UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer.

Sir,

In the January 26, 2004 issue, Petrioli reported a small phase II study of 41 patients with metastasic colorectal cancer treated with UFT/leucovorin and oxaliplatin or UFT/leucovorin and irinotecan alternatively. The overall response (58.5%), median progression-free survival (8.8 months) and median overall survival (17.3) months are comparable to those of previous reported combinations including either oxaliplatin or irinotecan (de Gramont ; Douillard ; Saltz ), but with no grade 4 toxicity. Nevertheless, this study is questionable by many aspects. The first point to discuss is the inevitable selection bias illustrated by the favourable general status and the wide predominance (93%) of patients with 1 or 2 metastatic sites. Many baseline characteristics have not been precised such as albumin, lactate dehydrogenase, alkaline phosphatases, or carcinoembryonic antigen levels. Metastasectomy has been performed in about 20% of cases despite very low-dose intensities. This secondary surgery introduces a major confusing factor since prolonged survival and probably cure rates of about 20% can be obtained (Elias ). Above all, there is a major recruitment bias since 85% of the patients have had been operated for a primary tumour, favouring the early detection of metastases, leading to the selection of patients with low tumour burden and, consequently, to a potential advantage in terms of therapeutic efficacy and tolerance. However, the dose intensities of irinotecan and oxaliplatin are only 36 and 17 mg m−2 in this study vs 90 and 50 mg m−2, respectively, in the FOLFIRI and FOLFOX6 regimens and up to 100 and 65 mg m−2 in the recent intensified FOLFIRI-3 (Mabro ) and FOLFOX7 versions (Maindrault-Goebel ). UFT also is administered at a dose which is that recommended for combination with a full dose of irinotecan (Alonso ; Mackay ). Given the rarity of diarrhoea under oxaliplatin, higher doses of UFT might be combined with this agent (Kim ).

In fact, the aim of the study may be discussed since efficacy should be privileged in such selected patients potentially candidates to secondary surgery. Possibly, more patients might have benefited from this approach with heavier regimens, taking into account progresses in surgery allowing the treatment of patients with liver and lung metastases (Mineo ). The question of the selection of resistant clones by low doses also must be addressed. The evaluation of response to either oxaliplatin or irinotecan is extremely difficult with the alternated regimens. Consequently, second-line chemotherapy should have been a dilemma since the investigators had to use mitomycin. This study contributes to demonstrate that, at present, the neoadjuvant approach should be clearly distinguished from palliative chemotherapy. There is also a need for rapid integration of biological predictive factors of response (Etienne ; Arango ; Fallik ; Mariadason ).