Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial

Mehdi Karoui, Anne Rullier, Alain Luciani, Franck Bonnetain, Marie-Luce Auriault, Antony Sarran, Geneviève Monges, Hervé Trillaud, Karine Le Malicot, Karen Leroy, Iradj Sobhani, Armelle Bardier, Marie Moreau, Isabelle Brindel, Jean François Seitz, Julien Taieb, Mehdi Karoui, Anne Rullier, Alain Luciani, Franck Bonnetain, Marie-Luce Auriault, Antony Sarran, Geneviève Monges, Hervé Trillaud, Karine Le Malicot, Karen Leroy, Iradj Sobhani, Armelle Bardier, Marie Moreau, Isabelle Brindel, Jean François Seitz, Julien Taieb

Abstract

Background: In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.

Methods/design: PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.

Trial registration: NCT01675999 (ClinicalTrials.gov).

Figures

Fig. 1
Fig. 1
Protocol overview. Temporal sequence of trial conduct in patients with RAS WT colon tumor (1A) or RAS mutated colon tumor (1B)
Fig. 2
Fig. 2
The Tumor Regression Grade (TRG), as simplified to three categories by Ryan (19). TRG1: Major response; TRG2: Intermediate response; TRG3: No response

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