Unresectable Intermediate-Size (3-5 cm) Colorectal Liver Metastases: Stereotactic Ablative Body Radiotherapy Versus Microwave Ablation (COLLISION-XL): Protocol of a Phase II/III Multicentre Randomized Controlled Trial.

BACKGROUND: Although microwave ablation (MWA) has a low complication rate and good efficacy for small-size (≤ 3 cm) colorectal liver metastases (CRLM), local control decreases with increasing size. Stereotactic body radiotherapy (SBRT) is gaining interest as a potential means to treat intermediate-size CRLM and might be less susceptible to increasing volume. The objective of this study is to compare the efficacy of MWA to SBRT in patients with unresectable, intermediate-size (3-5 cm) CRLM. METHODS: In this two-arm, multicentre phase II/ III randomized controlled trial, 68 patients with 1-3 unresectable, intermediate-size CRLM suitable for both MWA and SBRT, will be included. Patients will be treated with MWA or SBRT as randomised. The Primary endpoint is local tumour progression-free survival (LTPFS) at 1 year (intention-to-treat analysis). Main secondary endpoints are overall survival, overall and distant progression-free survival (DPFS), local control (LC) and procedural morbidity and mortality and assessment of pain and quality of life. DISCUSSION: Current guidelines lack clear recommendations for the local treatment of liver only intermediate-size, unresectable CRLM and studies comparing curative intent SBRT and thermal ablation are scarce. Although safety and feasibility to eradicate tumours ≤ 5 cm have been established, both techniques suffer from lower LTPFS and LC rates for larger-size tumours. For the treatment of unresectable intermediate-size CRLM clinical equipoise has been reached. We have designed a two-armed phase II/ III randomized controlled trial directly comparing SBRT to MWA for unresectable CRLM 3-5 cm. LEVEL OF EVIDENCE: Level 1, phase II/ III Randomized controlled trial. TRIAL REGISTRATION: NCT04081168, September 9th 2019.

Tissue Resistance Decrease during Irreversible Electroporation of Pancreatic Cancer as a Biomarker for the Adaptive Immune Response and Survival.

PURPOSE: To correlate irreversible electroporation (IRE) procedural resistance changes with survival outcomes and the IRE-induced systemic immune response in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Data on IRE procedural tissue resistance (R) features and survival outcomes were collected from patients with LAPC treated within the context of 2 prospective clinical trials in a single tertiary center. Preprocedural and postprocedural peripheral blood samples were prospectively collected for immune monitoring. The change (ie, decrease) in R during the first 10 test pulses (ΔR10p) and during the total procedure (ΔRtotal) were calculated. Patients were divided in 2 groups on the basis of the median change in R (large ΔR vs small ΔR) and compared for differences in overall survival (OS) and progression-free survival and immune cell subsets. RESULTS: A total of 54 patients were included; of these, 20 underwent immune monitoring. Linear regression modeling showed that the first 10 test pulses reflected the change in tissue resistance during the total procedure appropriately (P < .001; R2 = 0.91). A large change in tissue resistance significantly correlated with a better OS (P = .026) and longer time to disease progression (P = .045). Furthermore, a large change in tissue resistance was associated with CD8+ T cell activation through significant upregulation of Ki-67+ (P = .02) and PD-1+ (P = .047). Additionally, this subgroup demonstrated significantly increased expression of CD80 on conventional dendritic cells (cDC1; P = .027) and PD-L1 on immunosuppressive myeloid-derived suppressor cells (P = .039). CONCLUSIONS: IRE procedural resistance changes may serve as a biomarker for survival and IRE-induced systemic CD8+ T cell and cDC1 activation.

Improved Outcomes of Thermal Ablation for Colorectal Liver Metastases: A 10-Year Analysis from the Prospective Amsterdam CORE Registry (AmCORE).

BACKGROUND: To analyze long-term oncological outcomes of open and percutaneous thermal ablation in the treatment of patients with colorectal liver metastases (CRLM). METHODS: This assessment from a prospective, longitudinal tumor registry included 329 patients who underwent 541 procedures for 1350 CRLM from January 2010 to February 2021. Three cohorts were formed: 2010-2013 (129 procedures [53 percutaneous]), 2014-2017 (206 procedures [121 percutaneous]) and 2018-2021 (206 procedures [135 percutaneous]). Local tumor progression-free survival (LTPFS) and overall survival (OS) data were estimated using the Kaplan-Meier method. Potential confounding factors were analyzed with uni- and multivariable Cox regression analyses. RESULTS: LTPFS improved significantly over time for percutaneous ablations (2-year LTPFS 37.7% vs. 69.0% vs. 86.3%, respectively, P < .0001), while LTPFS for open ablations remained reasonably stable (2-year LTPFS 87.1% [2010-2013], vs. 92.7% [2014-2017] vs. 90.2% [2018-2021], P = .12). In the latter cohort (2018-2021), the open approach was no longer superior regarding LTPFS (P = .125). No differences between the three cohorts were found regarding OS (P = .088), length of hospital stay (open approach, P = .065; percutaneous approach, P = .054), and rate and severity of complications (P = .404). The rate and severity of complications favored the percutaneous approach in all three cohorts (P = .002). CONCLUSION: Over the last 10 years efficacy of percutaneous ablations has improved remarkably for the treatment of CRLM. Oncological outcomes seem to have reached results following open ablation. Given its minimal invasive character and shorter length of hospital stay, whenever feasible, percutaneous procedures may be favored over an open approach.

Microwave Ablation, Radiofrequency Ablation, Irreversible Electroporation, and Stereotactic Ablative Body Radiotherapy for Intermediate Size (3-5 cm) Unresectable Colorectal Liver Metastases: a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Based on good local control rates and an excellent safety profile, guidelines consider thermal ablation the gold standard to eliminate small unresectable colorectal liver metastases (CRLM). However, efficacy decreases exponentially with increasing tumour size. The preferred treatment for intermediate-size unresectable CRLM remains uncertain. This systematic review and meta-analysis compare safety and efficacy of local ablative treatments for unresectable intermediate-size CRLM (3-5 cm). RECENT FINDINGS: We systematically searched for publications reporting treatment outcomes of unresectable intermediate-size CRLM treated with thermal ablation, irreversible electroporation (IRE) or stereotactic ablative body-radiotherapy (SABR). No comparative studies or randomized trials were found. Literature to assess effectiveness was limited and there was substantial heterogeneity in outcomes and study populations. Per-patient local control ranged 22-90% for all techniques; 22-89% (8 series) for thermal ablation, 44% (1 series) for IRE, and 67-90% (1 series) for SABR depending on radiation dose. Focal ablative therapy is safe and can induce long-term disease control, even for intermediate-size CRLM. Although SABR and tumuor-bracketing techniques such as IRE are suggested to be less susceptible to size, evidence to support any claims of superiority of one technique over the other is unsubstantiated by the available evidence. Future prospective comparative studies should address local-tumour-progression-free-survival, local control rate, overall survival, adverse events, and quality-of-life.

Repeat Local Treatment of Recurrent Colorectal Liver Metastases, the Role of Neoadjuvant Chemotherapy: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study.

This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective Amsterdam Colorectal Liver Met Registry (AmCORE) met the inclusion criteria. Two cohorts of patients with recurrent CRLM were compared: patients who received chemotherapy prior to repeat local treatment (32 patients) versus upfront repeat local treatment (120 patients). Data from May 2002 to December 2020 were collected. Results on the primary endpoint overall survival (OS) and secondary endpoints local tumor progression-free survival (LTPFS) and distant progression-free survival (DPFS) were reviewed using the Kaplan-Meier method. Subsequently, uni- and multivariable Cox proportional hazard regression models, accounting for potential confounders, were estimated. Additionally, subgroup analyses, according to patient, initial and repeat local treatment characteristics, were conducted. Procedure-related complications and length of hospital stay were compared using chi-square test and Fisher's exact test. The 1-, 3-, and 5-year OS from date of diagnosis of recurrent disease was 98.6%, 72.5%, and 47.7% for both cohorts combined. The crude survival analysis did not reveal a significant difference in OS between the two cohorts (p = 0.834), with 1-, 3-, and 5-year OS of 100.0%, 73.2%, and 57.5% for the NAC group and 98.2%, 72.3%, and 45.3% for the upfront repeat local treatment group, respectively. After adjusting for two confounders, comorbidities (p = 0.010) and primary tumor location (p = 0.023), the corrected HR in multivariable analysis was 0.839 (95% CI, 0.416-1.691; p = 0.624). No differences between the two cohorts were found with regards to LTPFS (HR = 0.662; 95% CI, 0.249-1.756; p = 0.407) and DPFS (HR = 0.798; 95% CI, 0.483-1.318; p = 0.378). No heterogeneous treatment effects were detected in subgroup analyses according to patient, disease, and treatment characteristics. No significant difference was found in periprocedural complications (p = 0.843) and median length of hospital stay (p = 0.600) between the two cohorts. Chemotherapy-related toxicity was reported in 46.7% of patients. Adding NAC prior to repeat local treatment did not improve OS, LTPFS, or DPFS, nor did it affect periprocedural morbidity or length of hospital stay. The results of this comparative assessment do not substantiate the routine use of NAC prior to repeat local treatment of CRLM. Because the exact role of NAC (in different subgroups) remains inconclusive, we are currently designing a phase III randomized controlled trial (RCT), COLLISION RELAPSE trial, directly comparing upfront repeat local treatment (control) to neoadjuvant systemic therapy followed by repeat local treatment (intervention).

Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.

Thermal ablation and stereotactic ablative radiotherapy (SABR) are techniques to eradicate colorectal liver metastases (CRLM). This study compares the safety, efficacy and long-term oncological outcomes of these treatment methods. All prospectively registered patients (AmCORE registry) treated with thermal ablation or SABR alone for unresectable CRLM between 2007 and 2020 were analyzed using multivariate Cox-proportional hazard regression. In total 199 patients were included for analysis: 144 (400 CRLM) thermal ablation; 55 (69 CRLM) SABR. SABR patients were characterized by older age (p = 0.006), extrahepatic disease at diagnosis (p = 0.004) and larger tumors (p < 0.001). Thermal ablation patients were more likely to have synchronous disease, higher clinical risk scores (p = 0.030) and higher numbers of CRLMs treated (p < 0.001). Mortality was zero and morbidity low in both groups: no serious adverse events were recorded following SABR (n = 0/55) and nine (n = 9/144 [6.3%]; all CTCAE grade 3) after thermal ablation. SABR was associated with an inferior overall survival (OS) (median OS 53.0 months vs. 27.4 months; HR = 1.29, 95% CI 1.12-1.49; p = 0.003), local tumor progression-free survival (LTPFS) per-tumor (HR = 1.24, 95% CI 1.01-1.52; p = 0.044) and local control per-patient (HR = 1.57, 95% CI 1.20-2.04; p = 0.001) and per-tumor (HR = 1.89, 95% CI 1.44-2.49; p < 0.001). In this study thermal ablation was superior to SABR with regard to OS, LTPFS and local control, albeit at the cost of a limited risk of serious adverse events. Further studies are required to assess whether the worse outcomes following SABR were the effect of true differences in ablative treatment or a result of residual confounding.

Pancreatic Cancer and Immunotherapy: A Clinical Overview.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE).

The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study included 520 patients, 774 procedures, and 2101 tumors undergoing local treatment (resection and/or thermal ablation) from 2000 to 2021. Outcomes following local treatment were analyzed for primary tumor sidedness of CRC, RAS, and BRAF mutations and MSI status. The Kaplan-Meier method was used to estimate local tumor progression-free survival (LTPFS), local control (LC), distant progression-free survival (DPFS), and overall survival (OS). Uni- and multivariable analyses were performed based on Cox proportional hazards model. The chi-square test was used to analyze complications. Complications (p = 0.485), OS (p = 0.252), LTPFS (p = 0.939), and LC (p = 0.423) was not associated with tumor-sidedness. Compared to right-sided colon cancer (CC) (reference HR 1.000), DPFS was superior for left-sided CC and rectal cancer (p = 0.018) with an HR for left-sided CC of 0.742 (95% CI, 0.596-0.923) and for RC of 0.760 (95% CI, 0.597-0.966). Regarding RAS mutations, no significant difference was found in OS (p = 0.116). DPFS (p = 0.001), LTPFS (p = 0.039), and LC (p = 0.025) were significantly lower in the RAS mutation group. Though no difference in LTPFS was found between RAS wildtype and RAS mutated CRLM following resection (p = 0.532), LTPFS was worse for RAS mutated tumors compared to RAS wildtype following thermal ablation (p = 0.037). OS was significantly lower in the BRAF mutation group (p < 0.001) and in the MSI group (p < 0.001) following local treatment, while both did not affect DPFS, LTPFS, and LC. This AmCORE based study suggests the necessity of wider margins to reduce LTP rates in patients with RAS mutated CRLM, especially for thermal ablation. Upfront knowledge regarding molecular biomarkers may contribute to improved oncological outcomes.

Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol.

Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor's immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC's dismal prognosis.

Thermal Ablation Compared to Partial Hepatectomy for Recurrent Colorectal Liver Metastases: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study.

The aim of this study was to assess safety, efficacy and survival outcomes of repeat thermal ablation as compared to repeat partial hepatectomy in patients with recurrent colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study of two cohorts, repeat thermal ablation versus repeat partial hepatectomy, analyzed 136 patients (100 thermal ablation, 36 partial hepatectomy) and 224 tumors (170 thermal ablation, 54 partial hepatectomy) with recurrent CRLM from May 2002 to December 2020. The primary and secondary endpoints were overall survival (OS), distant progression-free survival (DPFS) and local tumor progression-free survival (LTPFS), estimated using the Kaplan-Meier method, and complications, analyzed using the chi-square test. Multivariable analyses based on Cox proportional hazards model were used to account for potential confounders. In addition, subgroup analyses according to patient, initial and repeat local treatment characteristics were performed. In the crude overall comparison, OS of patients treated with repeat partial hepatectomy was not statistically different from repeat thermal ablation (p = 0.927). Further quantification of OS, after accounting for potential confounders, demonstrated concordant results for repeat local treatment (hazard ratio (HR), 0.986; 95% confidence interval (CI), 0.517-1.881; p = 0.966). The 1-, 3- and 5-year OS were 98.9%, 62.6% and 42.3% respectively for the thermal ablation group and 93.8%, 74.5% and 49.3% for the repeat resection group. No differences in DPFS (p = 0.942), LTPFS (p = 0.397) and complication rate (p = 0.063) were found. Mean length of hospital stay was 2.1 days in the repeat thermal ablation group and 4.8 days in the repeat partial hepatectomy group (p = 0.009). Subgroup analyses identified no heterogeneous treatment effects according to patient, initial and repeat local treatment characteristics. Repeat partial hepatectomy was not statistically different from repeat thermal ablation with regard to OS, DPFS, LTPFS and complications, whereas length of hospital stay favored repeat thermal ablation. Thermal ablation should be considered a valid and potentially less invasive alternative for small-size (0-3 cm) CRLM in the treatment of recurrent new CRLM. While, the eagerly awaited results of the phase III prospective randomized controlled COLLISION trial (NCT03088150) should provide definitive answers regarding surgery versus thermal ablation for CRLM.

Locoregional Treatment of Metastatic Pancreatic Cancer Utilizing Resection, Ablation and Embolization: A Systematic Review.

The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains universally poor, requiring new and innovative treatment approaches. In a subset of oligometastatic PDAC patients, locoregional therapy, in addition to systemic chemotherapy, may improve survival. The aim of this systematic review was to explore and evaluate the current evidence on locoregional treatments for mPDAC. A systematic literature search was conducted on locoregional techniques, including resection, ablation and embolization, for mPDAC with a focus on hepatic and pulmonary metastases. A total of 59 studies were identified, including 63,453 patients. Although subject to significant bias, radical-intent local therapy for both the primary and metastatic sites was associated with a superior median overall survival from metastatic diagnosis or treatment (hepatic mPDAC 7.8-19 months; pulmonary mPDAC 22.8-47 months) compared to control groups receiving chemotherapy or best supportive care (hepatic mPDAC 4.3-7.6 months; pulmonary mPDAC 11.8 months). To recruit patients that may benefit from these local treatments, selection appears essential. Most significant is the upfront possibility of local radical pancreatic and metastatic treatment. In addition, a patient's response to neoadjuvant systemic chemotherapy, performance status, metastatic disease load and, to a lesser degree, histological differentiation grade and tumor marker CA19-9 serum levels, are powerful prognostic factors that help identify eligible subjects. Although the exact additive value of locoregional treatments for mPDAC patients cannot be distillated from the results, locoregional primary pancreatic and metastatic treatment seems beneficial for a highly selected group of oligometastatic PDAC patients. For definite recommendations, well-designed prospective randomized controlled trials with strict in- and exclusion criteria are needed to validate these results.

Locally Advanced Pancreatic Cancer: Percutaneous Management Using Ablation, Brachytherapy, Intra-arterial Chemotherapy, and Intra-tumoral Immunotherapy.

PURPOSE OF REVIEW: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasms, bearing a terrible prognosis. Stage III tumors, also known as locally advanced pancreatic cancer (LAPC), are unresectable, and current palliative chemotherapy regimens have only modestly improved survival in these patients. At this stage of disease, interventional techniques may be of value and further prolong life. The aim of this review was to explore current literature on locoregional percutaneous management for LAPC. RECENT FINDINGS: Locoregional percutaneous interventional techniques such as ablation, brachytherapy, and intra-arterial chemotherapy possess cytoreductive abilities and have the potential to increase survival. In addition, recent research demonstrates the immunomodulatory capacities of these treatments. This immune response may be leveraged by combining the interventional techniques with intra-tumoral immunotherapy, possibly creating a durable anti-tumor effect. This multimodality treatment approach is currently being examined in several ongoing clinical trials. The use of certain interventional techniques appears to improve survival in LAPC patients and may work synergistically when combined with immunotherapy. However, definitive conclusions can only be made when large prospective (randomized controlled) trials confirm these results.

Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase II, Two-Center, Single-Arm Clinical Trial.

Background Irreversible electroporation (IRE), an ablative technique that uses high-voltage electrical pulses, has shown promise for eradicating tumors near critical structures, including blood vessels and bile ducts. Purpose To investigate the efficacy and safety of IRE for colorectal liver metastases (CRLMs) unsuitable for resection or thermal ablation because of proximity to critical structures and for further systemically administered treatments. Materials and Methods Between June 2014 and November 2018, participants with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid CRLMs measuring 5.0 cm or smaller, unsuitable for partial hepatectomy and thermal ablation, underwent percutaneous or open IRE (ClinicalTrials.gov identifier: NCT02082782). Follow-up included tumor marker assessment and 18F-FDG PET/CT imaging. For the primary end point to be met, at least 50% of treated participants had to be alive without local tumor progression (LTP) at 12 months, defined as LTP-free survival. Secondary aims were safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival. Results A total of 51 participants (median age, 67 years [interquartile range, 62-75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 CRLMs (median tumor size, 2.2 cm; range, 0.5-5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median overall survival from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 adverse event). Conclusion Irreversible electroporation was effective and relatively safe for colorectal liver metastases 5.0 cm or smaller that were unsuitable for partial hepatectomy, thermal ablation, or further systemic treatment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.

The Role of Neoadjuvant Chemotherapy in Repeat Local Treatment of Recurrent Colorectal Liver Metastases: A Systematic Review and Meta-Analysis.

The additive value of neoadjuvant chemotherapy (NAC) prior to repeat local treatment of patients with recurrent colorectal liver metastases (CRLM) is unclear. A systematic search was performed in PubMed, Embase, Web of Science, and an additional search in Google Scholar to find articles comparing repeat local treatment by partial hepatectomy and/or thermal ablation with versus without NAC. The search included randomized trials and comparative observational studies with univariate/multivariate analysis and/or matching as well as (inter)national guidelines assessed using the AGREE II instrument. The search identified 21,832 records; 172 were selected for full-text review; 20 were included: 20 comparative observational studies were evaluated. Literature to evaluate the additive value of NAC prior to repeat local treatment was limited. Outcomes of NAC were often reported as subgroup analyses and reporting of results was frequently unclear. Assessment of the seven studies that qualified for inclusion in the meta-analysis showed conflicting results. Only one study reported a significant difference in overall survival (OS) favoring NAC prior to repeat local treatment. However, further analysis revealed a high risk for residual bias, because only a selected group of chemo-responders qualified for repeat local treatment, disregarding the non-responders who did not qualify. All guidelines that specifically mention recurrent disease (3/3) recommend repeat local treatment; none provide recommendations about the role of NAC. The inconclusive findings of this meta-analysis do not support recommendations to routinely favor NAC prior to repeat local treatment. This emphasizes the need to investigate the additive value of NAC prior to repeat local treatment of patients with recurrent CRLM in a future phase 3 randomized controlled trial (RCT).

Hospital variation in combined liver resection and thermal ablation for colorectal liver metastases and impact on short-term postoperative outcomes: a nationwide population-based study.

BACKGROUND: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation. METHODS: In this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery. RESULTS: Of 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy. CONCLUSION: Significant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy.

Transcatheter CT Hepatic Arteriography Compared with Conventional CT Fluoroscopy Guidance in Percutaneous Thermal Ablation to Treat Colorectal Liver Metastases: A Single-Center Comparative Analysis of 2 Historical Cohorts.

PURPOSE: To evaluate safety and efficacy of CT hepatic arteriography compared with conventional CT fluoroscopy guidance in percutaneous radiofrequency (RF) and microwave (MW) ablation to treat colorectal liver metastases (CRLM). MATERIALS AND METHODS: This single-center comparative, retrospective study analyzed data of 108 patients treated with 156 percutaneous ablation procedures (42 CT fluoroscopy guidance [25 RF ablation, 17 MW ablation]; 114 CT hepatic arteriography guidance [18 RF ablation, 96 MW ablation]) for 260 CRLM between January 2009 and May 2019. Local tumor progression-free survival (LTPFS) was assessed using univariate and multivariate Cox proportional hazard regression analyses. LTPFS and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: There were no complications related to the transarterial catheter procedure. CT hepatic arteriography proved superior to CT fluoroscopy regarding 2-year LTPFS (18/202 [8.9%] vs 19/58 [32.8%]; P < .001, respectively). CT hepatic arteriography versus CT fluoroscopy (hazard ratio = 0.28; 95% confidence interval, 0.15-0.54; P < .001) and MW ablation versus RF ablation (hazard ratio = 0.52; 95% confidence interval, 0.24-1.12; P = .094) were positive predictors for longer LTPFS. Multivariate analysis revealed that CT hepatic arteriography versus CT fluoroscopy (hazard ratio = 0.41; 95% confidence interval, 0.19-0.90; P = .025) was associated with a significantly superior LTPFS. OS was similar between the 2 cohorts (P = .3). CONCLUSIONS: While adding procedure time and marginal patient burden, transcatheter CT hepatic arteriography-guided ablation was associated with increased local disease control and superior LTPFS compared with conventional CT fluoroscopy. CT hepatic arteriography represents a safe and valid alternative to CT fluoroscopy, as it reduces the number of repeat ablations required without adding risk or detrimental effect on survival.

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.

Irreversible Electroporation for Locally Advanced Pancreatic Cancer.

Several minimally invasive image guided tumor ablation techniques have been added to the treatment spectrum for locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) might have a significant additive value in the management of this difficult-to-treat disease. As opposed to thermal ablative techniques, IRE induces cell death by the delivery of high-voltage electrical pulses. The electrical energy disrupts the cellular membrane integrity, causes loss of cellular homeostasis and ultimately results in cell death. The extracellular matrix of connective tissue in surrounding delicate structures such as bile ducts, bowel wall, and larger blood vessels is spared. The preservation of these structures makes IRE attractive for the treatment of pancreatic cancers that are unresectable due to their anatomical location (ie, LAPC and local recurrence after surgical resection). In addition to its cytoreductive abilities, evidence is emerging on IRE's capability to induce systemic immunomodulation through active in vivo vaccination against pancreatic cancer cells. These effects in combination with immunotherapy may offer a new treatment paradigm for tumors with low immunogenic potential like pancreatic ductal adenocarcinoma (PDAC). This review discusses several practical and technical issues of IRE for LAPC: clinical evaluation, indications, patient preparations, procedural steps, imaging characteristics, clinical results, and "tricks of the trade" used to improve the safety and efficacy of the treatment. Future directions such as the combination of IRE with immunotherapy will be shortly addressed.

High-Voltage Electrical Pulses in Oncology: Irreversible Electroporation, Electrochemotherapy, Gene Electrotransfer, Electrofusion, and Electroimmunotherapy.

This review summarizes the use of high-voltage electrical pulses (HVEPs) in clinical oncology to treat solid tumors with irreversible electroporation (IRE) and electrochemotherapy (ECT). HVEPs increase the membrane permeability of cells, a phenomenon known as electroporation. Unlike alternative ablative therapies, electroporation does not affect the structural integrity of surrounding tissue, thereby enabling tumors in the vicinity of vital structures to be treated. IRE uses HVEPs to cause cell death by inducing membrane disruption, and it is primarily used as a radical ablative therapy in the treatment of soft-tissue tumors in the liver, kidney, prostate, and pancreas. ECT uses HVEPs to transiently increase membrane permeability, enhancing cellular cytotoxic drug uptake in tumors. IRE and ECT show immunogenic effects that could be augmented when combined with immunomodulatory drugs, a combination therapy the authors term electroimmunotherapy. Additional electroporation-based technologies that may reach clinical importance, such as gene electrotransfer, electrofusion, and electroimmunotherapy, are concisely reviewed. HVEPs represent a substantial advancement in cancer research, and continued improvement and implementation of these presented technologies will require close collaboration between engineers, interventional radiologists, medical oncologists, and immuno-oncologists.

Percutaneous Irreversible Electroporation in Locally Advanced and Recurrent Pancreatic Cancer (PANFIRE-2): A Multicenter, Prospective, Single-Arm, Phase II Study.

Background Patients with locally advanced pancreatic cancer have a dismal prognosis, with a median overall survival (OS) of 12-14 months with systemic therapies. Irreversible electroporation (IRE), a nonthermal ablative technique, may prolong survival of patients with locally advanced pancreatic cancer. Purpose To investigate the safety and efficacy of percutaneous IRE for locally advanced pancreatic cancer and locally recurring pancreatic cancer in a prospective phase II trial. Materials and Methods Between December 2012 and September 2017, participants with locally advanced pancreatic cancer or postresection local recurrence were prospectively treated with percutaneous CT-guided IRE (ClinicalTrials.gov identifier: NCT01939665). The primary end point was median OS from diagnosis. The target median OS was 11.6 months for participants receiving no induction chemotherapy or gemcitabine-based induction chemotherapy and 14.9 months for those receiving induction 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Results Fifty participants (25 men and 25 women; median age, 61 years [interquartile range, 56-69 years]; 40 with locally advanced pancreatic cancer and 10 with local recurrence) were included. Median OS measured by using the Kaplan-Meier method was 17 months from diagnosis of locally advanced pancreatic cancer (95% confidence interval [CI]: 15 months, 19 months) and 10 months from IRE (95% CI: 8 months, 11 months). In the locally advanced pancreatic cancer group, 18 participants received no therapy or gemcitabine-based induction chemotherapy and 22 received FOLFIRINOX. The median OS from diagnosis was 17 months for both groups (95% CI: 7 months, 28 months and 15 months, 18 months, respectively; P = .26). For participants with postresection local recurrence, the median OS was 16 months from diagnosis of recurrence (95% CI: 11 months, 22 months) and 9 months from IRE (95% CI: 2 months, 16 months). After IRE, local recurrence developed in 23 of the 50 participants (46%). Tumor volume of 37 cm3 or greater (hazard ratio [HR], 2.9; P = .02), pre-IRE carbohydrate antigen 19-9 (CA 19-9) level of 2000 U/mL or greater (HR, 12.1; P = .001), and decrease in CA 19-9 level of 50% or less 3 months after IRE (HR, 3.1; P = .01) were predictors of worse survival. Fourteen minor and 21 major complications occurred in 29 of the 50 participants (58%). Two participants died less than 90 days after IRE; one of these deaths was likely related to IRE. Conclusion The target median overall survival with CT-guided percutaneous irreversible electroporation was exceeded in participants with locally advanced pancreatic cancer (17 months) and those with local recurrence (16 months). © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.