Rofo 2014; 186(10): 937-944
DOI: 10.1055/s-0034-1366081
Interventional Radiology
© Georg Thieme Verlag KG Stuttgart · New York

Chemosaturation with Percutaneous Hepatic Perfusions of Melphalan for Hepatic Metastases: Experience from Two European Centers

Chemosaturation mittels perkutaner hepatischer Perfusion von Melphalan zur Behandlung von Lebermetastasen: Erfahrungen von zwei europäischen Zentren
T. J. Vogl
1   Department of Diagnostic and Interventional Radiology, University Hospital of Frankfurt
,
S. Zangos
1   Department of Diagnostic and Interventional Radiology, University Hospital of Frankfurt
,
J. E. Scholtz
1   Department of Diagnostic and Interventional Radiology, University Hospital of Frankfurt
,
F. Schmitt
1   Department of Diagnostic and Interventional Radiology, University Hospital of Frankfurt
,
S. Paetzold
2   Department of Dermatology, Venerology and Allergology, University Hospital of Frankfurt
,
J. Trojan
3   Department of Medicine I, University Hospital of Frankfurt
,
F. Orsi
4   Unit of Interventional Radiology, European Institute of Oncology, Milan
,
G. Lotz
5   Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Frankfurt
,
P. Ferrucci
6   Translational Research on Melanoma, European Institute of Oncology, Milan
› Institutsangaben
Weitere Informationen

Publikationsverlauf

20. Februar 2013

26. Dezember 2013

Publikationsdatum:
11. April 2014 (online)

Abstract

Purpose: Chemosaturation with percutaneous hepatic perfusion (PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a minimally invasive, repeatable regional therapy for unresectable hepatic metastases. It uses a system of catheters and filters to isolate hepatic venous blood from the systemic circulation, allowing delivery of high-dose chemotherapy to the hepatic artery. Effluent hepatic venous blood is filtered before being returned to the systemic circulation, thereby reducing exposure to chemotherapy. We describe our experiences with chemosaturation-PHP at 2 European centers.

Materials and Methods: 14 patients presented unresectable hepatic metastases from solid tumors; 13 received 1 – 3 sessions of chemosaturation-PHP. Melphalan 2.0 (n = 1) or 3.0 (n = 12) mg/kg was given as a 30-minute infusion into the hepatic artery. 12 patients were evaluable for tumor response.

Results: One complete (cholangiocarcinoma, n = 1) and 6 partial responses (ocular, n = 3 or cutaneous melanoma, n = 3) were observed, 5 patients had stable disease (ocular melanoma, n = 3; breast cancer, n = 1; gastric cancer, n = 1). Mild to moderate filter-related toxicity (i. e. thrombocytopenia, anemia) was observed immediately post-procedure. Grade 3/4 melphalan-related pancytopenia developed after 1 – 2 weeks. All hematological events were managed effectively with transfusions and/or other supportive measures. The new high-efficiency filter showed milder toxicity and faster recovery. In one case, chemosaturation-PHP was abandoned prematurely due to heparin-induced vaginal bleeding, and one patient died due to retroperitoneal hemorrhage from heparin anti-coagulation.

Conclusion: Chemosaturation-PHP for non-resectable liver metastases is a feasible treatment option when performed by an experienced multi-disciplinary team. It may be a promising regional therapy for patients with no effective treatment options.

Citation Format:

• Vogl TJ, Zangos S, Scholtz JE et al. Chemosaturation with Percutaneous Hepatic Perfusions of Melphalan for Hepatic Metastases: Experience from Two European Centers. Fortschr Röntgenstr 2014; 186: 937 – 944

Zusammenfassung

Ziel: Chemosaturation mit perkutaner hepatischer Perfusion (PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) ist ein minimalinvasives, wiederholbares regionales Therapieverfahren bei nicht resezierbaren Lebermetastasen, das mithilfe eines Systems aus Kathetern und Filtern das venöse hepatische Blut vom Systemkreislauf isoliert und eine hochdosierte Chemotherapeutikagabe über die hepatischen Arterien ermöglicht. Der venöse hepatische Abfluss wird zur Reduktion von Nebenwirkungen des Chemotherapeutikums vor dem Rückführen in den systemischen Kreislauf gefiltert. Wir berichten über unsere Erfahrungen mit Chemosaturation-PHP an zwei europäischen Zentren.

Material und Methoden: 14 Patienten zeigten nicht resezierbare hepatische Metastasen solider Tumore; 13 Patienten wurden in 1 – 3 Therapiesitzungen mittels Chemosaturation-PHP behandelt. Melphalan 2,0 (n = 1) und 3,0 (n = 12) mg/kg wurde 30 Minuten in die hepatischen Arterien infundiert. Für das Tumoransprechen waren 12 Patienten auswertbar.

Ergebnisse: Komplette Remission wurde in einem Patienten beobachtet (Cholangiokarzinom, n = 1), partielle Remission in 6 Patienten (Aderhautmelanom, n = 3; malignes Melanom, n = 3), 5 Patienten zeigten stable disease (Aderhautmelanom, n = 3; Brustkrebs, n = 1; Magenkarzinom, n = 1). Milde bis mäßige filterassoziierte Nebenwirkungen (z. B. Thrombozytopenie, Anämie) wurden unmittelbar nach der Behandlung beobachtet. Grad 3/4 Melphalan-assoziierte Panzytopenien entwickelten sich nach 1 – 2 Wochen. Alle hämatologischen Ereignisse wurden effektiv mit Transfusionen und/oder anderen unterstützenden Maßnahmen behandelt. Mit dem neuen, hocheffizienten Filtersystem gab es geringere Nebenwirkungen und eine beschleunigte Erholung. In einem Fall musste das Verfahren aufgrund von einer heparininduzierten vaginalen Blutung vorzeitig abgebrochen werden und ein Patient starb aufgrund retroperitonealer Blutung unter Heparinantikoagulation.

Schlussfolgerung: Chemosaturation-PHP nicht resektabler Lebermetastasen ist eine geeignete Behandlungsoption, die von einem erfahrenen, multidisziplinären Team durchgeführt werden kann. Es scheint ein aussichtsreiches regionales Verfahren für Patienten ohne andere effektive Behandlungsmöglichkeiten zu sein.

 
  • References

  • 1 Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954; 30: 969-977
  • 2 Vogl TJ, Mack MG, Eichler K et al. Chemoperfusion und -embolisation von Lebermetastasen [Chemoperfusion and embolization in the treatment of liver metastases]. Fortschr Röntgenstr 2011; 183: 12-23
  • 3 Beheshti MV, Denny Jr DF, Glickman MG et al. Percutaneous isolated liver perfusion for treatment of hepatic malignancy: preliminary report. J Vasc Interv Radiol 1992; 3: 453-458
  • 4 Ravikumar TS, Pizzorno G, Bodden W et al. Percutaneous hepatic vein isolation and high-dose hepatic arterial infusion chemotherapy for unresectable liver tumors. J Clin Oncol 1994; 12: 2723-2736
  • 5 Curley SA, Newman RA, Dougherty TB et al. Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: a phase I study. Ann Surg Oncol 1994; 1: 389-399
  • 6 Hwu WJ, Salem RR, Pollak J et al. A clinical-pharmacological evaluation of percutaneous isolated hepatic infusion of doxorubicin in patients with unresectable liver tumors. Oncol Res 1999; 11: 529-537
  • 7 van Etten B, Brunstein F, van IJken MG et al. Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients with irresectable liver metastases using percutaneous balloon catheter techniques: a phase I and II study. Ann Surg Oncol 2004; 11: 598-605
  • 8 Verhoef C, de Wilt JH, Brunstein F et al. Isolated hypoxic hepatic perfusion with retrograde outflow in patients with irresectable liver metastases; a new simplified technique in isolated hepatic perfusion. Ann Surg Oncol 2008; 15: 1367-1374
  • 9 Pingpank JF, Libutti SK, Chang R et al. Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies. J Clin Oncol 2005; 23: 3465-3474
  • 10 Pingpank JF, Royal RE, Kammula US et al. High dose intra-arterial melphalan delivered via percutaneous hepatic perfusion (PHP) for patients with unresectable hepatic metastases from primary neuroendocrine tumors. Fort Lauderdale Florida, USA: American Hepato-Pancreato-Biliary Association Annual Meeting; 2008
  • 11 Pingpank J, Royal RE, Kammula US et al. Percutaneous hepatic perfusion (PHP) with melphalan for patients with unresectable liver metastases of neuroendocrine tumors (MNET) – NCT000960083. Eur J Cancer 2011; 47: S478 (Suppl. 1, abstr 6621)
  • 12 Pingpank JF, Hughes MS, Faries MB et al. A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma. J Clin Oncol 2010; 28 (suppl; abstr LBA8512)
  • 13 Pingpank JF, Hughes M, Alexander HR et al. Percutaneous hepatic perfusion (PHP) vs. best alternative care (BAC) for patients (pts) with melanoma liver metastases – efficacy update of the Phase 3 Trial (NCT00324727). Eur J Cancer 2011; 47: S653 (Suppl 1, abstr 9304)
  • 14 Lazarus HM, Herzig RH, Graham-Pole J et al. Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1983; 1: 359-367
  • 15 Leff RS, Thompson JM, Johnson DB et al. Phase II trial of high-dose melphalan and autologous bone marrow transplantation for metastatic colon carcinoma. J Clin Oncol 1986; 4: 1586-1591
  • 16 Alexander HR, Libutti SK, Bartlett DL et al. A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2000; 6: 3062-3070
  • 17 Alexander Jr HR, Libutti SK, Pingpank JF et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003; 9: 6343-6349
  • 18 Noter SL, Rothbarth J, Pijl ME et al. Isolated hepatic perfusion with high-dose melphalan for the treatment of uveal melanoma metastases confined to the liver. Melanoma Res 2004; 14: 67-72
  • 19 Rizell M, Mattson J, Cahlin C et al. Isolated hepatic perfusion for liver metastases of malignant melanoma. Melanoma Res 2008; 18: 120-126
  • 20 van Iersel LB, Gelderblom H, Vahrmeijer AL et al. Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients. Ann Oncol 2008; 19: 1127-1134
  • 21 Alexander Jr HR, Bartlett DL, Libutti SK et al. Analysis of factors associated with outcome in patients undergoing isolated hepatic perfusion for unresectable liver metastases from colorectal center. Ann Surg Oncol 2009; 16: 1852-1859
  • 22 Rothbarth J, Pijl ME, Vahrmeijer AL et al. Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver. Br J Surg 2003; 90: 1391-1397
  • 23 Feldman ED, Wu PC, Beresneva T et al. Treatment of patients with unresectable primary hepatic malignancies using hyperthermic isolated hepatic perfusion. J Gastrointest Surg 2004; 8: 200-207
  • 24 Grover AC, Libutti SK, Pingpank JF et al. Isolated hepatic perfusion for the treatment of patients with advanced liver metastases from pancreatic and gastrointestinal neuroendocrine neoplasms. Surgery 2004; 136: 1176-1182
  • 25 Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205-216
  • 26 Rose DM, Essner R, Hughes TM et al. Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience. Arch Surg 2001; 136: 950-955
  • 27 Papastefanou VP, Cohen VML. Uveal melanoma. J Skin Cancer 2011; 573974 , Epub 2011 Jun 30
  • 28 Feldman ED, Pingpank JF, Alexander Jr HR. Regional treatment options for patients with ocular melanoma metastatic to the liver. Ann Surg Oncol 2004; 11: 290-297