Resection Of Colorectal Cancer Liver Metastases Research Articles

Effect of adding bevacizumab to chemotherapy on pathologic response to preoperative systemic therapy of potentially resectable colorectal cancer liver metastases (CLM): A systematic review and meta-analysis.

151 Background: Perioperative CT and resection of CLM are potentially curative therapies in the management of metastatic colorectal cancer (mCRC). Retrospective studies suggest that preoperative bevacizumab increases pathologic response, which is a surrogate endpoint for overall survival (OS). We conducted the first systematic review and meta-analysis addressing the effect of bevacizumab on pathologic response to preoperative therapy of CLM. Methods: We systematically searched PubMed, Cochrane Library, Embase and LILACS from January/2004 to August/2019 for studies that have compared the pathologic response to CT plus bevacizumab versus CT alone as preoperative therapy of potentially resectable CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoint was major response (MaR) (0-50% residual cancer cells or tumor regression grade (TRG) 1-3 in liver specimen). The likelihood of preoperative therapy being associated with pCR or MaR has been expressed by odds ratio (OR) and 95% confidence intervals (CI) using a random-effects model. Results: Of the 1,319 studies yielded by the search, 9 studies were retained, totaling 1,202 patients (516 CT plus bevacizumab versus 686 CT alone). The addition of bevacizumab to CT increased the pCR rate, but it did not reach statistical significance (OR: 1.24, 95% CI 0.81 – 1.92, p = 0.32). However, MaR was significantly superior in the bevacizumab group (OR: 2.20, 95% CI 1.47 – 3.29, p < 0.001). A higher percentage of patients have been submitted to oxaliplatin-based regimens in bevacizumab group compared to CT alone group (84% versus 68%, p < 0.001), while irinotecan-based regimens have been more common in the CT alone group (11% versus 28%, p < 0.001). Conclusions: The addition of bevacizumab to preoperative CT was associated with higher rates of pathologic response in liver resection of CLM. Anti-angiogenics might potentially improve the recurrence-free survival and OS in the management of potentially resectable CLM and should be evaluated as preoperative therapy in randomized clinical trials.

Immune Response Assessed by Flow-Cytometry and Immunhistochemistry is Linked to Pathological Response after Preoperative Chemotherapy in Patients Undergoing Resection for Colorectal Liver Metastases

Background: Preoperative chemotherapy followed by curative-intent resection represents the mainstay in treatment of advanced colorectal cancer liver metastases (CRCLM). The host immune response classified by the presence of tumour-infiltrating lymphocytes (TILS) has been verified as a major contributor to oncological outcome in several malignant diseases including colorectal cancer. This study characterizes the immune cell distribution in different tumour compartments by flow cytometry and immunohistochemistry to establish a link between immune response and pathological tumour regression grading (TRG) in patients undergoing liver resection for CRCLM.

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis

ABSTRACT Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.

Analysis of pre and postoperative inflammatory scores in curative resections for colorectal cancer liver metastasis

Background: Inflammatory scores (neutrophil lymphocyte ratio NLR, platelet lymphocyte ratio PLR, Glasgow prognostic score GPS, prognostic nutritional index PNI, lymphocyte monocyte ratio LMR) predict oncologic survival after colorectal cancer liver metastasis (CRCLm). However, there are few studies analyzing their association with postoperative morbidity. Patients & Methods: Retrospective analysis of our CRCLm database from January 2014 to June 2018 at Valladolid University Clinic Hospital (Spain). Endpoints: morbidity according to Clavien-Dindo (CD) Classification, infectious complications, transfusion, length of stay (LOS). Study variables: aforementioned inflammatory scores (preoperative and postoperative day 1) and patient´s comorbidities. Results: 49 patients (males: 69.4%, age: 65.4±11.03years). Median number of resected CRCLm: 2 (IQR=1-3). Total tumor diameter (Σ): 34.8±19.6mm. Liver resection: segmentectomy (32.7%), metastasectomy (24.5%), left hepatectomy (18.4%), right hepatectomy (14.3%), left lateral sectionectomy (6.1%), right and left extended hepatectomy (2%), laparoscopic procedures: 2 cases (4.1%, no conversion). Additional intraoperative radiofrequency ablation: 6.1%. Neoadjuvant chemotherapy: 51%. Median LOS: 8(IQR= 6.5-11.5days). Comorbidities: arterial hypertension (12.2%), dyslipidemia (28.6%), smoking (18.4%), cardiovascular diseases (14.3%), diabetes mellitus (12.2%), alcohol consumption (8.2%), chronic obstructive pulmonary disease (4.1%). Postoperative complications: global (53.1%), infectious (24.5%), CD≥III (16.3%). 6.1% of patients required reoperation. No association between age, comorbidities, ASA and postoperative complications. Patients with pGPS=0 and pGPS=1 presented a median LOS of 9.2±6.4days and 22±8.2days respectively (p=0.001). Overall morbidity, CD≥III and reoperation rate was higher among patients with preoperative GPS(pGPS)=1 vs. pGPS=0(100% vs. 48.9%, p=0.05, 50% vs. 13.3%, p=0.05, and 50% vs 2.2%, p=0.015, respectively). 59% of patients with postoperative GPS(poGPS)=2 presented complications vs. 30% of patients with poGPS=1(p=0.1). Patients suffering overall complications had lower postoperative mean albumin values(2.93±0.46 vs. 3.39±0.42g/dL, p=0.001) and lower postoperative PNI(29.32±4.6 vs. 33.93±4.25, p=0.001). Conclusions: The pGPS could be a good predictor of complications following resection of CRCLm. Patients with complications had lower postoperative albumin and PNI values.

Rationale for Neoadjuvant Chemotherapy of Resectable Colorectal Cancer Liver Metastases: When is it Useful?

Rationale for Neoadjuvant Chemotherapy of Resectable Colorectal Cancer Liver Metastases: When is it Useful?

Microwave ablation versus resection for colorectal cancer liver metastases - A propensity score analysis from a population-based nationwide registry

Background: Recent studies indicate comparable survival after thermal ablation and liver resection for colorectal cancer liver metastases (CRCLM). Awating Results from randomized trials, the aim was to compare survival after microwave ablation (MWA) versus liver resection for CRCLM in a population-based study using propensity score matching. Materials and Methods: All patients undergoing liver resection or MWA as a first intervention for CRCLM measuring less than 3 cm in Sweden between 2013 and 2016 were included from a nationwide registry. Treatment effect was estimated after propensity score (PS) matching, adjusting for patient and tumour factors hypothesised to affect the choice of treatment approach. Survival was illustrated with Kaplan-Meier curves and compared with the log-rank test. Cox regression was used to estimate predictors of survival presented as hazard ratios (HR). Results: The unmatched cohorts (82 patients with MWA, 645 patients with resection) differed significantly regarding age, American Society of Anesthesiologists class, Charlson comorbidity index, primary tumour location, number of metastases and previous chemotherapy. Before matching, 3- and 4-year OS differed significantly favouring resection over MWA (76% and 69%, 67% and 42%, p=0.005). After PS matching (201 resection patients, 70 MWA patients), no difference in OS after 3 and 4 years was shown between both groups (76% and 76%, 68% and 54%, p=0.253). Univariate HR for OS was 1.43 (95% CI 0.772 - 2.651, p=0.255) for the matched MWA group compared with the resection group. Conclusion: No significant difference in OS was found in patients undergoing MWA versus resection as a first-line intervention for CRCLM in the PS analysis used to minimize the effect of confounding by indication. This supports the potential role of MWA as a valid first treatment for patients with CRCLM.

Microwave ablation versus resection for colorectal cancer liver metastases – A propensity score analysis from a population-based nationwide registry

IntroductionMany previous studies comparing liver resection versus thermal ablation for colorectal cancer liver metastases (CRCLM) are subject to severe selection bias. The aim of this study was to compare survival after microwave ablation (MWA) versus liver resection for CRCLM in a population-based cohort study using propensity score analysis to reduce confounding by indication. MethodsAll patients undergoing liver resection or MWA as a first intervention for CRCLM measuring ≤ 3 cm between 2013 and 2016 in Sweden were included from a nationwide registry. Treatment effect was estimated after propensity score matching, adjusting for patient and tumour factors known to affect the choice of treatment approach. Descriptive, regression and survival statistics were applied. ResultsThe unmatched cohorts (82 MWA patients, 645 resection patients) differed significantly regarding age, American Society of Anaesthesiologists class, Charlson comorbidity index, primary tumour location, number of metastases and previous chemotherapy, with 3-year overall survival (OS) favouring resection over MWA (76 and 69%, p = 0.005). After propensity score matching (70 MWA patients, 201 resection patients), no difference in 3-year OS was shown between resected and ablated patients (76% and 76%, p = 0.253), with a median OS of 54.7 (95% confidence interval 48.6 - 60.9) months and 48 (40.1–56.1) months, respectively. ConclusionAfter adjusting for factors known to affect treatment choice, no significant difference in OS was shown after MWA versus resection for CRCLM. This supports the potential role of MWA as a valid first-line treatment for patients with small CRCLM.

Combined test of third lumbar skeletal muscle index and prognostic nutrition index improve prognosis prediction power in resected colorectal cancer liver metastasis.

Background: In this paper, we aim to explore clinical value of skeletal muscle index (SMI) and prognostic nutrition index (PNI) on resected colorectal cancer liver metastasis (CRLM).Results: Among the 539 patients, 355 were males. Baseline lower SMI was associated with smaller BMI, smaller PNI, smaller pre-albumin and longer hospitalization days (P<0.05). Patients with lower SMI and PNI had significantly shorter duration of PFS and OS (P<0.05). SMI can reflect the postoperative treatment response. Postoperative 6-month’s and 12-month’s SMI and PNI can indicate overall prognosis. When combined SMI and PNI, prognostic AUC of ROC curves improved significantly.Conclusion: Combined monitor of SMI and PNI can improve the power at predicting prognosis. Postoperative 6-month’s record of SMI and PNI was more accurate and predictive for CRLM prognosis.Method: A total of 539 resected CRLM patients between January 2013 to December 2016 with complete clinical data were included. Computed tomography image was collected from each patient. Receiver-operating characteristic (ROC) curves were constructed; area under curves (AUC) were also determined. All clinical variables were analyzed in proper way.

107P - The efficacy of adjuvant chemotherapy according to the risk classification of recurrence based on the systemic inflammatory markers in patients with colorectal cancer liver metastases

BackgroundAlthough complete resection of colorectal cancer liver metastasis (CLM) is the only potentially curative treatment, surgery alone is not enough, as the recurrence rate after resection of CLM is high. Therefore, in clinical practice, adjuvant chemotherapy (AC) has been performed after resection of CLM. However, the evidence supporting the efficacy of AC after resection of CLM is not sufficient. Previous reports have noted that AC after resection of CLM is effective only in patients with a high risk of recurrence. The purpose of this study was to classify the risk of recurrence using systemic inflammatory markers, which have been reported to be associated with the clinical outcomes, and to evaluate the efficacy of AC according to the risk of recurrence. MethodsWe retrospectively reviewed the medical records of 119 patients with CLM who underwent potentially curative surgery. The C-reactive protein-to-albumin ratio (CAR) was calculated from the blood samples by dividing the serum C-reactive protein level by the serum albumin level. The optimal cut-off value of the CAR was determined according to the ROC curve analysis, and then the patients were classified into the high- or low-CAR group. We examined the relationship between the CAR and the relapse-free survival (RFS) after resection of CLM and evaluated the efficacy of AC according to the risk of recurrence. ResultsThe cut-off value of the CAR was set at 0.0471 based on the ROC curve analysis. The RFS rates were significantly better in the low-CAR group than in the high-CAR group. The efficacy of AC after resection of CLM was not recognized in the low-CAR group (with a low risk of recurrence), whereas the RFS rates were significantly better for the patients who were treated with AC after resection of CLM in the high-CAR group (with a high risk of recurrence). ConclusionsThe preoperative CAR was found to be useful as prognostic markers in patients with CLM who were treated with potentially curative resection. Furthermore, it was suggested that AC after resection of CLM may be effective for preventing recurrence in patients with high inflammatory markers who have a high risk of recurrence. Legal entity responsible for the studyOsaka City University. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Prognostic significance of perioperative chemotherapy on resectable colorectal mucinous adenocarcinoma liver metastasis.

Mucinous adenocarcinoma (MAC) is an uncommon subtype of colorectal cancer (CRC). For colorectal cancer liver metastasis (CRLM), perioperative chemotherapy (PCT) has been developed to improve the rate of resection and reduce the rate of early recurrence; however, its impact on long-term outcomes in MAC is unclear. From 1999 to 2016, 442 patients with CRLM were retrospectively reviewed, all of whom underwent CRC resection and liver metastasis resection. Among them, 34 were MAC, and the others were non-MAC. A total of 102 non-MAC patients with CRLM who underwent surgery at the same period were matched with 34 MAC patients in a ratio of 3:1 by using a random number table for analysis. Clinicopathologic characteristics for the MAC group (n=34) and non-MAC group (n=102) had no statistical difference. Both recurrence free survival (RFS) and overall survival (OS) did not significantly differ between the two groups. Nevertheless, in the non-MAC group, OS was fundamentally prolonged in patients with PCT compared to those who didn't have PCT (P=0.031). In this study, PCT had a survival benefit on non-MAC patients with CRLM while MAC patients with resectable CRLM do not benefit from PCT. When developing treatment like PCT or surgery alone for CRLM, mucinous histology should be considered as an important influence factor.

FDG-PET reflects tumor viability on SUV in colorectal cancer liver metastasis.

Liver resection is the most effective procedure for colorectal cancer liver metastasis (CRLM); however, early recurrence is an important problem that affects the postoperative prognoses of patients with CRLM. We previously suggested a therapeutic algorithm for CRLM using fluorodeoxyglucose-positron emission tomography (FDG-PET) and revealed the applicability of FDG-PET in predicting the prognosis after liver resection of CRLM. In this study, we assessed the correlation between FDG-PET and biological viability such as proliferation or metabolic activity. We retrospectively evaluated 61 patients who underwent hepatectomy for CRLM. We assessed hypoxia inducible factor-1α (HIF-1α), pyruvate kinase isozyme M2 (PKM2), glucose transporter 1 (GLUT1), and Ki-67 expression via immunohistochemistry and evaluated the correlation between standardized uptake value (SUV) and these factors. High HIF-1α, PKM2, and GLUT1 expression were positively correlated with high SUV expression (P = 0.0444, 0.0296, and 0.0245, respectively). Ki-67 and SUV were also positively correlated (P = 0.00164). HIF-1α expression and PKM2 expression were significantly correlated (P = 0.0430), and PKM2 expression and GLUT1 expression were extremely significantly correlated (P < 0.0001). SUV reflected tumor proliferation or metabolic factors in CRLM. FDG-PET could be a useful modality for assessing tumor viability and may provide useful information regarding the appropriate treatment strategy for CRLM.

566P - Validation of GAME score risk groups in resected colorectal cancer liver metastases and the prognostic relevance of KRAS, NRAS and BRAF mutation analysis

BackgroundHepatic resection of liver metastases is considered the optimal potentially curative treatment for colorectal liver metastases. Numerous clinical and pathological factors have been proved to be prognostic. The Genetic And Morphological Evaluation (GAME) has been proposed as a preoperative prognostic tool to select patients candidates for liver resection. This study aimed to validate the utility of GAME score risk groups in patients with colorectal liver metastases that underwent hepatic resection. MethodsClinical and pathological data were collected from 142 metastatic colorectal cancer patients undergoing liver resection (48% after neoadjuvant chemotherapy) between August 1999 and February 2018 at Sant Pau Hospital. The GAME score was calculated allocating points for KRAS mutation, CEA levels, lymph node metastasis, Tumour Burden score (TBS) and extrahepatic disease. We analysed the progression free survival (PFS) and overall survival (OS) according to the GAME score risk groups. Additionally, we considered other KRAS, NRAS and BRAF mutations not included in the original GAME score. Histopathological changes in malignant tissue and liver parenchyma were documented to identify potential prognostic factors for tumor recurrence. ResultsThe high-risk group (GAME score ≥ 4 points) had a median PFS of 15.8 months compared with 24.2 months for the low-risk group (GAME score 0–1 point; p=0.019). The high-risk group had a medium OS of 38.6 months compared with 68.8 months for the low-risk group (p=0.05). When all RAS and BRAF status was considered regardless of the GAME score a median OS of 66.2 months was observed in wild type tumours compared to 44.5 months for mutated tumours (p=0.005). Histological examination showed that a mixed and infiltrative growth pattern and the absence of a fibrotic pseudocapsule or liver cell rosettes were associated with a worse outcome. ConclusionsThe GAME score was validated as a useful preoperative prognostic tool in our cohort of patients. However, in our series, molecular profile was a prognostic factor regardless of the GAME score. Some pathologic characteristics may help on further clinical decisions after liver resection. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

RAS mutation: site of disease and recurrence pattern in colorectal cancer.

Somatic mutation status in metastatic colorectal cancer (CRC), and namely mutational activation of the Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene, is becoming more and more relevant in clinical practice. In this review, we describe the current data about the importance of associations between the mutational activation status of the KRAS oncogene and clinical outcomes, prognosis and metastatic patterns of CRC. The presence of a KRAS mutation is detected in approximately 30-50% of CRC and represents a powerful predictor of oncologic outcomes. It is associated with low response to systemic chemotherapy and for insensitivity to the anti-EGFR antibodies in the preoperative setting. It is more frequently associated with right colon cancer. In non-metastatic patients, KRAS mutation leads to more aggressive disease with shorter recurrence free survival (RFS) and more lung recurrences. After resection of CRC liver metastases (LiM), KRAS mutation is directly associated with increased risk of recurrence, worse overall survival (OS), and a distinct metastatic pattern with more invasive intrahepatic recurrence and increased recurrence outside of the liver, particularly in the lung, the peritoneum, and even in uncommon metastatic sites such as the brain and bones. As metastasectomy with curative intent is increasingly considered, a comprehensive approach of tumor biology is required to face the specific challenge of patients with metastatic CRCs. Thus, as it represents one of the strongest predictors of oncologic outcomes, integrating the KRAS mutational status at all the different stages of patient care appears crucial in order to adapt both medical and surgical strategies.

Outcomes of Resectability Assessment of the Dutch Colorectal Cancer Group Liver Metastases Expert Panel

Decision making on optimal treatment strategy in patients with initially unresectable colorectal cancer liver metastases (CRLM) remains complex because uniform criteria for (un)resectability are lacking. This study reports on the feasibility and short-term outcomes of The Dutch Colorectal Cancer Group Liver Expert Panel. The Expert Panel consists of 13 hepatobiliary surgeons and 4 radiologists. Resectability assessment is performed independently by 3 randomly assigned surgeons, and CRLM are scored as resectable, potentially resectable, or permanently unresectable. In absence of consensus, 2 additional surgeons are invited for a majority consensus. Patients with potentially resectable or unresectable CRLM at baseline are evaluated every 2 months of systemic therapy. Once CRLM are considered resectable, a treatment strategy is proposed. Overall, 398 panel evaluations in 183 patients were analyzed. The median time to panel conclusion was 7 days (interquartile range [IQR] 5-11 days). Intersurgeon disagreement was observed in 205 (52%) evaluations, with major disagreement (resectable vs permanently unresectable) in 42 (11%) evaluations. After systemic treatment, 106 patients were considered to have resectable CRLM, 84 of whom (79%) underwent a curative procedure. R0 resection (n= 41), R0 resection in combination with ablative treatment (n= 26), or ablative treatment only (n= 4) was achieved in 67 of 84 (80%) patients. This study analyzed prospective resectability evaluation of patients with CRLM by a panel of radiologists and liver surgeons. The high rate of disagreement among experienced liver surgeons reflects the complexity in defining treatment strategies for CRLM and supports the use of a panel rather than a single-surgeon decision.

Secondary technical resectability of colorectal cancer liver metastases after chemotherapy with or without selective internal radiotherapy in the randomized SIRFLOX trial.

BackgroundSecondary resection of initially unresectable colorectal cancer liver metastases (CRLM) can prolong survival. The added value of selective internal radiotherapy (SIRT) to downsize lesions for resection is not known. This study evaluated the change in technical resectability of CRLM with the addition of SIRT to FOLFOX‐based chemotherapy.MethodsBaseline and follow‐up hepatic imaging of patients who received modified FOLFOX (mFOLFOX6: fluorouracil, leucovorin, oxaliplatin) chemotherapy with or without bevacizumab (control arm) versus mFOLFOX6 (with or without bevacizumab) plus SIRT using yttrium‐90 resin microspheres (SIRT arm) in the phase III SIRFLOX trial were reviewed by three or five (of 14) expert hepatopancreatobiliary surgeons for resectability. Reviewers were blinded to one another, treatment assignment, extrahepatic disease status, and information on clinical and scanning time points. Technical resectability was defined as at least 60 per cent of reviewers (3 of 5, or 2 of 3) assessing a patient's liver metastases as surgically removable.ResultsSome 472 patients were evaluable (SIRT, 244; control, 228). There was no significant baseline difference in the proportion of technically resectable liver metastases between SIRT (29, 11·9 per cent) and control (25, 11·0 per cent) arms (P = 0·775). At follow‐up, significantly more patients in both arms were deemed technically resectable compared with baseline: 159 of 472 (33·7 per cent) versus 54 of 472 (11·4 per cent) respectively (P = 0·001). More patients were resectable in the SIRT than in the control arm: 93 of 244 (38·1 per cent) versus 66 of 228 (28·9 per cent) respectively (P < 0·001).ConclusionAdding SIRT to chemotherapy may improve the resectability of unresectable CRLM.

Circulating tumor cell-related transcripts in blood as prognostic biomarkers of early recurrence after liver resection for colorectal metastases.

Several prognostic factors were proposed to improve early detection of recurrence after liver resection of metastases of colorectal cancer. Circulating tumor cell-related transcripts were evaluated in colorectal cancer patients with conflicting results. The aim of this study was to investigate usefulness of carcinoembryonic antigen CAM5, epidermal growth factor receptor, and ERCC1 transcripts in the bloodstream as predictive factors of recurrence in patients who underwent liver resection for metastases of colorectal cancer. Peripheral blood was collected from 29 patients at the time of the colorectal cancer liver metastasis resection, and from 25 normal controls. Follow-up draws (FUDs) were also performed at 30 days, and 3 and 12 months since surgery. On each sample, carcinoembryonic antigen CAM5, ERCC1, and GAPDH mRNAs were examined by quantitative reverse transcription (qRT). Carcinoembryonic antigen transcript levels were linearly correlated to the number of spiked cells (qRT analytical limit = five cells). Among 29 patients (20 M/9 F; mean age 63 years (range 32-79), highly significant levels of carcinoembryonic antigen, if compared to the baseline, were detected in those relapsing after surgery (P <0.05). The main differences were between the 1st- and 12th-month FUDs. Significantly higher levels of carcinoembryonic antigen were also detected in patients who died from disease progression during the follow-up (as evaluated at 30 days and 90 days FUDs). Blood carcinoembryonic antigen-mRNA absolute copy number overtime variation can represent a valid early predictor of relapse after liver resection in colorectal liver metastases patients. Prospective studies, in the context of large clinical trials, will provide further data to also qualify ERCC1 as a predictive biomarker for decisions on therapeutic strategies.

Circulating Tumor Cells in Patients Undergoing Resection of Colorectal Cancer Liver Metastases. Clinical Utility for Long-Term Outcome: A Prospective Trial.

Patients with resected colorectal cancer liver metastases display heterogeneous clinical behavior. The identification of new prognostic factors would help in making more accurate decisions. The aim of this study was to evaluate the survival impact of circulating tumor cells (CTCs) in this setting. We conducted a prospective study of patients with resected liver metastases of colorectal cancer. Patients were included in the study from February 2009 to January 2013. The CellSearch System™ was employed for the detection of pre- and postsurgery CTCs. A positive test was defined as two or more CTCs/7.5mL of blood. Recurrence rate, disease-free survival, and overall survival were calculated, and univariate and multivariate analyses were performed. Forty-four patients were included in our study. After a median follow-up of 60months (range 28-74), 32 patients experienced recurrence (72.7%). TheCTCs number wasdetermined and the test was positive in 8 patients (18.6%) before surgery and 13 patients (29.5%) after surgery. The postoperative detection of CTCs was not related to any clinical outcome; however, the preoperative detection of CTCs was significantly related to behavior. All patients in the preoperative CTC-positive group relapsed, versus 65% in the CTC-negative group (p = 0.051). Disease-free survival was 19months in the preoperative CTC-negative group versus 7months in the CTC-positive group (p = 0.01). Additionally, overall survival was 69months in the preoperative CTC-negative group versus 17months in the CTC-positive group (p = 0.004). Preoperative CTC count remained significant in multivariate analysis. In this cohort of colorectal cancer liver metastases patients, the presence of two or more preoperative CTCs was associated with disease progression and poor survival despite complete resection.

Feasibility of a national expert panel to determine resectability in patients with initially unresectable colorectal cancer liver metastases (CRLM).

3562 Background: Decision on optimal treatment strategy for CRLM remains complex because uniform (un)resectability criteria are lacking. We hypothesize that the use of an expert panel can improve the identification of patients with potentially resectable CRLM. The Dutch Colorectal Cancer Group (DCCG) Expert Panel was established in conjunction with the CAIRO5 study (Huiskens J et al. BMC Cancer 2015), a multicenter, randomized, phase-3 trial, investigating optimal systemic induction treatment in patients with initially unresectable CRLM. Here, we present the feasibility of this panel. Methods: The DCCG Expert Panel consists of 13 liver surgeons and 4 radiologists. Consensus was reached on predefined (un)resectability criteria at baseline. An online platform allowed resectability-assessment by 3 surgeons in case of inter-surgeon agreement, and 5 surgeons if they disagreed. CRLM were assessed as 1) resectable 2) potentially resectable, or 3) permanently unresectable. Patients with initially unresectable CRLM were evaluated at baseline and subsequently every 2 months as long as CRLM were considered potentially resectable. Results: Overall, 397 panel evaluations in 183 patients were analyzed. Median time to panel conclusion was 7 days (IQR 5-11 days) and 204 (51%) evaluations showed inter-surgeon disagreement, with major disagreement (resectable versus permanently unresectable) in 24 (14%) and 12 (29%) evaluations after 2 and 4 months of systemic treatment. Ultimately, 84 (79%) patients with resectable CRLM underwent resection and 23 (27%) resections included portal vein embolization or 2-stage procedures. In resectable CRLM with inter-surgeon agreement versus disagreement, R0 resection was achieved in 39 (75%) versus 28 (52%) patients, p = 0.013. Median time to recurrence was similar between resections with panel agreement versus disagreement, 8 versus 6 months, p = 0.447. Conclusions: This study shows the feasibility of a national Liver Expert Panel for prospective resectability assessment of patients with initially unresectable CRLM. High inter-surgeon disagreement supports the use of a panel. We aim to further validate the panel with outcome parameters. Clinical trial information: NCT02162563.

Perioperative chemotherapy in patients with colorectal cancer liver metastasis

The incidence of colorectal cancer liver metastasis (CRLM) increased gradually in recent years. Surgical resection is the most important treatment for CRLM patients to obtain long-term survival, with a 5-year survival rate of about 50%. However, only 20% of the CRLM patients are initially resectable. The recurrence rate after surgery is more than 70%. Perioperative chemotherapy has been widely used with the development of effective chemotherapy regimens and targeted therapies. For patients with initially resectable liver metastases, perioperative chemotherapy may help reduce recurrence and prolong survival. For patients with unresectable liver metastases, conversion chemotherapy with high efficiency provides opportunity for radical resection. However, CRLM is a disease with high heterogeneity and with many factors influencing prognosis, and there is a lack of large-scale prospective clinical trial evidence in many problems. Hence there are still many controversies in the clinical practice of perioperative chemotherapy, including whether chemotherapy alone is the best preoperative treatment for resectable CRLM, whether preoperative chemotherapy combined with targeted therapy is superior to chemotherapy alone, who can benefit most from preoperative chemotherapy combined with targeted therapy, who are the exact patients suitable for conversion therapy, how to choose the best first-line conversion therapy. Here we discuss the current status of research on perioperative chemotherapy in three aspects: neoadjuvant chemotherapy, conversion therapy and adjuvant chemotherapy. We also emphasized the importance of multidisciplinary team during the treatment process to give patients individualized therapy considering their specific conditions.

Sub-millimeter surgical margin is acceptable in patients with good tumor biology after liver resection for colorectal liver metastases

BackgroundThe definition of R1 resection in colorectal cancer liver metastases (CRLM) remains debatable. This retrospective study was conducted to clarify the impact of R1 margin on patient survival after liver resection for CRLM, taking into consideration tumor biology, including RAS status and chemotherapy response. MethodsWe retrospectively analysed the clinical and survival data of 214 CRLM patients with initially resectable liver metastases who underwent liver resection after receiving neoadjuvant chemotherapy between January 2006 and December 2016. ResultsR1 resection significantly impacted patients’ overall survival (OS) and disease-free survival (DFS) in the overall patient cohort (5-year OS: 53.2% for R0 vs 38.2% for R1, P = 0.001; 5-year DFS: 26.5% for R0 vs 10.5% for R1, P = 0.002). In the RAS wild-type subgroup and respond to chemotherapy (RC) subgroup, R1 reached a similar OS to those who underwent R0 resection (RAS wild-type, P = 0.223; RC, P = 0.088). For the RAS mutated subgroup and no response to chemotherapy (NRC) subgroup, OS was significantly worse underwent R1 resection (RAS mutant, P = 0.002; NRC, P = 0.022). When considering tumor biology combining RAS and chemotherapy response status, R1 resection was only acceptable in patients with both RAS wild-type and RC (5-year OS: 66.4% for R0 vs 65.2% for R1, p = 0.884), but was significantly worse in those with either RAS mutation or NRC. ConclusionsTumor biology plays an important role in deciding the appropriate resection margin in patients with CRLM undergoing radical surgery. R1 resection margin is only acceptable in RAS wild-type patients who respond to chemotherapy.