Pharmacological treatment of hepatocellular carcinoma with cavoatrial tumor thrombus – case series and literature review

Tianzuo Zhan; Janina Sollors; Niels Steinebrunner; Hans Jürgen Schlitt; Christian Stroszczynski; Karl Heinz Weiss; Matthias P. Ebert; Andreas Teufel

doi:10.1055/a-0855-4469

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Z Gastroenterol 2019; 57(04): 501-507
DOI: 10.1055/a-0855-4469

Kasuistik

Pharmacological treatment of hepatocellular carcinoma with cavoatrial tumor thrombus – case series and literature review

Pharmakologische Therapie von Leberzellkarzinomen mit cavoatrialem Tumorthrombus – Fallserie und Literaturübersicht

Tianzuo Zhan^*

¹Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

²Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

,

Janina Sollors^*

¹Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

,

Niels Steinebrunner

³Department of Internal Medicine IV, University Hospital Heidelberg, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany

,

Hans Jürgen Schlitt

⁴Department of Surgery, University Medical Center, Regensburg, Germany

,

Christian Stroszczynski

⁵Department of Radiology, University Medical Center, Regensburg, Germany

,

Karl Heinz Weiss

³Department of Internal Medicine IV, University Hospital Heidelberg, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany

,

Matthias P. Ebert

¹Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

,

Andreas Teufel

¹Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

› Institutsangaben

Abstract

Hepatocellular carcinomas (HCC) that extend into the vena cava and the right atrium have a poor prognosis. Surgical approaches including partial hepatectomy and thrombectomy are the most frequently reported treatment options. However, most patients with advanced HCC are not eligible for complex surgical interventions due to reduced liver function, comorbidities, and metastases. At the same time, systemic treatment options of HCC have expanded in recent years. Here, we report 3 cases of patients with advanced HCC who developed a cavoatrial tumor thrombus (CATT) after initial surgical or interventional therapy. The patients were consequently treated with sorafenib or nivolumab. In all cases, the tumor responded to systemic treatment with disease stabilization or partial regression. Overall survival after diagnosis of CATT was 3 and 17 months for sorafenib and 7 + months for nivolumab. Compared to survival rates of alternative treatment options, systemic therapies demonstrated comparable outcomes. In summary, pharmacotherapy is an efficient and well worth option to treat patients with HCC and CATT and should be an integral part of a multimodal therapy concept.

Zusammenfassung

Hepatozelluläre Karzinome (HCC) mit Tumorthrombose in der Vena cava inferior und dem rechten Vorhof (CATT) sind mit einer schlechten Prognose assoziiert. In der Literatur wurden bisher vor allem chirurgische Therapieverfahren beschrieben, insbesondere die Hemihepatektomie mit Resektion des Tumorthrombus. Die meisten Patienten mit HCC werden jedoch im fortgeschrittenen Tumorstadium diagnostiziert oder haben eine eingeschränkte Leberfunktion, sodass eine chirurgische Therapie nicht möglich ist. Wir beschreiben hier drei Fälle von Patienten mit fortgeschrittenem HCC und CATT, die nach chirurgischer oder interventioneller Therapie einen Progress entwickelt haben und mit Sorafenib oder Nivolumab behandelt wurden. Bei allen drei Patienten wurde eine partielle Stabilisierung oder Remission der Erkrankung erreicht. Das Gesamtüberleben nach Diagnose eines CATT betrug 3 und 17 Monate für Sorafenib und 7 + Monate für Nivolumab. Im Vergleich zu anderen Behandlungsoptionen zeigte die Pharmakotherapie auch bei Patienten mit HCC und CATT ein vergleichbares Ergebnis. Sie sollte daher ein integraler Bestandteil eines multimodalen Therapiekonzepts sein.

Key words

liver - hepatitis C - hepatitis B - HCC - immunotherapy - liver cirrhosis

Schlüsselwörter

Leber - Hepatitis C - Hepatitis B - HCC - Immuntherapie - Leberzirrhose

Volltext

Referenzen

References
1 Torre LA, Bray F, Siegel RL. et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108
2 Ikai I, Arii S, Kojiro M. et al. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey. Cancer 2004; 101: 796-802
3 Dhir M, Melin AA, Douaiher J. et al. A review and update of treatment options and controversies in the management of hepatocellular carcinoma. Annals of Surgery 2016; 263: 1112-1125
4 Llovet JM, Ricci S, Mazzaferro V. et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390
5 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379: 54-63
6 Bruix J, Qin S, Merle P. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389: 56-66
7 Kudo M, Finn RS, Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391: 1163-1173
8 Zhu AX, Finn RS, Edeline J. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19: 940-952
9 El-Khoueiry AB, Sangro B, Yau T. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389: 2492-2502
10 Kojiro M, Nakahara H, Sugihara S. et al. Hepatocellular carcinoma with intra-atrial tumor growth. A clinicopathologic study of 18 autopsy cases. Arch Pathol Lab Med 1984; 108: 989-992
11 Edmondson HA, Steiner PE. Primary carcinoma of the liver. A study of 100 cases among 48900 necropsies. Cancer 1954; 7: 462-503
12 Anthony PP. Primary carcinoma of the liver: a study of 282 cases in Ugandan Africans. J Pathol 1973; 110: 37-48
13 Nakashima T, Okuda K, Kojiro M. et al. Pathology of hepatocellular carcinoma in Japan: 232 consecutive cases autopsied in ten years. Cancer 1983; 51: 863-877
14 Macdonald RA. Primary carcinoma of the liver; a clinicopathologic study of one hundred eight cases. AMA Arch Intern Med 1957; 99: 266-279
15 Miyazawa M, Torii T, Asano H. et al. Does a surgery for hepatocellular carcinoma with tumor thrombus highly occupying in the right atrium have significance? A case report and review of the literature. Hepatogastroenterology 2005; 52: 212-216
16 Wang Y, Yuan L, Ge R. et al. Survival benefit of surgical treatment for hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: results of a retrospective cohort study. Ann Surg Oncol 2013; 20: 914-922
17 Wakayama K, Kamiyama T, Yokoo H. et al. Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium. World J Surg Oncol 2013; 11: 259
18 Sengodan P, Grewal H, Gandhi S. Invasive hepatocellular carcinoma with recurrent pulmonary embolism: use of AngioVac cannula thrombectomy device for mechanical aspiration. J Invasive Cardiol 2014; 26: E100-E103
19 Vallakati A, Chandra PA, Frankel R. et al. Intra-atrial tumor thrombi secondary to hepatocellular carcinoma responding to chemotherapy. N Am J Med Sci 2011; 3: 435-437
20 Chang JY, Ka WS, Chao TY. et al. Hepatocellular carcinoma with intra-atrial tumor thrombi: a report of three cases responsive to thalidomide treatment and literature review. Oncology 2004; 67: 320-326
21 Duseja A. Staging of hepatocellular carcinoma. Clin Exp Hepatol 2014; 4: S74-S79
22 Sakamoto K, Nagano H. Outcomes of surgery for hepatocellular carcinoma with tumor thrombus in the inferior vena cava or right atrium. Surg Today 2017; 48: 819-824
23 Pesi B, Giudici F, Moraldi L. et al. Hepatocellular carcinoma on cirrhosis complicated with tumoral thrombi extended to the right atrium: results in three cases treated with major hepatectomy and thrombectomy under hypothermic cardiocirculatory arrest and literature review. World J Surg Oncol 2016; 14: 83
24 Finn RS, Zhu AX, Farah W. et al. Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: a systematic review and meta-analysis. Hepatology 2018; 67: 422-435
25 Duan F, Yu W, Wang Y. et al. Trans-arterial chemoembolization and external beam radiation therapy for treatment of hepatocellular carcinoma with a tumor thrombus in the inferior vena cava and right atrium. Cancer Imaging 2015; 15: 7
26 Dazai Y, Katoh T, Katoh I. et al. Effectiveness of chemoembolization therapy for metastatic right atrial tumor thrombus associated with hepatocellular carcinoma. Chest 1989; 96: 434-436
27 Miyahara K, Nouso K, Morimoto Y. et al. Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma. Hepatol Res 2014; 44: 296-301
28 Apostolidis L, Pfeiffenberger J, Gotthardt D. et al. Survival of hepatocellular carcinoma patients treated with sorafenib beyond progression. Gastrointest Tumors 2018; 5: 38-46
29 Lin HH, Hsieh CB, Chu HC. et al. Acute pulmonary embolism as the first manifestation of hepatocellular carcinoma complicated with tumor thrombi in the inferior vena cava: surgery or not?. Dig Dis Sci 2007; 52: 1554-1557
30 Zhu AX, Fuchs CS, Clark JW. et al. A phase II study of epirubicin and thalidomide in unresectable or metastatic hepatocellular carcinoma. Oncologist 2005; 10: 392-398
31 Lin AY, Brophy N, Fisher GA. et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 2005; 103: 119-125
32 Ikeda M, Sung MW, Kudo M. et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol 2018; 36: 4076
33 Stein S, Pishvaian M, Lee MS. et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J Clin Oncol 2018; 36: 4074
34 Akl EA, Vasireddi SR, Gunukula S. et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2014; 19: CD006649
35 Villa E, Cammà C, Marietta M. et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143: 1253-1260
36 Raskob GE, van Es N, Verhamme P. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378: 615-624
37 Farge D, Bounameaux H, Brenner B. et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2016; 17: e452-e466
38 Fujisaki M, Kurihara E, Kikuchi K. et al. Hepatocellular carcinoma with tumor thrombus extending into the right atrium: report of a successful resection with the use of cardiopulmonary bypass. Surgery 1991; 109: 214-219
39 Wu CC, Hseih S, Ho WM. et al. Surgical treatment for recurrent hepatocellular carcinoma with tumor thrombi in right atrium: using cardiopulmonary bypass and deep hypothermic circulatory arrest. J Surg Oncol 2000; 74: 227-231
40 Ohwada S, Tanahashi Y, Kawashima Y. et al. Surgery for tumor thrombi in the right atrium and inferior vena cava of patients with recurrent hepatocellular carcinoma. Hepatogastroenterology 1994; 41: 154-157
41 Li AJ, Yuan H, Yin L. et al. Cavoatrial thrombectomy in hepatocellular carcinoma with tumor thrombus in the vena cava and atrium without the use of cardiopulmonary bypass. Ann Vasc Surg 2014; 28: 1565.e5-1565.e8
42 Yogita S, Tashiro S, Harada M. et al. Hepatocellular carcinoma with extension into the right atrium: report of a successful liver resection by hepatic vascular exclusion using cardiopulmonary bypass. J Med Invest 2000; 47: 155-160
43 Georgen M, Regimbeau JM, Kianmanesh R. et al. Removal of hepatocellular carcinoma extending in the right atrium without extracorporal bypass. J Am Coll Surg 2002; 195: 892-894
44 Sung AD, Cheng S, Moslehi J. et al. Hepatocellular carcinoma with intracavitary cardiac involvement: a case report and review of the literature. Am J Cardiol 2008; 102: 643-645
45 Kashima Y, Miyazaki M, Kaiho T. et al. A successful treatment for hepatocellular carcinoma with atrial tumor thrombus. Hepatogastroenterology 1996; 43: 1040-1045
46 Luo X, Zhang B, Dong S. et al. Hepatocellular carcinoma with tumor thrombus occupying the right atrium and portal vein: a case report and literature review. Medicine (Baltimore) 2015; 94: e1049
47 Leo F, Rapisarda F, Stefano PL. et al. Cavo-atrial thrombectomy combined with left hemi-hepatectomy for vascular invasion from hepatocellular carcinoma on diseased liver under hypothermic cardio-circulatory arrest. Interact Cardiovasc Thorac Surg 2010; 10: 473-475
48 Inoue Y, Hayashi M, Katsumata T. et al. Hepatocellular carcinoma with right atrial tumor thrombus: report of a case. Surg Today 2011; 41: 1122-1129
49 Ohta M, Nakanishi C, Kawagishi N. et al. Surgical resection of recurrent extrahepatic hepatocellular carcinoma with tumor thrombus extending into the right atrium under cardiopulmonary bypass: a case report and review of the literature. Surg Case Reports 2016; 2: 110
50 Iemura J, Aoshima M, Ishigami N. et al. Surgery for hepatocellular carcinoma with tumor thrombus in the right atrium. Hepatogastroenterology 1997; 44: 824-825
51 Chern MC, Chuang VP, Cheng T. et al. Transcatheter arterial chemoembolization for advanced hepatocellular carcinoma with inferior vena cava and right atrial tumors. Cardiovasc Intervent Radiol 2008; 31: 735-744
52 Li W, Wang Y, Gao W. et al. HCC with tumor thrombus entering the right atrium and inferior vena cava treated by percutaneous ablation. BMC Surg 2017; 17: 21