Abstract
BackgroundIn 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/DesignPRODIGE 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 RegistrationNCT01675999 (ClinicalTrials.gov)
Highlights
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
In the MOSAIC study, high risk stage II patients defined as N0/M0 patients with a T4 primary tumor, bowel obstruction, tumor perforation, poorly differentiated tumor, tumors with satellite venous or lymphatic invasion, or less than 10 lymph nodes examined, a non-significant gain of 3 % in disease-free survival at 3-years was observed for the FOLFOX-4 arm compared with the LV5FU2 arm (HR: 0.72 [0.48-1.08]) [5]
The 20 to 30 % risk of local or distant recurrence observed in patients with stage II/III, non-metastatic CC operated in a curative intent and receiving adjuvant chemotherapy reflects the relative failure of such a strategy to prevent the risk of locoregional spread of tumor cells or eradicate distant micrometastases
Summary
With about 1 million new cases in developed countries annually and 500 000 annual deaths, colon cancer (CC) is the second leading cause of cancer death in Western countries and a significant public health issue [1]. In the MOSAIC study, high risk stage II patients defined as N0/M0 patients with a T4 primary tumor, bowel obstruction, tumor perforation, poorly differentiated tumor, tumors with satellite venous or lymphatic invasion, or less than 10 lymph nodes examined, a non-significant gain of 3 % in disease-free survival at 3-years was observed for the FOLFOX-4 arm compared with the LV5FU2 arm (HR: 0.72 [0.48-1.08]) [5]. The 20 to 30 % risk of local or distant recurrence observed in patients with stage II/III, non-metastatic CC operated in a curative intent and receiving adjuvant chemotherapy reflects the relative failure of such a strategy to prevent the risk of locoregional spread of tumor cells or eradicate distant micrometastases. In radiology, which allows a good prediction of tumor stage (wall penetration and nodal involvement) prior to surgery [13, 14]; ii) the histological response observed in primary colon tumors treated by systemic chemotherapy [15] and iii) the demonstrated benefit of combining preand postoperative chemotherapy and/or radiotherapy in various gastrointestinal tumors (oesophageal, gastric, rectal and colorectal liver metastases) by several randomized trials [16,17,18]
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