Resection Of Colorectal Cancer Liver Metastases Research Articles

Small Portable Interchangeable Imager of Fluorescence for Fluorescence Guided Surgery and Research

Fluorescence guided surgery (FGS) is a developing field of surgical and oncologic research. Practically, FGS has shown useful applications in urologic surgery, benign biliary surgery, colorectal cancer liver metastasis resection, and ovarian cancer debulking. Most notably in in cancer surgery, FGS allows for the clear delineation of cancerous tissue from benign tissue. FGS requires the utilization of a fluorescent contrast agent and an intraoperative fluorescence imaging device (IFID). Currently available IFIDs are expensive, unable to work with multiple fluorophores, and can be cumbersome. This study aims to describe the development and utility of a small, cost-efficient, and interchangeable IFID made from commercially available components. Extensive research was done to design and construct a light-weight, portable, and cost-effective IFID. We researched the capabilities, size, and cost of several camera types and eventually decided on a near-infrared (NIR) charged couple device (CCD) camera for its overall profile. The small portable interchangeable imager of fluorescence (SPIIF) is a "scout" IFID system for FGS. The main components of the SPIIF are a NIR CCD camera with an articulating light filter. These components and a LED light source with an attached heat sink are mounted on a small metal platform. The system is connected to a laptop by a USB 2.0 cable. Pixielink © software on the laptop runs the system by controlling exposure time, gain, and image capture. After developing the system, we evaluated its utility as an IFID. The system weighs less than two pounds and can cover a large area. Due to its small size, it is easily made sterile by covering it with any sterile plastic sheet. To determine the system's ability to detect fluorescent signal, we used the SPIIF to detect indocyanine green under ex and in-vivo conditions and fluorescein under ex-vivo conditions. We found the SPIIF was able to detect both ICG and fluorescein under different depths of a semi-opaque colloid. Second, we found that a concentration as low as 0.5 g/ml of indocyanine green dissolved in plasma was detectable. Lastly, in a murine and human cancer model, the SPIIF was able to detect indocyanine green signal within tumors and generate a signal-to-background ratio (SBR) of 3.75. This study shows that a low-cost IFID can be made from commercially available parts. Second, this IFID is capable of in and ex-vivo detection of multiple fluorophores without sacrificing its small size or favorable ergonomics.

Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors

BackgroundHepatic metastases develop in approximately 50% of colorectal cancer (CRC) cases. We performed a review and meta-analysis to evaluate survival after resection of CRC liver metastases (CLMs) and estimated the summary effect for seven prognostic factors.MethodsStudies published between 1999 and 2010, indexed on Medline, that reported survival after resection of CLMs, were reviewed. Meta-relative risks for survival by prognostic factor were calculated, stratified by study size and annual clinic volume. Cumulative meta-analysis results by annual clinic volume were plotted.ResultsFive- and 10-year survival ranged from 16% to 74% (median 38%) and 9% to 69% (median 26%), respectively, based on 60 studies. The overall summary median survival time was 3.6 (range: 1.7–7.3) years. Meta-relative risks (95% confidence intervals) by prognostic factor were: node positive primary, 1.6 (1.5–1.7); carcinoembryonic antigen level, 1.9 (1.1–3.2); extrahepatic disease, 1.9 (1.5–2.4); poor tumor grade, 1.9 (1.3–2.7); positive margin, 2.0 (1.7–2.5); >1 liver metastases, 1.6 (1.4–1.8); and >3 cm tumor diameter, 1.5 (1.3–1.8). Cumulative meta-analyses by annual clinic volume suggested improved survival with increasing volume.ConclusionThe overall median survival following CLM liver resection was 3.6 years. All seven investigated prognostic factors showed a modest but significant predictive relationship with survival, and certain prognostic factors may prove useful in determining optimal therapeutic options. Due to the increasing complexity of surgical interventions for CLM and the inclusion of patients with higher disease burdens, future studies should consider the potential for selection and referral bias on survival.

Up-front Hepatic Resection for Metastatic Colorectal Cancer Results in Favorable Long-term Survival

Hepatic metastasis from colorectal cancer (CRC) is best managed with a multimodal approach; however, the optimal timing of liver resection in relation to administration of perioperative chemotherapy remains unclear. Our strategy has been to offer up-front liver resection for patients with resectable hepatic metastases, followed by post-liver resection chemotherapy. We report the outcomes of patients based on this surgical approach. A retrospective review of all patients undergoing liver resection for CRC metastases over a 5-year period (2002-2007) was performed. Associations between clinicopathologic factors and survival were evaluated by the Cox proportional hazard method. A total of 320 patients underwent 336 liver resections. Median follow-up was 40 (range 8-80) months. The majority (n=195, 60.9%) had metachronous disease, and most patients (n=286, 85%) had a major hepatectomy (>3 segments). Thirty-six patients (11%) received preoperative chemotherapy, predominantly for downstaging unresectable disease. Ninety-day mortality was 2.1%, and perioperative morbidity occurred in 68 patients (20.2%). Actual disease-free survival at 3 and 5 years was 46.2% and 42%, respectively. Actual overall survival (OS) at 3 and 5 years was 63.7% and 55%, respectively. Multivariate analysis identified four factors that were independently associated with differences in OS (hazard ratio; 95% confidence interval): size of metastasis>6 cm (2.2; 1.3-3.5), positive lymph node status of the primary CRC (N1 (2.0; 1.0-3.8), N2 (2.4; 1.2-4.9)), synchronous disease (2.1; 1.3-3.5), and treatment with chemotherapy after liver resection (0.42; 0.23-0.75). Up-front surgery for patients with resectable CRC liver metastases, followed by chemotherapy, can lead to favorable OS.

KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab

The prognostic value of KRAS mutation in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab before liver resection is unclear. The KRAS and BRAF status of resected CLM was assessed in prospectively studied patients. Mutations were correlated with recurrence-free and overall survival. Only patients with remaining vital tumour cells in the resected specimen and those without disease progression were analysed; those with progressive disease did not undergo resection. A total of 60 patients were enrolled. Fifteen (25 per cent) had a KRAS mutation, but none of the 60 patients had a BRAF mutation. The radiological response to neoadjuvant chemotherapy including bevacizumab, assessed according to the Response Evaluation Criteria In Solid Tumours, was partial in 52 patients (87 per cent) and the remaining eight had stable disease. The partial response rate was similar in patients with a KRAS mutation and those with the wild-type gene (12 of 15 versus 40 of 45 patients; P = 0·400). KRAS mutation had a negative prognostic effect on recurrence-free survival (hazard ratio (HR) 2·48, 95 per cent confidence interval 1·26 to 4·89; P = 0·009) and overall survival (HR 3·51, 1·30 to 9·45; P = 0·013). This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM.

Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases.

Tumor-infiltrating lymphocyte (TIL) counts in colorectal cancer liver metastases (CRCLM) predict survival following resection. While CD4 and CD8 T cells have been correlated with outcome following CRCLM resection, the role of regulatory T cells (Treg) is not well defined. TIL in 188 patients who underwent CRCLM resection between 1998 and 2000 were analyzed by immunohistochemistry using tissue microarrays. Correlation between TIL composition and outcome was determined while controlling for established prognostic factors. Total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), and Treg (FoxP3) were analyzed. Median follow-up time was 40 months for all patients and 95 months for survivors. Overall survival (OS) at 5 and 10 years was 40 and 25%, respectively. The CD4 T cell count correlated with OS (p = .02) and recurrence-free survival (p = .04). A high number of CD8 T cells relative to total T cells (CD8:CD3 ratio) predicted longer OS times (p = .05). Analysis of Treg revealed that high FoxP3:CD4 (p = .03) and FoxP3:CD8 (p = .05) ratios were independent predictors of shorter OS. Patients with a high clinical risk score (CRS) were more likely to have a high number of intratumoral Treg, and patients ≥65 years old had a less robust CRCLM T cell infiltration. A high number of Treg relative to CD4 or CD8 T cells predicted poor outcome, suggesting an immunosuppressive role for FoxP3 + TIL. The intratumoral immune response was an independent predictor of outcome in patients with colorectal liver metastases.

Detailed Pathologic Characteristics of the Primary Colorectal Tumor Independently Predict Outcome after Hepatectomy for Metastases

Outcome after hepatic resection for colorectal cancer liver metastases (CRLM) is heterogeneous and accurate predictors of survival are lacking. This study analyzes the prognostic relevance of pathologic details of the primary colorectal tumor in patients undergoing hepatic resection for CRLM. Retrospective review of a prospective database identified patients who underwent resection for CRLM. Clinicopathological variables were investigated and their association with outcome was analyzed. From 1997-2007, 1,004 patients underwent hepatic resection for CRLM. The median follow-up was 59 months with a 5-year survival of 47%. Univariate analysis identified nine factors associated with poor survival; three of these related to the primary tumor: lymphovascular invasion (LVI, p<0.0001), perineural invasion (p=0.005), and degree of regional lymph node involvement (N0 vs. N1 vs. N2, p<0.0001). Multivariate analysis identified seven factors associated with poor survival, two of which related to the primary tumor: LVI (hazard ratio (HR) 1.3, 95% confidence interval (CI) 1.06-1.64, p=0.01) and degree of regional lymph node involvement [N1 (HR 1.3, 95% CI 1.04-1.69, p=0.02) vs. N2 (HR 1.7, 95% CI 1.27-2.21, p<0.0005)]. A significant decrease in survival along the spectrum of patients ranging from LVI negative/N0 to LVI positive/N2 was present. Patients who were LVI-positive/N2 had a median survival of 40 months compared with 74 months for patients who were LVI-negative/NO (p<0.0001). Histopathologic details of the primary colorectal tumor, particularly LVI and the detailed assessment of the degree of lymph node involvement, are strong predictors of survival. Future biomarker studies should consider exploring factors related to the primary colorectal tumor.

Laparoscopic hepatectomy: an alternative to open surgery for colorectal liver metastases?

BACKGROUND: It is not clear to what extent laparoscopic hepatectomies can replace conventional open liver resections for colorectal cancer liver metastases (CLM) following the same parenchymal sparing strategy. METHODS: Preoperative imaging results of 254 consecutive open liver resections for CLM were retrospectively analyzed regarding rates of potential laparoscopic resections and differences in the surgical strategy. RESULTS: Group A: the same strategy as in open surgery seemed possible in 77 (30.3%) resections; group B: a different laparoscopic strategy appeared necessary in 54 (21.3%) resections; and group C: laparoscopic resection was currently not recommendable in 123 (48.4%) resections. CONCLUSIONS: Laparoscopic resection seemed a feasible alternative to open surgery in 131 cases (groups A+B, 52%). Potential disadvantages of a more liberal use of large anatomical resections should limit laparoscopic surgery to patients undergoing the same type of resection as in open surgery (group A, 30.3%).

Combined portal vein embolization and preoperative chemotherapy prior to liver resection for colorectal cancer metastases

Objective. Compare perioperative course and long-term mortality after liver resection for colorectal cancer (CRC) metastases between patients who had preoperative treatment with portal vein embolization (PVE) and chemotherapy or chemotherapy alone. Methods.Among patients undergoing liver resection for CRC metastases following preoperative chemotherapy treatment, 17 patients who had received preoperative PVE (group A) were compared with 17 matched controls who had no PVE (group B). Perioperative course and long-term mortality were compared between groups A and B and between group A and the entire group of 75 cases with preoperative chemotherapy (group C). Results. Baseline characteristics for the matched groups A and B were similar. Group C included less major resections. Median intraoperative bleeding was 1600 ml in group A, 1200 ml in group B, and 1000 ml in group C (p < 0.05 vs. group A). Median postoperative stay was comparable in all groups (8–9 days). Operation time was 542 min in group A and 464 min in group B (p < 0.01). Mortality after 30 days and 1, 2, and 5 years was similar in all groups. Conclusion.Perioperative outcome and long-term survival did not differ when comparing liver resection for CRC liver metastases preceded by PVE and chemotherapy or chemotherapy alone, except for the operation time. The study supports the safety of this “aggressive” combination approach in patients in need of tumor “downstaging” by chemotherapy and PVE to increase the remnant liver volume.

Surgical resection and peri-operative chemotherapy for colorectal cancer (CRC) liver metastases in routine clinical practice: A population-based outcomes study.

3632 Background: Resection of liver metastases combined with peri-operative chemotherapy is an important treatment option for patients with advanced CRC. Most of the literature describes outcomes achieved in highly selected patients treated at a few high volume institutions. Here we report the results of a population-based study of the management and outcome of all patients who underwent resection of CRC liver metastases in Ontario, Canada. Methods: All cases of CRC in Ontario who underwent surgical resection of liver metastases in 1994-2009 were identified using the population-based Ontario Cancer Registry (OCR). The OCR captures diagnostic and demographic information on ~98% of all incident cancer cases in Ontario. We linked electronic records of treatment to the OCR to identify surgery, neoadjuvant (NACT) and adjuvant chemotherapy (ACT). We describe time trends in treatment and survival using 3 study periods: 1994-1999, 2000-2004, 2005-2009. Results: During 1994-2009, 2717 patients underwent resection of CRC liver metastases in Ontario; mean age was 65 years and 61% were male. From 1994-2009 there was a 103% increase in the number of patients undergoing resection of liver metastases (117/year to 237/year) while incident cases of CRC during this time increased by 31% (5285/year to 6956/year). Use of NACT increased over the study period: 94-99, 11% (78/700); 00-04, 15% (124/830); 05-09, 36%; (424/1187), (p&lt;0.001). Use of ACT also increased: 94-99, 38% (263/700); 00-04, 40% (335/830); 05-09, 45% (532/1187), (p=0.006). In 2005-2009 there was substantial variation across geographic regions in use of NACT (range 19% to 46%, p=0.029) and ACT (range 31% to 56%, p=0.015). Five year overall survival during the 3 study periods was 36% (95%CI 32-39%), 40% (95%CI 36-43%), and 47% (95%CI 43-51%) (p&lt;0.001). Conclusions: Resection of CRC liver metastases in routine practice in the general population of Ontario is associated with survival outcomes that are comparable to those reported in case series from leading comprehensive cancer centres. Survival improved over the study period despite a greater proportion of patients with CRC undergoing liver resection.

The histological growth pattern of colorectal cancer liver metastases has prognostic value

Little is known about the biological characteristics that determine the prognosis of colorectal cancer (CRC) liver metastases. In previous work we reported three different histological patterns of the tumour-liver interface of CRC liver metastases, termed the pushing, replacement and desmoplastic growth pattern (GP). The purpose of this study was to confirm differences in angiogenic and hypoxic properties of CRC liver metastases with different GPs in a large data set and to study the value of the GP as a prognostic factor. In 205 patients undergoing a resection of CRC liver metastases, the GP of the metastasis was determined using haematoxylin-eosin and Gordon Sweet's silver staining. The tumour cell proliferation fraction (TCP%), endothelial cell proliferation fraction (ECP%) and carbonic anhydrase 9 (CA9) expression were determined using immunohistochemistry. Standard clinicopathological data and overall survival were recorded. 27.8, 15.6, 34.6 and 17.6 % of liver metastases had a replacement, pushing, desmoplastic and mixed GP, respectively. Analyses of TCP%, ECP% and CA9 expression demonstrated that CRC liver metastases with a replacement GP are non-angiogenic, while the ones with a pushing GP are the most angiogenic with angiogenesis being, at least partially, hypoxia-driven. GP (pushing or not) was the only independent predictor of survival at 2 years. CRC liver metastases grow according to different GP patterns with different angiogenic properties. At 2 years of follow-up a GP with a pushing component was an independent predictor of poor survival, suggesting that the pushing GP is characterized by a more aggressive tumour biology. Further elucidation of the mechanisms and biological pathways involved in and responsible for the differences in GP between CRC liver metastases in different patients might lead to therapeutic agents and strategies taking advantage of this 2 year 'window of opportunity'.

Discovering pathways in the tumor microenvironment important for recurrence-free survival in patients with colorectal liver metastasis.

480 Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Curative treatment for CRC liver metastasis can be achieved by surgical resection, but 5 year survival ranges between 20-40%. Current treatment strategies to prevent recurrences after resection of CRC liver metastases have focused on the use of chemotherapy cytotoxic to malignant epithelial cells of the tumor. However, stromal components within the tumor microenvironment have recently been implicated as contributors to the aggressiveness of the malignancy. We hypothesized that genomic based signatures associated with tumor stroma would be prognostic for recurrence after CRC hepatic metastasectomy. Methods: Thirteen independent CRC liver metastatic samples were subjected to laser-capture microdissection to isolate the tumor epithelium and tumor-associated stroma separately. Microarray analysis using class neighbors and gene set enrichment analysis (GSEA) was applied to the stromal mRNA to identify differentially expressed genes and pathways between samples from patients with early recurrence (&lt;1yr) after resection (Group R) and those who remain disease free (&gt;2yrs) (Group NoR). Results: Class neighbor analysis revealed a greater number of genes associated with immunity and cell to cell adhesion in Group R compared to Group NoR (p&lt;0.05). Using GSEA, gene sets associated with T-cell immunity, Wnt pathway, and homeostasis were enriched in stroma Group R when compared to stroma Group NoR (p&lt;0.05). Conclusions: These findings suggest several pathways are prognostic for recurrence of CRC liver metastasis. Development of stroma-directed therapy combined with tumor-directed therapy in preclinical models could hold the promise of major advances in the treatment of colorectal cancer liver metastasis in order to improve the clinical outcomes of these patients.

Perioperative management of hepatic resection.

Colorectal cancer (CRC) represents the third most common malignancy in the United States, and almost half the affected patients will develop hepatic metastases during the course of their disease (1-3). Resection of CRC liver metastases remains the best option for potential cure for selected patients (4,5); however, hepatic resection is not without its inherent risks to the patient. Intraoperatively patients may be subjected to major hemorrhage and hypotension, while postoperatively, issues may include ongoing hemorrhage, coagulopathy, renal failure, cardiac, and pulmonary disturbances in addition to the inherent complications of hepatic resection such a biliary fistula and liver failure. After the initial steps of proper patient selection, management decisions made in the perioperative setting can have lasting implications for surgical recovery and patient survival. Many of the maneuvers aimed at preparing the patient with colorectal cancer liver metastases for the operating room are geared towards reducing blood loss during surgery, as acute blood loss anemia requiring blood product transfusion remains a challenge in liver surgery (6,7). Transfusion may be associated with poor surgical outcomes, early cancer recurrence, and reduced survival for this subset of patients (8-18). Prior reports have examined the role of transfusion for cancer patients in the perioperative period, and while the precise mechanism is unclear, the generalized immune dysregulation from transfusion has shown to potentially enhance tumor growth, hasten recurrence, and decrease cancer-specific survival (19,20). In the colorectal cancer patient with liver metastasis undergoing hepatectomy, the risk of blood transfusion has been found to be particularly concerning (8,21). Improvements in surgical technology and technique and perioperative management have resulted in marked reductions in mortality and morbidity over time (6,22). Despite this progress, considerable room remains for further improvement. This chapter will review established and innovative measures to manage CRC liver metastases patients in the perioperative setting. Attention will be given to anesthesia and analgesia, blood conservation and transfusion. Particular attention will be paid to perioperative strategies designed to decrease the need for blood transfusion.

Influence of Preoperative Chemotherapy on the Intraoperative and Postoperative Course of Liver Resection for Colorectal Cancer Metastases

Liver resection is a possibly curative treatment for colorectal cancer (CRC) liver metastases. Preoperative chemotherapy may make initially irresectable tumors resectable. The aim of this study was to compare perioperative course and short-term mortality after liver resection for CRC metastases between patients who were and were not treated with preoperative chemotherapy. Patients who had undergone liver resection for CRC metastases were included. A total of 97 patients treated with preoperative chemotherapy (group A) were compared with 136 who were not (group B). Intraoperative bleeding, operating time, complications, duration of stay, and mortality were compared using Pearson's χ(2) test, Fisher's exact test, and the Mann-Whitney U-test. Mean intraoperative bleeding, duration of stay, and operating time were not significantly different. Complications occurred in 62.9% and 63.2% in groups A and B, respectively. The 30- and 90-day mortality rates were zero in group A, comparable to 1.5% in group B. There were no significant differences in the perioperative course or postoperative mortality when comparing CRC patients with or without chemotherapy prior to liver resection. Consequently, this study suggests that preoperative chemotherapy before liver resection for CRC metastases does not negatively influence perioperative outcome and can therefore be applied if "downstaging" is indicated.

Prognostic Value of Putative Circulating Cancer Stem Cells in Patients Undergoing Hepatic Resection for Colorectal Liver Metastasis

Although surgery is the gold standard treatment of hepatic metastasis from colorectal cancer (CRC), many patients ultimately die of their disease. We tested the hypothesis that the detection of circulating tumor cells (CTC) might identify patients at high risk of dying of disease recurrence after apparently radical liver surgery. We considered 50 patients undergoing radical surgery for liver-confined hepatic metastasis from CRC. The expression of a panel of cancer-related genes, as assessed by quantitative real-time PCR, was used to detect CTC in the peripheral blood of these patients immediately before surgery. Survival analysis was performed by the Cox regression model. Univariate analysis of the expression levels of CD133 (a marker of colon cancer stem cells) and survivin (an antiapoptotic factor) resulted in statistically significant association with patient survival [hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.9-3.7, P < 0.0001; and hazard ratio 2.1, 95% CI 1.4-3.2, P < 0.0001, respectively]. Remarkably, multivariate analysis found that only the transcriptional amount of CD133 resulted in statistical significance (HR 2.6, 95% CI 1.9-3.6, P < 0.0001), indicating that this biomarker can independently predict the survival of these patients. CD133-positive CTC may represent a suitable prognostic marker to stratify the risk of patients who undergo liver resection for CRC metastasis, which opens the avenue to identifying and potentially monitoring the patients who are most likely to benefit from adjuvant treatments.

Improving the clinical risk score: An analysis of molecular biomarkers in the era of modern chemotherapy for resectable hepatic colorectal cancer metastases

The prognostic relevance of variations in expression of specific tumor genes in colorectal cancer liver metastases (CRCLMs) in patients treated with resection and modern chemotherapy is not known. Patients submitted to liver resection for CRCLM between January 2000 and October 2007 were studied. A clinical risk score (CRS; range, 0-5) was calculated for each patient. RNA was extracted from histologically confirmed tumor isolates, and using real-time polymerase chain reaction (PCR) studies, we assessed the quantitative expression of 12 genes with potential importance in chemotherapy resistance and tumor progression, including thymidylate synthase (TS; 5-fluorouracil), excision repair cross complementing gene-1, and xeroderma pigmentosum groups A through G (oxaliplatin), topoisomerase-I (irinotecan), c-met, and hepatocyte growth factor. Primary outcomes were recurrence-free survival (RFS) and disease-specific survival (DSS) after hepatic resection. One-hundred fifty-five patients with good quality tumor mRNA were identified. Median follow-up was 32 months for survivors, and the median CRS was 2. Eighty-seven patients (56%) received preoperative chemotherapy, and 124 (80%) received postoperative chemotherapy. Median RFS for all patients was 13 months, and 3-year DSS was 69%. Median RFS and 3-year DSS for patients with an increased CRS (3-5) was lower (7 vs 18 months [P < .0001] and 50% vs. 80% [P < .0001], respectively). Of the 12 genes studied, only increased TS expression was associated with a lower RFS (hazard ratio, 1.16; 95% confidence interval, 1.0-1.3; P = .03) and DSS (hazard ratio, 1.25; 95% confidence interval, 1.0-1.5; P = .03). Median RFS and 3-year DSS for patients with increased TS expression was decreased (9 vs. 15 months [P = .03] and 48% vs. 82% [P = .001], respectively). TS expression had prognostic value that was independent of CRS on multivariate analysis. In patients with hepatic CRCLM treated with resection and modern chemotherapy, increased expression of TS improves outcome stratification and appears to be a useful biomarker.

Does neoadjuvant chemotherapy reveal disease precluding surgical treatment of initially resectable colorectal cancer liver metastases?

The objective of this study is to determine whether neoadjuvant chemotherapy reveals occult disease precluding surgical extirpation of initially resectable colorectal cancer liver metastases (CRCLM). Demographics, clinicopathologic tumor characteristics, treatments, and post-operative outcomes of patients aged 18-80 years, with one to four initially resectable CRCLM, and without concurrent extra-hepatic (EHMD) or previous metastatic disease were reviewed. Two hundred and two patients evaluated from 2000 to 2010 met study criteria; 88 (43.6%) were given neoadjuvant chemotherapy. Patients treated with neoadjuvant chemotherapy were younger (median 58 years vs. 65 years, P = 0.0096), had shorter disease free interval from resection of primary tumor to CRCLM diagnosis (median 0 months vs. 12 months, P < 0.0001), and had more CRCLM (median 1 [1-3] vs. 1 [1-2], P = 0.0096) compared to untreated counterparts. There were no differences in rates of concurrent EHMD noted intra-operatively and not on pre-operative imaging (4.5% vs. 3.5%, P = 0.7290), greater intra-operatively observed CRCLM compared to pre-operative imaging (25.3% vs. 17.5%, P = 0.2449), hepatic resection and/or ablation (97.7% vs. 100.0%, P = 0.9853), or 6-month disease recurrence after surgical treatment (25.6% vs. 14.9%, P = 0.0882). Only two (2.3%) patients treated with neoadjuvant chemotherapy had disease progression precluding surgical extirpation. Neoadjuvant chemotherapy for initially resectable CRCLM does not reveal occult disease precluding surgical treatment.

Safety and efficacy of neoadjuvant combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil, and oxaliplatin with intravenous (iv) cetuximab in patients with unresectable liver metastases from colorectal cancer (CRC): Interim report from OPTILIV—A European multicenter phase II trial.

e14102 Background: HAI of chronomodulated irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O) (chronoIFO) as well as HAI of O combined with iv F and leucovorin allowed complete macroscopic resections of CRC liver metastases in patients with prior failure on systemic chemotherapy (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). Purpose: To evaluate the resection rate of CRC liver metastases through combining HAI of IFO with cetuximab (Cet) in the first prospective European trial (Lévi, ASCO 2010, TPS#198). Methods: Patients with wt KRAS CRC and unresectable liver metastases receive iv Cet (500 mg/m2, D 1 10:00-12:30) and chrono or conventional HAI of I (180 mg/m2 D1), F (2800 mg/m2/d D2-D3/4), and O (85 mg/m2 D2-3/4) q2 weeks. Grade 3-4 toxicities were managed with dose adaptation and/or supportive measures. Results: 23 patients (9F, 14 M; 33-76 y; PS 0-1) completed full assessment. They had bilateral liver lesions (82%), a median of 7 metastases [2-30; largest diameter, 38 mm (11-150)] and received ≥2 prior iv chemotherapy lines (61%). A median of 4 protocol courses (1-12) was given. Main grade 3-4 toxicities per patient were neutropenia (39%), abdominal pain (30%), fatigue (22%), and leukopenia (17%). An objective tumor response was achieved in 10/23 patients (43.4%). Seven patients underwent liver surgery (30.4%). 17 pts are alive with a median follow up of 16 months. One responding patient with 25 metastases measuring up to 6 cm and involving all liver segments had pathologic complete response in 24 of 25 lesions removed through three-stage hepatectomy. Conclusions: OPTILIV offers a safe and unusually effective treatment option. The trial aims at accruing 48 eligible patients to provide a statistical estimate of the complete macroscopic resection rate and survival in patients with liver metastases from refractory colorectal cancer receiving intravenous cetuximab and hepatic artery infusion of triplet chemotherapy.

Influence of KRAS status of colorectal cancer liver metastases in patients receiving neoadjuvant chemotherapy including bevacizumab prior liver resection.

10620 Background: The prognostic value of KRAS and BRAF mutation on recurrence-free survival in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab prior liver resection is unclear. Methods: KRAS and BRAF status of resected CLM (2005-2010) from 56 resectable patients of 3 prospective studies investigating neoadjuvant chemotherapy including bevacizumab was retrospectively assessed. Mutations were correlated to recurrence-free and overall survival. Only patients with remaining vital tumor cells in the resected specimens and those without progression were analysed (PD excluded from resection, overall < 5%). Patients received 3 neoadjuvant and 3 adjuvant cycles of oxaliplatin-containing regimens. Results:Of 56 patients, 13 showed KRAS mutation (mt), whereas BRAF mutation was not detected in a single patient. Radiological response assessment according to RECIST to neoadjuvant chemotherapy including bevacizumab revealed partial response (PR) in 49 and stable disease (SD) in 7 patients. Median Fong score of all 56 resected patients was 3 (range, 1-5). Although responses were improved compared to historicals, KRAS mt patients were less likely to have PR than patients with KRAS wild-type (wt) tumors but was not statistically significant (p=0.335). Recurrence-free survival trended to be better in KRAS wt patients (1-year 51.2%, 3-years 33.9%, 4-years 29%) compared to mt patients (1-year 38.5%, 3-years 15.4%, 4-years 15.4%), but this was also not statistically significant (log rank, p=0.093). Overall survival was significantly better in KRAS wt patients (1-year 97.4%, 3-years 88.6%, 4-years 71.8%) compared to mt (1-year 100%, 3-years 43.3%, 4-years 43.3%) (log rank, p=0.034). Conclusions: The addition of bevacizumab to oxaliplatin-based chemotherapy improved response rates irrespective of KRAS status. Primary high response to Oxaliplatin-based chemotherapy including Bevacizumab is especially desirable in mt patients as an anti-EGFR-targeted therapy cannot be alternatively offered which seems to be correlated with a prolongation of the overall survival.

Laparoscopic hepatic resection: Favorable short-term outcomes for colorectal cancer metastases of the left hemiliver.

347 Background: Recent reports demonstrate the feasibility of laparoscopic liver resection for patients with benign and malignant conditions. We hypothesized that patients who underwent laparoscopic resections for colorectal cancer (CRC) metastases of the left liver would have short-term outcomes similar to those who had open surgery. Methods: A retrospective review compared laparoscopic left liver resections for CRC metastases to open controls for the years 2005-2010. There were two anatomic left hepatectomies in each group, with lesser segmentectomies in the remainder. Demographic information, pathology, tumor characteristics, procedure related factors, complications, and mortality were assessed. Univariate analysis was performed with significance of p&lt;0.05. Results: Nine patients had laparoscopic resection during the study period, with 1 case converted to open (11%). There were no differences in demographics, tumor factors, margins, or major complications (Table). The laparoscopy group had significantly lower intraoperative blood loss and shorter length of stay compared to the open group. There were no deaths in either group. Conclusions: In this select group of patients undergoing resection of the left hemi-liver for CRC metastases, short-term outcomes favored the laparoscopic approach. Long- term data regarding disease recurrence and survival are needed in this group of patients. These results indicate that surgeons should consider laparoscopic resection of the left liver whenever technically feasible in the setting of CRC metastases. [Table: see text] No significant financial relationships to disclose.

Hilar Lymph Node Involvement in Colorectal Cancer Liver Metastases ? An Overview

Hepatectomy is the only possible option for cure in any treatment strategy of colorectal liver metastases, and several studies have shown good results, with five-year survival rates ranging from 27 to 56%. Several clinical and pathological predictive factors for survival after liver resection have been studied and the metastatic involvement of the hepatic hilum lymph nodes indicates a poor long-term prognosis. Despite variable results, some authors have reported a not-insignificant improvement in survival rate in liver-metastasis patients with hilar-lymph-node involvement who undergo combined liver resection and lymphadenectomy. Due to the low rates of morbidity and mortality for liverresection surgery, several specialized centers perform liver resections combined with lymphadenectomy in selected cases. It should be noted that the therapeutic value of systemic lymphadenectomy is not yet entirely understood, and only controlled studies comparing groups with and without lymphadenectomy can fully resolve the issue. In any case, hilar lymph node dissection has been shown to be a useful tool for improving the accuracy of extrahepatic disease staging, regardless of its impact on survival. The authors review the incidence and the clinical impact of hilar lymph node metastases, and analyses the possible beneficial role of systematic lymphadenectomy in patients who have undergone liver resection for colorectal-cancer metastases.