Thermal ablation in the management of oligometastatic colorectal cancer

PURPOSE To review available evidence on thermal ablation of oligometastatic colorectal cancer. METHODS Technical and cancer specific considerations for percutaneous image-guided thermal ablation of oligometastatic colorectal metastases in the liver and lung were reviewed. Ablation outcomes are compared to surgical and radiation therapy literature. RESULTS The application of thermal ablation varies widely based on tumor burden, technical expertise, and local cancer triage algorithms. Ablation can be performed in combination or in lieu of other cancer treatments. For surgically non-resectable liver metastases, a randomized trial has demonstrated the superiority of thermal ablation combined with chemotherapy compared to systemic chemotherapy alone in term of progression-free survival and overall survival (OS), with 5-, and 8-year OS of 43.1% and 35.9% in the combined arm vs. 30.3% and 8.9% in the chemotherapy alone arm. As ablation techniques and technology improve, the role of percutaneous thermal ablation may expand even into surgically resectable disease. Many of the prognostic factors for better OS after local treatment of lung metastases are the same for surgery and thermal ablation, including size and number of metastases, disease-free interval, complete resection/ablation, negative carcinoembryonic antigen, neoadjuvant chemotherapy, and controlled extra-pulmonary metastases. When matched for these factors, thermal ablation for lung and liver metastases appears to provide equivalent overall survival as surgery, in the range of 50% at 5 years. Thermal ablation has limitations that should be respected to optimize patient outcomes and minimize complications including targets that are well-visualized by image guidance, measure <3cm in diameter, and be located at least 3mm distance from prominent vasculature or major bronchi. CONCLUSIONS The routine incorporation of image-guided thermal ablation into the therapeutic armamentarium for the treatment of oligometastatic colorectal cancer can provide long survival and even cure

Biodegradable Pickering emulsions of Lipiodol for liver trans-arterial chemo-embolization

International audienceWater-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 mm at 25 mg/mL to 69 mm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. Statement of Significance We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations

Safety and Efficacy of Percutaneous Liver Microwave Ablation Using a Fully Water-Cooled Choke Ring Antenna: First Multicenter Clinical Report

Introduction: The safety and efficacy of a microwave ablation (MWA) system for the liver with novel technologies in field control, antenna cooling through the inner part of the choke ring, and dual temperature monitoring were evaluated in this multicenter retrospective study. Material and methods: Ablation characteristics and efficacy were assessed on follow-up imaging (computed tomography or magnetic resonance imaging). Safety was evaluated according to CTCAE classification. Results: Eighty-seven liver tumors (65 metastases and 22 hepatocellular carcinomas) measuring 17.8 ± 7.9 mm were treated in 68 patients. Ablation zones measured 35.6 ± 11 mm in longest diameter. The coefficients of variation of the longest and shortest ablation diameters were 30.1% and 26.4%, respectively. The mean sphericity index of the ablation zone was 0.78 ± 0.14. Seventy-one ablations (82%) had a sphericity index above 0.66. At 1 month, all tumors demonstrated complete ablation with margins of 0-5 mm, 5-10 mm, and greater than 10 mm achieved in 22%, 46%, and 31% of tumors, respectively. After a median follow-up of 10 months, local tumor control was achieved in 84.7% of treated tumors after a single ablation and in 86% after one patient received a second ablation. One grade 3 complication (stress ulcer) occurred, but was unrelated to the procedure. Ablation zone size and geometry in this clinical study were in accordance with previously reported in vivo preclinical findings. Conclusion: Promising results were reported for this MWA device. The high spherical index, reproducibility, and predictability of the resulting treatment zones translated to a high percentage of adequate safety margins, providing good local control rate

Electrochemotherapy in radiotherapy-resistant epidural spinal cord compression in metastatic cancer patients

Objective: To report efficacy and safety of percutaneous electrochemotherapy (ECT) in patients with radiotherapy-resistant metastatic epidural spinal cord compression (MESCC). Material/ methods: This retrospective study analyzed all consecutive patients treated with bleomycin-based ECT between February-2020 and September-2022 in a single tertiary referral cancer center. Changes in pain were evaluated with the Numerical Rating Score (NRS), in neurological deficit with the Neurological Deficit Scale, and changes in epidural spinal cord compression were evaluated with the epidural spinal cord compression scale (ESCCS) using an MRI. Results: Forty consecutive solid tumour patients with previously radiated MESCC and no effective systemic treatment options were eligible. With a median follow-up of 5.1 months [1-19.1], toxicities were temporary acute radicular pain (25%), prolonged radicular hypoesthesia (10%), and paraplegia (7.5%). At 1 month, pain was significantly improved over baseline (median NRS: 1.0 [0-8] versus 7.0 [1.0-10], P < .001) and neurological benefits were considered as marked (28%), moderate (28%), stable (38%), or worse (8%). Three-month follow-up (21 patients) confirmed improved over baseline (median NRS: 2.0 [0-8] versus 6.0 [1.0-10], P < .001) and neurological benefits were considered as marked (38%), moderate (19%), stable (33.5%), and worse (9.5%). One-month post-treatment MRI (35 patients) demonstrated complete response in 46% of patients by ESCCS, partial response in 31%, stable disease in 23%, and no patients with progressive disease. Three-month post-treatment MRI (21 patients) demonstrated complete response in 28.5%, partial response in 38%, stable disease in 24%, and progressive disease in 9.5%. Conclusions: This study provides the first evidence that ECT can rescue radiotherapy-resistant MESCC

Pickering-Emulsion for Liver Trans-Arterial Chemo-Embolization with Oxaliplatin

International audienc

Thermal ablation of ultrasound and non-contrast computed tomography invisible primary and secondary liver tumors: targeting by selective intra-arterial lipiodol injection

PURPOSETo evaluate the technical feasibility and outcomes of thermal ablation following selective intra-arterial lipiodol injection (SIALI) for targeting primary and secondary liver tumors invisible on ultrasound (US) and non-contrast computed tomography (CT).METHODSThis retrospective study included 18 patients with 20 tumors (67% male, mean age 60.8 ± 12.1 years). The 20 tumors included 15 liver metastases and 5 hepatocellular carcinomas. All patients underwent single-session SIALI and subsequent CT-guided thermal ablation. The primary outcome was a technical success, defined as visualization of the tumor after SIALI and successful thermal ablation. Secondary outcomes were local recurrence rate and procedure-related complications.RESULTSThe median tumor size was 1.5 (1–2.5) cm. In addition, SIALI was performed with a median volume of 3 (1–10) mL of lipiodol resulting in intra-tumoral iodized oil accumulation in 19 tumors and negative imprint with iodized oil accumulation of the surrounding liver parenchyma in 1 tumor. The technical success rate was 100%. No local occurrence was observed at a mean follow-up time of 3 ± 2.5 years.CONCLUSIONSIALI to tag liver tumors not visible with US and non-contrast CT before percutaneous ablation is highly feasible and has a high success rate for the treatment of both primary and secondary liver tumors

Immunothérapie anti-cancéreuse par administration locale d’anti-CTLA4

L’administration intratumorale (IT) d’immunothérapie est une stratégie thérapeutique en cours de développement rapide, qui nécessite une structuration spécifique pour permettre d’en évaluer les résultats et y adosser de la recherche translationnelle. Nous rapportons l’organisation mise en place au sein de notre groupe, avec comme élément central la création d’une réunion de concertation multidisciplinaire dédiée à l’intratumoral. L’expérience initiale, sur les 100 premiers patients traités par immunothérapie intratumorale à Gustave Roussy est rassurante sur la sécurité de cette méthode d’administration et montre des signaux d’efficacité intéressants.Une des immunothérapies, les anticorps anti-CTLA4 présente un intérêt particulier pour l’intratumoral du fait de leur propriété effet-dose.Nous avons confirmé la bonne tolérance et le bon taux de réponse locale et à distance sur un modèle murin (CT26).Le développement d’une formulation PLGA de relargage continu n’a pas permis d’améliorer l’efficacité de l’anti-CTLA4 en IT. La meilleure efficacité anti-tumorale étant obtenue par l’injection IT répétées de faibles doses d’anti-CTLA4 ( à une dose 10x inférieure à la dose IV).Nous rapportons également les résultats de l’essai clinique NIVIPIT qui a comparé de façon randomisée la sécurité d’utilisation et l’efficacité d’un anti-CTLA4 (ipilimumab) à faible dose par voie IT versus à dose normale en IV, en combinaison avec un anti-PD1 (Nivolumab) en IV chez des patients atteints de mélanome. Les patients traités dans le bras IT ont développé moins d’irAE de grade≥3, avec cependant un ORR et une OS inferieur au bras IV. L’exposition systémique d’Ipilimumab était entre 17 et 27 fois inferieure dans le bras IT comparativement au bras IV.Nous avons identifié que la présence d’une population CD4+CD25highCD39high dans les biopsies tumorales, ou de Granzyme B dans leur sécrétome était prédictif de réponse. Cette population de lymphocyte T diminue chez les répondeurs sous l’effet du traitement.De plus, une augmentation de l’expression de ICOS sur les Tregs et une augmentation de CD25 soluble étaient prédictifs d’irAEs de grade≥3 dans les deux bras.Local immunotherapy is a growing therapeutic strategy which requires a specific framework in order to perform effective translational research and evaluate properly the clinical outcomes. We report here the workflow and dedicated setting implemented in our institution for human intratumoral immunotherapy (HIT-IT). The cornerstone has been the creation of a weekly multidisciplinary HIT-IT board gathering multiple specialists (both clinicians and non-clinicians). Our initial experience with the first 100 patients treated with IT immunotherapies has proved the safety of the strategy and demonstrated some interesting signals of efficacy.One immunotherapy of specific interest has been the anti-CTLA4 monoclonal antibodies because of their dose/effect relationship.In a preclinical mouse model (CT26), IT anti-CTLA4 has shown a good safety profile and a high local and distant response rate.The development of a slow release, radiopaque PLGA delivery formulation did not allow to enhance efficacy, and low doses (10-fold lower than systemic doses) repeated regularly (4 injections) seemed to be the most favorable regimen. We also report the results of a randomized clinical trial (NIVIPIT) comparing anti-PD1 (nivolumab) blockade in combination with either intravenous or low dose intratumoral anti-CTLA4 (ipilimumab) in advanced melanoma patients.The intratumoral arm of the trial showed a favorable safety profile with significantly lower grade≥3 irAE and 72% response rate on injected lesions, while the overall ORR and OS were inferior to the systemic arm.The systemic exposure to ipilimumab was significantly lower in the IT arm (17 to 27-fold lower).The presence of CD4+CD25highCD39high in tumor biopsies at baseline was predictive of response whatever the treatment arm. This population of cells decreased among responders upon treatment.The presence of Granzyme B in the secretome of tumor biopsies at baseline and its increase at week 3 were also predictive of response.Finally, an increase in ICOS+ Tregs and in soluble CD25 under treatment were associated with grade≥3 treatment related irAEs

Immunothérapie anti-cancéreuse par administration locale d’anti-CTLA4

Local immunotherapy is a growing therapeutic strategy which requires a specific framework in order to perform effective translational research and evaluate properly the clinical outcomes. We report here the workflow and dedicated setting implemented in our institution for human intratumoral immunotherapy (HIT-IT). The cornerstone has been the creation of a weekly multidisciplinary HIT-IT board gathering multiple specialists (both clinicians and non-clinicians). Our initial experience with the first 100 patients treated with IT immunotherapies has proved the safety of the strategy and demonstrated some interesting signals of efficacy.One immunotherapy of specific interest has been the anti-CTLA4 monoclonal antibodies because of their dose/effect relationship.In a preclinical mouse model (CT26), IT anti-CTLA4 has shown a good safety profile and a high local and distant response rate.The development of a slow release, radiopaque PLGA delivery formulation did not allow to enhance efficacy, and low doses (10-fold lower than systemic doses) repeated regularly (4 injections) seemed to be the most favorable regimen.We also report the results of a randomized clinical trial (NIVIPIT) comparing anti-PD1 (nivolumab) blockade in combination with either intravenous or low dose intratumoral anti-CTLA4 (ipilimumab) in advanced melanoma patients.The intratumoral arm of the trial showed a favorable safety profile with significantly lower grade≥3 irAE and 72% response rate on injected lesions, while the overall ORR and OS were inferior to the systemic arm.The systemic exposure to ipilimumab was significantly lower in the IT arm (17 to 27-fold lower).The presence of CD4+CD25highCD39high in tumor biopsies at baseline was predictive of response whatever the treatment arm. This population of cells decreased among responders upon treatment.The presence of Granzyme B in the secretome of tumor biopsies at baseline and its increase at week 3 were also predictive of response.Finally, an increase in ICOS+ Tregs and in soluble CD25 under treatment were associated with grade≥3 treatment related irAEs.L’administration intratumorale (IT) d’immunothérapie est une stratégie thérapeutique en cours de développement rapide, qui nécessite une structuration spécifique pour permettre d’en évaluer les résultats et y adosser de la recherche translationnelle. Nous rapportons l’organisation mise en place au sein de notre groupe, avec comme élément central la création d’une réunion de concertation multidisciplinaire dédiée à l’intratumoral. L’expérience initiale, sur les 100 premiers patients traités par immunothérapie intratumorale à Gustave Roussy est rassurante sur la sécurité de cette méthode d’administration et montre des signaux d’efficacité intéressants.Une des immunothérapies, les anticorps anti-CTLA4 présente un intérêt particulier pour l’intratumoral du fait de leur propriété effet-dose.Nous avons confirmé la bonne tolérance et le bon taux de réponse locale et à distance sur un modèle murin (CT26).Le développement d’une formulation PLGA de relargage continu n’a pas permis d’améliorer l’efficacité de l’anti-CTLA4 en IT. La meilleure efficacité anti-tumorale étant obtenue par l’injection IT répétées de faibles doses d’anti-CTLA4 ( à une dose 10x inférieure à la dose IV).Nous rapportons également les résultats de l’essai clinique NIVIPIT qui a comparé de façon randomisée la sécurité d’utilisation et l’efficacité d’un anti-CTLA4 (ipilimumab) à faible dose par voie IT versus à dose normale en IV, en combinaison avec un anti-PD1 (Nivolumab) en IV chez des patients atteints de mélanome. Les patients traités dans le bras IT ont développé moins d’irAE de grade≥3, avec cependant un ORR et une OS inferieur au bras IV. L’exposition systémique d’Ipilimumab était entre 17 et 27 fois inferieure dans le bras IT comparativement au bras IV.Nous avons identifié que la présence d’une population CD4+CD25highCD39high dans les biopsies tumorales, ou de Granzyme B dans leur sécrétome était prédictif de réponse. Cette population de lymphocyte T diminue chez les répondeurs sous l’effet du traitement.De plus, une augmentation de l’expression de ICOS sur les Tregs et une augmentation de CD25 soluble étaient prédictifs d’irAEs de grade≥3 dans les deux bras