**5.1 Downstaging chemotherapy**

Downstaging chemotherapy is indicated for metastatic disease and for syncronicity in nonresectable disease. Intravenous or HAI downstaging chemotherapy showed a resectability of 20% (Fusai & Dadvison 2003). The advent of oxaliplatin and irinotecan reached response rates of up to 50% increased over 65% with the addition of bevazucimab and cetuximab. Although there are no reports of outcomes of liver resection after HAI, its complication rates are so high (57%) that it is dismissed as a first option.

When treating these patients, the question arises as to whether to continue treatment until reaching the maximal effect or stopping once the disease becomes resectable. In general, preoperative chemotherapy should be stopped once the intrahepatic disease has been downsized to the point where hepatic resection is feasible. Surgery should be considered after 3 or 4 cycles in order to reduce liver toxicity, and therefore surgical morbidity, and to avoid a complete clinical response, difficult to trace intraoperatively. In most patients receiving chemotherapy, a complete response on CT scan does not mean cure (Benoist et al. 2006) due to the fact that in over 80% of the cases there are viable cancer cells in the initial site of the metastasis. Current management of these ghost lesions is to remove all of them if possible, considering the future liver remnant. In general, all the original sites of disease noted on the pre-therapy imaging need to be resected or ablated.

Since post-operative morbidity affects long-term survival (Laurent et al. 2003), length of chemotherapy treatment must be taken into account. In recent years more and more patients with stable long-term disease (more than 20 months) are considered for surgical treatment. Irinotecan and oxaliplatin have been associated with the development of steatohepatitis. Among patients receiving these drugs, the rates of complications and death after major liver resection are likely to be higher compared to patients not receiving chemotherapy, although this is not completely clear. Albeit systemic treatment is very effective in reducing tumour burden and facilitates the surgical therapy in previously unresectable patients, the recurrence rate is high because of the presence of residual microscopic disease.
