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Objective: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe., Summary/background: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients., Methods: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers., Results: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries., Conclusions: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.

Colorectal cancer is a common malignancy and often presents with synchronous or metachronous distant spread. For patients with hepatic metastases, resection is the principal curative option. Liberalization of the indications for hepatic resection has introduced a number of challenges related to the size, distribution, and number of metastases as well as the condition of the future liver remnant. Advances in systemic therapy have solidified its role as both an important adjunct to surgery and also for many patients as a mechanism to facilitate resection. In patients whose disease is marginally resectable as a consequence of the distribution of hepatic lesions that precludes complete resection or out of concern for the future liver remnant, a number of strategies have been advocated, including prehepatectomy systemic therapy, staged surgical approaches, ablative technologies, and preoperative portal vein embolization. It is the purpose of this review to discuss ways in which to optimize the treatment of patients with potentially resectable disease, specifically those who are judged to have "borderline" resectable situations.

Objective: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC)., Background: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens., Methods: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study., Results: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group., Conclusions: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142).

Introduction: The optimal timing of primary and metastatic tumor management in patients with synchronous hepatic colorectal metastases remains controversial. We aimed to compare perioperative outcomes of simultaneous colorectal/liver resection (SCLR) with isolated resections utilizing a national clinical database., Methods: NSQIP data from 2005 to 2009 were examined to construct risk-adjusted generalized linear models and to calculate group-specific predicted estimates. These were used to compare 30-day perioperative outcomes among patients undergoing SCLR with colorectal (CR) and liver resections (LR) only in patients with metastatic colorectal cancer., Results: A total of 3,983 patients were identified, who underwent SCLR (192), LR (1,857), or CR (1,934). Rectal resection was performed in 45 (23.4 %) SCLR patients and 269 (13.9 %) CR patients (p < 0.001). Major hepatectomy was performed in 69 (35.9 %) SCLR patients and 774 (41.7 %) LR patients (p = 0.12). Median adjusted operation time (SCLR: 273 min, 95 % CI: 253-295; CR: 172, CI: 168-177; LR: 222, CI: 217-228; p < 0.001) and median adjusted length of hospital stay (SCLR: 9.5 days, CI: 8.8-10.4; CR: 8.1, CI: 7.9-8.3; LR: 6.4, CI: 6.3-6.6; p < 0.001) were longer for SCLR compared to CR and LR. Adjusted predicted risks for at least one postoperative complication were higher in SCLR (36.3 %) than in CR (26.6 %) and LR (19.8 %) (p < 0.003), mostly due to infectious/cardiopulmonary issues., Discussion: In SCLR patients, the risk of 30-day adverse outcomes is higher, and median operation time as well as length of hospital stay is longer compared to CR and LR patients. However, the expected combined morbidities of staged procedures though likely favor SCLR in carefully selected patients undergoing even complex hepatic and colorectal resections and should be considered.

Introduction: For colorectal cancer patients with liver metastases involving the hepatic dome or invading the diaphragm, a concomitant diaphragm resection is often required to achieve negative surgical margins. The purpose of this study is to determine whether diaphragm resection during partial hepatectomy for metastatic colorectal cancer influences short-term perioperative outcomes and overall survival., Methods: Demographics, treatments, and outcomes of 442 patients who underwent hepatic resection for metastatic colorectal cancer from 1996 to 2010 at a high-volume center were reviewed. Recurrence and survival were measured from the date of metastectomy. Actuarial curves were generated using the Kaplan-Meier method and compared using log-ranks testing. Multivariate predictors of worse survival were compared using a Cox-proportional hazards model., Results: A total of 442 patients underwent hepatectomy for metastatic colorectal cancer. Of these, 34 required simultaneous diaphragm resection (DR) and 408 did not (LR). No significant differences existed in patient demographics or comorbidities. The DR group had longer median operative times (336 vs. 267 min, p = 0.0008) but had comparable rates of perioperative morbidity and mortality. Median overall survival was shorter in the DR group compared to the LR group (18.8 vs. 36 months, p = 0.0017). When controlling for potential cofounders, liver metastases size > 5 cm (HR 1.45 95 % CI (1.08-1.99), p = 0.015) and diaphragm resection (HR = 1.72 95 % CI (1.03-2.86), p = 0.038) predicted worse survival., Conclusions: Simultaneous diaphragm resection during partial hepatectomy does not significantly influence perioperative morbidity or mortality despite longer operative times. However, patients who require diaphragm resection have less favorable survival rates as compared to those who do not.

Despite advances in contemporary chemotherapeutic strategies, long-term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. To validate our oxaliplatin sensitivity signature, patient-derived colorectal cancer explants (PDCCE) were developed in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (sensitivity = 87.5%; specificity = 100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer., (©2012 AACR.)

Mouse models have been developed to investigate colorectal cancer etiology and evaluate new anti-cancer therapies. While genetically engineered and carcinogen-induced mouse models have provided important information with regard to the mechanisms underlying the oncogenic process, tumor xenograft models remain the standard for the evaluation of new chemotherapy and targeted drug treatments for clinical use. However, it remains unclear to what extent explanted colorectal tumor tissues retain inherent pathological features over time. In this study, we have generated a panel of 27 patient-derived colorectal cancer explants (PDCCEs) by direct transplantation of human colorectal cancer tissues into NOD-SCID mice. Using this panel, we performed a comparison of histology, gene expression and mutation status between PDCCEs and the original human tissues from which they were derived. Our findings demonstrate that PDCCEs maintain key histological features, basic gene expression patterns and KRAS/BRAF mutation status through multiple passages. Altogether, these findings suggest that PDCCEs maintain similarity to the patient tumor from which they are derived and may have the potential to serve as a reliable preclinical model that can be incorporated into future strategies to optimize individual therapy for patients with colorectal cancer.

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.

Background: Patients with synchronous colorectal liver metastases (CLM) are typically treated with initial colorectal resection followed by arbitrary and prolonged courses of chemotherapy. Partial hepatectomy is considered only for patients without interval disease progression. This review describes the rationale for this treatment approach and the recent developments suggesting that this management paradigm should be reconsidered., Results: Because asymptomatic colorectal cancer often does not lead to complications, and given the potential benefit of chemotherapy in downsizing unresectable to resectable liver disease, most patients with asymptomatic primary tumors and unresectable synchronous CLM should be first treated with chemotherapy. In contrast, initial hepatic resection should be considered for resectable synchronous CLM. Survival benefits from prehepatectomy chemotherapy have not been established. Several reports demonstrate morbidity after hepatic resection from extended durations of irinotecan- and/or oxaliplatin-based prehepatectomy chemotherapy. Although shorter treatment periods may not have these deleterious effects on subsequent hepatic resection, prospective studies reveal that most patients with supposedly aggressive disease with short treatment durations will not be identified. Moreover, a complete radiologic response to prehepatectomy chemotherapy is not only rare but also does not equate with a complete pathological response. Finally, several studies suggest that simultaneous colorectal and minor hepatic resections can performed safely with benefits in total morbidity when compared with traditional staged procedures., Conclusions: The traditional treatment paradigm centering on the utility of prehepatectomy chemotherapy for resectable synchronous CLM should be reconsidered. Recent developments underscore the need for prospective randomized controlled trials evaluating the optimal timing of hepatectomy relative to chemotherapy.

The optimal timing of chemotherapy relative to resection of synchronous colorectal liver metastases (SCRLM) is not known. The objective of this retrospective multi-institutional study was to assess the influence of chemotherapy administered before and after hepatic resection on long-term outcomes among patients with initially resectable SCRLM treated from 1995 to 2005. Clinicopathologic data, treatments, and long-term outcomes from patients with initially resectable SCRLM who underwent partial hepatectomy at three hepatobiliary centers were reviewed. Four hundred ninety-nine consecutive patients underwent resection; 297 (59.5%) and 264 (52.9%) were treated with chemotherapy before and after resection. Chemotherapy strategies included pre-hepatectomy alone (n = 148, 24.7%), post-hepatectomy alone (n = 115, 23.0%), perioperative (n = 149, 29.0%), and no chemotherapy (n = 87, 17.4%). Male gender (p = 0.0029, HR = 1.41 [1.12-1.77]), node-positive primary tumor (p = 0.0046, HR = 1.40 [1.11-1.77]), four or more SCRLM (p = 0.0005, HR = 1.65 [1.24-2.18]), and post-hepatectomy chemotherapy treatment for 6 months or longer (p = 0.039, HR = 0.75 [0.57-0.99]) were associated with recurrence-free survival after discovery of SCRLM. Carcinoembryonic antigen >200 ng/ml (p = 0.0003, HR = 2.33 [1.48-3.69]), extrahepatic metastatic disease (p = 0.0025, HR = 2.34 [1.35-4.05]), four or more SCRLM (p = 0.033, HR = 1.43 [1.03-2.00]), and post-hepatectomy chemotherapy treatment for 2 months or longer (p < 0.0001, HR = 0.59 [0.45-0.76]) were associated with overall survival. Pre-hepatectomy chemotherapy was not associated with recurrence-free or overall survival. Patients treated with perioperative chemotherapy had similar outcomes as patients treated with post-hepatectomy chemotherapy only. We conclude that chemotherapy administered after but not before resection of SCRLM was associated with improved recurrence-free and overall survival. However, prospective randomized trials are needed to determine the optimal timing of chemotherapy.

Background: Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM., Methods: Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed., Results: From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27-1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25-0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32-3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06-3.02]) were associated with overall survival in multivariate analysis., Conclusions: The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.

Background: Although commonly used in combination with irinotecan or oxaliplatin (iri/oxal) for treatment of colorectal liver metastases before extirpation, the effects of preoperative bevacizumab on surgical outcomes are not established. The objective of this retrospective study was to determine if addition of bevacizumab to iri/oxal preoperative chemotherapy increases morbidity after hepatic resection., Study Design: We compared demographics, clinicopathologic data, treatments, and postoperative outcomes between patients given preoperative iri/oxal with and without bevacizumab and patients who underwent hepatic resection within and after 8 weeks from the last dose of bevacizumab., Results: From 1996 to 2006, 96 patients were treated with preoperative iri/oxal; 39 (40.6%) received concurrent bevacizumab. Preoperative bevacizumab treatment was associated with less blood loss (median 425 mL versus 600 mL, p=0.01) and lower RBC transfusion rates (43.9% versus 23.1%, p=0.06) after partial hepatectomy on univariable analysis. Only age>or=70 years (hazard ratio=8.52, 95% CI [2.00 to 36.45]) and concurrent extrahepatic procedures (hazard ratio=4.12, 95% CI [1.49 to 11.39]) independently predicted RBC transfusion and overall complications, respectively. There were no differences in overall (43.6% versus 38.6%), severe (28.2% versus 24.6%), hepatic (17.9% versus 26.3%), wound (10.3% versus 7%), or thromboembolic or bleeding (2.6% versus 5.3%) complications (all p > 0.05). For patients treated with iri/oxal and bevacizumab, overall complications were more common when resection was performed within 8 weeks after the last bevacizumab dose (62.5% versus 30.4%), but this difference was not statistically significant (p=0.06)., Conclusions: If discontinued at least 8 weeks before hepatic resection, addition of bevacizumab to preoperative iri/oxal does not increase morbidity after hepatic resection.

Background: The safety of simultaneous resections of colorectal cancer and synchronous liver metastases (SCRLM) is not established. This multi-institutional retrospective study compared postoperative outcomes after simultaneous and staged colorectal and hepatic resections., Methods: Clinicopathologic data, treatments, and postoperative outcomes from patients who underwent simultaneous or staged colorectal and hepatic resections at three hepatobiliary centers from 1985-2006 were reviewed., Results: 610 patients underwent simultaneous (n = 135) or staged (n = 475) resections of colorectal cancer and SCRLM. Seventy staged patients underwent colorectal and hepatic resections at the same institution. Simultaneous patients had fewer (median 1 versus 2) and smaller (median 2.5 versus 3.5 cm) metastases and less often underwent major (> or = three segments) hepatectomy (26.7% versus 61.3%, p < 0.05). Combined hospital stay was lower after simultaneous resections (median 8.5 versus 14 days, p < 0.0001). Mortality (1.0% versus 0.5%) and severe morbidity (14.1% versus 12.5%) were similar after simultaneous colorectal resection and minor hepatectomy compared with isolated minor hepatectomy (both p > 0.05). For major hepatectomy, simultaneous colorectal resection increased mortality (8.3% versus 1.4%, p < 0.05) and severe morbidity (36.1% versus 15.1%, p < 0.05). Combined severe morbidity after staged resections was lower compared to simultaneous resections (36.1% versus 17.6%, p = 0.05) for major hepatectomy but similar for minor hepatectomy (14.1% versus 10.5%, p > 0.05). Major hepatectomy independently predicted severe morbidity after simultaneous resections [hazard ratio (HR) = 3.4, p = 0.008]., Conclusions: Simultaneous colorectal and minor hepatic resections are safe and should be performed for most patients with SCRLM. Due to increased risk of severe morbidity, caution should be exercised before performing simultaneous colorectal and major hepatic resections.

Pathologic angiogenesis induced by a tumor is essential for its survival. The promise of tumor inhibition by targeting angiogenesis over the past several years has translated into numerous ongoing clinical trials. Recently, in a phase III trial involving patients with metastatic colorectal cancer, Bevacizumab (Genentech, Inc, San Francisco, CA), a recombinant humanized monoclonal antibody against vascular endothelial growth factor used in conjunction with standard chemotherapy was shown to increase survival, progression-free survival, response rate, and duration of response compared to chemotherapy alone. Thus far, duration of the increased response remains less than 6 months. The majority of deaths in patients with colorectal cancer are related to hepatic metastases. It is hoped that novel approaches directed at the complex interactions between tumor and microenvironment in the angiogenic process will strengthen the therapeutic armamentarium against hepatic malignancies.

Background and objectivesDelineation of adequate tumor margins is critical in oncologic surgery, particularly in resection of metastatic lesions. Surgeons are limited in visualization with bright-light surgery, but fluorescence-guided surgery (FGS) has been efficacious in helping the surgeon achieve negative margins.MethodsThe present study uses FGS in a mouse model that has undergone surgical orthotopic implantation (SOI) of colorectal liver metastasis tagged with green fluorescent protein (GFP). An anti-CEA antibody conjugated to DyLight 650 was used to highlight the tumor.ResultsThe fluorescent antibody clearly demarcated the lesion at deeper tissue depth compared to GFP. Fluorescence of the anti-CEA-DyLight650 showed maximal tumor-to-liver contrast at 72 hr. Fifteen mice underwent bright-light surgery (BLS) versus FGS with GFP versus FGS with anti-CEA-DyLight650. Mice that underwent FGS had a significantly smaller area of residual tumor (P