Metronomic cyclophosphamide: An alternative treatment for hepatic ...

Case Report

Metronomic cyclophosphamide: An alternative treatment for hepatic epithelioid hemangioendothelioma Zaher Lakkis1, Stefano Kim2, Eric Delabrousse3, Marine Jary2,4, Thierry Nguyen2, Georges Mantion1, Bruno Heyd1, Catherine Lassabe5, Christophe Borg2,4,⇑ 1

Department of Digestive Surgery and Liver Transplantation, University Hospital of Besançon, France; 2Department of Medical Oncology, University Hospital of Besançon, France; 3Department of Radiology, University Hospital of Besançon, France; 4INSERM, UMR1098, Besançon, France; 5Department of Pathology, Hospital of Belfort-Montbeliard, France

Abstract Hepatic epithelioid hemangioendothelioma is a rare liver mesenchymatous tumor with an epithelial aspect developed from endothelial cells with a lack of validated therapeutic options at metastatic stage. Metronomic chemotherapy has been described as an anti-angiogenic therapy leading to the depletion of circulating endothelial progenitors. We report the results of two patients treated for metastatic hemangioendothelioma with metronomic cyclophosphamide chemotherapy. Following initiation of metronomic cyclophosphamide chemotherapy (50 mg once a day continuously), the two patients exhibited significant clinical improvement and decrease in metastasis size without any clinically relevant side-effect. Metronomic cyclophosphamide could be proposed as a new therapeutic option to treat metastatic hepatic epithelioid hemangioendothelioma. Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction First described in 1982 by Weiss and Enzinger, hepatic epithelioid hemangioendothelioma (HEH) is a rare mesenchymatous tumor with low to intermediate grade of malignancy and may often be confused with other solitary fibrous tumors such as angiosarcoma [1]. In almost half of the cases, HEH is revealed at metastatic stage with preferential pulmonary and bone localization [2]. Surgery with partial hepatectomy or liver transplantation is the first-line treatment when HEH is confined to the liver. Other treatments have been reported such as chemotherapy, radiotherapy, hormonotherapy, and embolization. Low doses of metronomic chemotherapy have been shown to inhibit endothe-

Keywords: Hemangioendothelioma; Metronomic chemotherapy; Cyclophosphamide; Epithelioid tumor; Endothelial cells; Anti-angiogenic. Received 27 September 2012; received in revised form 28 January 2013; accepted 31 January 2013 ⇑ Corresponding author. Address: Department of Medical Oncology and Cancer Immunotherapy Unit, UMR 1098, INSERM/EFS/UFC, J. Minjoz University Teaching Hospital, 2 Boulevard Alexander Fleming, Besancon F-25020, France. Tel.: +33 3 81615615; fax: +33 3 81615617. E-mail address: [email protected] (C. Borg).

lial cell proliferation both in rodent models and in cancer patients [3]. Since HEH is characterized by a proliferation of endothelial cells exhibiting an epithelioid phenotype, we hypothesized that cyclophosphamide-based metronomic chemotherapy (CMC) could be an effective treatment. We report here two cases of patients with metastatic HEH treated by CMC at dose of 50 mg a day without interruption. Case reports We report the case of a 58-year-old woman who was referred to the university hospital for a grade III dyspnea appeared in early 2006. HEH was diagnosed using a transbronchial biopsy of secondary lesions. A CT scan also identified splenic and liver metastases. A first-line chemotherapy by bevacizumab was initiated with progression of the disease observed after only 3 months. Then 3 cycles of adriamycin regimen were administrated and discontinued because of clinical toxicity. After an exhaustive multidisciplinary discussion, CMC was introduced in July 2006. The rationale for the use of CMC was based on its known anti-angiogenic property, physiopathology of HEH with proliferation of endothelial cells, and no possibility to access novel targeted anti-angiogenic agents at that time. A radiological objective response was confirmed on CT scan. The complete response of the liver lesion identified by CT scan sustains the bioactivity of metronomic cyclophosphamide in this patient (Fig. 1). The clinical benefit of this strategy was also suggested by the relief of pain, dyspnea and anaemia. Of note, no toxicity was reported during the exposition to metronomic cyclophosphamide. Because of clinical progression of dyspnea, CMC therapy was interrupted in December 2006. During the following 6 months, three lines of chemotherapy were initiated including weekly paclitaxel, HELP protocol (etoposide, ifosfamide and cisplatin), and sunitinib. None of these treatments provided any clinical or radiological efficacy. Patient’s death occurred in May 2007 after initiation of best supportive cares. The second case report is about a 40-year-old man who underwent routine examinations in 1996 during the follow-up of occupational medicine, and HEH with lung metastasis was fortuitously diagnosed and confirmed by hepatic biopsy. A disease staging was performed and a simple monitoring was

Journal of Hepatology 2013 vol. 58 j 1254–1257

JOURNAL OF HEPATOLOGY

Fig. 1. A 58-year-old woman with HEH was treated with metronomic cyclophosphamide. The best response was observed in a liver metastasis located in the right liver. This liver lesion was measured at baseline with a maximum diameter of 20 mm (white arrowheads). A radiological response was observed following two months of CMC and the lesion totally disappeared thereafter.

Fig. 2. Treatment of a 40-year-old man bearing a metastatic HEH with metronomic cyclophosphamide. A symptomatic lung infiltrate of metastatic HEH was diagnosed. (A) The clinical efficacy of metronomic cyclophosphamide was suggested by the disappearance of lung micro-metastases. (B) A liver lesion was also diagnosed and displayed a long-term stable disease.

initiated because of the absence of symptoms. Four years later, symptomatic bone metastases appeared and were treated by sodium pamidronate every 4 weeks. The patient remained under simple surveillance until lung and liver progression in May 2008. Based on the former experience, CMC was initiated in July 2008 at the daily dose of 50 mg. Clinical and radiological responses were observed with decrease of the size of lesions at CT exams as well as complete pain relief with discontinuation of opioid drugs (Fig. 2). Treatment by CMC was maintained almost 2 years until May 2010 and was stopped at this date because of a haematological toxicity characterized by pancytopenia. Second-line treatment by etoposide was performed from December 2010 to April 2011 without efficacy, but clinical and biological toxicity. Best supportive cares were then started.

Discussion Hepatic epithelioid hemangioendothelioma is a rare mesenchymatous tumor with an epithelial aspect developed from endothelial cells. From 1984 to 2006, 434 cases of HEH have been reported with only 252 cases of liver primitive disease [4]. HEH has a low to intermediate grade of malignancy between liver haemangioma and angiosarcoma, but its evolution is unpredictable. HEH generally affects middle-aged adults predominantly women. Initial symptoms are usually abdominal pain rather in the right upper quadrant, with sometimes weight loss, but no alteration of performance status. Clinical examination may reveal hepatomegaly but is often poor. Biological tests are most of the time normal and may only reveal perturbation of liver enzymes. Tumor markers are always normal. Radiological tools may be


1255

Case Report helpful for diagnosis. Ultrasonography shows hepatic nodules either homogeneously hypoechogenic or centered by a hyperechogenic structure with a peripheral hypoechogenic structure. CT and MRI may reveal a ‘halo’ sign due to central coagulative necrosis and a ‘capsular retraction’ sign caused by an intense fibroproliferation [5]. A ‘lollypop’ sign has also been described as a sign of HEH [6]. Some authors also reported FDG-PET/CT as a contributive exam in HEH diagnosis and staging [7]. The definitive diagnosis of HEH is confirmed by histopathological analysis and immunohistochemistry with positive staining for FVIII-Rag, CD31, CD34 and Ulex europaeus 1 [8]. Treatment of localized HEH requires surgery with partial or total hepatectomy. Many authors reported a benefit on survival after liver resection [9]. Liver transplantation is another therapeutic option [10]. In metastatic HEH or non-operable patients, many regimens of chemotherapy have been tried without any evidence for a first-line treatment due to low incidence of HEH. The endothelial-related proliferation observed in HEH sustains the rationale for anti-angiogenic therapies in this disease [11]. Thus, thalidomide showed a significant and clinical effect on HEH in some studies due to properties of neo-angiogenesis inhibition [12]. Some efficacy was also reported for interferon-alpha in isolated cases of HEH and some authors evoked its anti-anti-angiogenic properties [13–17]. Of note, other anti-angiogenic targeted agents, such as sorafenib and bevacizumab, showed clinical benefit in isolated case reports of HEH from different sites [18–20]. Sorafenib led to a long-term tumor stabilization in a patient treated for HEH with lung and liver metastases [18]. Moreover, while our patients did not benefit from bevacizumab therapy, other reports have shown stabilization of HEH metastases and long-term disease control following bevacizumab initiation [19,20]. CMC consists of daily and continuous administration of cyclophosphamide at low concentration. Multifactorial modes of action, including immunological and anti-angiogenic functions, were described. Low doses of cyclophosphamide are able to enhance immune response against a variety of antigens. In the murine model, metronomic cyclophosphamide has shown a decreased activity of regulatory T cells (TREGs) implicated in tolerance to self-antigens, such as tumour-associated antigens [21]. Furthermore, CMC decreases the level of immunosuppressive cytokines, such as TGF-b, IL-10, and IL-2, and stimulates the recovery of IFN-gamma-producing natural killer T cells, and the maturation of dendritic cells, maintains the survival of memory T cells, and stimulates Galactin-1 expression in primary tumor, metastasis, and spleen cells [22]. Several studies demonstrated anti-angiogenic properties of CMC. Endothelial cells required in the neo-angiogenic process are susceptible to cytotoxicity induced by chemotherapy as any other dividing cells. It is now well established that under metronomic regimen, endothelial cell sub-lethal or lethal alterations are observed, and continuous exposure may definitively compromise their recovery [22–24]. In contrast to the high dose of cyclophosphamide, which induces mobilization of circulating endothelial cells, a few days after the end of a cycle of drug administration, CMC produces a long-lasting effect in endothelial and their circulating progenitor cells, inducing more durable tumor growth inhibition [25]. The antiangiogenic property of CMC regimen is also suggested by the overexpression of thrombospontin-1, an anti-angiogenic factor, in patients treated with this strategy [26,27].

1256

CMC regimen was already used in prospective phase II trials for several cancer types, mostly in advanced breast and prostate cancers [22]. In breast cancer, clinical benefit of CMC in combination with low dose methotrexate was demonstrated in several prospective phase II trials [28,29]. As second-line treatment in metastatic setting, the disease control rate was 31.7%, comparable to other second-line regimens [30]. Cost/effective analysis also favoured this regimen [31]. In prostate cancer, two prospective phase II studies evaluated CMC regimen as monotherapy in castration-refractory prostate cancer (CRPC). Raghavan et al. evaluated 30 patients with measurable disease. Disease control was observed in 18 out of 30 patients, and median OS was 12.7 months. Lord et al. reported 80 CRPC patients treated by metronomic chemotherapy after failure of conventional chemotherapies. Overall response rate was 34.5%, and PFS was 7.5 months. The treatment was well tolerated. The only grade III-IV toxicities were haematological, mostly lymphopenia [32,33]. Based on these findings, we hypothesized that CMC could be an attractive therapy to treat a vascular tumor as HEH. Of note, in the two case reports described here, lung micro-metastases were associated with liver lesions. In both cases, the initiation of CMC was decided because of symptoms such as dyspnea or pain. Our multidisciplinary team validated CMC in this orphan disease lacking a validated systemic treatment in advanced stage. In both cases, CMC induced a relief of symptoms with acceptable tolerance and easily manageable and reversible toxicities. Moreover, CMC was able to induce a partial radiological response, in line with a potential clinical interest of CMC in the disease. The efficacy of CMC is emphasized by the complete disappearance of the liver disease in patient 1 and of most lung micro-metastases in patient 2. Of note, in the two case reports described here, CMC was the only chemotherapy able to provide a clinical benefit or a radiological objective response. These results are also supported by another observation reported in 2011. This study assessed the clinical interest of metronomic cyclophosphamide delivering 100 mg of cyclophosphamide twice daily plus 20 mg of prednisolone the first week of a two-week cycle, in 26 advanced or metastatic soft tissue sarcoma, including one metastatic HEH [34]. CMC was associated with a 26.9% response rate. A complete response of the liver metastases of the HEH patient was observed. Altogether, these reports confirm the efficacy of CMC in this rare disease. HEH is a rare disease with low incidence that does not allow a comparative study between two regimens of chemotherapy. Because of clinical efficacy, good acceptance, low toxicity and low cost, CMC could be proposed as a new palliative therapeutic option to treat metastatic or non-operable HEH. Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970–981. [2] Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999;85:562–582.


JOURNAL OF HEPATOLOGY [3] Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res 2002;62:6938–6943. [4] Mehrabi A, Kashfi A, Fonouni H, Schemmer P, Schmied BM, Hallscheidt P, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 2006;107:2108–2121. [5] Kehagias DT, Moulopoulos LA, Antoniou A, Psychogios V, Vourtsi A, Vlahos LJ. Hepatic epithelioid hemangioendothelioma: MR imaging findings. Hepatogastroenterology 2000;47:1711–1713. [6] Alomari AI. The lollipop sign: a new cross-sectional sign of hepatic epithelioid hemangioendothelioma. Eur J Radiol 2006;59:460–464. [7] Nguyen BD. Epithelioid hemangioendothelioma of the liver with F-18 FDG PET imaging. Clin Nucl Med 2004;29:828–830. [8] Uchimura K, Nakamuta M, Osoegawa M, Takeaki S, Nishi H, Iwamoto H, et al. Hepatic epithelioid hemangioendothelioma. J Clin Gastroenterol 2001;32:431–434. [9] Mosoia L, Mabrut JY, Adham M, Boillot O, Ducerf C, Partensky C, et al. Hepatic epithelioid hemangioendothelioma: long-term results of surgical management. J Surg Oncol 2008;98:432–437. [10] Lerut JP, Orlando G, Adam R, Schiavo M, Klempnauer J, Mirza D, et al. The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry. Ann Surg 2007;246:949–957. [11] Emamaullee JA, Edgar R, Toso C, Thiesen A, Bain V, Bigam D, et al. Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: implications for treatment and surgical management. Liver Transpl 2010;16:191–197. [12] Mascarenhas RC, Sanghvi AN, Friedlander L, Geyer SJ, Beasley HS, Van Thiel DH. Thalidomide inhibits the growth and progression of hepatic epithelioid hemangioendothelioma. Oncology 2004;67:471–475. [13] Calabrò L, Di Giacomo AM, Altomonte M, Fonsatti E, Mazzei MA, Volterrani L, et al. Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferon-alpha: is there room for novel anti-angiogenetic treatments? J Exp Clin Cancer Res 2007;26:145–150. [14] Galvão FH, Bakonyi-Neto A, Machado MA, Farias AQ, Mello ES, Diz ME, et al. Interferon alpha-2B and liver resection to treat multifocal hepatic epithelioid hemangioendothelioma: a relevant approach to avoid liver transplantation. Transplant Proc 2005;37:4354–4358. [15] Kayler LK, Merion RM, Arenas JD, Magee JC, Campbell DA, Rudich SM, et al. Epithelioid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B. Transplantation 2002;74:128–130. [16] Vignon-Pennamen MD, Rybojad M, Verola O, Puissant A, Morel P. Epithelioid hemangioendothelioma: disease course in 3 cases. Ann Dermatol Venereol 1997;124:165–166. [17] Kassam A, Mandel K. Metastatic hepatic epithelioid hemangioendothelioma in a teenage girl. J Pediatr Hematol Oncol 2008;30:550–552. [18] Sangro B, Iñarrairaegui M, Fernández-Ros N. Malignant epithelioid hemangioendothelioma of the liver successfully treated with Sorafenib. Rare Tumors 2012;4:e34.

[19] Belmont L, Zemoura L, Couderc LJ. Pulmonary epithelioid haemangioendothelioma and bevacizumab. J Thorac Oncol 2008;3:557–558. [20] Trautmann K, Bethke A, Ehninger G, Folprecht G. Bevacizumab for recurrent hemangioendothelioma. Acta Oncol 2011;50:153–154. [21] Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105: 2862–2868. [22] Penel N, Adenis A, Bocci G. Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going? Crit Rev Oncol Hematol 2012;82:40–50. [23] Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 2002;62:2731–2735. [24] Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nature 2004;4:423–436. [25] Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045. [26] Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 2003;63:4342–4346. [27] Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J, et al. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 2004;64:1570. [28] Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K. The anti-tumor effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol 2006;58:354–360. [29] Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;13:73–80. [30] Orlando L, Cardillo A, Rocca A, et al. Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs 2006;17:961–967. [31] Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, et al. Cyclophosphamide-methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 2005;16:1243–1252. [32] Raghavan D, Cox K, Pearson BS. Oral cyclophosphamide for the management of hormone-refractory prostate cancer. Br J Urol 1993;72:625–628. [33] Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, et al. Low Dose Metronomic Oral Cyclophosphamide for Hormone Resistant Prostate Cancer: A Phase II Study. J Urology 2007;177:2136–2140. [34] Mir O, Domont J, Cioffi A, Bonvalot S, Boulet B, Le Pechoux C, et al. Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma. Eur J Cancer 2011;47:515–519.


1257