Prof. John Neoptolemos

Pancreatic cancer has a bad prognosis, but survival is increasing in patients with resectable disease due to improved surgery. Based on the pivotal randomized trials of ESPAC-1, -3 and -4, CONKO-001, JASPAC-1 and the PRODIGE-24, adjuvant chemotherapy also adds considerably to improved long-term survival in patients with resected cancers.^1,2 There is also emerging evidence that neoadjuvant treatment may improve survival in patients with borderline resectable cancer including the randomized ESPAC-5F trial.³ The PREOPANC trial also provides some supporting evidence for the use of neoadjuvant therapy for patients with borderline resectable pancreatic cancer but not, as claimed, for resectable tumors.^4,5Using adjuvant combination chemotherapies there is a three-year overall survival rate of 63.4 % with mFOLFIRINOX in selected patients and those aged less than 80 years, and a five year survival rate of 28.8% with gemcitabine-capecitabine in unselected patients, and corresponding median overall survival rates of 54.4 months and 28.0 months respectively in the PRODIGE-24 and ESPAC-4 trials.^1,2

The PREOPANC trial is confounded by including patients with resectable tumors, and with borderline-resectable tumors.^4,5 They were randomized to receive either upfront surgery and adjuvant mono-chemotherapy with gemcitabine, or neoadjuvant chemoradiation, followed by surgery and adjuvant gemcitabine.^4,5 Initially the results were not significant showing a median overall survival of 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery.⁴ Recently reported with longer term follow-up the median survival was 15.7 versus 14.3 months respectively and a 5-year overall survival rate of 20.5% versus 6.5% respectively.⁵

It is questionable however that PREOPANC would change current clinical practice as several concerns remain. Adjuvant mono-chemotherapy is no longer standard-of-care as combination chemotherapy regimens have been shown to be superior. Also chemoradiation in both adjuvant and neoadjuvant settings is not supported by randomized studies. In the Alliance A021501 phase II study in borderline disease neoadjuvant chemotherapy with chemoradiation had a median survival of only 17.1 months compared to 31.0 months in patients not given chemoradiation.⁶ The ESPAC-5F study with borderline resectable cancer, also found that neoadjuvant chemotherapy was superior to both upfront surgery, and to neoadjuvant chemoradiotherapy.³

The PREOPANC study is confounded by including patients with both resectable and borderline resectable tumors^. The hazard ratio in favor of neoadjuvant therapy was mostly due to the borderline patients with P=0.045 compared to the resectable group with a non-significant P=0.23.⁵ These findings are in line with ESPAC-5F showing an overall survival benefit for neoadjuvant chemotherapy in borderline resectable patients, whilst neoadjuvant chemotherapy was not advantageous in the SWOG-S1505 trial of resectable patients.^3,7

PREOPANC is also flawed because randomization was undertaken before full cancer staging was completed resulting in 26% having no resection at all.⁴ Moreover, the updated results were derived from a post-hoc analysis undermining its statistical significance. The original protocol presupposed hazard ratio that was required to provide a clinically meaningful result was not achieved in either the initial or in the post-hoc reports. The protocol did not specify further follow up, nor specify the P value and confidence intervals required to determine statistical significance. Thus the post-hoc analysis of the primary endpoint raises concerns of multiplicity. The role of neoadjuvant therapy in patients with pancreatic cancer will be further clarified with other currently ongoing randomized controlled trials.⁸

 

References:

1. Neoptolemos, J.P., et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017;389(10073):1011-24.
2. Conroy, T., et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406.
3. Ghaneh, P., et al. ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. J Clin Oncology 2020;38(suppl.15):4505.
4. Versteijne, E., et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020;38(16):1763-1773.
5. Versteijne, E., et al. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol. 2022;40(11):1220-30.
6. Katz, M.H.G., et al. Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. J Clin Oncology 2021;39(suppl.3):377.
7. Sohal, D.P.S., et al. Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 202;7(3):421-27.
8. Schwarz L, Vernerey D, Bachet JB, et al. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - A multicenter, noncomparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). BMC Cancer 2018;18(1):762.