The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer pts following R0/R1 resection of hepatic metastases. Stimuvax® (BLP25 Liposome Vaccine or L-BLP25) is an investigational therapeutic cancer vaccine co-developed by Oncothyreon Canada Inc. (formerly Biomira Inc., Edmonton, Canada), and Merck KGaA, Darmstadt, Germany for the use as an active specific immunotherapy for MUC1- expressing tumors. Details of the physical, chemical and pharmaceutical properties, the non-clinical trials and effects and safety in humans have been published elsewhere 2008) .
Colorectal cancer is amongst the three most frequent malignancies in Western countries [2, 3]. Survival is delineated by local recurrence, by lymphatic and predominantly by hematogenous dissemination . Mutations in tumor suppressor genes (APC, DCC, Smad-2, Smad-4, p53) and oncogenes (K-ras) are molecular determinants occurring during the development of sporadic colorectal cancer, which was first summarized in the adenoma-carcinoma sequence described by Vogelstein et al. [5–7]. Since only 8% of colorectal cancers harbor concomitant mutations of APC, K-ras, and p53, it seems very likely that additional pathogenic alterations instrumentally mediate progression and metastasis of colorectal cancer .
At the time of first diagnosis, about 35% of colorectal cancer patients have distant metastases . Distant metastases limited to the liver occur in 15-20% of all patients initially diagnosed with colorectal cancer [10–12]. However, only 15-20% of synchronic hepatic metastases are resected by surgery. Complete surgical resection of hepatic metastases represents the only curative option: cure is otherwise not attainable. The 5-year survival after R0-resection of liver metastases ranges between 28% to 39% [13, 14]. Unfortunately, recurrence rates after R0 resection of hepatic metastases peak at up to 70% in the long-term follow-up .
The decision as to whether metastases are to be treated by surgical resection or by other therapeutic options such as neoadjuvant chemotherapy, should be discussed and determined by interdisciplinary tumor boards . The requirements for surgical resections are (i) that there is no evidence of extra-hepatic tumor, (ii) less than 70% of the liver is tumor-bearing, (iii) fewer than 3 liver veins and fewer than 7 segments of the liver are affected. Further exclusion criteria for surgical resection of liver metastases are the presence of CHILD B/C cirrhosis and/or other severe concomitant diseases . Using scoring systems such as that described by Fong, the prognosis can be estimated preoperatively . The existence of at least two Fong points predicts a median survival of 47 months after surgical resection of liver metastasis. However, the Fong score is only an indirect correlation of evaluated parameters (N-stage, size and number of metastases, preoperative CEA value and duration of disease-free interval) with the probability of incidence of organ metastasis. Organ-bound micro-metastases (MM) or disseminated tumor cells (DTC) are considered precursors of metachronic solid liver metastases [18–20].
A relevant clinical problem after primary or secondary resection of hepatic metastases is the high recurrence rate, ranging up to 70% . According to de Jong and colleagues, the median RFS after resection of liver metastases is 23 months andthe median OS 36 months . The application of classical chemotherapeutic strategies has not been sufficiently successful. Adjuvant 5-FU has non-significantly increased recurrence free survival (RFS 1.6 yrs. vs. 2.3 yrs.; P = 0.06), however this did not translate into a prolonged overall survival (4.0 vs. 5.0 years; P = 0.09) . Similar data was published by Portier et al., prolonging the 5-year-RFS (33.5% vs. 26.7%; P = 0.028) without augmenting the 5-year-survival (51.1% vs. 41.1% P = 0.13) by an adjuvant 5-FU therapy (EBM grade 2b) . Parks et al. found that a 5-FU based adjuvant chemotherapy versus watch and wait significantly improved postoperative overall survival (P = 0.007); however these data were retrospectively analysed registered data and thus not applicable (EBM grade 3b) .
Nordlinger's approach using peri-operative FOLFOX non-significantly increased the 3-yrs RFS by 7.3% (28.1% vs. 35.4%;P = 0.058); however patients treated per protocol (per protocol analysis) benefited even more (9.2%; 3-yrs. RFS 33.2% vs. 42.2%; P = 0.025) (EBM grade 1b) . Other studies are limited by small numbers and do not augment EBM grade 2b [25, 26].
The German S3 Guideline recommends surgery of primary resectable liver metastases (recommendation grade A; evidence grade 3b; strong consensus). In contrast, a neoadjuvant chemotherapy of primary resectable metastases is considered optional and is limited to well-defined, exceptional cases (recommendation grade 0; evidence grade 3, strong consensus). Postoperative adjuvant chemotherapy after curative R0 resection of hepatic metastases is considered optional ("can be considered"; recommendation grade B; evidence grade 2, strong consensus) .
In contrast, according to the current consensus of the "European colorectal metastases treatment group" use of neoadjuvant/peri-operative combination chemotherapy (e.g. FOLFOX) is suggested in the case of primary resectable liver metastases whereas for potentially resectable liver metastases a neo-adjuvant combination chemotherapy (e.g. FOLFOX or FOLFIRI) plus application of a targeted therapy (bevacizumab, cetuximab, panitumumab) should be considered. Isolated adjuvant strategies are not recommended by the working group.
In summary, no generally accepted standard of care is available following curative-intent resection of hepatic metastases in colorectal cancer patients. L-BLP25 is a therapeutic vaccine that targets MUC1, a well known tumor-associated antigen. Recently, it has been shown that MUC1 is associated with cellular transformation as demonstrated by tumorigenicity  and can confer resistance to genotoxic agents . High levels of MUC1 cell surface expression [29, 30], reported immunosuppressive activities of its released ectodomain  and anti-adhesive properties [32, 33] all contribute to the ability of the MUC1 antigen to protect and promote tumor cell growth and survival, making MUC1 an attractive target for cancer immunotherapy.
Based on these results, L-BLP25 has a promising potential as adjuvant therapy after curative-intent resection of hepatic metastases in colorectal cancer patients.