Irreversible electroporation of localised prostate cancer downregulates immune suppression and induces systemic anti-tumour T-cell activation - IRE-IMMUNO study.

OBJECTIVES: To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa). PATIENTS AND METHODS: Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase (PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts. RESULTS: Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory T cells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) T cells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP. CONCLUSIONS: Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.

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.

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.

Recurrent Colorectal Liver Metastases: Upfront Local Treatment versus Neoadjuvant Systemic Therapy Followed by Local Treatment (COLLISION RELAPSE): Study Protocol of a Phase III Prospective Randomized Controlled Trial.

PURPOSE: The objective of the COLLISION RELAPSE trial is to prove or disprove superiority of neoadjuvant systemic therapy followed by repeat local treatment (either thermal ablation and/or surgical resection), compared to repeat local treatment alone, in patients with at least one recurrent locally treatable CRLM within one year and no extrahepatic disease. METHODS: A total of 360 patients will be included in this phase III, multicentre randomized controlled trial. The primary endpoint is overall survival. Secondary endpoints are distant progression-free survival, local tumour progression-free survival analysed per patient and per tumour, systemic therapy-related toxicity, procedural morbidity and mortality, length of hospital stay, pain assessment and quality of life, cost-effectiveness ratio and quality-adjusted life years. DISCUSSION: If the addition of neoadjuvant systemic therapy to repeat local treatment of CRLM proves to be superior compared to repeat local treatment alone, this may lead to a prolonged life expectancy and increased disease-free survival at the cost of possible systemic therapy-related side effects. LEVEL OF EVIDENCE: Level 1, phase III randomized controlled trial. TRIAL REGISTRATION: NCT05861505. May 17, 2023.

Consensus Guidelines of Irreversible Electroporation for Pancreatic Tumors: Protocol Standardization Using the Modified Delphi Technique.

Since no uniform treatment protocol for pancreatic irreversible electroporation (IRE) exists, the heterogeneity throughout literature complicates the comparison of results. To reach agreement among experts, a consensus study was performed. Eleven experts, recruited according to predefined criteria regarding previous IRE publications, participated anonymously in three rounds of questionnaires according to a modified Delphi technique. Consensus was defined as having reached ≥80% agreement. Response rates were 100, 64, and 64% in rounds 1 to 3, respectively; consensus was reached in 93%. Pancreatic IRE should be considered for stage III pancreatic cancer and inoperable recurrent disease after previous local treatment. Absolute contraindications are ventricular arrhythmias, implantable stimulation devices, congestive heart failure NYHA class 4, and severe ascites. The inter-electrode distance should be 10 to 20 mm and the exposure length should be 15 mm. After 10 test pulses, 90 treatment pulses of 1,500 V/cm should be delivered continuously, with a 90-µs pulse length. The first postprocedural contrast-enhanced computed tomography should take place 1 month post-IRE, and then every 3 months. This article provides expert recommendations regarding patient selection, procedure, and follow-up for IRE treatment in pancreatic malignancies through a modified Delphi consensus study. Future studies should define the maximum tumor diameter, response evaluation criteria, and the optimal number of preoperative FOLFIRINOX cycles.

Exploring the predictive potential of programmed death ligand 1 expression in healthy organs and lymph nodes as measured by 18F-BMS986-192 PET: pooled analysis of data from four solid tumor types.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using 18F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events. METHODS: Four 18F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV)mean, lymph node SUVmax) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted. RESULTS: Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUVmean 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUVmax 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUVmax 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity. CONCLUSION: PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer.

Local Treatment of Colorectal Liver Metastases in the Presence of Extrahepatic Disease: Survival Outcomes from the Amsterdam Colorectal Liver Met Registry (AmCORE).

BACKGROUND: The simultaneous presence of colorectal liver metastases (CRLMs) and extrahepatic metastases in patients with colorectal cancer (CRC) can be considered a relative contraindication for local treatment with curative intent. This study aims to assess the survival outcomes of patients with CRLMs and extrahepatic metastases after comprehensive local treatment of all metastatic sites. METHODS: Patients with CRLMs who received local treatment of all metastatic sites were extracted from the prospective AmCORE registry database and subdivided into two groups: CRLM only vs. CRLM and extrahepatic metastasis. To address potential confounders, multivariate analysis was performed. The primary endpoint was overall survival (OS). RESULTS: In total, 881 patients with CRLM only and 60 with CRLM and extrahepatic disease were included, and the median OS was 55.7 months vs. 42.7 months, respectively. Though OS was significantly lower in patients with concomitant extrahepatic metastases (HR 1.477; 95% CI 1.029-2.121; p = 0.033), the survival curve plateaued after 6.2 years. Extrahepatic manifestations were pulmonary (43.3%), peritoneal (16.7%) and non-regional lymph node metastases (10.0%). In patients with pulmonary and non-regional lymph node metastases, OS did not significantly differ from patients with CRLM-only disease; concomitant peritoneal metastases showed an inferior OS (HR 1.976; 95% CI 1.017-3.841, p = 0.041). CONCLUSIONS: In this comparative series, OS was inferior for patients with multi-organ metastatic CRC versus patients with CRLMs alone. Nonetheless, the long-term survival curve plateau seemed to justify local treatment in a subset of patients with multi-organ metastatic CRC, especially for patients with CRLMs and pulmonary or lymph node metastases.

The Added Value of Transcatheter CT Hepatic Angiography (CTHA) Image Guidance in Percutaneous Thermal Liver Ablation: An Experts' Opinion Pictorial Essay.

With the rapidly evolving field of image-guided tumor ablation, there is an increasing demand and need for tools to optimize treatment success. Known factors affecting the success of (non-)thermal liver ablation procedures are the ability to optimize tumor and surrounding critical structure visualization, ablation applicator targeting, and ablation zone confirmation. A recent study showed superior local tumor progression-free survival and local control outcomes when using transcatheter computed tomography hepatic angiography (CTHA) guidance in percutaneous liver ablation procedures. This pictorial review provides eight clinical cases from three institutions, MD Anderson (Houston, TX, USA), Gustave Roussy (Paris, France), and Amsterdam UMC (Amsterdam, The Netherlands), with the intent to demonstrate the added value of real-time CTHA guided tumor ablation for primary liver tumors and liver-only metastatic disease. The clinical illustrations highlight the ability to improve the detectability of the initial target liver tumor(s) and identify surrounding critical vascular structures, detect 'vanished' and/or additional tumors intraprocedurally, differentiate local tumor progression from non-enhancing scar tissue, and promptly detect and respond to iatrogenic hemorrhagic events. Although at the cost of adding a minor but safe intervention, CTHA-guided liver tumor ablation minimizes complications of the actual ablation procedure, reduces the number of repeat ablations, and improves the oncological outcome of patients with liver malignancies. Therefore, we recommend adopting CTHA as a potential quality-improving guiding method within the (inter)national standards of practice.

MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial.

BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal prognosis. Stage III locally advanced pancreatic cancer is considered unresectable and current palliative chemotherapy regimens only modestly improve survival. Guidelines suggest chemoradiation or stereotactic ablative body radiotherapy (SABR) could be beneficial in certain circumstances. Other local treatments such as irreversible electroporation could enhance patient outcomes by extending survival while preserving quality of life. We aimed to compare the efficacy and safety of MRI-guided SABR versus CT-guided percutaneous irreversible electroporation following standard FOLFIRINOX chemotherapy. METHODS: CROSSFIRE was an open-label, randomised phase 2 superiority trial conducted at the Amsterdam University Medical Centre (Amsterdam, Netherlands). Eligible patients were aged 18 years or older with confirmed histological and radiological stage III locally advanced pancreatic cancer. The maximum tumour diameter was 5 cm and patients had to be pretreated with three to eight cycles of FOLFIRINOX. Patients were randomly assigned (1:1) to MRI-guided SABR (five fractions of 8 Gy delivered on non-consecutive days) or CT-guided percutaneous irreversible electroporation using a computer-generated variable block randomisation model. The primary endpoint was overall survival from randomisation, assessed in the intention-to-treat population. Safety was assessed in the per-protocol population. A prespecified interim futility analysis was done after inclusion of half the original sample size, with a conditional probability of less than 0·2 resulting in halting of the study. The trial was registered at ClinicalTrials.gov, NCT02791503. FINDINGS: Between May 1, 2016, and March 31, 2022, 68 patients were enrolled and randomly assigned to SABR (n=34) or irreversible electroporation (n=34), of whom 64 were treated according to protocol. Of the 68 participants, 36 (53%) were male and 32 (47%) were female, with a median age of 65 years (IQR 57-70). Median overall survival from randomisation was 16·1 months (95% CI 12·1-19·4) in the SABR group versus 12·5 months (10·9-17·0) in the irreversible electroporation group (hazard ratio [HR] 1·39 [95% CI 0·84-2·30]; p=0·21). The conditional probability to demonstrate superiority of either technique was 0·13; patient accrual was therefore stopped early for futility. 20 (63%) of 32 patients in the SABR group versus 19 (59%) of 32 patients in the irreversible electroporation group had adverse events (p=0·8) and five (16%) patients in the SABR group versus eight (25%) in the irreversible electroporation group had grade 3-5 adverse events (p=0·35). The most common grade 3-4 adverse events were cholangitis (two [6%] in the SABR group vs one [3%] in the irreversible electroporation group), abdominal pain (one [3%] vs two [6%]), and pancreatitis (none vs two [6%]). One (3%) patient in the SABR group and one (3%) in the irreversible electroporation group died from a treatment-related adverse event. INTERPRETATION: CROSSFIRE did not identify a difference in overall survival or incidence of adverse events between MRI-guided SABR and CT-guided percutaneous irreversible electroporation after FOLFIRINOX. Future studies should further assess the added value of local ablative treatment over chemotherapy alone. FUNDING: Adessium Foundation, AngioDynamics.

Efficacy of Thermal Ablation for Small-Size (0-3 cm) versus Intermediate-Size (3-5 cm) Colorectal Liver Metastases: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE).

PURPOSE: Thermal ablation is widely recognized as the standard of care for small-size unresectable colorectal liver metastases (CRLM). For larger CRLM safety, local control and overall efficacy are not well established and insufficiently validated. The purpose of this comparative series was to analyze outcomes for intermediate-size versus small-size CRLM. MATERIAL AND METHODS: Patients treated with thermal ablation between December 2000 and November 2021 for small-size and intermediate-size CRLM were included. The primary endpoints were complication rate and local control (LC). Secondary endpoints included local tumor progression-free survival (LTPFS) and overall survival (OS). RESULTS: In total, 59 patients were included in the intermediate-size (3-5 cm) group and 221 in the small-size (0-3 cm) group. Complications were not significantly different between the two groups (p = 0.546). No significant difference between the groups was found in an overall comparison of OS (HR 1.339; 95% CI 0.824-2.176; p = 0.239). LTPFS (HR 3.388; p < 0.001) and LC (HR 3.744; p = 0.004) were superior in the small-size group. Nevertheless, the 1-, 3-, and 5-year LC for intermediate-size CRLM was still 93.9%, 85.4%, and 81.5%, and technical efficacy improved over time. CONCLUSIONS: Thermal ablation for intermediate-size unresectable CRLM is safe and induces long-term LC in the vast majority. The results of the COLLISION-XL trial (unresectable colorectal liver metastases: stereotactic body radiotherapy versus microwave ablation-a phase II randomized controlled trial for CRLM 3-5 cm) are required to provide further clarification of the role of local ablative methods for intermediate-size unresectable CRLM.

The Added Diagnostic Value of Transcatheter CT Hepatic Arteriography for Intraprocedural Detection of Previously Unknown Colorectal Liver Metastases During Percutaneous Ablation and Impact on the Definitive Treatment Plan.

PURPOSE: This study assessed the diagnostic value of CT hepatic arteriography (CTHA) for the intraprocedural detection of previously unknown colorectal liver metastases (CRLM) and the impact on the definitive treatment plan. MATERIALS AND METHODS: All patients treated with CTHA-guided percutaneous ablation for CRLM between January 2012 and March 2022 were identified from the Amsterdam Colorectal Liver Met Registry (AmCORE). Radiology reports of the ablative procedure and follow-up imaging were reviewed to see if (a) previously unknown CRLM were detected intra-procedurally and if (b) new CRLM, potentially missed on CTHA, appeared within 6 months following the procedure; three abdominal radiologists re-reviewed the baseline CTHA scans of these patients with early recurrence. To ratify immediate ablations of concomitantly detected CRLM, the upper limit of false positives was predefined at 10%. RESULTS: One hundred and fifty-two patients were included. With CTHA, a total of 17 additional tumours in 15 patients were diagnosed and treated immediately, two representing disappeared tumours following systemic chemotherapy. Compared to the conventional contrast-enhanced (ce)CT, ceMRI and 18F-FDG PET-CT, adding CTHA was superior for the detection of CRLM (P < .001). Within 12 months of follow-up 121, new CRLM appeared in 49/152 patients (32.2%); retrospective blinded assessment revealed 56 to already be visible on the baseline CTHA scan (46%); four lesions without substrate on follow-up scans were considered false positives (n = 4/60; 7%). Arterial ring enhancement was the most frequently reported imaging characteristic (n = 45/60; 75%). CONCLUSION: The subsequent use of CTHA has added value for the detection of previously unknown and vanished CRLM. Taking into account the low number of false positives (7%) and the favourable safety profile of percutaneous ablation, we believe that immediate ablation of typical ring-enhancing supplementary tumours is justified and sufficiently validated. LEVEL OF EVIDENCE: Level 3; individual cross-sectional study with consistently applied reference standard and blinding.

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.

[Irreversible electroporation: local tumor ablation with systemic immune effect]. / Irreversibele elektroporatie.

Irreversible electroporation (IRE) employs high-voltage electrical pulses for non-thermal image-guided tumor ablation in solid organs. The pulses disrupt the membrane potential of all cells within the ablation zone causing loss of tumour cell homeostasis resulting in death. IRE has the advantage of sparing extracellular matrix structures and thereby preserving the anatomical integrity of blood vessels, bile ducts, and ureters. This trait distinguishes IRE from more commonly used thermal ablation techniques like microwave- and radiofrequency ablation. Several prospective phase-1 and -2 studies demonstrated the safety and efficacy of IRE for the treatment of central liver, locally advanced pancreatic, and local prostate tumours. In addition, IRE induces a systemic immune response. When this immune effect can be amplified by combinatory treatment with immunotherapeutic drugs its synergy might form a bridge between local and systemic therapies with the potential to develop into a fundamentally new approach to cancer treatment.

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.

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.

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).

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.

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).

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.

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.