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Combination capecitabine and bevacizumab in the treatment of metastatic hepatic epithelioid hemangioendothelioma:

Combination capecitabine and bevacizumab in the treatment of metastatic hepatic epithelioid... 582206 TAM0010.1177/1758834015582206Therapeutic Advances in Medical OncologyA Lau, S Malangone research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Combination capecitabine and bevacizumab 2015, Vol. 7(4) 229 –236 DOI: 10.1177/ in the treatment of metastatic hepatic © The Author(s), 2015. Reprints and permissions: epithelioid hemangioendothelioma http://www.sagepub.co.uk/ journalsPermissions.nav Augustine Lau, Steve Malangone, Myke Green, Ambuga Badari, Kathryn Clarke and Emad Elquza Abstract: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, often misdiagnosed vascular neoplasm with clinical behaviors that range from indolent to highly aggressive. Even when the appropriate diagnosis is achieved, the best treatment for HEHE has not been defined or standardized, further complicating the care of these patients. We present a diagnostically challenging case of HEHE where we utilized capecitabine and bevacizumab as another novel treatment option. Keywords: metastatic, heptatic, epithelioid, hemangioendothelioma, capecitabine, bevacizumab Correspondence to: Introduction with multifocal, bilobar hepatic lesions with periph- Augustine Lau, MD First described in 1982, epithelioid hemangioen- eral enhancement (‘halo’ sign) and capsular retrac- Yuma Regional Medical Center, Yuma Regional dothelioma (EHE) is a rare vascular neoplasm of tion [Mistry et al. 2012; Mehrabi et al. 2006; Amin Cancer Center, 2375 S endothelial origin known to arise in various soft et  al. 2011]. Definitive diagnosis requires histo- Ridgeview Dr, Yuma, AZ tissue and visceral organs. Common sites of dis- pathologic examination. HEHE appears in nest or alau@yumaregional.org ease include liver, lungs, lymph nodes, perito- cords of epithelioid endothelial cells that are posi- Steve Malangone, ANP neum and bones [Mistry et  al. 2012]. The tive for CD31, CD34 and factor VIII on immuno- Myke R. Green, PharmD Kathryn Clarke, FNP estimated incidence of hepatic epithelioid heman- histochemistry [Mistry et  al. 2012; Mehrabi et  al. University of Arizona gioendothelioma (HEHE) is less than one in one 2006]. Furthermore, vascular endothelial growth Cancer Center, Department of Medicine, million [Mehrabi et al. 2006]. The clinical course factor (VEGF) has been found to be overexpressed Division of Hematology/ of HEHE can vary between benign hemangiomas in HEHE [Emamaullee et  al. 2010]. Importantly, Oncology, Tucson, AZ, USA to malignant angiosarcomas, thus rendering prog- podoplanin, a small mucin-like transmembrane Ambuga Badari, MD Yuma Regional Medical nosis unpredictable. Mostly afflicting people in protein involved in cell migration and invasion, is Center the third or fourth decade of life, there is no expressed in HEHE, distinguishing HEHE from Yuma Regional Cancer Center, Yuma, AZ, USA known etiology for HEHE. Cases reported in the other primary vascular tumors such as angiosar- Emad Elquza, MD literature have posited a causal relationship coma or hemangiomas, which lack podoplanin University of Arizona, College of Medicine between use of oral contraceptives, liver disease, expression [Mistry et al. 2012; Wicki and Christifori, and University of liver trauma, asbestos, vinyl chloride or thorotrast 2007]. In 63% of cases, chromosomal translocation Arizona Cancer Center, Department of Medicine, [Mistry et al. 2012; Mehrabi et al. 2006]. t(1;3)(p36.3;q25) causing gene fusion product Division of Hematology/ WWTR1-CAMTA1 has been identified, which Oncology, Tucson, AZ, USA Diagnosing HEHE is challenging given the rarity of plays a role in oncogenesis [Mistry et  al. 2012; the disease and lack of clinically useful diagnostic Woelfel et al. 2011; Errani et al. 2011]. tools. Misdiagnosis is common, occurring in up to 80% of cases [Mehrabi et al. 2006]. Up to 25% of There is no consensus on standard of care or patients are asymptomatic, and 15% have normal treatment strategies. Treatment experiences laboratory values including normal tumor markers reported in the literature are limited to case at time of diagnosis [Mistry et al. 2012]. Imaging, reports or retrospective case series from single including computerized tomography (CT) and institutions [Mehrabi et al. 2006; Rodriguez et al. magnetic resonance imaging (MRI), is also non- 2008; Cardinal et al. 2009]. The rarity of HEHE specific [Mistry et  al. 2012; Mehrabi et  al. 2006; precludes prospective studies to elucidate optimal Amin et  al. 2011]. A majority of patients presents management. Treatment approaches vary, but http://tam.sagepub.com 229 Therapeutic Advances in Medical Oncology 7(4) include liver resection, liver transplantation, radi- received two cycles of carboplatin and paclitaxel; oembolization/chemoembolization, radiotherapy, subsequent imaging showed stable liver disease. chemotherapy, combined-modality therapy and Given stability, she opted for a treatment break observation. In the proper candidate, liver trans- which lasted 14 weeks. Restaging imaging revealed plant has 5-year survival rates ranging from 43 to enlarged liver lesions. Her initial core liver biopsy 83%. Cumulative recurrence rate following liver was re-reviewed at another institution and the transplant is about 30%, including recurrence in consensus was that her liver findings were the the allograft [Mistry et  al. 2012; Mehrabi et  al. result of a bile duct carcinoma. This information 2006; Rodriquez et al. 2008; Cardinal et al. 2009]. prompted a change in regimen to single-agent In addition, extrahepatic HEHE at presentation oral capecitabine. She remained on capecitabine can range from 37 to 48% [Mehrabi et al. 2006; for 1 year with stable disease demonstrated with Grotz et al. 2010; Thomas et al. 2014]. The pres- repeat serial imaging. ence of extrahepatic disease does not significantly affect overall survival (OS) after liver transplanta- After a 4-month treatment break, subsequent tion [Grotz et al. 2010]. restaging imaging revealed enlarging liver lesions. Another biopsy of a liver lesion was performed. When treated with chemotherapy/radiotherapy IHC was positive for cytokeratins 7 and 8+18, alone, 5-year OS is estimated to be about 30% consistent with adenocarcinoma. Results of molec- [Mehrabi et  al. 2006]. Multiple single agent and ular profiling of the liver lesion biopsy suggested combination regimens have been used (Table 1). hepatocholangioma. She was treated with sorafenib However, there are no case reports in the litera- for 6 months at which point, she elected to stop ture regarding the use of capecitabine in combi- given adverse side effects and stable disease dem- nation with bevacizumab in the treatment of onstrated on imaging. After 4 years of observation, metastatic HEHE. We present a case of metastatic capecitabine was reinitiated after she complained HEHE currently being treated with capecitabine of right upper quadrant pain and imaging revealed and bevacizumab. enlarging liver lesions. Another liver lesion biopsy was performed, which confirmed HEHE. IHC was positive for CD31 and CD34. Case presentation A 56-year-old woman presented in 2007 with Bevacizumab was added to capecitabine given worsening wheezing and a dry cough for approxi- available data showing benefit [Grotz et al. 2010; mately 10 months. Her past medical history O’Grady, 2000; Lazarus et  al. 2011; Gaur et  al. included diabetes mellitus type II, allergic rhinitis 2012; Salech et  al. 2010; Agulnik et  al. 2013]. and a 38-pack year history of tobacco use. A CT After 6 months of treatment, the patient contin- scan of the chest, abdomen and pelvis found mul- ued to show response to treatment (Figure 2a–c) tiple bilateral subcentimeter pulmonary nodules as well as remaining asymptomatic. She is cur- and multiple rim enhancing liver masses with rently being evaluated for liver transplantation. liver capsular retraction (Figure 1a-c). A core biopsy of a liver lesion revealed immunohis- Discussion tochemistry (IHC) positivity for cytokeratin 8+18, Early therapeutic options other than surgery have cytokeratin 7, cytokeratin 20 and carcinoembrionic not been clearly defined or agreed upon for HEHE. antigen (CEA). Thyroid transcription factor 1 Despite poorer survival outcomes with the use of (TTF-1) and estrogen receptor (ER)/progesterone chemotherapy alone, numerous regimens have receptor (PR) were negative. Additionally, tri- been used with varying results [Mistry et al. 2012; chrome staining revealed fibrosis, favoring breast, Mehrabi et  al. 2006; Thomas et  al. 2014]. lung or upper gastrointestinal malignancy. A subse- Neoadjuvant biotherapy, specifically interferon-α, quent positron emission tomography (PET) scan for HEHE prior to liver transplant has been reported no abnormal uptake in the liver lesions. described; however, there is no standard neoadju- vant chemotherapy regimen known prior to sur- Given her history, symptoms and pathology, she gery. There were two cases where patients were free was treated with carboplatin and gemcitabine. of disease at follow up following orthotropic liver CT imaging after two cycles reported stable liver transplant after progressing with chemotherapy or lesions. The pulmonary nodules were not well embolization [Thomas et  al. 2014]. Additionally, visualized. Given minimal response, she then there have been limited case reports using adjuvant 230 http://tam.sagepub.com A Lau, S Malangone et al. http://tam.sagepub.com 231 Table 1. Various chemotherapeutics used in the treatment of epithelioid hemangioendothelioma and their outcomes. Reference Sites of disease Age No. Chemotherapy Dose Outcome Duration of (years) patient follow up Belmont et al. Lung 41 1 Carboplatin, paclitaxel, 15 mg/kg, every 21 Partial Response 13 months [2008] docetaxel, bevacizumab days (bevacizumab) Kim et al. Lung, liver, bone 44 1 Carboplatin, paclitaxel, 15 mg/kg, every 21 Progression Not [2010] bevacizumab days (bevacizumab) available Mizota et al. Lung, liver 59 1 Carboplatin, paclitaxel, 15mg/kg, every 21 Progression 3 month [2011] bevacizumab days (bevacizumab) Lazarus et al. Lung 42 1 Paclitaxel, bevacizumab Unknown Progression 1–2 months [2011] Lazarus et al. Lung 42 1 Carboplatin, etoposide, Unknown Progression 2–3 months [2011] bevacizumab Salech et al. Lung, liver 40 1 Thalidomide 300 mg daily Partial response 109 months [2010] Raphael et al. Lung, liver 53 1 Thalidomide 400 mg daily Stable disease 84 months [2010] Kassam and Lung, liver 13 1 Thalidomide 400 mg twice daily Progressive Not Mandel [2008] disease available Bolke et al. Liver, bone 47 1 Thalidomide Unknown Progressive Not [2006] disease/death available Mascarenhas Lung, liver 52 1 Thalidomide Unknown Partial response Not et al. [2005] available Sumrall et al. Brain, bone, liver, 31 1 Lenalidomide 25 mg daily for 21/28 Stable disease 48 months [2010] lung days Schilling et al. Lung, liver, spleen 33 1 Lenalidomide 30 mg daily for 21/28 Stable disease 6 months [2009] days Radzikowska Lung 62 1 Interferon α-2a 3 million units, 3 Stable disease 3 months et al. [2008] times/week Saleiro et al. Lung 39 1 Interferon α-2a Unknown Progressive 9 months [2008] disease Calabro et al. Lung, liver, spleen 53 1 Interferon α-2a Unknown Stable disease Not [2007] available Kayler et al. Liver, spleen, uterus, 21 1 Interferon α-2a 3 million units daily Partial response 4 months [2002] peritoneum (Continued) Therapeutic Advances in Medical Oncology 7(4) 232 http://tam.sagepub.com Table 1. (Continued) Reference Sites of disease Age No. Chemotherapy Dose Outcome Duration of (years) patient follow up Hassan et al. Thyroid 73 1 Interferon α 3 million units, 5 Progressive 2 months [2005] times/week disease Marsh Rde Breast, lung, liver 57 1 Interferon α 3 million units, 5 Complete 84 months et al. [2005] days/week for 1 year response Al-Shraim Lung, skin 51 1 Interferon α 7 million units, 3 Progressive 2 months et al. [2005] times/week disease Agulnik et al. Unknown Unknown 1 Bevacizumab 15 mg/kg, every 21 Partial response Not [2013] days available Agulnik et al. Unknown Unknown 1 Bevacizumab 15 mg/kg, every 21 Stable disease Not [2013] days available Agulnik et al. Unknown Unknown 1 Bevacizumab 15 mg/kg, every 21 Progression Not [2013] days available Lakkis et al. Lung, liver, spleen 58 1 Cyclophosphamide 50 mg daily, Progression 6 months [2013] continuous Lakkis et al. Lung, liver, bone 40 1 Cyclophosphamide 50 mg daily, Partial response 24 months [2013] continuous Kelly and Liver, bone 52 1 Liposomal doxorubicin 45 mg/m , every 21 Partial response 22 months O’Neil [2005] days Grenader Lung, liver 32 1 Liposomal doxorubicin 20 mg/m , every 21 Partial response 7 months et al. [2011] days Pintoffl et al. Lung, liver, bone 32 1 Gemcitabine 1000 mg/m , days 1, Stable disease 72 months [2009] 8, and 15, every 28 days Sangro et al. Lung, liver 22 1 Sorafinib 200 mg every 36 Partial response 6 months [2012] hours Trautmann Bone 19 1 Bevacizumab 7.5 mg/m every 21 Stable disease 16 months et al. [2011] days Coppo et al. Bone 70 1 Pamidronate 90 mg, twice monthly Complete 72 months [2004] response A Lau, S Malangone et al. Figure 1. Contrast enhanced axial computerized tomography images showing multiple attenuated lesions of hepatic epithelioid hemangioendothelioma. There are multiple lesions with varying size (A–C), the largest was 4.6 cm (A). Some lesions are rim enhancing and there is evidence of capsular retraction (C). chemotherapy with interferon-α with mixed results et al. 1996]. The use of systemic 5-fluorouracil in [Mehrabi et  al. 2006; Makhlouf et  al. 1999]. Our combination with other chemotherapy was also case report describes the use of capecitabine and attempted in a patient with HEHE who was ini- bevacizumab, which may prove to be a treatment tially diagnosed with cholangiocarcinoma, thus option other than surgery, especially in situations making 5-fluorouracil an option for systemic when surgical resection is impossible. Furthermore, therapy [Mehrabi et al. 2006; O’Grady, 2000]. combination capecitabine and bevacizumab has the potential to be a reasonable neoadjuvant option, Given VEGF expression in HEHE, there is the with the aim of converting patients to resection rationale to use anti-VEGF agents such as beva- candidates. cizumab either alone or in combination with other chemotherapy in the treatment of pulmo- Although capecitabine was utilized in this case nary and metastatic EHE. In particular, bevaci- before the accurate diagnosis was made, there is zumab has been used with carboplatin, evidence to support the use of 5-fluorouracil paclitaxel, docetaxel and/or etoposide [Grotz based therapy in patients with HEHE. Hepatic et al. 2010; O’Grady, 2000; Lazarus et al. 2011; intra-arterial 5-fluorouracil was used success- Gaur et al. 2012]. Most commonly, bevacizumab fully in HEHE to prolong survival [Makhlouf is used in combination with paclitaxel. et al. 1999; Holley and Cuschieri, 1989; Lauffer Regardless of the chemotherapy bevacizumab is http://tam.sagepub.com 233 Therapeutic Advances in Medical Oncology 7(4) Figure 2. Contrast enhanced axial magnetic resonance imaging (MRI) images while on capecitabine and bevacizumab. The initial hepatic lesion seen in Figure 1a is no longer visible (A). Index lesion at the junction of segment IV/VII (arrow) measures 2.6 cm × 2.2 cm (B). The index coalescent lesions seen in segments V/VI (arrow) measure approximately 5.3 cm × 3.4 cm (C). paired with, progression-free survival (PFS) and Grenader et  al. 2011; Kelly and O’Neil, 2005; OS varies from months to years [Grotz et  al. Pintoffl et  al. 2009; Coppo et  al. 2004; Lakkis 2010; Lazarus et  al. 2011; Gaur et  al. 2012; et al. 2013](see Table 1). Salech et  al. 2010]. A single-arm, multicenter, phase II trial utilizing single agent bevacizumab Capecitabine and bevacizumab have not been for unresectable EHE reported PFS and OS of previously described to treat HEHE. This proved 39 weeks and 143 weeks, respectively, when to be an effective, tolerable regimen for a patient bevacizumab was given at 15 mg/kg every 3 with metastatic hepatic hemangioendothelioma. weeks [Agulnik et al. 2013]. Although liver transplantation or resection may present the best options for improved survival, Other therapies reported include combination clinicians should consider the use of capecitabine or single-agent regimens of the following: with bevacizumab in the treatment of HEHE, interferon-α, sunitinib, sorafenib, thalidomide, especially in those awaiting liver transplantation lenalidomide, vinorelbine, dacarbazine, cispl- or nonsurgical candidates. atin, ifosfamide, etoposide, docetaxel, paclitaxel, nab-paclitaxel, liposomal doxorubicin, gemcit- Conflict of interest statement abine, pamidronate, cyclophosphamide and The authors declare no conflicts of interest in nonsteroidal anti-inflammatory drugs [Cardinal preparing this article. et al. 2009; Gaur et al. 2012; Sangro et al. 2012; Raphael et al. 2010; Sumrall et al. 2010; Schilling Funding et al. 2009; Sharif et al. 2004; Marquez-Medina This research received no specific grant from any et  al. 2004; Belmont et  al. 2008; Cronin and funding agency in the public, commercial, or not- Arenberg, 2004; Schattenberg et  al. 2008; for-profit sectors. 234 http://tam.sagepub.com A Lau, S Malangone et al. 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Combination capecitabine and bevacizumab in the treatment of metastatic hepatic epithelioid hemangioendothelioma:

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Abstract

582206 TAM0010.1177/1758834015582206Therapeutic Advances in Medical OncologyA Lau, S Malangone research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Combination capecitabine and bevacizumab 2015, Vol. 7(4) 229 –236 DOI: 10.1177/ in the treatment of metastatic hepatic © The Author(s), 2015. Reprints and permissions: epithelioid hemangioendothelioma http://www.sagepub.co.uk/ journalsPermissions.nav Augustine Lau, Steve Malangone, Myke Green, Ambuga Badari, Kathryn Clarke and Emad Elquza Abstract: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, often misdiagnosed vascular neoplasm with clinical behaviors that range from indolent to highly aggressive. Even when the appropriate diagnosis is achieved, the best treatment for HEHE has not been defined or standardized, further complicating the care of these patients. We present a diagnostically challenging case of HEHE where we utilized capecitabine and bevacizumab as another novel treatment option. Keywords: metastatic, heptatic, epithelioid, hemangioendothelioma, capecitabine, bevacizumab Correspondence to: Introduction with multifocal, bilobar hepatic lesions with periph- Augustine Lau, MD First described in 1982, epithelioid hemangioen- eral enhancement (‘halo’ sign) and capsular retrac- Yuma Regional Medical Center, Yuma Regional dothelioma (EHE) is a rare vascular neoplasm of tion [Mistry et al. 2012; Mehrabi et al. 2006; Amin Cancer Center, 2375 S endothelial origin known to arise in various soft et  al. 2011]. Definitive diagnosis requires histo- Ridgeview Dr, Yuma, AZ tissue and visceral organs. Common sites of dis- pathologic examination. HEHE appears in nest or alau@yumaregional.org ease include liver, lungs, lymph nodes, perito- cords of epithelioid endothelial cells that are posi- Steve Malangone, ANP neum and bones [Mistry et  al. 2012]. The tive for CD31, CD34 and factor VIII on immuno- Myke R. Green, PharmD Kathryn Clarke, FNP estimated incidence of hepatic epithelioid heman- histochemistry [Mistry et  al. 2012; Mehrabi et  al. University of Arizona gioendothelioma (HEHE) is less than one in one 2006]. Furthermore, vascular endothelial growth Cancer Center, Department of Medicine, million [Mehrabi et al. 2006]. The clinical course factor (VEGF) has been found to be overexpressed Division of Hematology/ of HEHE can vary between benign hemangiomas in HEHE [Emamaullee et  al. 2010]. Importantly, Oncology, Tucson, AZ, USA to malignant angiosarcomas, thus rendering prog- podoplanin, a small mucin-like transmembrane Ambuga Badari, MD Yuma Regional Medical nosis unpredictable. Mostly afflicting people in protein involved in cell migration and invasion, is Center the third or fourth decade of life, there is no expressed in HEHE, distinguishing HEHE from Yuma Regional Cancer Center, Yuma, AZ, USA known etiology for HEHE. Cases reported in the other primary vascular tumors such as angiosar- Emad Elquza, MD literature have posited a causal relationship coma or hemangiomas, which lack podoplanin University of Arizona, College of Medicine between use of oral contraceptives, liver disease, expression [Mistry et al. 2012; Wicki and Christifori, and University of liver trauma, asbestos, vinyl chloride or thorotrast 2007]. In 63% of cases, chromosomal translocation Arizona Cancer Center, Department of Medicine, [Mistry et al. 2012; Mehrabi et al. 2006]. t(1;3)(p36.3;q25) causing gene fusion product Division of Hematology/ WWTR1-CAMTA1 has been identified, which Oncology, Tucson, AZ, USA Diagnosing HEHE is challenging given the rarity of plays a role in oncogenesis [Mistry et  al. 2012; the disease and lack of clinically useful diagnostic Woelfel et al. 2011; Errani et al. 2011]. tools. Misdiagnosis is common, occurring in up to 80% of cases [Mehrabi et al. 2006]. Up to 25% of There is no consensus on standard of care or patients are asymptomatic, and 15% have normal treatment strategies. Treatment experiences laboratory values including normal tumor markers reported in the literature are limited to case at time of diagnosis [Mistry et al. 2012]. Imaging, reports or retrospective case series from single including computerized tomography (CT) and institutions [Mehrabi et al. 2006; Rodriguez et al. magnetic resonance imaging (MRI), is also non- 2008; Cardinal et al. 2009]. The rarity of HEHE specific [Mistry et  al. 2012; Mehrabi et  al. 2006; precludes prospective studies to elucidate optimal Amin et  al. 2011]. A majority of patients presents management. Treatment approaches vary, but http://tam.sagepub.com 229 Therapeutic Advances in Medical Oncology 7(4) include liver resection, liver transplantation, radi- received two cycles of carboplatin and paclitaxel; oembolization/chemoembolization, radiotherapy, subsequent imaging showed stable liver disease. chemotherapy, combined-modality therapy and Given stability, she opted for a treatment break observation. In the proper candidate, liver trans- which lasted 14 weeks. Restaging imaging revealed plant has 5-year survival rates ranging from 43 to enlarged liver lesions. Her initial core liver biopsy 83%. Cumulative recurrence rate following liver was re-reviewed at another institution and the transplant is about 30%, including recurrence in consensus was that her liver findings were the the allograft [Mistry et  al. 2012; Mehrabi et  al. result of a bile duct carcinoma. This information 2006; Rodriquez et al. 2008; Cardinal et al. 2009]. prompted a change in regimen to single-agent In addition, extrahepatic HEHE at presentation oral capecitabine. She remained on capecitabine can range from 37 to 48% [Mehrabi et al. 2006; for 1 year with stable disease demonstrated with Grotz et al. 2010; Thomas et al. 2014]. The pres- repeat serial imaging. ence of extrahepatic disease does not significantly affect overall survival (OS) after liver transplanta- After a 4-month treatment break, subsequent tion [Grotz et al. 2010]. restaging imaging revealed enlarging liver lesions. Another biopsy of a liver lesion was performed. When treated with chemotherapy/radiotherapy IHC was positive for cytokeratins 7 and 8+18, alone, 5-year OS is estimated to be about 30% consistent with adenocarcinoma. Results of molec- [Mehrabi et  al. 2006]. Multiple single agent and ular profiling of the liver lesion biopsy suggested combination regimens have been used (Table 1). hepatocholangioma. She was treated with sorafenib However, there are no case reports in the litera- for 6 months at which point, she elected to stop ture regarding the use of capecitabine in combi- given adverse side effects and stable disease dem- nation with bevacizumab in the treatment of onstrated on imaging. After 4 years of observation, metastatic HEHE. We present a case of metastatic capecitabine was reinitiated after she complained HEHE currently being treated with capecitabine of right upper quadrant pain and imaging revealed and bevacizumab. enlarging liver lesions. Another liver lesion biopsy was performed, which confirmed HEHE. IHC was positive for CD31 and CD34. Case presentation A 56-year-old woman presented in 2007 with Bevacizumab was added to capecitabine given worsening wheezing and a dry cough for approxi- available data showing benefit [Grotz et al. 2010; mately 10 months. Her past medical history O’Grady, 2000; Lazarus et  al. 2011; Gaur et  al. included diabetes mellitus type II, allergic rhinitis 2012; Salech et  al. 2010; Agulnik et  al. 2013]. and a 38-pack year history of tobacco use. A CT After 6 months of treatment, the patient contin- scan of the chest, abdomen and pelvis found mul- ued to show response to treatment (Figure 2a–c) tiple bilateral subcentimeter pulmonary nodules as well as remaining asymptomatic. She is cur- and multiple rim enhancing liver masses with rently being evaluated for liver transplantation. liver capsular retraction (Figure 1a-c). A core biopsy of a liver lesion revealed immunohis- Discussion tochemistry (IHC) positivity for cytokeratin 8+18, Early therapeutic options other than surgery have cytokeratin 7, cytokeratin 20 and carcinoembrionic not been clearly defined or agreed upon for HEHE. antigen (CEA). Thyroid transcription factor 1 Despite poorer survival outcomes with the use of (TTF-1) and estrogen receptor (ER)/progesterone chemotherapy alone, numerous regimens have receptor (PR) were negative. Additionally, tri- been used with varying results [Mistry et al. 2012; chrome staining revealed fibrosis, favoring breast, Mehrabi et  al. 2006; Thomas et  al. 2014]. lung or upper gastrointestinal malignancy. A subse- Neoadjuvant biotherapy, specifically interferon-α, quent positron emission tomography (PET) scan for HEHE prior to liver transplant has been reported no abnormal uptake in the liver lesions. described; however, there is no standard neoadju- vant chemotherapy regimen known prior to sur- Given her history, symptoms and pathology, she gery. There were two cases where patients were free was treated with carboplatin and gemcitabine. of disease at follow up following orthotropic liver CT imaging after two cycles reported stable liver transplant after progressing with chemotherapy or lesions. The pulmonary nodules were not well embolization [Thomas et  al. 2014]. Additionally, visualized. Given minimal response, she then there have been limited case reports using adjuvant 230 http://tam.sagepub.com A Lau, S Malangone et al. http://tam.sagepub.com 231 Table 1. Various chemotherapeutics used in the treatment of epithelioid hemangioendothelioma and their outcomes. Reference Sites of disease Age No. Chemotherapy Dose Outcome Duration of (years) patient follow up Belmont et al. Lung 41 1 Carboplatin, paclitaxel, 15 mg/kg, every 21 Partial Response 13 months [2008] docetaxel, bevacizumab days (bevacizumab) Kim et al. Lung, liver, bone 44 1 Carboplatin, paclitaxel, 15 mg/kg, every 21 Progression Not [2010] bevacizumab days (bevacizumab) available Mizota et al. Lung, liver 59 1 Carboplatin, paclitaxel, 15mg/kg, every 21 Progression 3 month [2011] bevacizumab days (bevacizumab) Lazarus et al. Lung 42 1 Paclitaxel, bevacizumab Unknown Progression 1–2 months [2011] Lazarus et al. Lung 42 1 Carboplatin, etoposide, Unknown Progression 2–3 months [2011] bevacizumab Salech et al. Lung, liver 40 1 Thalidomide 300 mg daily Partial response 109 months [2010] Raphael et al. Lung, liver 53 1 Thalidomide 400 mg daily Stable disease 84 months [2010] Kassam and Lung, liver 13 1 Thalidomide 400 mg twice daily Progressive Not Mandel [2008] disease available Bolke et al. Liver, bone 47 1 Thalidomide Unknown Progressive Not [2006] disease/death available Mascarenhas Lung, liver 52 1 Thalidomide Unknown Partial response Not et al. [2005] available Sumrall et al. Brain, bone, liver, 31 1 Lenalidomide 25 mg daily for 21/28 Stable disease 48 months [2010] lung days Schilling et al. Lung, liver, spleen 33 1 Lenalidomide 30 mg daily for 21/28 Stable disease 6 months [2009] days Radzikowska Lung 62 1 Interferon α-2a 3 million units, 3 Stable disease 3 months et al. [2008] times/week Saleiro et al. Lung 39 1 Interferon α-2a Unknown Progressive 9 months [2008] disease Calabro et al. Lung, liver, spleen 53 1 Interferon α-2a Unknown Stable disease Not [2007] available Kayler et al. Liver, spleen, uterus, 21 1 Interferon α-2a 3 million units daily Partial response 4 months [2002] peritoneum (Continued) Therapeutic Advances in Medical Oncology 7(4) 232 http://tam.sagepub.com Table 1. (Continued) Reference Sites of disease Age No. Chemotherapy Dose Outcome Duration of (years) patient follow up Hassan et al. Thyroid 73 1 Interferon α 3 million units, 5 Progressive 2 months [2005] times/week disease Marsh Rde Breast, lung, liver 57 1 Interferon α 3 million units, 5 Complete 84 months et al. [2005] days/week for 1 year response Al-Shraim Lung, skin 51 1 Interferon α 7 million units, 3 Progressive 2 months et al. [2005] times/week disease Agulnik et al. Unknown Unknown 1 Bevacizumab 15 mg/kg, every 21 Partial response Not [2013] days available Agulnik et al. Unknown Unknown 1 Bevacizumab 15 mg/kg, every 21 Stable disease Not [2013] days available Agulnik et al. Unknown Unknown 1 Bevacizumab 15 mg/kg, every 21 Progression Not [2013] days available Lakkis et al. Lung, liver, spleen 58 1 Cyclophosphamide 50 mg daily, Progression 6 months [2013] continuous Lakkis et al. Lung, liver, bone 40 1 Cyclophosphamide 50 mg daily, Partial response 24 months [2013] continuous Kelly and Liver, bone 52 1 Liposomal doxorubicin 45 mg/m , every 21 Partial response 22 months O’Neil [2005] days Grenader Lung, liver 32 1 Liposomal doxorubicin 20 mg/m , every 21 Partial response 7 months et al. [2011] days Pintoffl et al. Lung, liver, bone 32 1 Gemcitabine 1000 mg/m , days 1, Stable disease 72 months [2009] 8, and 15, every 28 days Sangro et al. Lung, liver 22 1 Sorafinib 200 mg every 36 Partial response 6 months [2012] hours Trautmann Bone 19 1 Bevacizumab 7.5 mg/m every 21 Stable disease 16 months et al. [2011] days Coppo et al. Bone 70 1 Pamidronate 90 mg, twice monthly Complete 72 months [2004] response A Lau, S Malangone et al. Figure 1. Contrast enhanced axial computerized tomography images showing multiple attenuated lesions of hepatic epithelioid hemangioendothelioma. There are multiple lesions with varying size (A–C), the largest was 4.6 cm (A). Some lesions are rim enhancing and there is evidence of capsular retraction (C). chemotherapy with interferon-α with mixed results et al. 1996]. The use of systemic 5-fluorouracil in [Mehrabi et  al. 2006; Makhlouf et  al. 1999]. Our combination with other chemotherapy was also case report describes the use of capecitabine and attempted in a patient with HEHE who was ini- bevacizumab, which may prove to be a treatment tially diagnosed with cholangiocarcinoma, thus option other than surgery, especially in situations making 5-fluorouracil an option for systemic when surgical resection is impossible. Furthermore, therapy [Mehrabi et al. 2006; O’Grady, 2000]. combination capecitabine and bevacizumab has the potential to be a reasonable neoadjuvant option, Given VEGF expression in HEHE, there is the with the aim of converting patients to resection rationale to use anti-VEGF agents such as beva- candidates. cizumab either alone or in combination with other chemotherapy in the treatment of pulmo- Although capecitabine was utilized in this case nary and metastatic EHE. In particular, bevaci- before the accurate diagnosis was made, there is zumab has been used with carboplatin, evidence to support the use of 5-fluorouracil paclitaxel, docetaxel and/or etoposide [Grotz based therapy in patients with HEHE. Hepatic et al. 2010; O’Grady, 2000; Lazarus et al. 2011; intra-arterial 5-fluorouracil was used success- Gaur et al. 2012]. Most commonly, bevacizumab fully in HEHE to prolong survival [Makhlouf is used in combination with paclitaxel. et al. 1999; Holley and Cuschieri, 1989; Lauffer Regardless of the chemotherapy bevacizumab is http://tam.sagepub.com 233 Therapeutic Advances in Medical Oncology 7(4) Figure 2. Contrast enhanced axial magnetic resonance imaging (MRI) images while on capecitabine and bevacizumab. The initial hepatic lesion seen in Figure 1a is no longer visible (A). Index lesion at the junction of segment IV/VII (arrow) measures 2.6 cm × 2.2 cm (B). The index coalescent lesions seen in segments V/VI (arrow) measure approximately 5.3 cm × 3.4 cm (C). paired with, progression-free survival (PFS) and Grenader et  al. 2011; Kelly and O’Neil, 2005; OS varies from months to years [Grotz et  al. Pintoffl et  al. 2009; Coppo et  al. 2004; Lakkis 2010; Lazarus et  al. 2011; Gaur et  al. 2012; et al. 2013](see Table 1). Salech et  al. 2010]. A single-arm, multicenter, phase II trial utilizing single agent bevacizumab Capecitabine and bevacizumab have not been for unresectable EHE reported PFS and OS of previously described to treat HEHE. This proved 39 weeks and 143 weeks, respectively, when to be an effective, tolerable regimen for a patient bevacizumab was given at 15 mg/kg every 3 with metastatic hepatic hemangioendothelioma. weeks [Agulnik et al. 2013]. Although liver transplantation or resection may present the best options for improved survival, Other therapies reported include combination clinicians should consider the use of capecitabine or single-agent regimens of the following: with bevacizumab in the treatment of HEHE, interferon-α, sunitinib, sorafenib, thalidomide, especially in those awaiting liver transplantation lenalidomide, vinorelbine, dacarbazine, cispl- or nonsurgical candidates. atin, ifosfamide, etoposide, docetaxel, paclitaxel, nab-paclitaxel, liposomal doxorubicin, gemcit- Conflict of interest statement abine, pamidronate, cyclophosphamide and The authors declare no conflicts of interest in nonsteroidal anti-inflammatory drugs [Cardinal preparing this article. et al. 2009; Gaur et al. 2012; Sangro et al. 2012; Raphael et al. 2010; Sumrall et al. 2010; Schilling Funding et al. 2009; Sharif et al. 2004; Marquez-Medina This research received no specific grant from any et  al. 2004; Belmont et  al. 2008; Cronin and funding agency in the public, commercial, or not- Arenberg, 2004; Schattenberg et  al. 2008; for-profit sectors. 234 http://tam.sagepub.com A Lau, S Malangone et al. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Apr 22, 2015

Keywords: metastatic; heptatic; epithelioid; hemangioendothelioma; capecitabine; bevacizumab

References