A Randomized Phase III Study Comparing Adjuvant 5-fluorouracil/Folinic Acid with FOLFIRI in Patients Following Complete Resection of Liver Metastases from Colorectal Cancer
Abstract
Background: Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting.
Patients and methods: LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety.
Results: Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%).
Conclusion: FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.
Introduction
Colorectal cancer (CRC) is in the top four most common cancers worldwide and was responsible for over 500 000 deaths in 2002.[1] Up to 25% of CRC patients present with metastatic disease (mCRC), with the most common site for metastases being the liver.[2] An additional 35%–45% of patients will develop liver metastases during the course of their disease, with 20%–30% of patients having liver-limited metastases (LMCRC).[2, 3] The prognosis for mCRC patients is poor with 5-year survival rates of 4% reported for untreated patients[4] and 3-year survival rates of 5%–10% in patients treated with palliative 5-fluorouracil (5-FU) and folinic acid (FA).[5] A proportion of LMCRC patients are eligible for surgery with curative intent, which if successful has been reported to achieve 5-year survival rates of between 25% and 40%.[6–8] However, most treatment failures are due to local hepatic recurrences or metastases to the lungs, occurring within the first 2 years of surgery, raising the question of whether adjuvant therapy should be used in this setting.
Adjuvant 5-FU-based chemotherapy following surgery in patients suffering stage III CRC provides significant improvements in disease-free survival (DFS) and overall survival (OS) compared with surgery alone,[9–11] providing a rationale for its use in the adjuvant treatment of LMCRC patients following complete resection of metastases. A number of small studies indicate that significant patient benefit may be obtained from such an approach.[12–15] In a study in which LMCRC patients were randomized to receive postoperative local hepatic arterial infusion (HAI) of floxuridine in combination with i.v. continuous 5-FU or surgery alone, a significant improvement in 4-year recurrence-free rate (46% versus 25%) was reported in patients receiving adjuvant therapy.[15] However, in a comparable larger study, adjuvant treatment was stopped due to toxicity associated with HIA.[16] More recently, Portier et al.[17] demonstrated in a multicenter randomized study, a significant improvement in 5-year DFS rate (33.5% versus 26.7%) in LMCRC following complete resection receiving systemic adjuvant 5-FU/FA compared with patients receiving surgery alone.
The combination of 5-FU/FA with irinotecan (FOLFIRI) has been reported to provide a significant improvement in the palliative treatment of mCRC patients compared with 5-FU/FA alone, with median survival times in excess of 20 months reported.[18–21] A small phase II study reported tolerability of single-agent irinotecan in CRC patients previously treated with 5-FU following complete resection of colorectal hepatic metastasis.[22] However, there are currently no published randomized studies on the use of FOLFIRI in the adjuvant treatment of completely resectable LMCRC patients. In the present study, we report the results from a multicenter, randomized, phase III trial comparing FOLFIRI versus simplified 5-FU with leucovorin (LV, also known as FA) (LV5FUs) as adjuvant treatment in LMCRC patients following complete resection of metastases.
Article taken from sciencedirect.com
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