Cetuximab in combination with 5-fluorouracil, leucovorin and irinotecan as a neoadjuvant chemotherapy in patients with initially unresectable colorectal liver metastases.

Cetuximab in combination with 5-fluorouracil, leucovorin and irinotecan as a neoadjuvant chemotherapy in patients with initially unresectable colorectal liver metastases 

Min BS, Kim NK, Ahn JB et al.

Onkologie, 2007, 30, 637-643

The treatment of liver metastases of colorectal cancer is one of the best examples of the value of multidisciplinary teams - and of the development of treatment options during recent years. The recent advances in chemotherapy, especially the increasing response rates with modern systemic therapy for metastatic colorectal cancer, are part of that improvement in treatment options.

Bismuth et al. reported the results of the first large series of patients who became resectable for liver metastases that were initially deemed not to be curatively resectable [1]. This report and further publications appeared after the newer cytotoxic drugs irinotecan [2] and oxaliplatin [3,4] were introduced as treatment options for colorectal cancer. Because tumour shrinkage is the sine qua non of resection if liver metastases are initially non-resectable, further therapy intensification has been investigated to increase the response rate in the general population of patients with metastatic colorectal cancer, and in the neoadjuvant setting for non-resectable liver metastases.

The combination of all cytotoxic drugs in one regimen [5-fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI)] increased the response rate and resection rate in a randomised study [5], and adding cetuximab to irinotecan- or oxaliplatin-based chemotherapy also increases the response rates. In the Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer CRYSTAL) study [5-fluorouracil, leucovorin and irinotecan (FOLFIRI) [+ or -] cetuximab], the rate of liver resection was increased from 1.5% to 4.3% with addition of cetuximab [6]. Thus adding cetuximab is an effective approach to increase the treatment efficacy, at least in patients without k-ras mutations [7].

In this paper by Min et al., the authors present a small study investigating the concept of neoadjuvant treatment with cetuximab/FOLFIRI in patients with non-resectable liver metastases. Thirteen out of the 23 patients were pretreated with chemotherapy; eight patients had prior treatment with oxaliplatin or irinotecan. With that background, the investigators achieved a high response rate of 39%. A multidisciplinary tumour board discussed the cases of all patients before chemotherapy and every month thereafter. Seven patients could undergo liver intervention after chemotherapy. This rate of 30% is within the expected range [8].

Firm conclusions cannot be drawn from this study because of the small number of patients involved, and therefore over-interpretation should be avoided; however, two observations should be noted. Firstly, these patients need an effective first-line therapy. Although the majority of the enrolled patients received some prior treatment (14/23), only one of the resected patients had received chemotherapy previously, and none of the patients with intervention was pretreated with irinotecan or oxaliplatin. This observation illustrates again the fact that the most active first-line schedule should be used if the resection of liver metastases is the treatment aim [8]. Within this small first-line cohort, six out of nine patients were resected. This fact illustrates the effectiveness of the chosen treatment regimen.

Secondly, extrahepatic disease is not a contraindication to liver resection and to combined neoadjuvant concepts. The authors state that three out of the seven resected patients had extrahepatic lesions. With a median follow-up of 11 months, one patient had disease recurrence. However, the approach is useful for patients only if all the metastatic sites may be resected with curative intent. Patient selection is crucial for studies in this target population. As in previous studies [9,10], the authors describe a relevant patient group of seven (23%) additional patients who were not enrolled into the trial because a positron emission tomography scan identified additional extrahepatic metastases not previously detected by the conventional computed tomography or magnetic resonance imaging scans.

However, further studies are clearly needed to optimise our treatment strategy and to identify the patients who will receive benefit from an aggressive multidisciplinary approach, which may include liver resection, but also local ablation. Furthermore, we need more information on the influence of the different interventions on disease-free and overall survival.

References

[1.] Bismuth H, Adam R, Levi F et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg, 1996, 224, 509-520.

[2.] Pozzo C, Basso M, Cassano A et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol, 2004, 15, 933-939.

[3.] Alberts SR, Horvath WL, Sternfeld WC et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol, 2005, 23, 9243-9249.

[4.] Adam R, Delvart V, Pascal G et al. Rescue Surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg, 2004, 240, 644-657.

[5.] Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: The Gruppo Oncologico Nord Ovest. J Clin Oncol, 2007, 25, 1670-1676.

[6.] Van Cutsem E, Nowacki MP, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (MCRC): the CRYSTAL trial. Proc ASCO, 2007, 25, Abstr. 4000.

[7.] Khambata-Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K-Ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol, 2007, 25, 3230-3237.

[8.] Folprecht G, Grothey A, Alberts S et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol, 2005, 16, 1311-1319.

[9.] Taylor RA, Tuorto SJ, Akhurst TJ et al. Evaluation with positron emission tomography before hepatic resection for metastatic colorectal cancer improves survival in patients with a high clinical risk score. Proc Gastrointestinal Cancer Symposium, 2007, Abstr. 240.

[10.] Wiering B, Krabbe PF, Dekker HM et al. The role of FDG-PET in the selection of patients with colorectal liver metastases. Ann Surg Oncol, 2007, 14, 771-779.

Commentary by Gunnar Folprecht (1) and Claus-Henning Kohne

(1) University Hospital Carl Gustav Carus, Dresden 01307, Germany