Post-gemcitabine therapy for patients with advanced pancreatic cancer – Are comparisons across current randomized trials feasible?: Beyond the Abstract

The prognosis of patients with pancreatic cancer is extremely poor, with a European systematic review of real-world, observational data reporting a median overall survival (OS) of 4.6 months.1 It is a major and growing cause of cancer-related deaths, demonstrating a significant unmet need for improved treatment.

A minority of patients are eligible for surgery with curative intent and progression after therapy for non-metastatic disease is inevitable. First-line treatment for metastatic pancreatic cancer comprises FOLFIRINOX (folinic acid/leucovorin [LV], 5-fluorouracil [5‑FU], irinotecan, and oxaliplatin), gemcitabine+nab-paclitaxel or gemcitabine monotherapy, depending on performance status. However, there is no universally-accepted second-line standard of care: irinotecan- and oxaliplatin-based chemotherapy regimens are options for patients who have progressed on gemcitabine-based chemotherapy regimens, but these have not been directly compared in randomized controlled trials (RCTs), as insufficient data were available to justify the use of these arms as comparator therapies. There is conflicting evidence regarding the efficacy of oxaliplatin combined with 5-FU and LV,2,3 and no evidence for the efficacy of conventional irinotecan or FOLFIRI (irinotecan+5-FU/LV) in this setting. Promising results have been reported for liposomal irinotecan (nal-IRI) in combination with 5-FU/LV,4 leading to approval in the US, Europe, Taiwan and Australia. nal-IRI comprises a novel stabilization technology, encapsulating irinotecan within liposome particles, designed to prevent premature metabolism and enrich accumulation of the active metabolite SN-38 in the tumor.

An indirect treatment comparison (ITC) is a network meta-analysis that compares treatments in the absence of head-to-head RCT data. To determine if key factors of the published trials were sufficiently similar for an ITC, we systematically reviewed RCTs evaluating oxaliplatin- or irinotecan-based therapies in patients with advanced pancreatic cancer previously treated with gemcitabine. PubMed, key oncology conference abstracts and ClinicalTrials.gov were screened, and the following four trials were identified: NAPOLI‑1,4 CONKO-003,3 PANCREOX,2 and Yoo et al.5 (Figure 1).


Figure 1. Overview of NAPOLI-1, CONKO-003, PANCREOX, and Yoo et al. 2009.2-5 The Phase 3 studies compared experimental arms (NAPOLI-1: nal-IRI [not shown] or nal‑IRI+5‑FU/LV; CONKO-003: OFF; PANCREOX: mFOLFOX6) with a comparator arm of 5-FU/LV, while Yoo et al. 2009 compared mFOLFOX with mFOLFIRI3. Regimens and doses of therapy differed between the trials.
5-FU, fluorouracil; FF, 5-FU/LV; LV, leucovorin/folinic acid; mFOLFOX/mFOLFOX6, modified oxaliplatin+5-FU/LV; mFOLFIRI3, modified irinotecan+5-FU/LV; nal-IRI, liposomal irinotecan; NR, not reported; OFF, oxaliplatin+5-FU/LV


Fundamental differences were found across these trials in study design, patient and treatment characteristics, and outcomes. Differences included the proportion of patients with metastatic vs. locally advanced disease, patient stratification variables, reasons for discontinuing therapy, time between first- and second-line therapies, as well as prior and subsequent treatments. Treatment regimens varied in terms of dose, infusion time and frequency of administration.

Furthermore, differences in primary and secondary endpoints and outcomes were also noted (e.g., substantially higher OS in the control 5-FU/LV arm of PANCREOX compared with other trials), which could not all be adequately explained by known variables, such as time since diagnosis or post-progression therapy. The possibility of cross-trial comparisons was also limited by differences in treatment-related data reported and small sample sizes in several arms or subgroups.

Based on our comparative review, we deemed the four trials insufficiently similar to perform a formal ITC, and conclude that they should be interpreted separately (http://www.ncbi.nlm.nih.gov/pubmed/27676174).

It could be questioned whether it is still appropriate to use oxaliplatin-based regimens as the comparator arm in post-gemcitabine trials, as was recently the case in a study comparing selumetinib and MK-2206 with modified oxaliplatin+5-FU/LV in patients with metastatic pancreatic cancer following progression after gemcitabine-based treatment.6 In the absence of a head-to-head trial comparing oxaliplatin+5-FU/LV with nal‑IRI+5-FU/LV, the preferred treatment approach following progression after gemcitabine-based therapy requires consideration of additional factors. nal‑IRI+5-FU/LV is approved in this setting while oxaliplatin is not; there have been significant improvement in OS with nal-IRI+5-FU/LV vs. 5‑FU/LV alone while the data for oxaliplatin are conflicting; oxaliplatin is associated with a risk of dose-limiting neuropathy and ESMO guidelines support nal-IRI as the most suitable option for the second-line treatment of patients with pancreatic cancer after gemcitabine-based treatment.7 These considerations support nal‑IRI+5‑FU/LV as an evident chemotherapy backbone option, similar to gemcitabine+nab‑paclitaxel in the first-line setting, and as the preferred standard chemotherapy comparator in future post-gemcitabine trials.

Written by: Arndt Vogel, Floris A. de Jong, Fortunato Ciardiello, Richard A. Hubner, Jean-Frédéric Blanc, Alfredo Carrato, Yoojung Yang, Dipen A. Patel, Varun Ektare and Sharlene Gill, with editorial support from Physicians World Europe GmbH

References

1. Carrato A, Falcone A, Ducreux M, et al. A Systematic Review of the Burden of Pancreatic Cancer in Europe: Real-World Impact on Survival, Quality of Life and Costs. J Gastrointest Cancer 2015;46:201-11.

2. Gill S, Ko YJ, Cripps C, et al. PANCREOX: A Randomized Phase III Study of 5-Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol 2016;34:3914-20.

3. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:2423-9.

4. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016;387:545-57.

5. Yoo C, Hwang JY, Kim JE, et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer 2009;101:1658-63.

6. Chung V, McDonough S, Philip PA, et al. Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. JAMA Oncol 2016; doi 10.1001/jamaoncol.2016.5383.

7. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26 Suppl 5:v56-68.

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