The Role of Adipocytes Recruited as Part of Tumor Microenvironment in Promoting Colorectal Cancer Metastases.

Adipose tissue dysfunction, which is associated with an increased risk of colorectal cancer (CRC), is a significant factor in the pathophysiology of obesity. Obesity-related inflammation and extracellular matrix (ECM) remodeling promote colorectal cancer metastasis (CRCM) by shaping the tumor microenvironment (TME). When CRC occurs, the metabolic symbiosis of tumor cells recruits adjacent adipocytes into the TME to supply energy. Meanwhile, abundant immune cells, from adipose tissue and blood, are recruited into the TME, which is stimulated by pro-inflammatory factors and triggers a chronic local pro-inflammatory TME. Dysregulated ECM proteins and cell surface adhesion molecules enhance ECM remodeling and further increase contractibility between tumor and stromal cells, which promotes epithelial-mesenchymal transition (EMT). EMT increases tumor migration and invasion into surrounding tissues or vessels and accelerates CRCM. Colorectal symbiotic microbiota also plays an important role in the promotion of CRCM. In this review, we provide adipose tissue and its contributions to CRC, with a special emphasis on the role of adipocytes, macrophages, neutrophils, T cells, ECM, and symbiotic gut microbiota in the progression of CRC and their contributions to the CRC microenvironment. We highlight the interactions between adipocytes and tumor cells, and potential therapeutic approaches to target these interactions.

The efficacy and safety of anti-EGFR target agents in patients with potentially resectable metastatic colorectal cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: Adding anti-epidermal growth factor receptor (anti-EGFR) target agents to conversion therapy may improve the resection rates and survival of patients with potentially resectable metastatic colorectal cancer (mCRC). This study aims to analyze the efficacy and safety of additional anti-EGFR target agents. METHODS: A systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library. And all relevant studies published in English before January 2023 were collected to explore the impact of additional anti-EGFR targeted agent on the efficacy and safety of patients with potentially resectable mCRC (PROSPERO: CRD42022340523, https://www.crd.york.ac.uk/PROSPERO/ ). RESULTS: This study included a total of 8 articles, including 2618 patients. The overall response rate (ORR) and R0 resection rates of the experimental group were higher than those of the control group, while there was no significant difference in progression-free survival (PFS) and overall survival (OS) between the two groups. In RAS/KRAS wild-type patients, the ORR (RR: 1.20, 95% Cl: 1.02-1.41, p = 0.03), R0 resection rate (RR: 1.60, 95% Cl: 1.17-2.20, p = 0.003), PFS (HR: 0.80, 95% Cl: 0.68-0.93, p = 0.003), and OS (HR: 0.87, 95% Cl: 0.76-0.99, p = 0.031) of the experimental group were higher than those of the control group. While in KRAS mutant patients, there was no statistical difference between the two groups in ORR, R0 resection rate, PFS, and OS. CONCLUSION: The addition of anti-EGFR targeted agents can improve the prognosis of RAS/KRAS wild-type patients with potentially resectable mCRC, while KRAS mutant patients may not benefit. In addition, the overall safety factor was controllable.

Promising clinical performance of pretargeted immuno-PET with anti-CEA bispecific antibody and gallium-68-labelled IMP-288 peptide for imaging colorectal cancer metastases: a pilot study.

INTRODUCTION: This pilot study evaluated the imaging performance of pretargeted immunological positron emission tomography (immuno-PET) using an anti-carcinoembryonic antigen (CEA) recombinant bispecific monoclonal antibody (BsMAb), TF2 and the [68Ga]Ga-labelled HSG peptide, IMP288, in patients with metastatic colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients requiring diagnostic workup of CRC metastases or in case of elevated CEA for surveillance were prospectively studied. They had to present with elevated CEA serum titre or positive CEA tumour staining by immunohistochemistry of a previous biopsy or surgical specimen. All patients underwent endoscopic ultrasound (EUS), chest-abdominal-pelvic computed tomography (CT), abdominal magnetic resonance imaging (MRI) and positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET). For immuno-PET, patients received intravenously 120 nmol of TF2 followed 30 h later by 150 MBq of [68Ga]Ga-labelled IMP288, both I.V. The gold standard was histology and imaging after 6-month follow-up. RESULTS: Eleven patients were included. No adverse effects were reported after BsMAb and peptide injections. In a per-patient analysis, immuno-PET was positive in 9/11 patients. On a per-lesion analysis, 12 of 14 lesions were positive with immuno-PET. Median SUVmax, MTV and TLG were 7.65 [3.98-13.94, SD 3.37], 8.63 cm3 [1.98-46.64; SD 14.83] and 37.90 cm3 [8.07-127.5; SD 43.47] respectively for immuno-PET lesions. Based on a per-lesion analysis, the sensitivity, specificity, positive-predictive value and negative-predictive value were, respectively, 82%, 25%, 82% and 25% for the combination of EUS/CT/MRI; 76%, 67%, 87% and 33% for FDG-PET; and 88%, 100%, 100% and 67% for immuno-PET. Immuno-PET had an impact on management in 2 patients. CONCLUSION: This pilot study showed that pretargeted immuno-PET using anti-CEA/anti-IMP288 BsMAb and a [68Ga]Ga-labelled hapten was safe and feasible, with promising diagnostic performance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02587247 Registered 27 October 2015.

Prognosis in patients with synchronous colorectal cancer metastases after complete resection of the primary tumor and the metastases.

BACKGROUND: Synchronous metastases are considered a negative prognostic factor in patients with metastatic colorectal cancer (CRC). We investigated the outcomes of stage IV CRC patients undergoing complete gross resection (R0/1) of both the primary tumor and the metastases under the guidance of a multidisciplinary team (MDT). METHODS: All CRC patients with synchronous metastases were retrieved from a prospective database. Patients treated from 2006 to 2017 who underwent complete resection were analyzed. Various factors, including multiple metastatic sites and complex procedures, were investigated. Univariate and multivariate overall survival (OS) calculations were performed. RESULTS: Of 330 consecutive patients with synchronous metastases, 101 (30.6%) achieved an R0/1 status including 12 (11.9%) patients with multiple metastatic sites. Complex procedures were necessary in 45 (44.6%) patients. Five-year OS was 53.0% for the R0/1 patient group. Multivariate analysis could not detect factors associated with prognosis. CONCLUSIONS: With modern treatment, the prognosis of patients with synchronous CRC metastases can be improved. Decisions made by a MDT offered one-third of patients a potentially curative approach to their stage IV disease. Despite the treatment of a high rate of patients with complex metastases necessitating complex procedures, we achieved a favorable 5-year OS rate.

Toward a better understanding of the mechanism of action for intra-arterial delivery of irinotecan from DC Bead(TM) (DEBIRI).

DC Bead is designed for the embolization of liver malignancies combined with local sustained chemotherapy delivery. It was first demonstrated around a decade ago that irinotecan could be loaded into DC Bead and used in a transarterially directed procedure to treat colorectal liver metastases, commonly referred to as drug-eluting bead with irinotecan (DEBIRI). Despite numerous reports of its safe and effective use in treating colorectal liver metastases patients, there remains a perceived fundamental paradox as to how this treatment works. This review of the mechanism of action of DEBIRI provides a rationale for why intra-arterial delivery of this prodrug from an embolic bead provides for enhanced tumor selectivity, sparing the normal liver while reducing adverse side effects associated with the irinotecan therapy.

Differential impact of obesity and diabetes mellitus on survival after liver resection for colorectal cancer metastases.

BACKGROUND: Data on the potential effect of obesity and diabetes mellitus on survival after liver resection due to colorectal cancer (CRC) metastases are very limited. METHODS: Patients undergoing liver resection for CRC metastases in a European institution in 2004-2011 were retrospectively enrolled. Relevant data, such as body mass index, extent of resection, chemotherapy, and perioperative outcome, were collected from medical records. The relation of obesity and diabetes mellitus with overall and disease-free survival was assessed using adjusted Cox models. RESULTS: Thirty of 207 patients (14.4%) included in the study were obese (BMI ≥30 kg/m(2)) and 25 (12%) had diabetes mellitus. Major hepatectomy was performed in 46%. Although both obese patients and those with diabetes had higher American Society of Anesthesiologist scores (P < 0.05 for both), neither obesity nor diabetes was significantly related to primary tumor characteristics, liver metastasis features, extent or radicality of resection, extrahepatic disease at hepatectomy, preoperative or postoperative oncologic therapy, or perioperative outcome (P > 0.05 for all). Patients were followed up for a median of 39 mo posthepatectomy (interquartile range, 13-56 mo). After adjustment for confounders, obesity was an independent predictor of improved (hazard ratio, 0.305, 95% confidence interval, 0.103-0.902) and diabetes of worse overall survival (hazard ratio, 3.298, 95% confidence interval, 1.306-8.330). Obese patients with diabetes had also worse disease-free survival compared with the rest of the cohort (P < 0.05). CONCLUSIONS: After hepatectomy for CRC metastases, obesity does not seem to be associated to poor outcome while diabetes mellitus has a negative impact on prognosis.

Retrospective review of efficacy of radiofrequency ablation for treatment of colorectal cancer liver metastases from a Canadian perspective.

PURPOSE: A retrospective single-center review of ultrasound-guided radiofrequency ablation (RFA) treatment of colorectal cancer liver metastases was performed. This study reviews the primary and secondary technical effectiveness, overall survival of patients, recurrence-free survival, tumour-free survival, rates of local recurrence, and postprocedural RFA complications. Technical effectiveness and rates of complication with respect to tumour location and size were evaluated. Our results were compared with similar studies from Europe and North America. METHODS: A total of 63 patients (109 tumours) treated with RFA between February 2004 and December 2009 were reviewed. Average and median follow-up time was 19.4 and 16.5 months, respectively (range, 1-54 months). Data from patient charts, pathology, and Picture Archiving and Communication System was integrated into an Excel database. Statistical Analysis Software was used for statistical analysis. RESULTS: Primary and secondary technical effectiveness of percutaneous and intraoperative RFA were 90.8% and 92.7%, respectively. Average (SE) tumour-free survival was 14.4 ± 1.4 months (range, 1-43 months), and average (SE) recurrence-free survival was 33.5 ± 2.3 months (range, 2-50 months). Local recurrence was seen in 31.2% of treated tumours (range, 2-50 months) (34/109). Overall survival was 89.4% at 1 year, 70.0% at 2 years, and 38.1% at 3 years, with an average (SE) overall survival of 37.0 ± 2.8 months. There were 14 postprocedural complications. There was no statistically significant difference in technical effectiveness for small tumours (1-2 cm) vs intermediate ones (3-5 cm). There was no difference in technical effectiveness for peripheral vs parenchymal tumours. CONCLUSIONS: This study demonstrated good-quality outcomes for RFA treatment of colorectal cancer liver metastases from a Canadian perspective and compared favorably with published studies.

Liver resection for colorectal cancer metastases.

QUESTIONS: Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)?What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy ("conversion")?What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy? PERSPECTIVES: Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%-10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required. METHODOLOGY: Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline. PRACTICE GUIDELINE: These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent. 1(a). Patients with liver and lung metastases should be seen in consultation with a thoracic surgeon. Combined or staged metastasectomy is recommended when, taking into account anatomic and physiologic considerations, the assessment is that all pulmonary metastases can also be completely removed. Furthermore, liver resection may be indicated in patients who have had a prior lung resection, and vice versa.1(b). Routine liver resection is not recommended in patients with portal nodal disease. This group includes patients with radiologically suspicious portal nodes or malignant portal nodes found preoperatively or intraoperatively. Liver plus nodal resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-in cases with limited nodal involvement and with metastases that can be completely resected.1(c). Routine liver resection is not recommended in patients with nonpulmonary ehms. Liver plus extrahepatic resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-for metastases that can be completely resected.2(a). Perioperative chemotherapy, either before and after resection, or after resection, is recommended in patients with resectable liver metastatic disease. This recommendation extends to patients with ehms that can be completely resected (R0). Risks and potential benefits of perioperative chemotherapy should be discussed for patients with resectable liver metastases. The data on whether patients with previous oxaliplatin-based chemotherapy or a short interval from completion of adjuvant therapy for primary crc might benefit from perioperative chemotherapy are limited.2(b). Liver resection is recommended in patients with initially unresectable metastatic liver disease who have a sufficient downstaging response to conversion chemotherapy. If complete resection has been achieved, postoperative chemotherapy should be considered.3. Surgical resection of all lesions, including lesions with rcr, is recommended when technically feasible and when adequate functional liver can be left as a remnant. When a lesion with rcr is present in a portion of the liver that cannot be resected, surgery may still be a reasonable therapeutic strategy if all other visible disease can be resected. Postoperative chemotherapy might be considered in those patients. Close follow-up of the lesion with rcr is warranted to allow localized treatment or further resection for an in situ recurrence.

Role of advanced imaging techniques in the evaluation of oncological therapies in patients with colorectal liver metastases.

In patients with colorectal liver metastasis (CRLMs) unsuitable for surgery, oncological treatments, such as chemotherapy and targeted agents, can be performed. Cross-sectional imaging [computed tomography (CT), magnetic resonance imaging (MRI), 18-fluorodexoyglucose positron emission tomography with CT/MRI] evaluates the response of CRLMs to therapy, using post-treatment lesion shrinkage as a qualitative imaging parameter. This point is critical because the risk of toxicity induced by oncological treatments is not always balanced by an effective response to them. Consequently, there is a pressing need to define biomarkers that can predict treatment responses and estimate the likelihood of drug resistance in individual patients. Advanced quantitative imaging (diffusion-weighted imaging, perfusion imaging, molecular imaging) allows the in vivo evaluation of specific biological tissue features described as quantitative parameters. Furthermore, radiomics can represent large amounts of numerical and statistical information buried inside cross-sectional images as quantitative parameters. As a result, parametric analysis (PA) translates the numerical data contained in the voxels of each image into quantitative parameters representative of peculiar neoplastic features such as perfusion, structural heterogeneity, cellularity, oxygenation, and glucose consumption. PA could be a potentially useful imaging marker for predicting CRLMs treatment response. This review describes the role of PA applied to cross-sectional imaging in predicting the response to oncological therapies in patients with CRLMs.

Treatment of metachronous colorectal cancer metastases in the Netherlands: A population-based study.

BACKGROUND: This study aimed to describe the treatment of metachronous colorectal cancer metastases in a recent population-based cohort. METHOD: Patients with stage I-III colorectal cancer (CRC), diagnosed between January 1st and June 30th, 2015 who were surgically treated with curative intent were selected from the Netherlands Cancer Registry. Follow-up was at least 3 years after diagnosis of the primary tumour. Treatment of metachronous metastases was categorized into local treatment, systemic treatment, and best supportive care. Overall survival was estimated using Kaplan-Meier method. RESULTS: Out of 5412 patients, 782 (14%) developed metachronous metastases, of whom 393 (50%) underwent local treatment (LT) with or without systemic therapy, 30% of patients underwent only systemic therapy (ST) and 19% only best supportive care (BSC). The most common metastatic site was the liver (51%) followed by lungs (33%) and peritoneum (22%). LT rates were 69%, 66%, and 44% for liver-only, lung-only and, peritoneal-only metastases respectively. Patients receiving LT and ST were significantly younger than patients receiving LT alone, while patients receiving BSC were significantly older than the other groups (p < 0.001). Patients with liver-only or lung-only metastases had a 3-year OS of 50.2% (43.3-56.7 95% CI) and 61.5% (50.7-70.6 95% CI) respectively. Patients with peritoneal-only disease had a lower 3-year OS, 18.1% (10.1-28.0 95% CI). CONCLUSION: Patients with metastases confined to the liver and lung have the highest rates of local treatment for metachronous metastatic colorectal cancer. The number of patients who underwent local treatment is higher than reported in previous Dutch and international studies.

Long-Term Effects of Pedicle Clamping during Major Hepatectomy for Colorectal Liver Metastases.

The use of the Pringle maneuver (PM) varies widely among surgical departments. Its use depends on the operator and type of liver resection. The aim of this study was to determine the impact of the PM on patient outcomes when undergoing major liver resections. This retrospective study comprised 179 colorectal liver metastasis patients from two liver centers from Leeds and Warsaw. Only right or right extended hepatectomies with negative oncological margins were included. The primary outcome measure was the 5-year overall survival (OS). The PM was applied during 60 (33.5%) major hepatectomies included in the study and was associated with a higher peak 3-day postoperative bilirubin concentration (p = 0.002), yet not with the peak 3-day alanine aminotransferase activity (p = 0.415). The 5-year OS after liver resections with the PM and without the PM were 55.0% and 33.4%, respectively (p = 0.019). Following stratification by the Tumor Burden Score, after resections with the use of the PM, superior survival was particularly found in the subgroup of patients at intermediate risk of recurrence (p = 0.004). However, the use of the PM had no significant effect on the 5-year overall survival following adjustment for the confounding effect of the carcinoembryonic antigen concentration (p = 0.265). The use of the PM had no negative effects on the long-term outcomes in patients undergoing major, oncologically radical liver resections for colorectal metastases.

New Indications for Liver Transplantation.

Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.

Positron Emission Tomography Combined With Computed Tomography vs. No Positron Emission Tomography Combined With Computed Tomography for the Management of Patients With Resectable Colorectal Cancer Liver Metastases and Synchronous Extrahepatic Disease.

INTRODUCTION: Selected patients with colorectal cancer liver metastases (CRLM) and synchronous extrahepatic disease (EHD) are considered for surgery. OBJECTIVES: To evaluate the change in surgical management and long-term survival (disease-free survival [DFS] and overall survival [OS]) for patients with CRLM and EHD who undergo positron emission tomography combined with computed tomography (PET-CT) vs no PET-CT. METHODS: Patients with CRLM were enrolled in a trial evaluating the effect of PET-CT (vs no PET-CT) on surgical management, DFS, and OS. This is a sub-study of the trial, including only patients with synchronous EHD. Cox proportional hazard models were used to calculate risks for recurrence and death. Survival were described by Kaplan-Meier method and compared with log-rank test. RESULTS: Of 25 patients with EHD (PET-CT arm: 14/270 (5%) and no PET-CT arm: 11/134 (8%)), PET-CT changed surgical management in 14%, all of which avoided liver resection due to more extensive disease. Complete metastasectomy was achieved in 36% (5/14) and 72% (8/11), respectively. Respectively, PET-CT vs no PET-CT had statistically similar median DFS, 5.6 months (95% confidence interval (CI) 3.6-18) vs 7.6 months (95% CI 2.9-15) and median OS, 42 months (95% CI 25-48) vs 29 months (95% CI 17-41). EHD was associated with worse DFS (hazard ratio HR = 1.89, 95% CI 1.41-2.52) and OS (HR = 2.47, 95% CI 1.6-3.83). CONCLUSIONS: Preoperative PET-CT for the management of resectable CRLM did not improve long-term outcomes among patients who had synchronous EHD; however, it changed surgical management in a relatively significant proportion of patients.

Tertiary Lymphoid Structures in Colorectal Cancer Liver Metastases: Association With Immunological and Clinical Parameters and Chemotherapy Response.

BACKGROUND/AIM: The presence of TLS (tertiary lymphoid structures) is detectable in the microenvironment of human cancers and linked to better patient outcomes. The role of TLS in colorectal cancer liver metastases (CRCLM) is unclear. PATIENTS AND METHODS: Medical records of patients with CRCLM were reviewed (n=33) and corresponding tissue samples (n=21) were obtained. Whole slide imaging analyses on immunohistochemical staining of immune cell infiltrates and TLS were correlated to clinical outcomes (including chemotherapy response) and other parameters. RESULTS: Neither the size (p=0.6) nor the quantity (p=0.47) of TLS was associated with the clinical course. When considering spatial differences, TLS in the invasive margin (IM) were associated with progression-free survival (p=0.03), while TLS in the LM (liver metastasis) were not. Also, TLS in the IM were associated with the presence of CD3+ T cells, which itself was prognostically favorable (p<0.001). CONCLUSION: TLS in the IM are associated with good prognosis in CRCLM, but not chemotherapy response.

Colorectal cancer metastases to the thyroid gland: A case report.

BACKGROUND: Secondary malignancies of the thyroid gland are a rare finding in clinical practice. In addition, colorectal metastasis to the thyroid (CMT) is even more infrequently diagnosed. The source of the primary tumor follows demographic and ethnic patterns, which reflects the most prevalent malignancies in the different populations. Colorectal cancer is one of the most common types of cancer worldwide; nevertheless, CMT is infrequently diagnosed. Most of them are identified during the follow-up of gastrointestinal primary malignancies. Due to the improvement of image techniques, oncological treatment, and follow-up, survival and consequent diagnosis of metastatic disease are more frequent. Those facts make this entity a diagnostic and therapeutic challenge, due to the lack of information and the difficulties performing clinical trials and research. CASE SUMMARY: Here, we present a case report of a patient diagnosed with CMT of adenocarcinoma of the rectum evidenced during follow-up, 4 years after neoadjuvant chemoradiotherapy, who had subsequent curative surgical treatment of the primary tumor and inter-current lung bilateral metastases. CONCLUSION: Thyroid metastases of extra-thyroid origin are an uncommon finding, even rarer in cases of CMT. The diagnostic process, as well as survival of oncologic patients is improving, and consequently the number of metastases to the thyroid gland is increasing.

Does the Addition of Biologic Agents to Chemotherapy in Patients with Unresectable Colorectal Cancer Metastases Result in a Higher Proportion of Patients Undergoing Resection? A Systematic Review and Meta-analysis.

BACKGROUND: Surgical resection provides the best opportunity for cure for metastatic colorectal cancer. Whether addition of a biologic agent to chemotherapy improves the rate of conversion from unresectable to resectable disease remains uncertain. We carried out a systematic review of the literature and meta-analysis to define the impact of biologic agents on resection. METHODS: We searched Medline, Embase, CENTRAL, and PubMed for randomized controlled trials published up until April 2017 comparing chemotherapy and biologics (intervention) vs. chemotherapy alone (control) in treatment-naïve patients with unresectable metastatic colorectal cancer. Study selection, data abstraction, risk of bias, and quality of evidence assessment were performed in duplicate. Random-effects meta-analysis was used to estimate the pooled odds ratio (OR) for resection rate and corresponding confidence interval (CI). RESULTS: Nine studies, including a total of 4345 patients, were analyzed. Seven studies assessed epithelial growth factor receptor (EGFR)-directed monoclonal antibodies, and two used antiangiogenic agents. The addition of a biologic agent to chemotherapy was associated with higher resection rate (OR 1.47, 95% CI 1.07-2.02; resection rate 8.4 vs. 6.1%). Subgroup analysis based on mechanism of action of drugs showed benefit for resection rate only with EGFR-directed agents (OR 1.70, 95% CI 1.10-2.64). Heterogeneity among studies was low (I 2  = 34%). CONCLUSIONS: The addition of biologic agents to systemic chemotherapy in patients with initially unresectable metastatic colorectal cancer improved resection rate. The optimal biologic agent for this outcome cannot yet be determined.

Postoperative chemotherapy with single-agent fluoropyrimidines after resection of colorectal cancer liver metastases: a meta-analysis of randomised trials.

Surgical resection is the only option of cure for patients with metastatic colorectal cancer. Risk of recurrence after metastasectomy is around 75%. Use of adjuvant chemotherapy after metastasectomy is controversial. AIM: To address whether adjuvant systemic therapy after colorectal cancer metastasectomy offers any survival benefit compared with surgery alone. METHODS: Systematic review of literature and meta-analysis of all available randomised evidence. Relative hazards (RHs) were summarised across trials and heterogeneity was assessed with the Q and I2 statistics. RESULTS: Five trials were eligible. Three trials, all using single-agent fluoropyrimidine chemotherapy, presented data valuable for analyses. 482 patients were included in the meta-analysis: 238 randomly assigned to receive postoperative chemotherapy and 244 to metastasectomy only. We found no overall survival (OS) benefit with the use of postoperative single-agent fluoropyrimidines compared with surgery alone, even if a trend for benefit was observed (relative hazard (RH)=0.781, 95% CI 0.593 to 1.030, p=0.080). Significant disease-free survival benefit with the use of postoperative chemotherapy was observed (RH=0.645, 95% CI 0.509 to 0.818, p=0.001). No quality of life (QL) data were available. All trials showed accrual delay, two stopped and one recruiting after 10 years. Long follow-up needs were evidenced since OS curves split only after 3.5 years. CONCLUSIONS: No OS benefit was documented from the use of postoperative monochemotherapy. Metastasectomy alone continues to be the standard of care. Combination chemotherapy regimens should be evaluated along with QL assessment in future trials appropriately designed for long-term accrual and follow-up.

Preoperative Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Perioperative Liver-Related Complications Following Liver Resection for Colorectal Cancer Metastases.

BACKGROUND AND AIMS: There are limited data on the potential role of preoperative non-invasive markers, specifically the aspartate-to-alanine aminotransferase ratio and the aspartate aminotransferase-to-platelet ratio index, in predicting perioperative liver-related complications after hepatectomy for colorectal cancer metastases. METHODS: Patients undergoing liver resection for colorectal cancer metastases in a European institution during 2003-2010 were retrospectively enrolled. Relevant data, such as neoadjuvant chemotherapy, preoperative liver function tests, and perioperative complications, were collected from medical records. The nontumorous liver parenchyma in the surgical specimens of 31 patients was re-evaluated. RESULTS: Overall, 215 patients were included. In total, 40% underwent neoadjuvant chemotherapy and 47% major resection, while 47% had perioperative complications (6% liver-related). In multivariate regression analysis, the aspartate aminotransferase-to-platelet ratio index was independently associated with liver-related complications (odds ratio: 1.149, p = 0.003) and perioperative liver failure (odds ratio: 1.155, p = 0.012). The latter was also true in the subcohort of patients with neoadjuvant chemotherapy (odds ratio: 1.157, p = 0.004) but not in those without such therapy (p = 0.062). The aspartate-to-alanine aminotransferase ratio was not related to liver-related complications (p = 0.929). The area under the receiver operating characteristics curve for the aspartate aminotransferase-to-platelet ratio index as a predictor of liver-related complications was 0.857 (p = 0.008) in patients with neoadjuvant chemotherapy. Increasing aspartate aminotransferase-to-platelet ratio index was observed with an increase in degrees of sinusoidal obstruction syndrome (p = 0.01) but not for fibrosis (p = 0.175) or steatosis (p = 0.173) in the nontumorous liver in surgical specimens. CONCLUSION: The preoperative aspartate aminotransferase-to-platelet ratio index, but not the aspartate-to-alanine aminotransferase ratio, predicts perioperative liver-related complications following hepatectomy due to colorectal cancer metastases, in particular after neoadjuvant chemotherapy. The aspartate aminotransferase-to-platelet ratio index is related to sinusoidal obstruction syndrome in the nontumorous liver.

Potentially resectable metastatic colorectal cancer: an individualized approach to conversion therapy.

Colorectal cancer is one of the most common cancers worldwide. In recent years, the survival of patients with metastatic disease has improved due to the developments in both medical and surgical care. Patients with technically unresectable metastatic disease could benefit from a multidisciplinary approach for their possible shift toward a technically resectable condition; the choice of the most effective systemic treatment is then crucial to allow conversion to resectability. Systemic conversion therapy may include chemotherapy agents' combinations (fluoropyrimidine, irinotecan and oxaliplatin), with or without targeted agents (cetuximab, panitumumab, bevacizumab). The choice of the best treatment option has to be evaluated by taking into account each patient's baseline characteristics, biological and pathological information and surgical strategy. In particular, the role of some biologic characteristics of the disease, namely the mutational status of EGFR-pathway oncogenes, is emerging as an important predictive factor of response to anti-EGFR targeted agents. Patients presenting with colorectal cancer metastases should be evaluated for multimodal management with curative intent as the appropriate chemotherapy regimen may induce tumor shrinkage, conversion to resectability and improved survival.