The relationship between primary colorectal cancer histology and the histopathological growth patterns of corresponding liver metastases.

BACKGROUND: The histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in colorectal cancer liver metastasis (CRLM). This study evaluates the relationship between the HGP and primary colorectal cancer (CRC) histopathology. METHODS: A total of 183 treatment-naive patients with resected CRC and CRLM were included. Thirteen CRC histopathology markers were determined and compared between the desmoplastic and non-desmoplastic HGP; tumour sidedness, pT&pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn's-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. Logistic regression analysis was performed using both CRC and CRLM characteristics. RESULTS: Unfavourable CRC histopathology was more frequent in non-desmoplastic CRLM for all markers evaluated, and significantly so for a lower TIL density, absent Crohn's-like lymphoid reaction, and a "non-mature" stroma (all p < 0.03). The cumulative prevalence of unfavourable CRC histopathology was significantly higher in patients with non-desmoplastic compared to desmoplastic CRLM, with a median (IQR) of 4 (3-6) vs 2 (1-3.5) unfavourable characteristics observed, respectively (p < 0.001). Multivariable regression with 9 CRC histopathology markers and 2 CRLM characteristics achieved good discriminatory performance (AUC = 0.83). CONCLUSIONS: The results of this study associates primary CRC histopathology with the HGP of corresponding liver metastases.

Follow-up strategy and survival for five common cancers: A meta-analysis.

BACKGROUND: This meta-analysis aimed to evaluate the effectiveness of intensive follow-up after curative intent treatment for five common solid tumours, in terms of survival and treatment of recurrences. METHODS: A systematic literature search was conducted, identifying comparative studies on follow-up for colorectal, lung, breast, upper gastro-intestinal and prostate cancer. Outcomes of interest were overall survival (OS), cancer specific survival (CSS), and treatment of recurrences. Random effects meta-analyses were conducted, with particular focus on studies at low risk of bias. RESULTS: Fourteen out of 63 studies were considered to be at low risk of bias (8 colorectal, 4 breast, 0 lung, 1 upper gastro-intestinal, 1 prostate). These studies showed no significant impact of intensive follow-up on OS (hazard ratio, 95% confidence interval) for colorectal (0.99; 0.92-1.06), breast 1.06 (0.92-1.23), upper gastro-intestinal (0.78; 0.51-1.19) and prostate cancer (1.00; 0.86-1.16). No impact on CSS (hazard ratio, 95% confidence interval) was found for colorectal cancer (0.94; 0.77-1.16). CSS was not reported for other cancer types. Intensive follow-up increased the rate of curative treatment (relative risk; 95% confidence interval) for colorectal cancer recurrences (1.30; 1.05-1.61), but not for upper gastro-intestinal cancer recurrences (0.92; 0.47-1.81). For the other cancer types, no data on treatment of recurrences was available in low risk studies. CONCLUSION: For colorectal and breast cancer, high quality studies do not suggest an impact of intensive follow-up strategies on survival. Colorectal cancer recurrences are more often treated locally after intensive follow-up. For other cancer types evaluated, limited high quality research on follow-up is available.

Absence of association between CT-assessed skeletal muscle mass and long-term oncological outcomes after curative therapy for colorectal liver metastasis.

BACKGROUND: Sarcopenia is associated with impaired short- and long-term outcomes in gastrointestinal cancers. Whether sarcopenia is associated with impaired survival after local therapy of Colorectal Cancer Liver Metastases (CRLM) remains controversial. This study aimed to determine the influence of sarcopenia on long-term outcomes after curative-intent therapy for CRLM. METHODS: Patients undergoing local therapy for CRLM between 2003 and 2019 were retrospectively analyzed using the skeletal muscle index at the level of the third lumbar vertebra as an indicator of sarcopenia. Factors associated with overall (OS) and disease-free (DFS) survival were analyzed using univariable and multivariable cox regression. RESULTS: In total 213/465 patients (46%) were considered sarcopenic. Sarcopenic patients had no impaired 5-year OS or DFS compared to non-sarcopenic patients, 38% vs 44% (p = 0.153) and 19 vs 23% (p = 0.339) respectively. Sarcopenia was not associated with impaired OS (HR = 1.11, 95%CI = 0.85-1.46, p = 0.43) or DFS (HR = 0.99, 95%CI = 0.77-1.28, p = 0.96) in multivariable analysis. There were no significant differences in postoperative complications (p = 0.47), the incidence (p = 0.65) and treatment (p = 0.37) of recurrent metastases. Five-year OS after resection for recurrences was 14% (sarcopenic) and 22% (non-sarcopenic) p 0.716. CONCLUSION: Sarcopenia assessed by computed tomography was not associated with impaired survival outcomes in the group of CRLM patients overall.

Predicting 10-year survival after resection of colorectal liver metastases; an international study including biomarkers and perioperative treatment.

BACKGROUND: The aim of this study was to develop a prediction model for 10-year overall survival (OS) after resection of colorectal liver metastasis (CRLM) based on patient, tumour and treatment characteristics. METHODS: Consecutive patients after complete resection of CRLM were included from two centres (1992-2019). A prediction model providing 10-year OS probabilities was developed using Cox regression analysis, including KRAS, BRAF and histopathological growth patterns. Discrimination and calibration were assessed using cross-validation. A web-based calculator was built to predict individual 10-year OS probabilities. RESULTS: A total of 4112 patients were included. The estimated 10-year OS was 30% (95% CI 29-32). Fifteen patient, tumour and treatment characteristics were independent prognostic factors for 10-year OS; age, gender, location and nodal status of the primary tumour, disease-free interval, number and diameter of CRLM, preoperative CEA, resection margin, extrahepatic disease, KRAS and BRAF mutation status, histopathological growth patterns, perioperative systemic chemotherapy and hepatic arterial infusion pump chemotherapy. The discrimination at 10-years was 0.73 for both centres. A simplified risk score identified four risk groups with a 10-year OS of 57%, 38%, 24%, and 12%. CONCLUSIONS: Ten-year OS after resection of CRLM is best predicted with a model including 15 patient, tumour, and treatment characteristics. The web-based calculator can be used to inform patients. This model serves as a benchmark to determine the prognostic value of novel biomarkers.

Histopathological growth patterns of resected non-colorectal, non-neuroendocrine liver metastases: a retrospective multicenter study.

BACKGROUND: Distinct Histopathological Growth Patterns can be identified in liver metastases from melanoma, breast and colorectal cancers. For each of these distinct liver metastasis types the HGP has proven a biomarker for survival after partial hepatectomy, with the desmoplastic type marking favourable prognosis. Whether HGPs can be considered a pan-cancer phenomenon remains unknown. This study therefore evaluates the presence of HGPs and their prognostic value across non-colorectal non-neuroendocrine liver metastases. METHODS: A retrospective multicentre cohort study was performed in patients who underwent curative intent resection of non-colorectal non-neuroendocrine liver metastasis. HGPs were assessed on Haematoxylin and Eosin slides according to consensus guidelines and classified as desmoplastic or non-desmoplastic. Overall- and recurrence-free survival were evaluated using Kaplan-Meier and multivariable Cox regression analysis. RESULTS: In total, 132 patients with liver metastasis from 25 different tumour types were eligible for analysis, of which 26 (20%) had a desmoplastic HGP. Five-year OS and RFS (95%CI) were 53% (36-78%) versus 40% (30-53%), and 33% (19-61%) versus 15% (9-27%) for patients with desmoplastic compared to non-desmoplastic metastases, respectively (p = 0.031 & p = 0.004). On multivariable analysis (adjusted HR [95%CI]) a desmoplastic HGP was prognostic for both OS (0.46 [0.25-0.86]) and RFS (0.38 [0.21-0.69]). CONCLUSIONS: This study demonstrates that HGPs apply to liver metastases across a wide variety of primary tumour origins. They hold a prognostic value in these cases, suggesting that HGPs could represent a pan-cancer biomarker for survival after surgical resection of liver metastases.

Local tumour control after radiofrequency or microwave ablation for colorectal liver metastases in relation to histopathological growth patterns.

BACKGROUND: Regrowth after ablation is common, but predictive factors for local control are scarce. This study investigates whether histopathological growth patterns (HGP) can be used as a predictive biomarker for local control after ablation of colorectal liver metastases (CRLM). METHODS: Patients who received simultaneous resection and ablation as first treatment for CRLM between 2000 and 2019 were considered eligible. HGPs were determined on resected CRLM according to international guidelines and were classified as desmoplastic or non-desmoplastic. As minimal inter-tumoural heterogeneity has been demonstrated, the HGP of resected and ablated CRLM were presumed to be identical. Local tumour progression (LTP) was assessed on postoperative surveillance imaging. Uni- and multivariable competing risk methods were used to compare LTP. RESULTS: In total 221 patients with 443 ablated tumours were analysed. A desmoplastic HGP was found in 60 (27.1%) patients who had a total of 159 (34.7%) ablated lesions. Five-year LTP [95%CI] was significantly higher for ablated CRLM with a presumed non-desmoplastic HGP (37% [30-43] vs 24% [17-32], Gray's-test p = 0.014). On multivariable analysis, a non-desmoplastic HGP (adjusted HR [95%CI]; 1.55 [1.03-2.35]) was independently associated with higher LTP rates after ablation. CONCLUSION: HGP is an independent predictor of local tumour progression following ablation of CRLM.

Limited Effect of Perioperative Systemic Therapy in Patients Selected for Repeat Local Treatment of Recurrent Colorectal Cancer Liver Metastases.

Objectives: The aim of this study was to determine the potential benefit of perioperative systemic therapy on overall and progression-free survival after repeat local treatment in patients suffering from recurrent colorectal cancer liver metastasis (CRLM). Background: The optimal treatment strategy in patients with recurrent CRLM needs to be clarified, in particular for those suffering from early recurrence of CRLM. Methods: In this multicenter observational cohort study, consecutive patients diagnosed with recurrent CRLM between 2009 and 2019 were retrospectively identified in 4 academic liver surgery centers. Disease-free interval after initial local treatment of CRLM was categorized into recurrence within 6, between 6 and 12, and after 12 months. Perioperative systemic therapy consisted of induction, (neo)adjuvant, or combined regimens. Overall and progression-free survival after repeat local treatment of CRLM were analyzed by multivariable Cox regression analyses, resulting in adjusted hazard ratios (aHRs). Results: Out of 303 patients included for analysis, 90 patients received perioperative systemic therapy for recurrent CRLM. Favorable overall (aHR, 0.45; 95% confidence interval [CI], 0.26-0.75) and progression-free (aHR, 0.53; 95% CI, 0.35-0.78) survival were observed in patients with a disease-free interval of more than 12 months. No significant difference in overall and progression-free survival was observed in patients receiving perioperative systemic therapy at repeat local treatment of CRLM, stratified for disease-free interval, previous exposure to chemotherapy, and RAS mutation status. Conclusions: No benefit of perioperative systemic therapy was observed in overall and progression-free survival after repeat local treatment of recurrent CRLM.

Adjuvant intra-arterial chemotherapy for patients with resected colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: The practice of adjuvant hepatic arterial infusion chemotherapy (HAIC) for colorectal liver metastasis (CRLM) varies widely. This meta-analysis investigates the effectiveness of adjuvant HAIC and the influence of variations in HAIC treatment in patients with resected CRLM. METHODS: PRISMA guidelines were followed for this study. The search was limited to comparative studies (HAIC vs non-HAIC) for overall survival. Subgroup meta-analyses using random-effects were performed for type of intra-arterial drug, method of catheter insertion, use of concomitant adjuvant systemic chemotherapy, and study design. RESULTS: Eighteen eligible studies were identified. After excluding overlapping cohorts, fifteen studies were included in the quantitative analysis, corresponding to 3584 patients. HAIC was associated with an improved overall survival (pooled hazard ratio (HR) 0.77; 95%CI 0.64-0.93). Survival benefit of HAIC was most pronounced in studies using floxuridine (HR 0.76; 95%CI: 0.62-0.94), surgical catheter insertion with subcutaneous pump (HR 0.71; 95%CI: 0.61-0.84), and concomitant adjuvant systemic chemotherapy (HR 0.75; 95%CI: 0.59-0.96). The pooled HR of RCTs was 0.91 (95%CI 0.72-1.14), of which only 3 used floxuridine. CONCLUSION: Adjuvant HAIC is a promising treatment for patients with resectable CRLM, in particular HAIC with floxuridine using a surgically placed catheter and a subcutaneous pump, and concomitant systemic chemotherapy.

Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases.

Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour-liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (ß [95% confidence interval, CI]: 24.57 [18.28-30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (ß [95% CI]: 24.18 [18.70-29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (ß [95% CI]: 23.29 [1.78-44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

Systematic review and meta-analysis of validated prognostic models for resected hepatocellular carcinoma patients.

BACKGROUND: Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. METHODS: All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. RESULTS: Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4-9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. CONCLUSIONS: Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.

Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: Does the primary disease site matter?

BACKGROUND: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown. METHODS: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed. RESULTS: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio [HR]: 1.58, 95% CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95% CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95% CI 1.22-1.99; codon 13, HR 2.10 95% CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy. CONCLUSIONS: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.

Sarcopenia and long-term survival outcomes after local therapy for colorectal liver metastasis: a meta-analysis.

BACKGROUND: Sarcopenia is defined as either low pre-operative muscle mass or low muscle density on abdominal CT imaging. It has been associated with worse short-term outcomes after surgery for colorectal liver metastases. This study aimed to evaluate whether sarcopenia also impacts long-term survival outcomes in these patients. METHODS: A random-effects meta-analysis was conducted following the PRISMA guidelines. Overall survival (OS) and disease-free survival (DFS) outcomes were evaluated. RESULTS: Eleven studies were included, ten reporting on the impact of low muscle mass and four on low muscle density. Sample sizes ranged between 47 and 539 (2124 patients in total). Altogether, 897 (42%) patients were considered sarcopenic, although definitions varied between studies. Median follow-up was 21-74 months. Low muscle mass (hazard ration (HR) 1.35, 95%CI 1.08-1.68) and low muscle density (HR 1.97, 95%CI 1.07-3.62) were associated with impaired OS. Low muscle mass (pooled HR 1.17, 95%CI 0.94-1.46) and low muscle density (pooled HR 1.13, 95%CI 0.85-1.50) were not associated with impaired RFS. DISCUSSION: Sarcopenia is associated with poorer OS, but not RFS, in patients with CRLM. Additional studies with standardized sarcopenia definitions are needed to better assess the impact of sarcopenia in patients with CRLM.

Histopathological Growth Patterns and Survival After Resection of Colorectal Liver Metastasis: An External Validation Study.

Background: After resection of colorectal cancer liver metastases (CRLM), 2 main histopathological growth patterns can be observed: a desmoplastic and a nondesmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation. Methods: An international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at 3 tertiary hospitals in the United States and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin and eosin-stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared with patients with a nondesmoplastic phenotype (any nondesmoplastic growth observed). Cutoff analyses on the extent of nondesmoplastic growth were performed. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided. Results: In total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% vs 3.6%, P = .01). Desmoplastic patients had superior 5-year OS (73.4%, 95% confidence interval [CI] = 64.1% to 84.0% vs 44.2%, 95% CI = 38.9% to 50.2%, P < .001) and DFS (32.0%, 95% CI = 22.9% to 44.7% vs 14.7%, 95% CI = 11.7% to 18.6%, P < .001) compared with their nondesmoplastic counterparts. A desmoplastic phenotype was associated with an adjusted hazard ratio for death of 0.36 (95% CI = 0.23 to 0.58) and 0.50 (95% CI = 0.37 to 0.66) for cancer recurrence. Prognosis was independent of KRAS and BRAF status. The cutoff analyses found no prognostic relationship between either OS or DFS and the extent of nondesmoplastic growth observed (all P > .1). Conclusions: This external validation study confirms the remarkably good prognosis after surgery for CRLM in patients with a desmoplastic phenotype. The extent of nondesmoplastic growth does not affect prognosis.

Disease recurrence after colorectal cancer surgery in the modern era: a population-based study.

PURPOSE: This population-based study determined the cumulative incidence (CI) of local, regional, and distant recurrences, examined metastatic patterns, and identified risk factors for recurrence after curative treatment for CRC. METHODS: All patients undergoing resection for pathological stage I-III CRC between January 2015 and July 2015 and registered in the Netherlands Cancer Registry were selected (N = 5412). Additional patient record review and data collection on recurrences was conducted by trained administrators in 2019. Three-year CI of recurrence was calculated according to sublocation (right-sided: RCC, left-sided: LCC and rectal cancer: RC) and stage. Cox competing risk regression analyses were used to identify risk factors for recurrence. RESULTS: The 3-year CI of recurrence for stage I, II, and III RCC and LCC was 0.03 vs. 0.03, 0.12 vs. 0.16, and 0.31 vs. 0.24, respectively. The 3-year CI of recurrence for stage I, II, and III RC was 0.08, 0.24, and 0.38. Distant metastases were found in 14, 12, and 16% of patients with RCC, LCC, and RC. Multiple site metastases were found often in patients with RCC, LCC, and RC (42 vs. 32 vs. 28%). Risk factors for recurrence in stage I-II CRC were age 65-74 years, pT4 tumor size, and poor tumor differentiation whereas in stage III CRC, these were ASA III, pT4 tumor size, N2, and poor tumor differentiation. CONCLUSIONS: Recurrence rates in recently treated patients with CRC were lower than reported in the literature and the metastatic pattern and recurrence risks varied between anatomical sublocations.

Quality and performance of validated prognostic models for survival after resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND: The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset. Furthermore, it sought to identify common prognostic factors across models, and assess methodological quality of the studies in which the models were developed. METHODS: The PRISMA guidelines were followed. External validation studies of prognostic models for patients with iCCA were searched in 5 databases. Model performance was assessed by discrimination and calibration. RESULTS: Thirteen external validation studies were identified, validating 18 different prognostic models. The Wang model was the sole model with good performance (C-index above 0.70) for overall survival. This model incorporated tumor size and number, lymph node metastasis, direct invasion into surrounding tissue, vascular invasion, Carbohydrate antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Methodological quality was poor in 11/12 statistical models. The Wang model had the highest score with 13 out of 17 points. CONCLUSION: The Wang model for prognosis after resection of iCCA has good quality and good performance at external validation, while most prognostic models for iCCA have been developed with poor methodological quality and show poor performance at external validation.

Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases.

Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study evaluates whether HGPs can predict the effectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000-2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.37-0.73, p < 0.001), and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75-4.21, p = 0.19). In pretreated patients no significant effect of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49-1.42, p = 0.50) nor in the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71-1.29, p = 0.79). Similar results were found for DFS, with a superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55-0.93, p < 0.001) that were not pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this effect was only observed in patients that were not treated with chemotherapy.

The impact of hepatic arterial infusion pump chemotherapy on hepatic recurrences and survival in patients with resected colorectal liver metastases.

BACKGROUND: The objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM). METHODS: Recurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses. RESULTS: 2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60-0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57-0.78,p < 0.001). CONCLUSION: Adjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.

Primary tumor location and the prognosis of patients after local treatment of colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: Recently numerous studies have reported primary tumor location as a potential prognostic factor after surgery for colorectal liver metastases (CRLM). The aim of this study was to comprehensively review and analyze all the available literature on the impact of primary tumor location in patients after local treatment of CRLM. METHODS: Studies examining the association of right- and left-sided colorectal cancer and overall survival (OS) and recurrence free survival (RFS) after local treatment (resection and/or ablation) of CRLM were identified. Random-effects models were used for both clinicopathological and outcome variables. Pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were shown for both OS and RFS. RESULTS: Ten studies (including 11 patient cohorts) were eligible for inclusion, representing 3962 patients. Right-sided tumors (i.e. proximal to the splenic flexure) were observed in 1340 patients (33.8%). Median follow-up ranged from 25 to 137 months. Patients with right-sided tumors had a significantly decreased OS (HR 1.60, 95% CI 1.30-1.98, p < 0.001) and RFS (HR 1.35, 95% CI 1.04-1.77, p = 0.03), when compared to patients with left-sided tumors. CONCLUSION: This meta-analysis suggests that patients with right-sided primaries suffer from a worse prognosis, compared to patients with left-sided primaries in patients after local treatment of CRLM.

Recurrence Patterns After Resection of Colorectal Liver Metastasis are Modified by Perioperative Systemic Chemotherapy.

BACKGROUND: This study investigated the impact of perioperative systemic chemotherapy on the recurrence rate and pattern following resection of colorectal liver metastases. METHODS: A retrospective cohort study was conducted in two centers. Rates and patterns of recurrence and overall survival (OS) were compared between patients treated with and without perioperative systemic chemotherapy. The clinical risk score (CRS) was used to stratify patients in low risk (CRS 0-2) and high risk (CRS 3-5) of recurrence. RESULTS: A total of 2020 patients were included, of whom 1442 (71%) received perioperative systemic chemotherapy. The median follow-up was 88 months, and 1289 patients (64%) developed a recurrence. The recurrence pattern was independent of chemotherapy in low-risk patients: intrahepatic recurrences (30% vs. 30%, p = 0.97) and extrahepatic recurrences (38% vs. 39%, p = 0.52). In high-risk patients, no difference in intrahepatic recurrences was found (48% vs. 50%, p = 0.59). However, a lower rate of extrahepatic recurrences (43% vs. 55%, p = 0.007) was observed with perioperative systemic chemotherapy, mainly due to a reduction in pulmonary recurrences (25% vs. 35%, p = 0.007). In competing risk analysis, the cumulative incidence of extrahepatic recurrence was significantly lower with perioperative systemic chemotherapy in high-risk patients only (5-year cumulative incidence 44% vs. 59%, p < 0.001). Perioperative chemotherapy was associated with improved OS in high-risk patients (adjusted HR 0.73, 95% CI 0.57-0.94, p = 0.02), but not in low-risk patients (adjusted HR 0.99, 95% CI 0.82-1.19, p = 0.90). CONCLUSIONS: Perioperative systemic chemotherapy had no association with intrahepatic recurrence, but was associated with fewer pulmonary recurrences and superior OS in high-risk patients only.

Histopathological growth patterns and positive margins after resection of colorectal liver metastases.

BACKGROUND: Histopathological growth patterns (HGPs) of colorectal liver metastases (CRLM) may be an expression of biological tumour behaviour impacting the risk of positive resection margins. The current study aimed to investigate whether the non-desmoplastic growth pattern (non-dHGP) is associated with a higher risk of positive resection margins after resection of CRLM. METHODS: All patients treated surgically for CRLM between January 2000 and March 2015 at the Erasmus MC Cancer Institute and between January 2000 and December 2012 at the Memorial Sloan Kettering Cancer Center were considered for inclusion. RESULTS: Of all patients (n = 1302) included for analysis, 13% (n = 170) had positive resection margins. Factors independently associated with positive resection margins were the non-dHGP (odds ratio (OR): 1.79, 95% confidence interval (CI): 1.11-2.87, p = 0.016) and a greater number of CRLM (OR: 1.15, 95% CI: 1.08-1.23 p < 0.001). Both positive resection margins (HR: 1.41, 95% CI: 1.13-1.76, p = 0.002) and non-dHGP (HR: 1.57, 95% CI: 1.26-1.95, p < 0.001) were independently associated with worse overall survival. CONCLUSION: Patients with non-dHGP are at higher risk of positive resection margins. Despite this association, both positive resection margins and non-dHGP are independent prognostic indicators of worse overall survival.