Julien Edeline1,2, Yann Touchefeu3, Boris Guiu4, Olivier Farge5, David Tougeron6, Isabelle Baumgaertner7, Ahmet Ayav8, Boris Campillo-Gimenez1,9, Luc Beuzit10, Marc Pracht1, Astrid Lièvre11,12, Samuel Le Sourd1, Karim Boudjema13, Yan Rolland14, Eveline Boucher1, Etienne Garin15. 1. Department of Medical Oncology, Centre Eugène Marquis, Rennes, France. 2. Université Rennes, IndianaSERM, IndianaRA, Centre de Lutte contre le Cancer Eugène Marquis, Institut NUMECAN (Nutrition Metabolisms and Cancer), Rennes, France. 3. Centre Hospitalier Universitaire Nantes, Nantes, France. 4. Centre Hospitalier Universitaire Montpellier, Montpellier, France. 5. Centre Hospitalier Universitaire Beaujon, Clichy, France. 6. Centre Hospitalier Universitaire Poitiers, Poitiers, France. 7. Centre Hospitalier Universitaire Mondor, Créteil, France. 8. Centre Hospitalier Universitaire Nancy, Nancy, France. 9. INSERM, LTSI U1099, Université Rennes 1, Rennes, France. 10. Radiology, Centre Hospitalier Universitaire Pontchaillou, Rennes, France. 11. Gastroenterology, Centre Hospitalier Universitaire Pontchaillou, Rennes, France. 12. Univ Rennes, Inserm, Regional Cancer Center Eugène Marquis, Chemistry Oncogenesis Stress Signaling-UMR1242, Rennes, France. 13. Hepatobiliary Surgery, Centre Hospitalier Universitaire Pontchaillou, Rennes, France. 14. Radiology, Centre Eugène Marquis, Rennes, France. 15. Nuclear Medicine, Centre Eugène Marquis, Rennes, France.
Abstract
IMPORTANCE: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge. OBJECTIVE: To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019. INTERVENTIONS: Concomitant first-line chemotherapy with cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2 (gemcitabine reduced to 300 mg/m2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y90 microspheres. MAIN OUTCOMES AND MEASURES: Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria. RESULTS: Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection. CONCLUSIONS AND RELEVANCE: Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.
IMPORTANCE: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge. OBJECTIVE: To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019. INTERVENTIONS: Concomitant first-line chemotherapy with cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2 (gemcitabine reduced to 300 mg/m2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y90 microspheres. MAIN OUTCOMES AND MEASURES: Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria. RESULTS: Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection. CONCLUSIONS AND RELEVANCE: Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.
Authors: Angela Lamarca; Alvaro Santos-Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio I R Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M Banales; Juan W Valle Journal: Hepatology Date: 2021-06 Impact factor: 17.425
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