Radiofrequency and Microwave Ablation Compared to Systemic Chemotherapy and to Partial Hepatectomy in the Treatment of Colorectal Liver Metastases:A Systematic Review and Meta-Analysis

To assess safety and outcome of radiofrequency ablation (RFA) and microwave ablation (MWA) as compared to systemic chemotherapy and partial hepatectomy (PH) in the treatment of colorectal liver metastases (CRLM). MEDLINE, Embase and the Cochrane Library were searched. Randomized trials and comparative observational studies with multivariate analysis and/or matching were included. Guidelines from National Guideline Clearinghouse and Guidelines International Network were assessed using the AGREE II instrument. The search revealed 3530 records; 328 were selected for full-text review; 48 were included: 8 systematic reviews, 2 randomized studies, 26 comparative observational studies, 2 guideline-articles and 10 case series; in addition 13 guidelines were evaluated. Literature to assess the effectiveness of ablation was limited. RFA + systemic chemotherapy was superior to chemotherapy alone. PH was superior to RFA alone but not to RFA + PH or to MWA. Compared to PH, RFA showed fewer complications, MWA did not. Outcomes were subject to residual confounding since ablation was only employed for unresectable disease. The results from the EORTC-CLOCC trial, the comparable survival for ablation + PH versus PH alone, the potential to induce long-term disease control and the low complication rate argue in favour of ablation over chemotherapy alone. Further randomized comparisons of ablation to current-day chemotherapy alone should therefore be considered unethical. Hence, the highest achievable level of evidence for unresectable CRLM seems reached. The apparent selection bias from previous studies and the superior safety profile mandate the setup of randomized controlled trials comparing ablation to surgery

Study Protocol PROMETHEUS:Prospective Multicenter Study to Evaluate the Correlation Between Safety Margin and Local Recurrence After Thermal Ablation Using Image Co-registration in Patients with Hepatocellular Carcinoma

Purpose: The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions < 5 cm each) are eligible. Patients will undergo dual-phase contrast-enhanced computed tomography directly before and after ablation. Ablation margins will be quantitatively assessed using co-registration software, blinding assessors (i.e. two experienced radiologists) for outcome. Presence and location of recurrence are evaluated independently on follow-up scans by two other experienced radiologists, blinded for the quantitative margin analysis. A sample size of 189 tumors (~ 145 patients) is required to show with 80% power that the risk of local recurrence is confidently below 10%. A two-sided binomial z-test will be used to test the null hypothesis that the local recurrence rate is ≥ 10% for patients with a minimal ablation margin ≥ 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan–Meier estimates are used to assess local and overall recurrence, disease-free and overall survival. Discussion: It is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success. Trial registration The Netherlands Trial Register (NL9713), https://www.trialregister.nl/trial/9713

Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer:A multicenter prospective cohort

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC. Materials and methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy. Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34). Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd

Trends and overall survival after combined liver resection and thermal ablation of colorectal liver metastases:a nationwide population-based propensity score-matched study

Background: In colorectal liver metastases (CRLM) patients, combination of liver resection and ablation permit a more parenchymal-sparing approach. This study assessed trends in use of combined resection and ablation, outcomes, and overall survival (OS). Methods: This population-based study included all CRLM patients who underwent liver resection between 2014 and 2022. To assess OS, data was linked to two databases containing date of death for patients treated between 2014 and 2018. Hospital variation in the use of combined minor liver resection and ablation versus major liver resection alone in patients with 2–3 CRLM and ≤3 cm was assessed. Propensity score matching (PSM) was applied to evaluate outcomes. Results: This study included 3593 patients, of whom 1336 (37.2%) underwent combined resection and ablation. Combined resection increased from 31.7% in 2014 to 47.9% in 2022. Significant hospital variation (range 5.9–53.8%) was observed in the use of combined minor liver resection and ablation. PSM resulted in 1005 patients in each group. Major morbidity was not different (11.6% vs. 5%, P = 1.00). Liver failure occurred less often after combined resection and ablation (1.9% vs. 0.6%, P = 0.017). Five-year OS rates were not different (39.3% vs. 33.9%, P = 0.145). Conclusion: Combined resection and ablation should be available and considered as an alternative to resection alone in any patient with multiple metastases.</p

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

Locally advanced pancreatic cancer: Work-up, staging, and local intervention strategies

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel (gem-nab) has had major implications for the management and outcome of patients with LAPC. After 4–6 months induction chemotherapy, the majority of patients have stable disease or even tumor-regression. Of these, 12 to 35% are successfully downstaged to resectable disease. Several studies have reported a 30–35 months overall survival after resection; although it currently remains unclear if this is a result of the resection or the good response to chemotherapy. Following chemotherapy, selection of patients for resection is difficult, as contrast-enhanced computed-tomography (CT) scan is unreliable in differentiating between viable tumor and fibrosis. In case a resection is not considered possible but stable disease is observed, local ablative techniques are being studied, such as irreversible electroporation, radiofrequency ablation, and stereotactic body radiation therapy. Pragmatic, multicenter, randomized studies will ultimately have to confirm the exact role of both surgical exploration and ablation in these patients. Since evidence-based guidelines for the management of LAPC are lacking, this review proposes a standardized approach for the treatment of LAPC based on the best available evidence

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017