Letter to the Editor 577
Chinese patients should be explored in future. However, the potential limitation of this study is that it has only a small number of BCS patients enrolled prospectively during a 6-month period, which might require external validity. Certainly, it is often difficult to obtain a larger sample size from a single center during a relatively short period, given the rarity of this disease. Ideally, a nationwide epidemiological study should be carried out to evaluate the prevalence of thrombotic risk factors in Chinese BCS patients.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3
4
5
6
7
Valla DC. Primary Budd–Chiari syndrome. J Hepatol 2009; 50:195–203. Seijo S, Plessier A, Hoekstra J, Dell’era A, Mandair D, Rifai K, et al. Good long-term outcome of Budd–Chiari syndrome with a step-wise management. Hepatology 2013; 57:1962–1968. Qi X, Wu F, Ren W, He C, Yin Z, Niu J, et al. Thrombotic risk factors in Chinese Budd–Chiari syndrome patients. An observational study with a systematic review of the literature. Thromb Haemost 2013; 109:878–884. Qi X, Zhang C, Han G, Zhang W, He C, Yin Z, et al. Prevalence of paroxysmal nocturnal hemoglobinuria in Chinese patients with Budd–Chiari syndrome or portal vein thrombosis. J Gastroenterol Hepatol 2013; 28:148–152. Qi X, He C, Han G, Yin Z, Wu F, Zhang Q, et al. Prevalence of the JAK2 V617F mutation in Chinese patients with Budd–Chiari syndrome and portal vein thrombosis: a prospective study. J Gastroenterol Hepatol 2012; 27:1036–1043. Wang H, Sun G, Zhang P, Zhang J, Gui E, Zu M, et al. JAK2 V617F mutation and 46/1 haplotype in Chinese Budd–Chiari syndrome patients. J Gastroenterol Hepatol 2014; 29:208–214. Cheng D, Xu H, Lu ZJ, Hua R, Qiu H, Du H, et al. Clinical features and etiology of Budd–Chiari syndrome in Chinese patients: a single-center study. J Gastroenterol Hepatol 2013; 28:1061–1067.
Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation: does mTOR inhibitors association augment toxicity? Giovanni Perricone, Andrea Mancuso, Luca S. Belli, Chiara Mazzarelli and Claudio Zavaglia, Hepatology and Gastroenterology Unit, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, Milan, Italy Correspondence to Giovanni Perricone, MD, Hepatology and Gastroenterology Unit, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy Table 1
Tel: + 39 026 444 4454; fax: + 39 026 444 2895; e-mails: [email protected], [email protected] Received 30 January 2014 Accepted 31 January 2014
Although sorafenib has shown a survival benefit in cirrhotics with advanced hepatocellular carcinoma (HCC), its efficacy and safety in the post-liver transplantation (LT) setting have scarcely been studied. Few retrospective cohort studies have been published so far. Recently, Sposito et al. [1] compared the outcome of 15 patients with HCC recurrence after LT treated with sorafenib with 24 historical controls who received best supportive care. The median survival from the start of treatment was 10.6 months for the sorafenib group compared with 2.2 months in the control group. No severe adverse event was registered. In the same setting, Staufer et al. [2] observed grade 3–4 adverse events in 92% of 13 patients (nine treated with mTOR inhibitors). Sorafenib was discontinued in 77%. We have already published data in 11 patients treated with sorafenib, with or without everolimus, for recurrent HCC after LT [3]. The median survival from the start of treatment was 5 months. One patient died because of massive gastrointestinal bleeding [4]. Adverse events or intolerance motivated sorafenib withdrawal in 36% and dose reduction in 91%. From July 2010 to July 2013, we treated four additional patients with sorafenib, in association with everolimus (Table 1). The maximum daily tolerated dose of sorafenib was 400 mg. The median treatment duration was 111 days (range 77–144 days). Grade 2 adverse events occurred in two patients. Grade 3 cholestasis occurred in another patient. The last patient was hospitalized for severe diarrhea 4 months after starting sorafenib. He started to complain of diarrhea 2 weeks after starting treatment. After reduction of sorafenib to 400 mg daily, intermittent diarrhea persisted but the patient’s condition improved. He had stable disease at computed tomographic scan performed 3 months after the start of treatment. During hospitalization, grade 3 diarrhea associated with
Main characteristics of four patients with recurrent hepatocellular carcinoma after liver transplantation treated with sorafenib
Patient Age/sex Time to recurrence (months) Localization of recurrence Baseline serum a-fetoprotein (ng/ml) Immune suppression Maximum sorafenib dose (mg/day) Duration of treatment with sorafenib (days) Adverse events (grades 3–4) Best tumor response Outcome Survival after OLT (days) Survival after sorafenib start (days)
1
2
3
4
56/F 3 Lung 217 EVR 400 183 Noa Progression Dead 628 532
56/M 31 Liver, bone 1210 TAC-EVR 400 77 Grade 3 cholestasis Progression Dead 1431 488
53/M 46 Liver, lung, peritoneum 2 EVR 400 78 Nob Progression Alive 1501 104
50/M 15 Liver, lung 4 EVR 400 144 Grade 3 diarrhea Stable disease Dead 978 161
EVR, everolimus; F, female; M, male; OLT, orthotopic liver transplantation; TAC, tacrolimus. a Grade 2 fatigue and cholestasis. b Grade 2 fatigue, urticaria, and hand–foot skin reaction; grade 1 fever and weight loss.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
578 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 5
worsening conditions persisted despite interruption of treatment with sorafenib and everolimus. Blood, urine, and stools cultures were negative. Stools were also negative for Clostridium difficile toxin, adenovirus, rotavirus, and parasites. The patient’s clinical conditions worsened progressively and he developed coma. Seventeen days after admission, he died. Overall, including the 11 patients of the first series, from the start of the treatment, the median survival was 5 months (range 1–18 months). From the date of LT, the median survival was 33 months (range 6–106 months). Grade 3 adverse events occurred in 7/15 patients. Two patients (13%) died, probably because of drug toxicity. Interestingly, both the patients were taking everolimus plus sorafenib and showed a partial response at computed tomographic scan. Our data confirm that in patients with recurrent HCC after LT, the combination regimen sorafenib plus everolimus is poorly tolerated and can be associated with relevant treatment-related mortality. Albeit difficult to
perform, we advocate an international multicenter randomized sorafenib versus placebo study to assess this controversial topic.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
Sposito C, Mariani L, Germini A, Reyes MF, Bongini M, Grossi G, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case–control study. J Hepatol 2013; 59:59–66. Staufer K, Fischer L, Seegers B, Vettorazzi E, Nashan B, Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int 2012; 25:1158–1164. Zavaglia C, Airoldi A, Mancuso A, Vangeli M, Vigano` R, Cordone G, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. Eur J Gastroenterol Hepatol 2013; 25:180–186. Mancuso A, Airoldi A, Vigano R, Pinzello G. Fatal gastric bleeding during sorafenib treatment for hepatocellular carcinoma recurrence after liver transplantation. Dig Liver Dis 2011; 43:754.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Chinese patients should be explored in future. However, the potential limitation of this study is that it has only a small number of BCS patients enrolled prospectively during a 6-month period, which might require external validity. Certainly, it is often difficult to obtain a larger sample size from a single center during a relatively short period, given the rarity of this disease. Ideally, a nationwide epidemiological study should be carried out to evaluate the prevalence of thrombotic risk factors in Chinese BCS patients.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3
4
5
6
7
Valla DC. Primary Budd–Chiari syndrome. J Hepatol 2009; 50:195–203. Seijo S, Plessier A, Hoekstra J, Dell’era A, Mandair D, Rifai K, et al. Good long-term outcome of Budd–Chiari syndrome with a step-wise management. Hepatology 2013; 57:1962–1968. Qi X, Wu F, Ren W, He C, Yin Z, Niu J, et al. Thrombotic risk factors in Chinese Budd–Chiari syndrome patients. An observational study with a systematic review of the literature. Thromb Haemost 2013; 109:878–884. Qi X, Zhang C, Han G, Zhang W, He C, Yin Z, et al. Prevalence of paroxysmal nocturnal hemoglobinuria in Chinese patients with Budd–Chiari syndrome or portal vein thrombosis. J Gastroenterol Hepatol 2013; 28:148–152. Qi X, He C, Han G, Yin Z, Wu F, Zhang Q, et al. Prevalence of the JAK2 V617F mutation in Chinese patients with Budd–Chiari syndrome and portal vein thrombosis: a prospective study. J Gastroenterol Hepatol 2012; 27:1036–1043. Wang H, Sun G, Zhang P, Zhang J, Gui E, Zu M, et al. JAK2 V617F mutation and 46/1 haplotype in Chinese Budd–Chiari syndrome patients. J Gastroenterol Hepatol 2014; 29:208–214. Cheng D, Xu H, Lu ZJ, Hua R, Qiu H, Du H, et al. Clinical features and etiology of Budd–Chiari syndrome in Chinese patients: a single-center study. J Gastroenterol Hepatol 2013; 28:1061–1067.
Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation: does mTOR inhibitors association augment toxicity? Giovanni Perricone, Andrea Mancuso, Luca S. Belli, Chiara Mazzarelli and Claudio Zavaglia, Hepatology and Gastroenterology Unit, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, Milan, Italy Correspondence to Giovanni Perricone, MD, Hepatology and Gastroenterology Unit, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy Table 1
Tel: + 39 026 444 4454; fax: + 39 026 444 2895; e-mails: [email protected], [email protected] Received 30 January 2014 Accepted 31 January 2014
Although sorafenib has shown a survival benefit in cirrhotics with advanced hepatocellular carcinoma (HCC), its efficacy and safety in the post-liver transplantation (LT) setting have scarcely been studied. Few retrospective cohort studies have been published so far. Recently, Sposito et al. [1] compared the outcome of 15 patients with HCC recurrence after LT treated with sorafenib with 24 historical controls who received best supportive care. The median survival from the start of treatment was 10.6 months for the sorafenib group compared with 2.2 months in the control group. No severe adverse event was registered. In the same setting, Staufer et al. [2] observed grade 3–4 adverse events in 92% of 13 patients (nine treated with mTOR inhibitors). Sorafenib was discontinued in 77%. We have already published data in 11 patients treated with sorafenib, with or without everolimus, for recurrent HCC after LT [3]. The median survival from the start of treatment was 5 months. One patient died because of massive gastrointestinal bleeding [4]. Adverse events or intolerance motivated sorafenib withdrawal in 36% and dose reduction in 91%. From July 2010 to July 2013, we treated four additional patients with sorafenib, in association with everolimus (Table 1). The maximum daily tolerated dose of sorafenib was 400 mg. The median treatment duration was 111 days (range 77–144 days). Grade 2 adverse events occurred in two patients. Grade 3 cholestasis occurred in another patient. The last patient was hospitalized for severe diarrhea 4 months after starting sorafenib. He started to complain of diarrhea 2 weeks after starting treatment. After reduction of sorafenib to 400 mg daily, intermittent diarrhea persisted but the patient’s condition improved. He had stable disease at computed tomographic scan performed 3 months after the start of treatment. During hospitalization, grade 3 diarrhea associated with
Main characteristics of four patients with recurrent hepatocellular carcinoma after liver transplantation treated with sorafenib
Patient Age/sex Time to recurrence (months) Localization of recurrence Baseline serum a-fetoprotein (ng/ml) Immune suppression Maximum sorafenib dose (mg/day) Duration of treatment with sorafenib (days) Adverse events (grades 3–4) Best tumor response Outcome Survival after OLT (days) Survival after sorafenib start (days)
1
2
3
4
56/F 3 Lung 217 EVR 400 183 Noa Progression Dead 628 532
56/M 31 Liver, bone 1210 TAC-EVR 400 77 Grade 3 cholestasis Progression Dead 1431 488
53/M 46 Liver, lung, peritoneum 2 EVR 400 78 Nob Progression Alive 1501 104
50/M 15 Liver, lung 4 EVR 400 144 Grade 3 diarrhea Stable disease Dead 978 161
EVR, everolimus; F, female; M, male; OLT, orthotopic liver transplantation; TAC, tacrolimus. a Grade 2 fatigue and cholestasis. b Grade 2 fatigue, urticaria, and hand–foot skin reaction; grade 1 fever and weight loss.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
578 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 5
worsening conditions persisted despite interruption of treatment with sorafenib and everolimus. Blood, urine, and stools cultures were negative. Stools were also negative for Clostridium difficile toxin, adenovirus, rotavirus, and parasites. The patient’s clinical conditions worsened progressively and he developed coma. Seventeen days after admission, he died. Overall, including the 11 patients of the first series, from the start of the treatment, the median survival was 5 months (range 1–18 months). From the date of LT, the median survival was 33 months (range 6–106 months). Grade 3 adverse events occurred in 7/15 patients. Two patients (13%) died, probably because of drug toxicity. Interestingly, both the patients were taking everolimus plus sorafenib and showed a partial response at computed tomographic scan. Our data confirm that in patients with recurrent HCC after LT, the combination regimen sorafenib plus everolimus is poorly tolerated and can be associated with relevant treatment-related mortality. Albeit difficult to
perform, we advocate an international multicenter randomized sorafenib versus placebo study to assess this controversial topic.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
Sposito C, Mariani L, Germini A, Reyes MF, Bongini M, Grossi G, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case–control study. J Hepatol 2013; 59:59–66. Staufer K, Fischer L, Seegers B, Vettorazzi E, Nashan B, Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int 2012; 25:1158–1164. Zavaglia C, Airoldi A, Mancuso A, Vangeli M, Vigano` R, Cordone G, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. Eur J Gastroenterol Hepatol 2013; 25:180–186. Mancuso A, Airoldi A, Vigano R, Pinzello G. Fatal gastric bleeding during sorafenib treatment for hepatocellular carcinoma recurrence after liver transplantation. Dig Liver Dis 2011; 43:754.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
