Chemosaturation durch perkutane hepatische Perfusion mit Melphalan bei hepatisch metastasiertem Aderhautmelanom: eine Überlebens- und Sicherheitsanalyse

Zusammenfassung

Ziel Die Chemosaturation mittels perkutaner hepatischer Perfusion mit Melphalan (CS-PHP) ist ein palliatives Therapieverfahren für Patienten mit nicht kurativ behandelbaren Lebertumoren. Die CS-PHP erlaubt eine selektive intrahepatische Anreicherung von hochdosiertem Melphalan bei minimaler systemischer Toxizität durch venöse Hämofiltration. Ziel dieser Studie war es, das Ansprechen und Überleben sowie die Sicherheit der CS-PHP-Prozedur bei Patienten mit leberdominant metastasiertem Aderhautmelanom zu evaluieren.

Material und Methoden Gesamtansprechrate (overall response rate, ORR) und Krankheitskontrollrate (disease control rate, DCR) wurden anhand von Response Evaluation Criteria In Solid Tumors (RECIST1.1) ermittelt. Medianes Gesamtüberleben (mOS), medianes progressionsfreies Überleben (mPFS) und hepatisches mPFS (mhPFS) wurden mittels Kaplan-Meier-Schätzer ermittelt. Nebenwirkungen wurden entsprechend der einheitlichen Terminologie-Kriterien für Nebenwirkungen (CTCAE) v5 klassifiziert.

Ergebnisse 30 Patienten wurden zwischen Oktober 2014 und Januar 2019 mit 70 Chemosaturationen behandelt. Die ORR betrug 42,3 % und die DCR 80,8 %. Das mOS betrug 12 (95 %-Konfidenzintervall (KI) 7–15) Monate, das mPFS 6 (95 %-KI 4–10) und das mhPFS ebenfalls 6 (95 %-KI 4–13) Monate. Signifikante, aber transiente hämatotoxische Nebenwirkungen waren häufig (87 % Grad-3/4-Thrombozytopenie), hepatische Toxizität bis Leberversagen (n = 1/70) sowie kardiovaskuläre Komplikationen (ischämischer Insult, n = 1/70) waren selten.

Schlussfolgerung Das palliative Therapiekonzept der Chemosaturation ist bei Patienten mit hepatisch metastasiertem Aderhautmelanom effektiv. Die interventionelle Prozedur ist sicher, seltene, aber schwerwiegende kardiovaskuläre und hepatische Komplikationen erfordern eine sorgfältige Patientenselektion und intensive Aufmerksamkeit.

Abstract

Purpose Chemosaturation percutaneous hepatic perfusion (CS-PHP) allows selective intrahepatic delivery of high dose cytotoxic melphalan in patients with curatively untreatable liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. Aim of this study was to investigate the response to therapy, survival and safety of the CS-PHP procedure in patients with liver-dominant metastatic uveal melanoma (UM).

Materials and Methods Overall response rate (ORR) and disease control rate (DCR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median overall survival (mOS), median progression-free survival (mPFS) and hepatic progression-free survival (mhPFS) were analyzed using Kaplan-Meier estimation. Adverse events were evaluated with Common Terminology Criteria for Adverse Events (CTCAE) v5.

Results Overall, 30 patients were treated with 70 CS-PHP in a salvage setting from October 2014 to January 2019. In total, ORR and DCR were 42.3 % and 80.8 %, respectively. Overall, mOS was 12 (95 % confidence interval (CI) 7–15) months, and both, mPFS and mhPFS were 6 months, respectively (95 % CI 4–10; 95 % CI 4–13). Adverse events (AE) most frequently included significant but transient hematologic toxicities (87 % of grade 3/4 thrombocytopenia), less frequent AEs were hepatic injury extending to liver failure (3 %), cardiovascular events including one case of ischemic stroke (3 %).

Conclusion Salvage treatment with CS-PHP is effective in selected patients with UM. The interventional procedure is safe. Serious hepatic and cardiovascular events, although rare, require careful patient selection and should be closely monitored.

Key words

angiography - chemotherapy - interventional procedures - percutaneous - interventional oncology

Publication History

Article published online:
04 October 2021

• Literatur

• 1 Yang J, Manson DK, Marr BP. et al. Treatment of uveal melanoma: where are we now?. Ther Adv Med Oncol 2018; 10: 175883401875717
• 2 Larkin J, Chiarion-Sileni V, Gonzalez R. et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373: 23-34
• 3 Karydis I, Gangi A, Wheater MJ. et al. Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease. J Surg Oncol 2018; 117: 1170-1178
• 4 Triozzi PL, Singh AD. Adjuvant Therapy of Uveal Melanoma: Current Status. Ocul Oncol Pathol 2015; 1 (01) 54-62
• 5 Development of Metastatic Disease After Enrollment in the COMS Trials for Treatment of Choroidal Melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol 2005; 123: 1639
• 6 Abbott AM, Doepker MP, Kim Y. et al. Hepatic Progression-free and Overall Survival After Regional Therapy to the Liver for Metastatic Melanoma. American Journal of Clinical Oncology 2018; 41: 747-753
• 7 Kirstein MM, Marquardt S, Jedicke N. et al. Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors. J Cancer Res Clin Oncol 2017; 143: 2113-2121
• 8 Marquardt S, Kirstein MM, Brüning R. et al. Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: European multicentre study on safety, short-term effects and survival. Eur Radiol 2019; 29: 1882-1892
• 9 Hughes MS, Zager J, Faries M. et al. Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases. Ann Surg Oncol 2016; 23: 1309-1319
• 10 Meijer TS, Burgmans MC, Fiocco M. et al. Safety of Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Liver Metastases from Ocular Melanoma Using the Delcath Systems’ Second-Generation Hemofiltration System: A Prospective Non-randomized Phase II Trial. Cardiovasc Intervent Radiol 2019; 42: 841-852
• 11 Artzner C, Mossakowski O, Hefferman G. et al. Chemosaturation with percutaneous hepatic perfusion of melphalan for liver-dominant metastatic uveal melanoma: a single center experience. Cancer Imaging 2019; 19: 31
• 12 Vogl T, Zangos S, Scholtz J. et al. Chemosaturation with Percutaneous Hepatic Perfusions of Melphalan for Hepatic Metastases: Experience from Two European Centers. Fortschr Röntgenstr 2014; 186: 937-944
• 13 Vogel A, Gupta S, Zeile M. et al. Chemosaturation Percutaneous Hepatic Perfusion: A Systematic Review. Adv Ther 2016; 33: 2122-2138
• 14 Moeslein FM, McAndrew EG, Appling WM. et al. Evaluation of Delcath Systems’ Generation 2 (GEN 2) Melphalan Hemofiltration System in a Porcine Model of Percutaneous Hepatic Perfusion. Cardiovasc Intervent Radiol 2014; 37: 763-769
• 15 Schwartz LH, Litière S, de Vries E. et al. RECIST 1.1—Update and clarification: From the RECIST committee. European Journal of Cancer 2016; 62: 132-137
• 16 Schönfeld L, Hinrichs JB, Marquardt S. et al Chemosaturation with percutaneous hepatic perfusion is effective in patients with ocular melanoma and cholangiocarcinoma. J Cancer Res Clin Oncol [Internet] 20. Juni 2020 [zitiert 8. Juli 2020]; Verfügbar unter: http://link.springer.com/10.1007/s00432-020-03289-5
• 17 Feldman ED, Pingpank JF, Alexander HR. Regional Treatment Options for Patients With Ocular Melanoma Metastatic to the Liver. Ann Surg Oncol 2004; 11: 290-297
• 18 Jovanovic P, Mihajlovic M, Djordjevic-Jocic J. et al. Ocular melanoma: an overview of the current status. Int J Clin Exp Pathol 2013; 6: 1230-1244
• 19 S3-Leitlinie zur Diagnostik, Therapie und Nachsorge des Melanoms, Version 3.2, AWMF, Register-Nummer: 032/024OL 2019.
• 20 Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Research 2019; 29: 561-568
• 21 Rowcroft A, Loveday BPT, Thomson BNJ. et al. Systematic review of liver directed therapy for uveal melanoma hepatic metastases. HPB 2020; 22: 497-505
• 22 Khoja L, Atenafu EG, Suciu S. et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Annals of Oncology 2019; 30: 1370-1380
• 23 Heppt MV, Amaral T, Kähler KC. et al. Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. j immunotherapy cancer 2019; 7: 299