Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 Background Colorectal cancer (CRC) is the most frequently diag- nosed cancer in Europe and one of the leading causes of cancer death worldwide [1,2]. About 20-25% of patients with CRC present with metastatic disease at time of diagnosis, and further 20-25% of patients will develop metastases after curative resection, of whom 20-30% present with liver metastases only [3,4]. Upfront stratifi- cation of patients with metastatic CRC (mCRC) into clinical groups according to clinical presentation and treatment aim by a multidisciplinary team is of utmost importance for the prognosis of the individual patient [5]. Clinical groups based on current guidelines and recommendations are displayed in Table 1 [6,7]. Recent retrospective series demonstrated profound improve- ments in outcome of patients with colorectal cancer over the last 20 years due to advancements in chemotherapy and dramatic increase in patients undergoing liver resec- tion for either primarily or secondarily resectable colo- rectal liver metastases (CLM), resulting in an overall survival (OS) comparable to that of stage III (UICC) colon cancer [8,9]. Management of R0 resectable liver metastases Resection of CLM is a potentially curative treatment, and reported 5-year survival rates are about 40% [10,11]. Further follow up after resection of liver metastases from colorectal cancer demonstrated long-term survival and finally cure for every fifth patient even in the presence of poor prognostic factors [12-15]. However, with the majority of patients relapsing after liver resection, either intrahepatic (about 70%), extrahepatic (about 50%), or both, further research is urgently warranted [16]. Selection of patients for a potentially curative approach The selection of patients for hepatic surgery is a contro- versial issue. The most commonly used scoring system for prediction of OS described by Fong and colleagues incor- porates five risk factors: node-positive primary, disease- free interval <12 months, >1 lesion, size >5 cm, and CEA >200 ng/m. Patients with 5 risk factors had a 5 year OS rate (5-yOSR) of 14% with a median of 22 months com- pared to a 5-yOSR of 44% and a median of 51 months in Table 1 Clinical groups for first-line treatment stratification group 0 1 2 3 clinical presentation clearly R0-resectable liver and/or lung metastases unresectable liver and/or lung metastasis potentially resectable after downsizing, comorbidities allowing surgery multiple metastasis, rapid progression, risk of rapid deterioration, unlikely to become resectable never resectable and no symptoms or risk of deterioration Page 2 of 10 case of one risk factor [14]. Recently, the international liver metastases survey, including data of about 4500 patients with preoperatively treated CLM, confirmed the poor prognosis of patients with lymph node positive pri- mary, abnormal CEA levels, and a high number of CLM, although cut off value was >3 [15]. Whereas the estimation of survival is broadly accepted, criteria for resectability are far from being well and uniformly defined [17-21]. Generally, a post-resection remnant liver of less than 30%, unfavourable location of metastases, co-morbidities excluding major surgery, aggressive tumour biology, and/or presence of extrahe- patic disease are regarded as limitations for liver surgery. However, liver resection should have the potential for complete macroscopic resection in curative intent [21]. Perioperative treatment for resectable CLM The EORTC 40983 trial accrued 364 patients to be randomized to two treatment arms: surgery alone or chemotherapy with 5-FU/LV and oxaliplatin (FOLFOX4 regimen), administered 3 months pre- and postopera- tively. [22]. Patients had to be technically resectable (assessed by CT scan) with a maximum of 4 CLM and no prior treatment with chemotherapy. Despite favour- able patients’ characteristics, with more than 50% bear- ing only a single CLM and about 80% with up to 2, respectively, and performance of surgery in “high qual- ity” institutions, the reported 3 year progression free survival rates (3-yPFSR) were relatively poor. In the group of patients (n=171) receiving the planned chemo- therapy and resection of CLM 3-yPFSR significantly increased from 33.2% (surgery alone) to 42.4% (HR 0.73, 95% CI 0.55 to 0.97). However, in the “intent to treat analyses”, the difference was not statistically signifi- cant due to ineligibility of 6% of patients (HR 0.79, 95% CI 0.62 to 1.02). No unusual toxicities occurred in the chemotherapy arm, and about 80% of patients completed the preoperative part. After resection, 76% of patients received postoperative treatment with the ma- jority (52%; n=80) completing all 6 cycles. Results of two single arm phase II trials using capecita- bine, oxaliplatin and bevacizumab as neoadjuvant treat- ment in about 100 patients with CLM either clearly R0 resectable or unlikely R0 resectable with poor prognosis demonstrated feasibility of this regimen with an overall response rate (ORR) of 73-78% and a conversion rate of 40% (12 of 30) in the unlikely resectable group [23,24]. Postoperative systemic treatment Two randomized phase III trials have compared adju- vant systemic chemotherapy with 5FU/LV after resection of CLM to surgery alone, but both were closed prema- turely due to slow accrual. By the time of closure, a small but statistically significant improvement in disease