**4. Chemotherapy and surgery**

152 Liver Tumors

lymphadenectomy, provided that involved nodes are in the hepatoduodenal-retropancreatic area and not in the common hepatic artery/celiac-axis region (Adam et al. 2008; Jaeck 2003). Although patients with microscopic involvement may derive a benefit from hepatic resection, gross involvement of the hilar nodes should be considered a relative

At present, the criteria for resectability include any patient in whom all disease can be removed with a negative margin and who has adequate hepatic reserve. That is to say, instead of resectability being defined by what is removed, now it is sustained by what will remain after resection, including patients with extrahepatic disease (Pawlik et al. 2008). Interestingly, none of the traditional adverse prognostic indicators of recurrence, such as carcinoembryonic antigen more than 200 ng/mL, short disease-free interval, node-positive primary, tumour size more than 5 cm, multiple tumours, or synchronous presentation,

precluded long-term survival, except for a positive resection margin (Vauthey 2007).

et al. 2006; Adam et al. 2006; Donadon et al. 2007; Garden et al. 2006).

In 2006, the Consensus Conference on Colorectal Liver Metastases of the American Hepato-Pancreato-Biliary Association (AHPBA) established that CRC liver metastases should be defined as resectable when the disease can be completely resected, two adjacent liver segments can be spared with an adequate vascular inflow and outflow and biliary drainage, and the volume of the liver remaining after resection (future liver remnant [FLR]) will be adequate (at least 20% of the total estimated liver volume for normal parenchyma, 30–60% if the liver is injured by chemotherapy, steatosis or hepatitis, or 40–70% in the presence of cirrhosis, depending on the degree of underlying hepatic dysfunction) (Vauthey 2006). When hepatic metastatic disease is not optimally resectable based on insufficient remnant liver volume, pre-operative chemotherapy, portal vein embolization or staged liver resection can be considered. Also, ablative techniques may be considered alone or in conjunction with resection. All original sites of disease need to be amenable to ablation or resection (Abdalla

Resection should be offered to all patients who are suitable candidates and neoadjuvant chemotherapy should be considered in patients who are deemed unresectable at initial evaluation (Doan et al. 2010). Novel chemotherapeutic regimens combining 5-FU, folinic acid and oxaliplatin and/or irinotecan have been associated with improved response rates (approximately 50%), allowing 10-30% of the patients with initially unresectable disease to be successfully treated with liver surgery (Adam et al. 2004). In addition, combination with biologic agents that target angiogenesis and the epidermal growth factor receptor (EGFR), bevacizumab and cetuximab, achieves response rates of up to 70%, increasing these figures (Vauthey 2006). Re-evaluation for resection should be done after 2 or 3 months of pre-operative chemotherapy and every 2 months thereafter. Tumour progression before surgery is associated with a poor outcome, even after potentially curative hepatectomy. Tumour control before surgery is crucial to offer a chance of prolonged remission in patients with multiple metastases (Adam et al. 2004). Patients should be referred early for evaluation for resection. The peri-operative complication rate, including hepatobiliary complications, is higher with lengthy pre-operative chemotherapy and is likely related to the prolonged and sequential use of multiple regimens (de Haas et

Once patients have been diagnosed and a decision made in a multidisciplinary setting that resection is appropriate, it is essential to ensure that patients undergo repeat high quality

contraindication to resection.

al. 2011).

The high recurrence rate and the overall poor "true" survival after surgical resection of CRC liver metastases led to the incorporation of the use of chemotherapy. This treatment can be administered in different strategies: neoadjuvant, peri-operative, adjuvant and conversion or downstaging. The latter is administrated to patients with unresectable disease with the goal of downsizing the tumour, re-staging it and re-considering its resection.

Chemotherapy seems to improve outcomes compared with surgery alone. Current chemotherapeutic regimens lead to improved survival in patients with unresectable liver metastases. Resection of the primary tumour and the liver lesions is the optimal management of stage IV CRC with liver metastases. For patients with extensive liver metastases, FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin) and FOLFIRI (irinotecan instead of oxaliplatin) have improved resection rates and survival. Upfront chemotherapy in the asymptomatic patient compared with resection of the primary tumour does not appear to affect survival significantly. However, given that 60% of the patients were alive after 2 years, resection of the primary lesion for palliative reasons and local control must be considered in rectal cancer (Cellini et al. 2010).

Optimal regimens and sequencing of chemotherapies when liver resection is an option are unclear. Some suggest that treatment of resectable liver metastases, in the absence of highrisk features (Fong score) should begin with surgery and consider adjuvant chemotherapy after surgery (Fong et al. 1999). If high-risk features are present, most physicians prefer a short course of systemic pre-operative chemotherapy. Peri-operative therapy and regional therapy with hepatic arterial infusion (HAI) increase disease-free survival (DFS) when compared with surgery alone. In unresectable disease, systemic chemotherapy with or without a biologic agent or HAI with systemic therapy must be considered. If the disease becomes resectable, adjuvant treatment should follow surgery. Adjuvant chemotherapy is usually FOLFOX, but HAI combined with systemic chemotherapy is also an option. The role of adjuvant treatment after liver resection should not be viewed in isolation, but rather in the context of prior treatment, surgical preference and individual patient characteristics. Conducting randomized trials examining the role of adjuvant chemotherapy has been difficult because of the rapidly changing chemotherapy regimens and drugs (Power & Kemeny 2010).

Operated patients with a perforated tumour or a considerable lymphatic burden are considered candidates for neoadjuvant chemotherapy before liver surgery, followed by a reevaluation after 3 months (Garden et al. 2009). The algorithm of the treatment may be that shown in Figure 1 (Kopetz & Vauthey 2008).

During the treatment with 5-fluorouracil/folinic acid plus oxaliplatin or 5 fluorouracil/folinic acid plus irinotecan, the patients deemed to be resectable should be considered as surgical candidates regardless of the associated adverse predictive factors. The emergence of EGFR antibody agents, which act effectively in patients with K-ras wildtype tumour, fosters treatment individualization (Shimada et al. 2009).

Fig. 1. \*Pre-operative therapy depends on the multidisciplinary team and the analyses of the individual case. In some cases, the first option can be resection without pre-operative chemotherapy. \*\*Portal vein embolization (PVE) can be associated to these approaches according to future liver remnants (FLR) volume and the status of the liver (normal, postchemotherapy and cirrhotic).

The efficacy of the peri-operative chemotherapy on survival benefit for resectable liver metastases has not been justified. However, the timing and the indication of the surgery are dramatically changing with the development of chemotherapeutic agents. The overwhelming majority of patients with resectable metastases receive some sort of chemotherapy, although it is not known if the adjuvant regimen is better than the neoadjuvant. The EORTC 40983 study did not demonstrate a clear advantage of preoperative chemotherapy in patients with initially resectable metastasis, but it could not

**Liver metastasis of colorectal cancer**

Resectable Unresectable

2-3 months\* Resectable First line

chemotherapy Re-evaluatation 2-3 months

Second-line chemotherapy. Re-evaluation.

Third-line chemotherapy. Re-evaluation.

Fig. 1. \*Pre-operative therapy depends on the multidisciplinary team and the analyses of the individual case. In some cases, the first option can be resection without pre-operative chemotherapy. \*\*Portal vein embolization (PVE) can be associated to these approaches according to future liver remnants (FLR) volume and the status of the liver (normal,

The efficacy of the peri-operative chemotherapy on survival benefit for resectable liver metastases has not been justified. However, the timing and the indication of the surgery are dramatically changing with the development of chemotherapeutic agents. The overwhelming majority of patients with resectable metastases receive some sort of chemotherapy, although it is not known if the adjuvant regimen is better than the neoadjuvant. The EORTC 40983 study did not demonstrate a clear advantage of preoperative chemotherapy in patients with initially resectable metastasis, but it could not

postchemotherapy and cirrhotic).

Preoperative theraphy

Hepatectomy (one, two-stage, in-situ, ante-situ, ex-situ)\*\*

> Postoperative therapy

answer either if neoadjuvant, adjuvant or peri-operative chemotherapy is superior. Detractors claim that chemotherapy delays surgery while supporters point out that surgery is facilitated and that the treatment provides information on tumour biology (Nordlinger et al. 2008). The surgeon's main concern is to operate on patients with livers affected by chemotherapy, which are usually more rigid, more difficult to manage and tend to bleed more easily. The same study demonstrated that no patient progressed from a resectable disease to an unresectable one, that short cycles of treatment provided minimal liver toxicity, that morbidity was similar in both groups and that survival improved in the chemotherapy sub-group. However, the problem persists over the timing of administering chemotherapy and the management of "ghost lesions" after complete response that cannot be detected with IOUS.
