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Neoadjuvant Chemo Flops Versus Upfront Surgery for Resectable Pancreatic Cancer

— Survival 13 months better with surgery, but "curiosities" in neoadjuvant arm muddy the results

Ƶ MedicalToday

CHICAGO -- Neoadjuvant chemotherapy failed to match upfront surgery for survival in resectable pancreatic cancer, a small randomized trial showed.

Unexpectedly, patients assigned to surgery first lived more than a year longer than those who received a short course of FOLFIRINOX chemotherapy before surgery. The result was especially surprising given that neoadjuvant therapy was associated with a higher rate of negative surgical margins (R0), and more patients in the treatment arm achieved node-negative status.

"Additional follow-up may better elucidate the long-term effects of the improvement in R0 and N0 rates in the neoadjuvant group," said Knut Jørgen Labori, MD, of the University of Oslo in Norway, at the American Society of Clinical Oncology (ASCO) meeting. "The results do not support neoadjuvant FOLFIRINOX as standard of care in resectable pancreatic cancer."

The outcome surprised invited discussant Andrew H. Ko, MD, of the University of California San Francisco, and he agreed that they do not support neoadjuvant FOLFIRINOX as an alternative to upfront surgery. But neither do they rule out the possibility. Several curiosities about the study preclude a definitive statement about the future status of neoadjuvant FOLFIRINOX.

Barely half the patients completed the four cycles of neoadjuvant chemotherapy, Ko noted, "which is far lower than I would expect of this patient population, for whom four cycles of treatment is ordinarily not prohibitively difficult... Second, why would the more favorable surgical and pathologic outcomes [R0, N0 status] translate into trends toward inferior outcomes in the neoadjuvant group? Third, when we look at the adjuvant setting, only a minority of patients received the protocol-specified FOLFIRINOX. The majority of patients, for unclear reasons, ended up pivoting to a gemcitabine-based regimen instead."

"So we really can't draw firm conclusions from this study regarding the specific impact of perioperative FOLFIRINOX on survival outcomes...FOLFIRINOX is very much still out there, and several ongoing trials will hopefully provide a clear answer regarding its potential benefit in resectable disease."

Surgery plus effective systemic therapy achieves the best outcomes in resectable pancreatic cancer, Labori noted. Traditionally, standard of care has consisted of upfront surgery followed by adjuvant chemotherapy. However, neoadjuvant therapy, followed by surgery and adjuvant chemotherapy, has begun to win favor with many oncologists.

Neoadjuvant therapy offers a number of potential options, Labori continued: early control of systemic disease, improved delivery of chemotherapy, and improved histopathologic outcomes (R0, N0). However, no randomized trial to date has clearly demonstrated a survival benefit for neoadjuvant chemotherapy.

To address the lack of randomized-trial data, investigators at 12 centers in Norway, Sweden, Denmark, and Finland enrolled patients with resectable pancreatic head cancer. Patients randomized to upfront surgery received 12 cycles of adjuvant modified FOLFIRINOX (mFOLFIRINOX). Those allocated to neoadjuvant therapy received four cycles of FOLFIRINOX, followed by restaging and surgery, followed by eight cycles of adjuvant mFOLFIRINOX. The primary endpoint was overall survival (OS), and the trial had statistical power to show an increase in 18-month survival from 50% with upfront surgery to 70% with neoadjuvant FOLFIRINOX.

The data included 140 randomized patients with ECOG performance status 0 or 1. In the surgery-first arm, 56 of 63 (89%) underwent surgery, and 47 (75%) started adjuvant chemotherapy. Of the 77 patients allocated to neoadjuvant therapy, 64 (83%) initiated therapy, 40 (52%) completed the therapy, 63 (82%) underwent resection, and 51 (66%) started adjuvant therapy.

Grade ≥3 adverse events (AEs) occurred in 55.6% of those who received neoadjuvant chemotherapy, primarily diarrhea, nausea and vomiting, and neutropenia. During adjuvant chemotherapy, about 40% of patients in each treatment group had grade ≥3 AEs.

By intention-to-treat analysis, neoadjuvant therapy was associated with a median OS of 25.1 months versus 38.5 months for upfront surgery, for a 52% increase in the survival hazard for neoadjuvant chemotherapy (95% CI 0.94-2.46, P=0.06). The 18-month OS was 60% with neoadjuvant FOLFIRINOX and 73% for upfront surgery. A per-protocol analysis yielded similar results.

Histopathologic findings favored neoadjuvant chemotherapy, as 56% of patients achieved R0 status versus 39% with upfront surgery (P=0.076) and N0 status in 29% versus 14% of patients (P=0.060). The per-protocol analysis showed a statistically significant difference favoring neoadjuvant FOLFIRINOX for R0 status (59% vs 33%, P=0.011) and N0 status (37% vs 10%, P=0.002).

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The study was supported by the Norwegian Cancer Society, South-Eastern Norway regional Health Authority, the Sjöberg Foundation of Sweden, and Helsinki University Hospital.

Labori had no relationships with industry.

Ko disclosed relationships with Clinical Care Options, Gerson Lehrman Group, Medscape, MJH Life Sciences, Research to Practice, AADi, FibroGen, Genentech, GRAIL, Ipsen, Merus, Roche, AbGenomics, Apexigen, Astellas, BioMed Valley Discoveries, Bristol Myers Squibb, Celgene, CrystalGenomics, Leap Therapeutics, and Merck.

Primary Source

American Society of Clinical Oncology

Labori KJ, et al "Short-course neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer: A multicenter randomized phase II trial (NORPACT-1)" ASCO 2023; Abstract LBA4005.