Local Ablative Therapy Research Articles

The efficacy of treatment for hepatocellular carcinoma in elderly patients.

Despite the increasing proportion of elderly patients with hepatocellular carcinoma (HCC) over time, treatment efficacy in this population is not well established. Data collected from the Korean Primary Liver Cancer Registry, a representative cohort of patients newly diagnosed with HCC in Korea between 2008 and 2017, were analyzed. Overall survival (OS) according to tumor stage and treatment modality was compared between elderly and non-elderly patients with HCC. Among 15,186 study patients, 5,829 (38.4%) were elderly. A larger proportion of elderly patients did not receive any treatment for HCC than non-elderly patients (25.2% vs. 16.7%). However, OS was significantly better in elderly patients who received treatment compared to those who did not (median, 38.6 vs. 22.3 months; P<0.001). In early-stage HCC, surgery yielded significantly lower OS in elderly patients compared to non-elderly patients (median, 97.4 vs. 138.0 months; P<0.001), however, local ablation (median, 82.2 vs. 105.5 months) and transarterial therapy (median, 42.6 vs. 56.9 months) each provided comparable OS between the two groups after inverse probability of treatment weighting (IPTW) analysis (all P>0.05). After IPTW, in intermediate-stage HCC, surgery (median, 66.0 vs. 90.3 months) and transarterial therapy (median, 36.5 vs. 37.2 months), and in advanced-stage HCC, transarterial (median, 25.3 vs. 26.3 months) and systemic therapy (median, 25.3 vs. 26.3 months) yielded comparable OS between the elderly and non-elderly HCC patients (all P>0.05). Personalized treatments tailored to individual patients can improve the prognosis of elderly patients with HCC to a level comparable to that of non-elderly patients.

Survival Evidence of Local Control for Colorectal Cancer Liver Metastases by Hepatectomy and/or Radiofrequency Ablation.

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) therapy in CRLM patients from a large multi-institutional database. A total of 20,251 patients with colorectal cancer, 4521 of whom were with CRLM, were screened for eligibility. Finally, 2612 patients (637 hepatectomy, 93 RFA, 92 combined hepatectomy and RFA, and 1790 non-aggressive treatment) were enrolled. Frequency matching analysis was used to adjust for baseline differences. The 5-year overall survival (OS) was as follows: hepatectomy alone was 47.8%, combined hepatectomy plus RFA was 35.9%, RFA alone was 29.2%, and the non-aggressive treatment group was 7.4%. Kaplan-Meier curves showed that hepatectomy, RFA, and combination were significantly associated with a better OS compared to those without aggressive local therapy (p < 0.001). Multivariate Cox regression analysis showed that male gender (hazard ratio (HR) 0.89; 95% confidence interval (CI), 0.81-0.97; p = 0.011), old age (≥60 years) (HR 1.20; 95% CI, 1.09-1.32; p < 0.001), high CEA level (>5 ng/mL) (HR 2.14; 95% CI, 1.89-2.42; p < 0.001), primary right-sided cancer (HR 1.35; 95% CI, 1.22-1.51; p < 0.001), extrahepatic metastasis (HR 1.46; 95% CI, 1.33-1.60; p < 0.001), systemic therapy (HR 0.7; 95% CI, 0.62-0.79; p < 0.001), and aggressive local therapy (hepatectomy vs. non-local therapy HR 0.22; 95% CI, 0.20-0.26; p < 0.001; RFA vs. non-local therapy HR 0.29; 95% CI, 0.29-0.41; p < 0.001) were independent factors associated with OS. In the frequency matching analysis, patients receiving hepatectomy and/or RFA resulted in a better OS than those without (p < 0.001). In conclusion, aggressive local treatment provides survival advantages over systemic therapy alone among CRLM patients.

Survival after combined resection and ablation is not inferior to that after resection alone, in patients with four or more colorectal liver metastases

PurposeColorectal liver metastases (CRLM) are the predominant factor limiting survival in patients with colorectal cancer. Multimodal treatment strategies are frequently necessary to achieve total tumor elimination. This study examines the efficacy of liver resection combined with local ablative therapy in comparison to liver resection only, in the treatment of patients with ≥ 4 CRLM.MethodsThis retrospective cohort study was conducted at the University Hospital RWTH Aachen, Germany. Patients with ≥ 4 CRLM in preoperative imaging, who underwent curative resection between 2010–2021, were included. Recurrent resections and deaths in the early postoperative phase were excluded. Ablation modalities included radiofrequency or microwave ablation, and irreversible electroporation. Differences in overall- (OS) and recurrence-free-survival (RFS) between patients undergoing combined resection-ablation vs. resection only, were examined.ResultsOf 178 included patients, 46 (27%) underwent combined resection-ablation and 132 (73%) resection only. Apart from increased rates of adjuvant chemotherapy in the first group (44% vs. 25%, p = 0.014), there were no differences in perioperative systemic therapy. Kaplan–Meier and log-rank test analyses showed no statistically significant differences in median OS (36 months for both, p = 0.638) or RFS (9 months for combined resection-ablation vs. 8 months, p = 0.921). Cox regression analysis showed a hazard ratio of 0.891 (p = 0.642) for OS and 0.981 (p = 0.924) for RFS, for patients undergoing resection only.ConclusionFor patients with ≥ 4 CRLM, combined resection-ablation is a viable option in terms of OS and RFS. Therefore, combined resection-ablation should be considered for complete tumor clearance, in patients with multifocal disease.

Chemoembolization versus Radiotherapy for Single Hepatocellular Carcinomas of ≤3 cm Unsuitable for Image-Guided Tumor Ablation.

Local ablation therapy (LAT) is primarily recommended for solitary inoperable hepatocellular carcinomas (HCCs) of ≤3 cm in diameter. However, only two-thirds of uninodular small HCCs are suitable for LAT, and the second-best treatment option for managing these nodules is unclear. We aimed to compare the therapeutic outcomes of chemoembolization and radiotherapy in small HCCs unsuitable for LAT. The study included 651 patients from a tertiary referral center who underwent planning sonography for LAT. These patients had 801 solitary HCCs of ≤3 cm in diameter and were treated with LAT, chemoembolization, or radiotherapy. Local tumor progression (LTP)-free survival and overall survival (OS) were measured according to the type of treatment of the index nodule. LAT, chemoembolization, and radiotherapy were used to treat 561, 185, and 55 nodules in 467, 148, and 36 patients, respectively. LTP-free survival was significantly shorter in patients treated with chemoembolization than for those treated with LAT (multivariate hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.61 to 3.47) but not for those treated with radiotherapy (HR, 0.83; 95% CI, 0.38 to 1.83). However, OS was not affected by treatment modality. Matching and weighting analyses confirmed that radiotherapy gave comparable results to chemoembolization in terms of OS despite better LTP-free survival (HR, 2.91; 95% CI, 1.13 to 7.47 and HR, 3.07; 95% CI, 1.11 to 8.48, respectively). Our data suggest that chemoembolization and radiotherapy are equally effective options for single small HCCs found to be unsuitable for LAT after sonographic planning. Betterfit indications for each procedure should be established by specifically designed studies.

Second chance for cure: Stereotactic ablative radiotherapy in oligometastatic disease.

154 Background: Local ablative therapy, such as radiation therapy or surgery plays a key role in treatment of patients with oligometastatic disease. Stereotactic ablative radiotherapy (SABR) comes to the fore as a safe and effective treatment option for patients with a limited number of metastases, even those located in hard-to-reach body sites. Many researchers have suggested that metastatic direct therapy (MDT) could improve long-term progression-free and overall survival (PFS and OS) in patients with 1-5 metastatic lesions. Methods: This was a retrospective, single-arm, observational, evaluation study between July 2015 to February 2022. In our institute 60 patients with controlled primary tumors and 1-5 metastases were treated with SABR.We did not exclude patients who subsequently had intracranial metastases from the analysis (n 3). Prescribed radiation doses ranged from 24 to 60 Gy administered in one to seven fractions. Primary endpoint was PFS and the secondary endpoints were OS and toxicity. Results: The most common primary malignancy types were prostate cancer (n 14), colon (n 10), lung (n 7), breast (n 6), melanoma (n 6) and gynecology malignancies (n 6). Median follow-up was 30 months, ranging from 9 to 79. The 1, 3 and 5-year OS rate was 98,3%, 84,4% and 73,8% respectively, the median time to first progression was 15 (range 2 - 32) months. 36 (60%) patients have no recurrence. Two of three patients with intracranial metastases were alive at the end of the study. There were no grade 3-5 adverse events related to specific treatment of SABR. In our analysis, neither the number of metastases nor the primary site were independent prognostic factors. Conclusions: In our retrospective analysis, SABR was associated with high levels of PFS and OS in patients with oligometastatic disease. The limitations of our study were lacking high-level evidence, randomized studies to compare SABR and palliative standard-of-care are mandatory.

Circulating miR-21 as a prognostic biomarker in HCC treated by CT-guided high-dose rate brachytherapy

Background and aimsPrognostic biomarkers identifying patients with early tumor progression after local ablative therapy remain an unmet clinical need. The aim of this study was to investigate circulating miR-21 and miR-210 levels as prognostic biomarkers of HCC treated by CT-guided high-dose rate brachytherapy (HDR-BT).Materials and Methods24 consecutive HCC patients (BCLC A and B) treated with CT-guided HDR-BT (1 × 15 Gy) were included in this prospective IRB-approved study. RT-PCR was performed to quantify miR-21 and miR-210 levels in blood samples acquired prior to and 2 d after HDR-BT. Follow-up imaging (contrast-enhanced liver MRI and whole-body CT) was performed in 3 months follow-up intervals. Therapy response was assessed with patients classified as either responders or non-responders (12 each). Responders were defined as having no local or diffuse systemic progression within 6 months and no diffuse systemic progression exceeding 3 nodules/nodule diameter > 3 cm from 6 months to 2 years. Non-responders had recurrence within 6 months and/or tumor progression with > 3 nodules or individual lesion diameter > 3 cm or extrahepatic disease within two years, respectively. Biostatistics included parametric and non-parametric testing (Mann–Whitney-U-test), as well as Kaplan–Meier curve construction.ResultsThe responder group demonstrated significantly decreasing miR-21 values 2 d post therapy compared to non-responders (median miR-21 2−ΔΔCт: responders 0.73 [IQR 0.34], non-responders 1.53 [IQR 1.48]; p = 0.0102). miR-210 did not show any significant difference between responders and non-responders (median miR-210 2−ΔΔCт: responders 0.74 [IQR 0.45], non-responders 0.99 [IQR 1.13]; p = 0.8399). Kaplan–Meier curves demonstrated significantly shorter time to systemic progression for increased miR-21 (p = 0.0095) but not miR-210 (p = 0.7412), with events accumulating > 1 year post therapy in non-responders (median time to systemic progression 397 days).ConclusionIncreasing circulating miR-21 levels are associated with poor response and shorter time to systemic progression in HDR-BT-treated HCC. This proof-of-concept study provides a basis for further investigation of miR-21 as a prognostic biomarker and potential stratifier in future clinical trials of interventional oncology therapies.Trial registration: In this monocentric clinical study, we analyzed prospectively acquired data of 24 patients from the “ESTIMATE” patient cohort (Studiennummer: DRKS00010587, Deutsches Register Klinischer Studien). Ethical approval was provided by the ethics committee “Ethikkommission bei der LMU München” (reference number “17-346”) on June 20, 2017 and August 26, 2020.

Image-Guided Ablation Therapies for Extrahepatic Metastases from Hepatocellular Carcinoma: A Review.

The most common sites of extrahepatic metastases from hepatocellular carcinoma (HCC) are the lungs, intra-abdominal lymph nodes, bones, and adrenal glands, in that order. Although systemic therapies are a common treatment for patients with extrahepatic metastases, local ablative therapies for the extrahepatic metastatic lesions can be performed in selected patients. In this article, the literature on image-guided thermal ablation for metastasis to each organ was reviewed to summarize the current evidence. Radiofrequency ablation was the most commonly evaluated technique, and microwave ablation, cryoablation, and percutaneous ethanol injection were also utilized. The local control rate of thermal ablation therapy was relatively favorable, at approximately 70-90% in various organs. The survival outcomes varied among the studies, and several studies reported that the absence of viable intrahepatic lesions was associated with improved survival rates. Since only retrospective data from relatively small studies has been available thus far, more robust studies with prospective designs and larger cohorts are desired to prove the usefulness of thermal ablation for extrahepatic metastases from HCC.

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

Effect of electrochemotherapy on myogenesis of mouse C2C12 cells in vitro

Electrochemotherapy (ECT) is a local ablative therapy for the treatment of different skin and subcutaneous tumors and certain tumors in internal organs. Skeletal muscle represents a major tumor- surrounding tissue, exposed to side effects of ECT. At the cellular level, side-effects of ECT on skeletal muscle and underlying mechanisms have not been examined yet. Thus, we aimed to determine the effect of ECT in the mouse muscle cell line C2C12 during in vitro myogenesis. We evaluated the electroporation efficiency and viability of C2C12 myotubes at increasing voltages (200–1300 V/cm) using propidium iodide (PI). Permeabilization of PI into the cells was voltage-dependent accounting up to 97 % efficiency at the highest voltage. High cell viability and myotube integrity were maintained until 4 days after electroporation. ECT with the cytostatic drugs bleomycin and cisplatin decreased the viability of C2C12 myoblasts and myotubes in a dose-dependent manner. However, myoblasts were more sensitive to ECT than myotubes. Increased secretion of IL-6, observed 3 days after ECT, confirming its effects on early myogenesis. Only minor effects of ECT were observed in treated myotubes. These results contribute to the safety profile of ECT in tumor treatment.

CT-guided local ablative interventions

Applicator-based local ablations under computed tomography (CT) guidance for the treatment of malignant tumors have found their way into clinical routine. The basic principles of the different ablation technologies and their specific clinical field of application are described. Acomprehensive literature review regarding applicator-based ablation techniques was carried out. Radiofrequency (RFA) and microwave ablation (MWA) represent two image-guided hyperthermal treatment modalities that have been established for the treatment of primary and secondary liver malignancies. In addition, both techniques are also applied for local ablative therapy of lung- and kidney tumors. Cryoablation is mainly used for the local ablation of T1 kidney cancer and due to its intrinsic analgetic characteristics for application in the musculoskeletal system. Nonresectable pancreatic tumors and centrally located liver malignancies can be treated with irreversible electroporation. This nonthermal ablation modality preserves the structure of the extracellular matrix including blood vessels and ducts. Technical advancements in the field of CT-guided interventions include the use of robotics, different tracking and navigation technologies and the use of augmented reality with the goal to achieve higher precision, shorter intervention time and thereby reduce radiation exposure. Percutaneous ablation techniques under CT guidance are an essential part of interventional radiology and they are suited for local treatment of malignancies in most organ systems.

Safety and Feasibility of Vulvar Cancer Treatment with Electrochemotherapy

Electrochemotherapy is a local ablative therapy used for the treatment of various superficial and deep-seated tumors. Electrochemotherapy involves the application of electric pulses locally to tumors to destabilize cell membranes and facilitate the entry of cytotoxic drugs, thereby enhancing their cytotoxicity locally. The aim of our study is to investigate the safety and feasibility of electrochemotherapy in patients with vulvar cancer recurrence used for nonpalliative purposes. Ten patients with single local vulvar cancer recurrence were treated with intravenous bleomycin, followed by a local application of electric pulses (electrochemotherapy) to the tumor. Adverse events were determined using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The feasibility of treating vulvar cancer with electrochemotherapy was determined by an appropriate selection of electrodes based on the size and location of the tumor with safety margins included. Electrochemotherapy was feasible in all patients. No electrochemotherapy-related or other serious adverse events occurred. Our data suggest that electrochemotherapy is a feasible and safe technique for the treatment of vulvar cancer recurrence for nonpalliative purposes. Based on our results, electrochemotherapy might be a viable therapeutic tool for patients who would otherwise undergo surgery involving a mutilation of the external genitalia.

Efficacy of local ablative therapies in patients with solid tumors treated with immune checkpoint inhibitors and oligoprogression: a single-center analysis.

The concept of oligoprogression reflects a situation where a limited number of metastatic tumor sites have progressed and other metastatic sites are under control with current systemic therapy. The optimal management of oligoprogression remains unclear. In this retrospective study, we evaluated the contribution of local ablative treatment approaches after oligoprogression to progression-free survival and response rates (RRs) in patients with renal cell carcinoma ( N : 5), nonsmall cell lung cancer ( N : 1) and melanoma ( N : 21) who received immunotherapy. We found that patients received local ablative therapies after oligoprogression had longer progression-free survival and higher RR compared to those who did not. Specifically, patients who received concurrent radiotherapy had a median survival time of 24.7 months compared to 14.5 months in those who did not. Our results suggest that local ablative therapies may have a beneficial impact on progression-free survival and RR in patients with oligoprogression who are being treated with immune checkpoint inhibitors. Further studies are needed to confirm these findings and determine the optimal use of local ablative therapies in this setting.

Long-term follow-up of “adjuvant” pembrolizumab following locally ablative therapy for oligometastatic non-small cell lung cancer.

9061 Background: Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) benefit from local ablative therapies (LAT); however, the role of adjuvant systemic therapies post LAT remains less clear. In a single-arm Phase II clinical trial (NCT02316002), we demonstrated that patients with OM NSCLC treated with adjuvant pembrolizumab following LAT had superior progression free survival (PFS) compared to historical controls. Here, we present long term follow-up on PFS and overall survival (OS). Methods: Patients with OM (≤ 4 metastatic sites) NSCLC treated with LAT to all sites received pembrolizumab every 21 days for up to 16 cycles from February 1, 2015 through September 30, 2017. Other key inclusion criteria included ECOG PS 0-1 and the absence of autoimmune diseases. Patients were eligible regardless of the number of prior therapies or PD-L1 status. Our study design was an intention to treat analysis with a null hypothesis that PFS would be equivalent to historical controls (6.6 months) compared with the alternative that PFS would be greater than 10 months. Assuming 42 patients enrolled over 2 years, we calculated 80% power to detect improvement in PFS with a 1-sided 5% significance level. Primary efficacy endpoint was PFS from the start of pembrolizumab and was defined as evidence of progressive disease (PD) via RESCIST v1.1 criteria, death, or last contact. Secondary endpoints included OS, determined by date of death or last contact, and safety. Cox proportional hazard models were performed to assess associations between clinicopathologic features and PFS or OS. Results: 51 patients enrolled in the study; 45 patients (median age, 64 years [range, 46-82]; 21 [47%] women; 31 [69%] with solitary OM site) received pembrolizumab following LAT. Patients received a median of 11 cycles of pembrolizumab; 18 (40%) patients completed 16 cycles. At the data cutoff (December 1, 2022; median f/u, 65.8 months), 32 patients had PD, 19 patients died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% CI, 7.6-31.7 months); median OS was not reached (95% CI, NR-NR). OS rate at 5 years was 60.0% (SE, 7.4%). Upon PD, 94% of patients received salvage therapies. Median OS from the time of PD was 39.7 months (95% CI, 13.8-65.6 months). Metachronous OM disease was significantly associated with improved OS (HR, 3.2 [95% CI, 1.5-6.7] and PFS (HR, 2.9 [95% CI, 1.2-7.5]) via multivariate Cox proportional-hazard models. The number of OM sites, CNS disease, nodal stage at diagnosis, or tumor PD-L1 status was not significantly associated with PFS or OS. We did not observe new safety signals for pembrolizumab following LAT aside from those previously reported. Conclusions: Pembrolizumab following LAT for OM NSCLC results in promising PFS and OS compared to historical experience with a tolerable safety profile. Further investigation of this approach with a randomized trial is warranted. Clinical trial information: NCT02316002 .

High dose alkylating chemotherapy for patients with oligometastatic breast cancer harboring homologous recombination deficiency: Results from the randomized phase 3 OLIGO study.

1097 Background: Oligometastatic breast cancer (OMBC) is a clinical entity with favorable prognosis compared to MBC in general, but the optimal treatment for individual patients remains unclear. We compared high dose chemotherapy (HDCT) to conventional dose chemotherapy (CDCT) in patients receiving local ablative therapy (LAT) of all disease sites in HER2-negative OMBC that harbors homologous recombination deficiency (HRD). Methods: In this open-label phase 3 study, we randomly assigned patients with OMBC after 3 cycles of induction CDCT to either continue with CDCT (up to a maximum total of 8 cycles) or switch to HDCT. OMBC was defined as 1-3 distant metastatic lesions, with or without locoregional disease, all amenable to LAT. Main eligibility criteria included pathologic proof of a distant metastatic lesion, HRD (based on either germline BRCA1/2 mutation and/or a BRCA-like profile in the tumor), and a favorable response to induction CDCT. The primary endpoint was event-free survival (EFS), defined as time since randomization to recurrence or death. Overall survival (OS), safety and quality of life (QoL) were key secondary endpoints. Following the advice of the independent data monitoring committee, analyses were performed before the prespecified number of events was reached. Results: Between November 2012 and May 2022, 36 patients were allocated to HDCT and 39 to CDCT. 52 (69%) tumors were triple negative and 23 (31%) were hormone receptor positive; 39 patients (52%) had a solitary metastasis and 43 (57%) had synchronous OMBC. After a median follow-up of 52 months (interquartile range 28-97), 42 EFS-events had occurred. Median EFS in the HDCT-group was 28 months (95% CI 21 – not reached (NR)) compared to 25 months (95% CI 14 – NR) in the CDCT-group (hazard ratio (HR) 0.78 (95% CI 0.42 – 1.42, p = 0.411). Median OS was 67 months (95% CI 37 – NR) in the HDCT-group versus 36 months (95% CI 26 – NR) in the CDCT-group (HR 0.74, 95% CI 0.37 – 1.48, p = 0.398). 5-year EFS was 40% and 30%, and 5-year OS was 51% and 49% in the HDCT- and CDCT-group, respectively. 34 (94%) patients in the HDCT-group experienced grade 3 or higher adverse events, compared to 25 (64%) patients in the CDCT-group; no grade 5 adverse events occurred. QoL was comparable between groups at 12 months. Conclusions: HDCT does not improve outcome compared to CDCT in patients with OMBC harboring HRD and can therefore not be recommended. Survival in this highly selected group of patients with OMBC, all receiving LAT, compares favorably to survival in the overall MBC population. The optimal systemic therapy for patients with OMBC requires further study. Clinical trial information: NCT01646034 .

Clinical characteristics and initial treatment patterns of patients with HCC in Korea: A multi-center real-world database analysis from the LINK research network.

e16116 Background: In Korea, liver cancer is the fifth most frequently diagnosed cancer and has the second highest cancer mortality rate. Despite recent advances in systemic therapy, patients with Hepatocellular carcinoma (HCC) continue to have poor prognoses as many are diagnosed at an advanced disease stage. To better understand the current treatment landscape and contribute to improved patient outcomes, the LINK (Liver Cancer in Korea) research network was established as a longitudinal real-world HCC database with annual data refresh. The aim was to provide current and up-to-date real-world insights into HCC patient characteristics, treatment patterns, and outcomes. Methods: LINK’s data sources are the electronic medical records of three leading academic hospitals (Asan Medical Center, Samsung Medical Center, Severance Hospital). Extracted data are standardized using a study-specific common data model to ensure comparability across hospitals. Adult patients with primary diagnosis of HCC (ICD-10: C22.0) in 2015-2020 were included and followed until death, loss to follow-up, or June 2021, whichever occurred first. Patients without valid treatment records or morphology codes or with other primary cancer diagnosis were excluded. Data on key patient and clinical characteristics, treatments, such as systemic anti-cancer therapy (SACT) regimens, and real-world outcomes were collected. Rule-based algorithms were developed to define initial treatments and lines of therapy in palliative SACT. Results: Of 25,480 HCC patients identified, 10,298 (40%) met eligibility criteria and were included in the analysis. The median age was 60 years and 19% were female. There were 74% of patients classified as Child-Pugh (CP) class A, 16% as B, 1% as C, and 9% with unknown CP at diagnosis. For albumin-bilirubin (ALBI) grade at diagnosis, 49% of patients were classified as grade 1, 45% as 2, 5% as 3, and 1% unknown. Loco-regional therapy was the most common initial treatment, with 54% and 13% of patients receiving transarterial therapy and local ablation therapy, respectively. A total of 628 patients (6%) undergone liver transplantation regardless of preceding treatments and 15% of patients were initially treated with hepatectomy. Only 2% received radiation therapy (RT) or RT in combination with cytotoxic chemotherapy as initial treatment. Among 3,026 patients who received SACT either as an initial (10%) or subsequent treatment, 67%, 20%, and 13% received 1 line, 2 lines, and 3 lines of therapy. The most common first-line SACT was sorafenib, followed by lenvatinib. Conclusions: The LINK database can serve as a multi-center research platform to facilitate fast and reliable real-world evidence generation for HCC patients. Future updates and subgroup analyses of interest can further evaluate the impact of new therapies and changes to HCC treatment guidelines in Korea.

Alliance A022101: A pragmatic, randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: Evaluating Radiation, Ablation, and Surgery (ERASur).

TPS3629 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov identifier: NCT05673148 Clinical trial information: NCT05673148 .

The effectiveness of calcium electroporation combined with gene electrotransfer of a plasmid encoding IL-12 is tumor type-dependent.

In calcium electroporation (CaEP), electroporation enables the cellular uptake of supraphysiological concentrations of Ca2+, causing the induction of cell death. The effectiveness of CaEP has already been evaluated in clinical trials; however, confirmatory preclinical studies are still needed to further elucidate its effectiveness and underlying mechanisms. Here, we tested and compared its efficiency on two different tumor models to electrochemotherapy (ECT) and in combination with gene electrotransfer (GET) of a plasmid encoding interleukin-12 (IL-12). We hypothesized that IL-12 potentiates the antitumor effect of local ablative therapies as CaEP and ECT. The effect of CaEP was tested in vitro as well as in vivo in murine melanoma B16-F10 and murine mammary carcinoma 4T1 in comparison to ECT with bleomycin. Specifically, the treatment efficacy of CaEP with increasing calcium concentrations alone or in combination with IL-12 GET in different treatment protocols was investigated. We closely examined the tumor microenvironment by immunofluorescence staining of immune cells, as well as blood vessels and proliferating cells. In vitro, CaEP and ECT with bleomycin reduced cell viability in a dose-dependent manner. We observed no differences in sensitivity between the two cell lines. A dose-dependent response was also observed in vivo; however, the efficacy was better in 4T1 tumors than in B16-F10 tumors. In 4T1 tumors, CaEP with 250 mM Ca resulted in more than 30 days of growth delay, which was comparable to ECT with bleomycin. In contrast, adjuvant peritumoral application of IL-12 GET after CaEP prolonged the survival of B16-F10, but not 4T1-bearing mice. Moreover, CaEP with peritumoral IL-12 GET modified tumor immune cell populations and tumor vasculature. Mice bearing 4T1 tumors responded better to CaEP in vivo than mice bearing B16-F10 tumors, even though a similar response was observed in vitro. Namely, one of the most important factors might be involvement of the immune system. This was confirmed by the combination of CaEP or ECT with IL-12 GET, which further enhanced antitumor effectiveness. However, the potentiation of CaEP effectiveness was also highly dependent on tumor type; it was more pronounced in poorly immunogenic B16-F10 tumors compared to moderately immunogenic 4T1 tumors.

Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols.

Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation of patterns of recurrence and metastatic spread. A retrospective analysis of patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998- 2019 was performed (n=447). Univariate and multivariate analysis identified patterns of recurrence and predictors of survival. Median overall survival (mOS) improved over time (6.7months in 1998-2007 to 11.8months in 2008-2019, p= .006). Predictors of worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2-2.6), high neutrophil/lymphocyte ratio (HR, 2.1 [1.4-3.0], disease-free interval (DFI) ≤6months (HR, 1.4 [1.02-2.0]), and poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1-3.4). In this cohort, 50.6% of recurrences occurred within 6months of treatment completion, 72.5% occurred within 1year, and 88.6% occurred within 2years. Metachronous distant metastases were more likely to occur in patients with HPV-positive disease (odds ratio [OR], 2.3 [1.4-4.0]), DFI >6months (OR, 2.4 [1.5-4.0]), and body mass index ≥30 (OR, 2.3 [1.1-4.8]). Oligometastatic disease treated with local ablative therapy was associated with improved survival over polymetastatic disease (HR, 0.36; 95% CI, 0.24-0.55). These data regarding patterns of distant metastasis in HNSCC support the clinical utility of early detection of recurrence. Patterns of recurrence in this population can be used to inform individualized surveillance programs as well as to risk-stratify eligible patients for clinical trials. After treatment for head and neck cancer (HNC), patients are at risk of recurrence at prior sites of disease or at distant sites in the body. This study includes a large group of patients with recurrent or metastatic HNC and examines factors associated with survival outcomes and recurrence patterns. Patients with human papillomavirus (HPV)-positive HNC have good survival outcomes, but if they recur, this may be in distant regions of the body and may occur later than HPV-negative patients. These data argue for personalized follow-up schedules for patients with HNC, perhaps incorporating imaging studies or novel blood tests.

Endoscopic Ultrasound-Guided Local Ablative Therapies for the Treatment of Pancreatic Neuroendocrine Tumors and Cystic Lesions: A Review of the Current Literature.

Since its emergence as a diagnostic modality in the 1980s, endoscopic ultrasound (EUS) has provided the clinician profound access to gastrointestinal organs to aid in the direct visualization, sampling, and subsequent identification of pancreatic pathology. In recent years, advancements in EUS as an interventional technique have promoted the use of local ablative therapies as a minimally invasive alternative to the surgical management of pancreatic neuroendocrine tumors (pNETs) and pancreatic cystic neoplasms (PCNs), especially for those deemed to be poor operative candidates. EUS-guided local therapies have demonstrated promising efficacy in addressing a spectrum of pancreatic neoplasms, while also balancing local adverse effects on healthy parenchyma. This article serves as a review of the current literature detailing the mechanisms, outcomes, complications, and limitations of EUS-guided local ablative therapies such as chemical ablation and radiofrequency ablation (RFA) for the treatment of pNETs and PCNs, as well as a discussion of future applications of EUS-guided techniques to address a broader scope of pancreatic pathology.

Anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia: A scoping review

IntroductionData describing safety and tolerability of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia (HHT), the second-most-common inherited bleeding disorder, is limited. MethodsWe performed a scoping review, searching MEDLINE and EMBASE from inception to March 2023 for eligible studies reporting detailed clinical data describing antithrombotic use in HHT. Data extracted included study design, patient population, and characteristics and outcomes of antithrombotic therapy. ResultsOf 625 unique manuscripts identified through database search, 77 were included: 64 case reports/case series describing 65 patients and 13 cohort studies. Data were extracted on a total of 466 patients with HHT, covering 587 episodes of antithrombotic therapy. The most common reasons for antithrombotic therapy were venous thromboembolism (VTE) (44.6 %), atrial arrhythmias (17.8 %) and stroke (10.5 %). anticoagulation was used in in 356 episodes (61.9 %), antiplatelet therapy in 140 episodes (24.3 %), and both together in 50 episodes (8.7 %). Complications of therapy included worsened HHT-associated bleeding (primarily epistaxis and gastrointestinal bleeding) in 198 antithrombotic treatment episodes (38.9 %) and premature antithrombotic therapy discontinuation in 142 episodes (28.9 %). Bleeding-directed therapy (local ablative therapy and systemic therapies) were employed to address worsening bleeding in 14.6 % of episodes. No specific complications of therapy were reported in 322 total antithrombotic events (58.4 %). Rates of bleeding (8.3 % to 80 %), therapy discontinuation (14.3 % to 57.1 %), and other complications ranged considerably from study to study. ConclusionCurrent publications vary widely on the outcomes and tolerability of antithrombotics in HHT, but confirm the clinical challenge of adequate antithrombotic therapy in this population. More formal studies are needed to better guide optimal antithrombotic use in HHT.