**3. Current criteria for resectability**

150 Liver Tumors

lesion size is insensitive to early, treatment-related changes (Koh et al. 2006). In summary, DWI is a simple and sensitive method for screening focal hepatic lesions and is useful for

FDG PET is a highly sensitive and specific imaging study detecting hepatic metastases from CRC (92–100% and 85–100% respectively), although for some authors the strength of these data is moderate (Lucey et al. 2006). Several studies have also shown the utility of FDG PET in identifying additional metastatic lesions when initial CT showed single hepatic metastases and, thus, changed the management strategy. Nevertheless, false negative and false positive findings in FDG PET for hepatic metastases are not negligible (Udayasankar et al. 2008) and its positive predictive value (PPV) is not high, leading to some authors to confirm histologically the FDG PET findings suggesting non-resectability (Valls et al. 2009). Two meta-analyses have demonstrated high diagnostic values of PET in the evaluation of hepatic metastases (Bipat et al. 2005; Wiering et al. 2005), as well as a recent review (Patel et al. 2011) confirming the superior sensitivity of FDG PET for detecting liver metastases on a per patient basis, but not on a per lesion basis. Other papers have shown FDG PET/CT to be slightly less sensitive than MRI with liver-specific contrast agents or dedicated sequences for small lesions (Coenegrachts et al. 2009), but more sensitive than MDCT alone (Kong et al. 2008; Selzner et al. 2004), although its role is not yet clear owing to the small number of studies (Niekel et al. 2010). In the context of CRC metastases, the role of FDG PET/CT is to avoid unnecessary surgery, based on its ability to detect extrahepatic foci of disease (nodal metastases, lung nodules) that are not depicted or characterized as malignant by other imaging methods (Sørensen et al. 2007). In addition, this technology is not suitable for liver resection planning. In patients evaluated with FDG PET prior to surgery, a lower risk of "non-therapeutic laparotomy" (Pawlik et al. 2009) and improved survival (Fernandez et al.

A recent meta-analysis reviewing more than 3,000 patients found that sensitivity of CT, MR imaging and FDG PET on a per lesion basis were 74.4%, 80.3% and 81.4%, respectively, while on a per patient basis, the sensitivities were 83.6%, 88.2% and 94.1%, respectively. Specificity estimates were comparable. No differences were seen for lesions measuring at least 10 mm. Data about FDG PET/CT were too limited for comparisons with other

In brief, although every modality has benefited from advances in technology, MDCT scanning remains a dominant imaging modality not only for lesion detection and preoperative planning, but also for treatment monitoring and post-treatment surveillance. High-resolution CT with contrast combined with FDG PET/CT may obviate the need for additional studies and may improve patient management (Bipat et al. 2007; Doan et al. 2010; Vauthey 2006). Dynamic gadolinium-based contrast-enhanced MRI should be reserved for problem solving. MRI has the highest sensitivity for lesion detection, but because of its low sensitivity in detecting extrahepatic disease in the peritoneum and chest, it is not a desirable primary imaging modality (Vauthey 2006) except for evaluating patients who have not previously undergone therapy (Lucey et al. 2006; Niekel et al. 2010). Ultimately, the modality used must be tailored not only to the patient and the clinical situation, but also to

differential diagnosis (Koike et al. 2009).

**2.4 Positron Emission Tomography** 

2004) has been observed, reflecting better patient selection.

modalities (Niekel et al. 2010).

the imaging expertise within the institution.

Improvements in pre-operative imaging techniques, patient selection and surgical techniques, as well as the introduction of new cytotoxic and biologic agents for preoperative and post-operative chemotherapy have improved the resectability rate and almost doubled the 5-year survival rate for patients with CRC liver metastases, from about 30% two decades ago to nearly 60%. In this setting, with the care of these patients rapidly evolving, the standards of care needed to be redefined. The criteria for resectability of these metastases have changed dramatically. Features such as the number of lesions (1 to 3 unilobar metastases), the size of the lesion (less than 5 cm), preferably presenting at least 12 months after resection of the primary tumour, resectable with a minimum margin of 1 cm in width and without hilar adenopathy or extrahepatic disease, are no longer considered as determinant factors regarding resectability and, thereby, are invalid to deny a patient the opportunity of lengthy survival.

Regarding the number of metastasis, Altendorf-Hofmann did not find long-term differences in the survival rates between patients with 1 to 3 metastasis and those with 4 or more, if a R0 resection had been obtained (Altendorf-Hofmann et al. 2003). Moreover, some studies have shown that the degree of response to chemotherapy is a stronger predictor factor for longterm survival than the number of metastasis. Regarding tumour size and prognosis, reports have been conflicting. Evidence shows that size is not a resectability factor, but a factor related to tumour aggressiveness.

It has been shown that the actual width of the surgical margin has no effect on survival as long as the margin is microscopically negative (Figueras et al. 2007; Lordan 2007; Pawlik et al. 2005). A margin greater than 10mm is considered to be optimum, although this has changed too (Casanova et al. 2004). Although surgeons should continue to plan hepatic resection to preserve a "safety zone" and should avoid routine use of "minimum margin" surgery, a predicted margin of less than 1 cm should no longer be considered an exclusion criterion for resection.

Historically, extrahepatic disease has been almost universally accepted as a contraindication to liver resection. Recently, however, some series have shown a 5-year survival rate of 12% to 37% after liver resection in selected patients with extrahepatic disease, independent of the location of that disease (lung, primary colorectal recurrence, retroperitoneal or hepatic pedicle lymph nodes, peritoneal carcinomatosis, miscellaneous) (Elias et al. 2003, 2005). In most cases, incidental peritoneal disease found at laparotomy would contraindicate hepatic resection. In general, resection in such patients should only be considered after documentation of stable/responsive disease with systemic chemotherapy and when an R0 resection of both intrahepatic and extrahepatic disease is feasible. From an anatomic and prognostic perspective, it seems appropriate to recommend that patients with combined liver and extrahepatic disease be reported separately from those meeting the traditional resectable criteria, and be designated as borderline resectable (Vauthey 2007).

Positive hilar lymph nodes are associated with a poor outcome and have been traditionally considered as a contraindication to hepatic resection of CRC liver disease. Recent papers have reported long-term survival in some patients with hilar nodal metastases and have concluded that this patient population may still benefit from hepatic resection and 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 contraindication to resection.

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).

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

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 al. 2011).

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 abdominopelvic CT (or MRI) within a month of the date of surgery. Chest CT should also be performed at this time.
