Simultaneous Resection of Primary Colorectal Cancer and Synchronous Liver Metastases: Contemporary Practice, Evidence and Knowledge Gaps

The timing of surgical resection of synchronous liver metastases from colorectal cancer has been debated for decades. Several strategies have been proposed, but high-level evidence remains scarce. Simultaneous resection of the primary tumour and liver metastases has been described in numerous retrospective audits and meta-analyses. The potential benefits of simultaneous resections are the eradication of the tumour burden in one procedure, overall shorter procedure time, reduced hospital stay with the likely benefits on quality of life and an expected reduction in the use of health care services compared to staged procedures. However, concerns about accumulating complications and oncological outcomes remain and the optimal selection criteria for whom simultaneous resections are beneficial remains undetermined. Based on the current level of evidence, simultaneous resection should be restricted to patients with a limited liver tumour burden. More high-level evidence studies are needed to evaluate the quality of life, complication burden, oncological outcomes, as well as overall health care implications for simultaneous resections

Preoperative Inflammatory Markers in Liver Resection for Colorectal Liver Metastases: A National Registry-Based Study

Background Preoperative inflammatory markers were shown to be associated with prognosis following surgery for hepato-pancreato-biliary cancer. Yet little evidence exists about their role in patients with colorectal liver metastases (CRLM). This study aimed to examine the association between selected preoperative inflammatory markers and outcomes of liver resection for CRLM. Methods Data from the Norwegian National Registry for Gastrointestinal Surgery (NORGAST) was used to capture all liver resections performed in Norway within the study period (November 2015–April 2021). Preoperative inflammatory markers were Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS) and C-reactive protein to albumin ratio (CAR). The impact of these on postoperative outcomes, as well as on survival were studied. Results Liver resections for CRLM were performed in 1442 patients. Preoperative GPS C 1 and mGPS C 1 were present in 170 (11.8%) and 147 (10.2%) patients, respectively. Both were associated with severe complications but became non-significant in the multivariable model. GPS, mGPS, CAR were significant predictors for overall survival in the univariable analysis, but only CAR remained such in the multivariable model. When stratified by the type of surgical approach, CAR was a significant predictor for survival after open but not laparoscopic liver resections. Conclusions GPS, mGPS and CAR have no impact on severe complications after liver resection for CRLM. CAR outperforms GPS and mGPS in predicting overall survival in these patients, especially following open resections. The prognostic significance of CAR in CRLM should be tested against other clinical and pathology parameters relevant for prognosis

Practice patterns in diagnostics, staging, and management strategies of gallbladder cancer among Nordic tertiary centers

Background and objective: Gallbladder cancer (GBC) is a rare malignancy in the Nordic countries and no common Nordic treatment guidelines exist. This study aimed to characterize the current diagnostic and treatment strategies in the Nordic countries and disclose differences in these strategies. Methods: This was a survey study with a cross-sectional questionnaire of all 19 university hospitals providing curative-intent surgery for GBC in Sweden, Norway, Denmark, and Finland. Results: In all Nordic countries except Sweden, neoadjuvant/downstaging chemotherapy was used in GBC patients. In T1b and T2, majority of the centers (15–18/19) performed extended cholecystectomy. In T3, majority of the centers (13/19) performed cholecystectomy with resection of segments 4b and 5. In T4, majority of the centers (12–14/19) chose palliative/oncological care. The centers in Sweden extended lymphadenectomy beyond the hepatoduodenal ligament, whereas all other Nordic centers usually limited lymphadenectomy to the hepatoduodenal ligament. All Nordic centers except those in Norway used adjuvant chemotherapy routinely for GBC. There were no major differences between the Nordic centers in diagnostics and follow-up. Conclusions: The surgical and oncological treatment strategies of GBC vary considerably between the Nordic centers and countries.publishedVersio

Resection rates and predictors of survival after surgery for colorectal liver metastases

Introduction: Occurrence of liver metastases is common following colorectal cancer (CRC), and resection is the only option with a potential for cure offered to a minor part of these patients. During the last decades there have been major improvements in the oncosurgical treatment, along with expansions in inclusion criteria for surgery. The majority of the patients will unfortunately experience post-resection recurrence. Divergent results have been presented regarding the need of clear resection margins (RMs) to accomplish an optimal outcome. Data on national resection rates in patients with CLM are sparse. Aim of the thesis: I: To study RMs and the correlation with local recurrence (LR) pattern, time to recurrence (TTR) and overall survival (OS) in patients resected for CLM. II: To study patterns of recurrence, and post-recurrence survival (PRS) according to sites of recurrence following resection for CLM. III: To study resection rates in patients diagnosed with CLM in Norway, focusing on characteristics like age, geographical regions and primary tumour. Methods: Paper I and II are based on a combined retrospective (1998-2008) and prospective (2009-2012) retrieved database of consecutive patients treated with resection for CLM at Haukeland University Hospital. Paper III is based on synchronized data from the Norwegian Patient Registry (NPR) and the Cancer Registry of Norway (CRN) where patients with a diagnosis of CRC (ICD-10: C18-20) and liver metastases (C78.7) were enrolled (2011-2013). Cumulative resection rates (CRR) following CLM were retrieved from any registration of hepatic resection (NCSP: JJB) in the data set. TTR, OS and CRR (paper I-III) were obtained using Kaplan Meier method with Log-rank test (univariate) and COX regression analysis (multivariate). All the studies were accepted by the Regional Committee for Medical and Health Research Ethics (REKVest). Results: A total of 242, 311 and 2960 patients were enrolled in paper I, II and III, respectively. In paper I the patients were grouped according to the width of the resection margins; <1 mm/R1 (n = 48), 1 to 4 mm (n = 77), 5 to 9 mm (n = 46) and ≥10 mm (n = 71). LR was significantly higher in patients with RM <5 mm. A significant difference in OS was discovered between RO and R1 (univariate), and was nearly verified in the multivariate analysis (p = 0.067). Neoadjuvant chemotherapy did not alter this finding. In paper II a total of 209 patients (67.4 %) developed recurrence after a median of 4.2 years, and were further stratified between sites; hepatic (n = 90), extrahepatic (n = 59) and both (n = 60). Median TTR and OS were 14 and 45 months, respectively. Synchronous disease, ASA score, increased number and size of metastases were all independently correlated to a reduction in TTR. Hepatic TTR was influenced by synchronous disease, multiple lesions, ASA score and R1 resections, while extrahepatic TTR was correlated to lymph nodes positive of the primary, size and number of metastases. Perioperative chemotherapy increased TTR and OS in the multivariate analysis. Single site recurrence in liver or lungs was most common and with a potential for longevity. In paper III a total of 20 % (CRR) of the patients with CLM in Norway were resected. In the multivariate analysis the resection rates varied according to age, extrahepatic metastases, disease-free interval and geographical region. In patients diagnosed with CLM, resection doubled the chance for survival. The 3-year survival after resection was 73.2 %. In the region with the highest CRR, the lowest OS was observed after resection. However the highest OS in the whole cohort of patients with CLM was obtained in this region. Conclusion: Positive margins were correlated to adverse outcomes, and were not influenced by preoperative chemotherapy. RMs <5 mm increased the risk for LR. Number and size of metastases, ASA score, synchronous disease and perioperative chemotherapy influenced time to recurrence. Single-site recurrence had a potential for longevity through repeated resections and multimodal treatment. One in five patients with CLM in Norway are offered resection, depending on geographical regions, age and disease advancements

Surgery for colorectal liver metastases: the impact of resection margins on recurrence and overall survival

Background: Several reports have presented conflicting results regarding the association between resection margins (RMs) and outcome after surgery for colorectal liver metastases (CLM), especially in the era of modern chemotherapy. The purpose of this study was to evaluate the impact of RMs on overall survival (OS), time to recurrence (TTR) and local recurrence (LR) status, particularly for patients treated with preoperative chemotherapy. Methods: A combined retrospective (1998 to 2008) and prospective (2008 to 2010) cohort study of consecutive patients with CLM without extrahepatic disease treated with primary resection at a medium volume centre. Results: A total of 253 patients with known R status and 242 patients with defined margin width were included in the study. Patients were stratified according to margin width; A: R1, <1 mm (n = 48, 19%), B: 1 to 4 mm (n = 77), C: 5 to 9 mm (n = 46) and D: ≥10 mm (n = 71). Median time to recurrence was 12.8 months, and after five years 21.5% had no recurrence. LR (inclusive combined recurrence in other hepatic sites or extrahepatic) occurred in 40 (16.5%) cases, most frequently seen with RMs below 5 mm. Five-year OS was 42.5% in R0 and 16.1% in R1 resections (P = 0.011). Patients were also stratified according to preoperative chemotherapy (n = 88), and the difference in five-year OS between R0 (45.1%) and R1 (14.7%) was maintained (P = 0.037). By multiple Cox regression analysis R1 resections tended to an adverse outcome (P = 0.067), also when adjusting for preoperative chemotherapy (P = 0.081). Conclusions: R1 resections for colorectal liver metastases predict adverse outcome. RMs below 5 mm increased the risk for LR and shortened the time to recurrence. Preoperative chemotherapy did not alter an adverse outcome in R1 vs. R0 patients

Percutaneous cholecystostomy in acutecholecystitis; a retrospective analysis of a largeseries of 104 patients

Background: The purpose of this study was to evaluate the clinical course and possible benefit of a percutaneous cholecystostomy in patients with acute cholecystitis. Methods: Retrospective study of 104 patients with severe cholecystitis or cholecystitis not responding to antibiotic therapy treated with percutaneous drainage of the gall bladder (PC) during the period 2007 – 2013. Primary outcome was relief of cholecystitis, complications following the procedure and need for later cholecystectomy. Results: There were 57 men and 47 women with a median age of 73,5 years (range 22 – 96). 43% of the patients were ASA III or IV and 91% had cholecystitis Grade 2 or 3. About 60% of the patients had severe comorbidity (cardiovascular disease or active cancer). Drain insertion was successful in all but one patient and complications were mild, apart from two patients that needed percutaneous drainage of intraabdominal fluid collection due to bile leakage. The drain was left in place for 1 – 75 days (median 6,5). When evaluated clinically and by blood tests (CRP and white blood cell counts) we found resolution of symptoms in 101 patients (97,2%), whereas 2 patients had no obvious effect of drainage. Four patients died within 30 days, no deaths were related to the drainage procedure. Follow-up after drainage was median 12 months (range 0 – 78). During that time cholecystectomy was performed in 30 patients and 24 patients had died. Following cholecystectomy, two had died, both from cancer and more than one year after the operation. Conclusion: Patients with acute cholecystitis were promptly relieved from their symptoms following PC. There were only minor complications following the procedure and only about 30% of the patients had a later cholecystectomy

Performance comparison of three BRAF V600E detection methods in malignant melanoma and colorectal cancer specimen

Personalized cancer care requires reliable biomarkers. While the BRAF V600E mutation is implemented in the clinic, no method for its detection has so far been established as reference. We aimed to perform a comprehensive comparison of three methods currently being used for V600E detection in clinical samples. We analysed genomic DNA from 127 malignant melanomas (77 patients) and 389 tumours from 141 colorectal cancer patients (383 liver metastases and 6 primary tumours) by Sanger sequencing and a single probe-based high-resolution melting assay (LightMix). Formalin-fixed paraffin-embedded (FFPE) tissue from a subset of these lesions (n = 77 and 304, respectively) was analysed by immunohistochemistry (IHC) using the V600E-specific antibody VE1. In a dilution series of V600E-mutated DNA in wild-type DNA, the detection limit for the LightMix assay was 1:1000 mutated alleles while it was 1:10 for Sanger sequencing. In line with this, we detected 15 additional mutated melanoma samples and two additional mutated metastatic colorectal cancer samples by the LightMix assay compared to Sanger sequencing. For the melanoma samples, we observed high concordance between DNA-based methods and analysis by IHC. However, in colorectal samples, IHC performed poorly with 12 samples being scored as V600E positive exclusively by IHC and nine samples being scored as V600E negative exclusively by IHC. In conclusion, the VE1 antibody is not recommendable for clinical tests of colorectal cancer samples. For melanoma samples, IHC may be useful as a screening tool guiding further analytical approaches. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited

Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases

We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions

Predictive factors for time to recurrence, treatment and post-recurrence survival in patients with initially resected colorectal liver metastases

Background: Despite progress in resection for colorectal liver metastases (CLM), the majority of patients experience recurrence. We aimed to evaluate factors influencing time to recurrence (TTR), treatment and post-recurrence survival (PRS) related to site of recurrence. Methods: This is a retrospective population-based cohort study (1998–2012) of consecutive patients without extrahepatic disease treated with resection for CLM in a referral centre. Results: A total of 311 patients underwent resection for CLM. After a median follow-up of 4.2 years (range 1.2–15.2), 209 (67.4 %) patients developed recurrence, hepatic 90, extrahepatic 59 and both 60. Median TTR was 14.0 months, and 5-year recurrence-free status was 25.7 %. Five- and 10-year overall survival (OS) was 38.8 and 22.0 %, respectively. Median OS was 45 months. A multivariate analysis displayed synchronous disease (hazard ratio (HR) 1.50), American Society of Anaesthesiologists (ASA) score (HR 1.40), increasing number (HR 1.24) and size of metastases (HR 1.08) to shorten TTR (all p < 0.05). Perioperative chemotherapy (n = 59) increased overall TTR (HR 0.63) and overall survival (OS; HR 0.55). Hepatic TTR was correlated to synchronous disease (HR 2.07), number of lesions (HR 1.20), R1 resection (HR 2.00) and ASA score (HR 1.69), whereas extrahepatic TTR was correlated to N stage of the primary (HR 1.79), number (HR 1.27) and size of metastases (HR 1.16). Single-site recurrence was most common (135 of 209, 64.5 %), while 58 patients had double- and 16 triple-site relapses. Median PRS was 24.3 months. There was a difference in median PRS (months) according to site of relapse: liver 30.5, lung 32.3, abdominal 22.0, liver and lung 14.3, others 14.8 (p = 0.002). Repeated liver resections were performed in n = 57 patients resulting in 40.6 months median OS and 36.8 % 5-year OS. Conclusions: An adverse overall TTR was correlated to number and size of metastases, ASA score and synchronous disease. Perioperative chemotherapy increased TTR and OS after surgery for CLM. Patients with solitary post-resection relapse in the liver or lungs had the potential for longevity due to multimodal treatment

Simultaneous Resection of Primary Colorectal Cancer and Synchronous Liver Metastases: Contemporary Practice, Evidence and Knowledge Gaps

The timing of surgical resection of synchronous liver metastases from colorectal cancer has been debated for decades. Several strategies have been proposed, but high-level evidence remains scarce. Simultaneous resection of the primary tumour and liver metastases has been described in numerous retrospective audits and meta-analyses. The potential benefits of simultaneous resections are the eradication of the tumour burden in one procedure, overall shorter procedure time, reduced hospital stay with the likely benefits on quality of life and an expected reduction in the use of health care services compared to staged procedures. However, concerns about accumulating complications and oncological outcomes remain and the optimal selection criteria for whom simultaneous resections are beneficial remains undetermined. Based on the current level of evidence, simultaneous resection should be restricted to patients with a limited liver tumour burden. More high-level evidence studies are needed to evaluate the quality of life, complication burden, oncological outcomes, as well as overall health care implications for simultaneous resections