeks. In arm 2, 33-40 Gy of SBRT or 25 Gy of HIGRT was given in 5 fractions.

Event free survival (EFS) was also evaluated which also favored patients on FOLFIRINOX alone at 15.0 (95% CI, 11.2-21.9) months vs 10.2 (95% CI, 6.7-17.3) months in the FOLFIRINOX and radiation therapy arm.

“A clear role exists for the administration of systemic chemotherapy in the perioperative setting for this patient population,” said lead investigator Matthew Katz, MD, chair of Surgical Oncology at The University of Texas MD Anderson Cancer Center, in a press release.2 “This research demonstrates that pancreatic cancers that appear to involve major blood vessels can safely be removed following FOLFIRINOX with favorable results.”

The 18-month OS rate observed in arm 1 also surpassed the researcher’s benchmark of an 18-month OS rate of 63%, which is equivalent to a median OS of 27 months, based off a literature review of data from 2004-2015 that set a 50% or lower 18-month OS rate as the null hypothesis.

However, researchers noted that delays of FOLFIRINOX were observed in 32 patients in arm 1 and 33 patients in arm 2. Dose omissions were slightly higher in arm 1 with 9 patients having their doses emitted vs 8 in arm 2, however, dose reductions were experienced by 39 patients in arm 1 compared with 41 patients in arm 2. Only 1 patient in arm 2 had their radiotherapy interrupted.

At least 1 grade 3 or higher adverse event (AE) possibly related to treatment was experienced by slightly more patients in arm 1 compared with arm 2 at 37 patients vs 35 patients, respectively. Moreover, most of these AEs occurred during FOLFIRINOX treatment with the most common being diarrhea (18%), hypokalemia (14%), and neutropenia (12%). In comparison, the most common grade 3 or higher AE during radiotherapy was anemia (5%). No patients experienced a grade 4 AE possibly related to treatment, but 2 patients in arm 1 had a grade 5 AE with 1 unrelated to their pre-operative therapy, but 1 possibly related to treatment.

After pre-operative therapy, researchers observed the outcomes of patients from both arms who did not show disease progression and moved to surgery, and then post-operative therapy. The median duration between the patients last treatment and surgery with just FOLFIRINOX was 42 days (range, 28-76 days) compared with 44 days (range, 26-62 days) for patients on radiation therapy.

Thirty-eight patients (58%) in arm 1 underwent surgery on protocol compared to 28 patients (51%) in arm 2, with 32 patients in arm 1 and 19 patients in arm 2 undergoing pancreatectomy. R0 resection was achieved in 28 patients (88%) in arm 1 vs 14 (72%) in arm 2, and in arm 2 pCR was identified in 2 patients with further evaluation showing one patient had adenocarcinoma. Furthermore, 22 patients in arm 1 and 13 patients initiated postoperative therapy on FOLFOX (oxaliplatin, fluorouracil, and folinic acid [leucovorin]), and 69% of patients in each group also underwent pancreatectomy.

Prior to post-operative therapy, one or more grade 3 or higher AEs possibly related to treatment were observed in 9 patients in arm 1 and 9 patients in arm 2. The most common AEs between both arms were weight loss (14%), anemia (8%), wound infection (6%), and hypoalbuminemia (6%). After surgery, 6 patients from arm 1 and 1 patient from arm 2 experienced at least 1 grade 3 AE possibly related to post-operative treatment. The most common of these was neutropenia (11%), weight loss (9%), and leukopenia (6%). However, 20 patients from arm 1 still completed all therapy per protocol compared with 10 patients from arm 2.

“Given these study results, we believe all patients with tumors described as ‘borderline resectable’ should be treated with four months of FOLFIRINOX in anticipation of subsequent pancreatectomy,” Katz concluded. “These data provide the basis on which to build future studies for borderline resectable pancreatic cancer and to provide better treatments and outcomes for our patients.”

References

1. 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. doi:10.1001/jamaoncol.2022.2319

2. Preoperative combination chemotherapy improved survival in patients with pancreatic cancer. MD Anderson News Release. July 14th, 2022. Accessed: August 3rd, 2022. https://bit.ly/3zxyNLJ

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