Clinical Significance of Circulating Tumor Cells in Epithelial Appendiceal Neoplasms with Peritoneal Metastases.

Appendiceal tumors are uncommon and, at times, discovered incidentally during histological examination. The histopathological classification of the disease is complex and has generated some controversy. The analysis of circulating tumor cells can be used for the early detection of metastatic potential. The aim of the present study was to examine the prognostic value of circulating tumor cells in patients with appendiceal tumors and peritoneal metastases. To our knowledge, this is the first study to examine CTCs in appendiceal tumors. We performed a prospective cohort study of consecutive patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between 2015 and 2019 at a HIPEC referral center. In total, 31 patients were included in the analysis, and circulating tumor cells were detected in 15 patients (48%). CTC positivity was not associated with overall or recurrence-free survival, nor was it correlated with PCI score or histopathological grading. Surprisingly, however, CTCs were found in almost half the patients. The presence or quantities of these cells did not, on their own, predict systemic metastatic potential during the observed time, and they did not appear to significantly correlate with the oncological outcomes recorded.

Clinical significance of circulating tumor cells in colorectal cancer with peritoneal metastases: a prospective cohort study using a novel method for monitoring treatment response, and assessing minimal residual disease.

BACKGROUND: The treatment for patients with colorectal cancer with metastases to the peritoneum is complex and may involve both surgery and chemotherapy. Circulating tumor cells (CTCs) have been poorly investigated in peritoneal metastatic colorectal cancer. The aim of the study is to examine the role of circulating tumor cells (CTCs) as a biomarker for monitoring disease progression, treatment response and residual disease using CellMate® - a new promising in vitro diagnostic platform technology. MATERIALS AND METHODS: We prospectively followed clinical outcomes of 46 patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer with peritoneal metastases and examined whether CTCs were present the week of surgery. The CTC measurements were made with the CellMate® technology, which is a platform technology to detect CTCs based on the difference in biomechanical properties compared to blood resident cells. The study was registered online (ClinicalTrials.gov). RESULTS: CTCs were detected in 17 (37%) patients. The presence of CTCs was associated with shorter recurrence-free survival and overall survival after CRS and HIPEC. Both recurrence free survival (HR 4.00, 95%CI 1.15-13.9; P=0.029) and overall survival (HR 5.91; 95% CI 1.18-29.7; P=0.03) were significantly worse if CTCs were detected after neoadjuvant treatment. In the subgroup of patients with CTCs detected, adjuvant therapy tended to improve the prognosis while in CTC negative patients it did not. CONCLUSIONS: Pending a prospective multi-center trial to validate these findings, CTCs may in the future be used as a dynamic personalized biomarker for prognostication, predicting response to therapy, and for monitoring disease progression in colorectal cancer with metastases to the peritoneum.

Change in tissue resistance after irreversible electroporation in liver tumors as an indicator of treatment success - A multi-center analysis with long term follow-up.

INTRODUCTION: A nationwide multicenter study was performed to examine whether there is a correlation between decrease in tissue resistance and time to local tumor recurrence after irreversible electroporation (IRE) in patients with hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRCLM). METHODS: All patients treated with IRE for liver tumors in Sweden from 2011 until 2018 were included. Patient characteristics and recurrence patterns were obtained from medical records and radiological imaging. All procedural data from the IRE hardware at the three hospitals performing IRE were retrieved. The resistance during each pulse and the change during each treatment were calculated. The electrode pair with the smallest decrease in tissue resistance was used and compared with the time to LTP. RESULTS: 149 patients with 206 tumors were treated. Exclusion due to missing and inaccurate data resulted in 124 patients with 170 tumors for the analyses. In a multivariable Cox regression model, a smaller decrease in tissue resistance and larger tumor size were associated with shorter time to local tumor recurrence for CRCLM, but not for HCC. CONCLUSION: There was an association between a decrease in tissue resistance and time to local tumor recurrence for CRCLM. The decrease in resistance, in combination with a rise in current, may be the parameters the interventionist should use during IRE to decide if the treatment is successful.

Importance of resection margin after resection of colorectal liver metastases in the era of modern chemotherapy: population-based cohort study.

BACKGROUND: Resection margin has been associated with overall survival following liver resection for colorectal liver metastasis. The aim of this study was to examine how resection margins of 0.0 mm, 0.1-0.9 mm and ≥1 mm influence overall survival in patients resected for colorectal liver metastasis in a time of modern perioperative chemotherapy and surgery. METHODS: Using data from the national registries Swedish Colorectal Cancer Registry and Swedish National Quality Registry for Liver, Bile Duct and Gallbladder Cancer, patients that had liver resections for colorectal liver metastasis between 2009 and 2013 were included. In patients with a narrow or unknown surgical margin the original pathological reports were re-reviewed. Factors influencing overall survival were analysed using a Cox proportional hazard model. RESULTS: A total of 754 patients had a known margin status, of which 133 (17.6%) patients had a resection margin <1 mm. The overall survival in patients with a margin of 0 mm or 0.1-0.9 mm was 42 (95% c.i. 31 to 53) and 48 (95% c.i. 35 to 62) months respectively, compared with 75 (95% c.i. 65 to 85) for patients with ≥1 mm margin, P < 0.001. Margins of 0 mm or 0.1-0.9 mm were associated with poor overall survival in the multivariable analysis, HR 1.413 (95% c.i. 1.030 to 1.939), P = 0.032, and 1.399 (95% c.i. 1.025 to 1.910), P = 0.034, respectively. CONCLUSIONS: Despite modern chemotherapy the resection margin is still an important factor for the survival of patients resected for colorectal liver metastasis, and a margin of ≥1 mm is needed to achieve the best possible outcome.

Efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil monotherapy for refractory metastatic colorectal cancer: a retrospective cohort study.

Background: Several studies demonstrated trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) had better efficacy than the monotherapy of TAS-102 in refractory metastatic colorectal cancer (mCRC). However, it remains unclear whether Chinese population can benefit from this combination or not. Hence, we conducted this retrospective cohort study to compare the efficacy and safety between TAS-102 plus BEV with TAS-102 monotherapy in refractory mCRC. Methods: This retrospective cohort study enrolled patients (any age) with refractory mCRC from Hunan Cancer Hospital. The main inclusion criteria were histopathologically and/or radiographically confirmed refractory mCRC, World Health Organization (WHO) performance status of 0 to 2, adequate organ function, and initial treatment of TAS-102 with or without BEV between November 2020 and October 2022. Previous therapy with fruquintinib or regorafenib was allowed but not mandatory. Baseline demographic and clinical characteristics were collected appropriately. Every 2 or 3 treatment cycles, the patients were assessed by computed tomography (CT) scans and clinical assessments until disease progression or loss to follow-up. The National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 (NCI-CTCAE 5.0) were presented as n (%). The primary endpoint was investigator-evaluated overall survival (OS). As this is a retrospective cohort study, sample size calculation was not performed. Eligible patients would be enrolled as many as possible. Results: A total of 90 patients were enrolled, including 58 patients who received TAS-102 plus BEV and another 32 patients who received TAS-102 monotherapy. The known baseline characteristics were comparable (P<0.05). With a median follow-up of 4.60 months (range, 0.20-22.80), the median OS (mOS) time in the TAS-102 plus BEV group was longer than that in the TAS-102 monotherapy group (10.83 vs. 7.43 months), but the difference was not significant (P=0.79). The median progression-free survival (mPFS) time was comparable between the two groups (4.67 vs. 4.30 months, P=0.96). Multivariate Cox regression analysis demonstrated that undergoing therapy after TAS-102 either with or without BEV was an independent risk factor for OS [hazard ratio (HR) =0.25; 95% confidence interval (CI): 0.09-0.71, P<0.01], and previous treatment with cetuximab was an independent protective factor for PFS (HR =0.17; 95% CI: 0.03-0.91, P=0.04). Of the 70 patients who were evaluated, those receiving TAS-102 plus BEV showed trend of a higher objective response rate (ORR) and disease control rate (DCR) than those who received TAS-102 monotherapy (P=0.16 and P=0.29, respectively). Adverse events (AEs) were similar between the two groups, except that the incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group. Conclusions: There was a trend in favor of the combination of BEV plus TAS-102 regarding OS and DCR, without reaching statistical significance, and it means that there was no clear advantage of one over the other in terms of efficacy. Further prospective studies are still necessary to draw a definite conclusion.

Irreversible electroporation of hepatocellular carcinoma and colorectal cancer liver metastases: A nationwide multicenter study with short- and long-term follow-up.

INTRODUCTION: A nationwide multicenter study was performed to examine short- and long-term effects of irreversible electroporation (IRE) for hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRCLM). IRE is an alternative method when thermal ablation is contraindicated because of risk for serious thermal complications. METHODS: All consecutive patients in Sweden treated with IRE because of HCC or CRCLM, were included between 2011 and 2018. We evaluated medical records and radiological imaging to obtain information regarding patient-, tumor-, and treatment characteristics. We also assessed local tumor progression, and survival. RESULTS: In total 206 tumors in 149 patients were treated with IRE. Eighty-seven patients (58.4%) had colorectal cancer liver metastases, and 62 patients (41.6%) had hepatocellular carcinoma. Median tumor size was 20 mm (i.q.r. 14-26 mm). Median overall survival for CRCLM and HCC, were 27.0 months (95% CI 22.2-31.8 months), and 35.0 months (95% CI 13.8-56.2 months), respectively. Median follow-up time was 58 months (95% CI 50.6-65.4). Local ablation success at six and twelve months for HCC was 58.3% and 40.3%, and for CRCLM 37.7% and 25.4%. The median time to local tumor progression (LTP) for HCC was 21.0 months (95% CI: 9.5-32.5 months), and for CRCLM 6.0 months (95% CI: 4.5-7.5 months). At 30-day follow-up, 15.4% (n = 23) of patients suffered from a complication rated as Clavien-Dindo grade 1-3a. Three patients (2.0%) had grade 3b-5 with one death in a thromboembolic event. CONCLUSION: IRE is a safe ablation modality for patients with liver tumors that are located in such a way that other treatment options are unsuitable.

A comparison of the simultaneous, liver-first, and colorectal-first strategies for surgical treatment of synchronous colorectal liver metastases at two major liver-surgery institutions in Sweden.

BACKGROUND: The optimal treatment strategy for patients with synchronous colorectal liver metastases (CRLM) is unclear. The aim of this study was to compare the outcome of the simultaneous, liver-first, and colorectal-first surgical approaches. METHODS: All consecutive patients who had been resected with curative intent for CRLM were included. A Cox regression model was constructed, and an intention-to-treat analysis was performed between the liver-first and the simultaneous approaches, after propensity score matching. RESULTS: 658 patients were included in the analysis. 92 patients had a simultaneous resection, 163 patients had liver-first, and 403 patients had a colorectal-first approach. Overall survival was 54.9 months (95% CI 39.2-70.4) in the liver-first group, 54.5 months (95% CI 46.8-62.3) in colorectal-first group, and 59.6 months (95% CI 42.2-77.0) in the simultaneous group (log-rank p =0.850). In the matched cohort there were no differences in Clavien-Dindo 3a (p = 0.992) or 3b and greater (p = 0.999). Median overall survival was for liver-first group 42.2 months (95% CI 26.3-58.2), and for the simultaneous group 56.2 months (95% CI 47.1-65.4) (stratified log-rank p = 0.455). CONCLUSION: A simultaneous approach was not associated with worse overall survival or morbidity compared to a liver-first approach.

Composite Score: prognostic tool to predict survival in patients undergoing surgery for colorectal liver metastases.

BACKGROUND: Several existing scoring systems predict survival of patients with colorectal liver metastases. Many lack validation, rely on old clinical data, and have been found to be less accurate since the introduction of chemotherapy. This study aimed to construct and validate a clinically relevant preoperative prognostic model for patients with colorectal liver metastases. METHODS: A predictive model with data available before surgery was developed. Survival was analysed by Cox regression analysis, and the quality of the model was assessed using discrimination and calibration. The model was validated using multifold cross-validation. RESULTS: The model included 1212 consecutive patients who underwent liver resection for colorectal liver metastases between 2005 and 2015. Prognostic factors for survival included advanced age, raised C-reactive protein level, hypoalbuminaemia, extended liver resection, larger number of metastases, and midgut origin of the primary tumour. A Composite Score was developed based on the prognostic variables. Patients were classified into those at low, medium, and high risk. Survival differences between the groups were significant; median overall survival was 87.4 months in the low-risk group, 50.1 months in the medium-risk group, and 22.6 months in the high-risk group. The discriminative performance, assessed by the concordance index, was 0.71, 0.67, and 0.67 respectively at 1, 3, and 5 years. Calibration, assessed graphically, was close to perfect. A multifold cross-validation of the model confirmed its internal validity (C-index 0.63 versus 0.62). CONCLUSION: The Composite Score categorizes patients into risk strata, and may help identify patients who have a poor prognosis, for whom surgery is questionable.

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy with single drug versus multiple drug treatment for colorectal cancer with peritoneal metastases: an observational cohort study.

BACKGROUND: Long-term survival for selected patients with peritoneal metastases (PM) from colorectal cancer (CRC) is possible when treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The objective of this study was to compare three different oxaliplatin-based (OX)-HIPEC regimens. Primary end-point was disease-free survival (DFS), and secondary endpoints, morbidity and overall survival (OS). METHODS: This is a retrospective study of all patients with colorectal PM treated with CRS and HIPEC between 2004 and 2015 from the prospectively maintained Uppsala HIPEC database. One hundred and thirty-three patients were identified. Three HIPEC regimens were included: OX-HIPEC, OX-HIPEC + post-operative intraperitoneal chemotherapy (EPIC) with 5-fluorouracil (5-FU), and oxaliplatin-irinotecan-based (OXIRI)-HIPEC. Multivariable Cox regression for DFS was performed. RESULTS: Sixty-one patients received OX-HIPEC, 24 patients received OX-HIPEC + 5-FU EPIC, and 48 patients received OXIRI-HIPEC. The DFS for the OX-HIPEC group was 10.5 months, OX-HIPEC + EPIC 11.9 months, and OXIRI-HIPEC 13.4 months (OX-HIPEC vs. OXIRI HIPEC, P=0.049). The morbidity and OS did not differ between the groups. In the multivariable analysis, low peritoneal cancer index (PCI), absence of liver metastases, low completeness of cytoreduction (CC) score, and multiple drug (EPIC or OXIRI) HIPEC regimen were independent prognostic factors for DFS. CONCLUSIONS: This study showed improved DFS with an intensification of HIPEC by adding irinotecan or EPIC compared to oxaliplatin alone without an increase in morbidity or mortality.

The prognostic value of C-reactive protein and albumin in patients undergoing resection of colorectal liver metastases. A retrospective cohort study.

BACKGROUND: The systemic inflammation-based Glasgow Prognostic Score (GPS) and modified GPS (mGPS), as measured by preoperative C-reactive protein (CRP) and albumin, correlate with poor survival in several cancers. This study evaluates the prognostic value of these scores in patients with colorectal liver metastases (CRLM). METHODS: This retrospective study assessed the prognostic role of preoperatively measured GPS and mGPS in patients undergoing liver resection because of CRLM. Clinicopathological data were retrieved from local databases. The prognostic value of GPS and mGPS were compared and a Cox regression model was used to find independent predictors of overall survival. RESULTS: In total, 849 consecutive patients between January 2005 and December 2015 were included. Patients with GPS 0 had a median survival of 70 months compared to 49 months in patients with GPS 1, and 27 months in patients with GPS 2. Multivariable analyses showed that GPS 1 (HR = 1.51, 95%CI [1.14-2.01]) and GPS 2 (HR = 2.78, 95%CI [1.79-4.31]), after correction for age >70 years (HR = 1.75 [1.36-2.26]), and extended resection (HR = 2.53, 95%CI[1.79-3.58]), were associated with poor overall survival. CONCLUSION: A preoperative GPS is an independent prognostic factor in patients with CRLM, and appears to be a better prognostic tool than mGPS.