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Totadri S, Trehan A, Bansal D, Jain R. Sinusoidal Obstruction Syndrome during Treatment for Wilms' Tumor: A Life-threatening Complication. Indian J Med Paediatr Oncol 2018; 38:447-451. [PMID: 29333010 PMCID: PMC5759062 DOI: 10.4103/ijmpo.ijmpo_188_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Context: Survival rates exceed 90% in Wilms' tumor (WT). Actinomycin-D (ACT-D) which is indispensable in the management of WT is associated with the development of sinusoidal obstruction syndrome (SOS), a potentially fatal complication. Aims: The aim is to study the presentation, management, and outcome of SOS complicating ACT-D administration in WT. Settings and Design: Retrospective file review conducted in a Pediatric Hematology-Oncology unit. Materials and Methods: Patients diagnosed and treated for WT from January 2012 to December 2015 were analyzed. SOS was diagnosed clinically, based on McDonalds criteria, requiring two of the following: jaundice, hepatomegaly and/or right upper quadrant pain, weight gain with or without ascites. Results: Of 104 patients treated, SOS occurred in 5 (4.8%). Age: 6 months to 5 years, 3 were girls. Tumor involved left kidney in 3, right in 1 and a horseshoe kidney in 1. Histopathology was consistent with WT in 4 and clear cell sarcoma kidney in 1. One had pulmonary metastases. Three developed SOS preoperatively and two during adjuvant chemotherapy. None received radiotherapy. Clinical manifestations comprised of jaundice, hepatomegaly, ascites/weight gain, respiratory distress, hypotension, and encephalopathy. Laboratory findings included thrombocytopenia, elevated serum transaminases, and coagulopathy. Treatment included fluid restriction, broad spectrum antibiotics, and transfusional support. Two children received N-acetyl cysteine infusion. Defibrotide was administered to two patients. Four recovered and one succumbed to multi-organ failure. Two patients were safely re-challenged with 50% doses of ACT-D. Conclusions: SOS is a clinical diagnosis. Systematic supportive care can enable complete recovery. Under close monitoring, re-challenge of ACT-D can be performed in gradually escalating doses.
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Affiliation(s)
- Sidharth Totadri
- Department of Pediatrics, Advanced Pediatrics Center, Pediatric Hematology-Oncology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amita Trehan
- Department of Pediatrics, Advanced Pediatrics Center, Pediatric Hematology-Oncology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepak Bansal
- Department of Pediatrics, Advanced Pediatrics Center, Pediatric Hematology-Oncology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Richa Jain
- Department of Pediatrics, Advanced Pediatrics Center, Pediatric Hematology-Oncology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Hepatic sinusoidal obstruction syndrome during chemotherapy for childhood medulloblastoma: report of a case and review of the literature. J Pediatr Hematol Oncol 2014; 36:76-80. [PMID: 24276042 PMCID: PMC3872829 DOI: 10.1097/mph.0b013e3182a8f352] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatic sinusoidal obstruction syndrome (HSOS), also known as veno-occlusive disease, is a well-recognized toxic complication after autologous and allogeneic hematopoietic stem cell transplant, during treatment of Wilms tumor and rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy due to oral 6-thioguanine. However, its occurrence in the context of chemotherapy regimens for other childhood malignancies is rare. We report a 5-year-old girl with high-risk anaplastic medulloblastoma, who developed severe HSOS during her second cycle of maintenance chemotherapy, consisting of vincristine, cisplatin, and cyclophosphamide. She was treated with defibrotide with complete resolution of the HSOS. These findings and a review of the literature, highlight the occurrence of HSOS in children outside the established settings of hematopoietic stem cell transplantation, Wilms tumor, rhabdomyosarcoma, and acute lymphoblastic leukemia.
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Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, Veys P, Potter MN. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol 2013; 163:444-57. [PMID: 24102514 DOI: 10.1111/bjh.12558] [Citation(s) in RCA: 220] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
DIAGNOSIS It is recommended that the diagnosis of veno-occlusive disease (sinusoidal obstruction syndrome) [VOD (SOS)] be based primarily on established clinical criteria (modified Seattle or Baltimore criteria) (1A). Ultrasound imaging may be helpful in the exclusion of other disorders in patients with suspected VOD (SOS) (1C). It is recommended that liver biopsy be reserved for patients in whom the diagnosis of VOD (SOS) is unclear and there is a need to exclude other diagnoses (1C). It is recommended that liver biopsies are undertaken using the transjugular approach in order to reduce the risks associated with the procedure (1C). It is suggested that the role of plasminogen activator inhibitor 1 levels remains an area for further research but that these levels should not form part of the routine diagnostic work-up for VOD (SOS) at present (2C). RISK FACTORS It is recommended that patients are assessed for risk factors for VOD (SOS) and that these risk factors are addressed prior to haematopoietic stem cell transplantation (1A). PROPHYLAXIS Defibrotide is recommended at a dose of 6.25 mg/kg intravenously four times daily for the prevention of VOD (SOS) in children undergoing allogeneic stem cell transplantation with the following risk factors: pre-existing hepatic disease, second myeloablative transplant, allogeneic transplant for leukaemia beyond second relapse, conditioning with busulfan-containing regimens, prior treatment with gemtuzumab ozogamicin, diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis (1A). Defibrotide is suggested at a dose of 6.25 mg/kg intravenously four times daily for the prevention of VOD (SOS) in adults undergoing allogeneic stem cell transplantation with the following risk factors: pre-existing hepatic disease, second myeloablative transplant, allogeneic transplant for leukaemia beyond second relapse, conditioning with busulfan-containing regimens, prior treatment with gemtuzumab ozogamicin, diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis (2B). Prostaglandin E1 is not recommended in the prophylaxis of VOD (SOS) due to lack of efficacy and toxicity (1B). Pentoxifylline is not recommended in the prophylaxis of VOD (SOS) due to lack of efficacy (1A). Ursodeoxycholic acid is suggested for use in the prophylaxis of VOD (SOS) (2C). Heparin (unfractionated and low molecular weight) is not suggested for use in the prophylaxis of VOD (SOS) due to the risk of increased toxicity (2B). Antithrombin is not suggested for the prophylaxis of VOD (SOS) due to lack of efficacy (2B). TREATMENT Defibrotide is recommended in the treatment of VOD (SOS) in adults and children (1B). Tissue plasminogen activator is not recommended for use in the treatment of VOD (SOS) due to the associated risk of haemorrhage (1B). N-acetylcysteine is not routinely recommended for use in the treatment of veno-occlusive disease due to lack of efficacy (1A). Methylprednisolone may be considered for use in the treatment of veno-occlusive disease with the appropriate caveats of caution regarding infection (2C). Judicious clinical care, particularly in the management of fluid balance, is recommended in the management of VOD (SOS) (1C). Early discussion with critical care specialists and a specialist hepatology unit is recommended in the management of VOD (SOS) and other treatment options including transjugular intrahepatic portosystemic shunt or hepatic transplantation may be considered (1C). SUMMARY A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of veno-occlusive disease of the liver following haematopoietic stem cell transplantation (HSCT). This guideline includes recommendations for both prophylaxis and treatment of the condition and includes recommendations for children and adults undergoing HSCT.
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Affiliation(s)
- Fiona L Dignan
- Department of Haematology, Central Manchester NHS Foundation Trust, Manchester, UK
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Cheuk DK. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies. World J Transplant 2012; 2:27-34. [PMID: 24175193 PMCID: PMC3782230 DOI: 10.5500/wjt.v2.i2.27] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 10/18/2011] [Accepted: 03/20/2012] [Indexed: 02/05/2023] Open
Abstract
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a major complication of hematopoietic stem cell transplantation and it carries a high mortality. Prophylaxis for hepatic VOD is commonly given to transplant recipients from the start of conditioning through the early weeks of transplant. However, high quality evidence from randomized controlled trials is scarce with small sample sizes and the trials yielded conflicting results. Although various treatment options for hepatic VOD are available, most have not undergone stringent evaluation with randomized controlled trial and therefore it remains uncertain which treatment offers real benefit. It remains controversial whether VOD prophylaxis should be given, which prophylactic therapy should be given, who should receive prophylaxis, and what treatment should be offered once VOD is established.
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Affiliation(s)
- Daniel Kl Cheuk
- Daniel KL Cheuk, Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
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5
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Lee ACW, Goh PYT. Dactinomycin-induced Hepatic Sinusoidal Obstruction Syndrome Responding to Treatment with N-acetylcysteine. J Cancer 2011; 2:527-531. [PMID: 22043237 PMCID: PMC3204401 DOI: 10.7150/jca.2.527] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2011] [Accepted: 10/20/2011] [Indexed: 02/05/2023] Open
Abstract
Hepatic sinusoidal obstruction syndrome is commonly described in pediatric oncology as a complication of chemotherapy. It has also been occasionally reported in adult cancer patients. Treatment is largely supportive with fluid restriction. A 16-month-old girl with stage II Wilms tumor receiving post-nephrectomy chemotherapy with dactinomycin and vincristine developed hepatic sinusoidal obstruction syndrome with painful hepatomegaly, ascites with significant weight gain, grossly deranged liver function, severe thrombocytopenia, and reversal of blood flow in the portal vein on Doppler sonography. Treatment with N-acetylcysteine was followed by complete resolution of clinical signs and amelioration of laboratory abnormalities within 72 hours of treatment. N-acetylcysteine is a safe and probably an effective treatment for dactinomycin-induced hepatic sinusoidal obstructive syndrome.
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Affiliation(s)
- Anselm Chi-wai Lee
- 1. Children's Haematology and Cancer Centre, Mount Elizabeth Hospital, Singapore
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Farruggia P, Macaluso A, Tropia S, Di Marco F, Russo D, Grigoli A, Trizzino A, D'Angelo P. Hepatopathy-thrombocytopenia syndrome (HTS) after actinomycin-D therapy: report of three cases and review of the literature. Pediatr Hematol Oncol 2011; 28:237-43. [PMID: 21271778 DOI: 10.3109/08880018.2010.535118] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Hepatopathy-thrombocytopenia syndrome (HTS) is a severe complication very similar to vein occlusive disease (VOD), also known as hepatic sinusoidal obstructive syndrome (SOS), characterized by fever, hepatopathy (hepatomegaly with abnormal liver function tests), ascites, weight gain, jaundice, and thrombocytopenia (platelet count less than 25 × 10(3)/μL). It has been generally observed in patients with Wilms tumor, and is commonly associated to administration of actinomycin D. We report three children with Wilms tumor, with severe HTS/SOS, but had a different outcome, in spite of vigorous supportive therapy.
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Affiliation(s)
- Piero Farruggia
- Pediatric Hematology and Oncology, G. Di Cristina Children's Hospital, Italy
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7
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Cefalo MG, Maurizi P, Arlotta A, Scalzone M, Attinà G, Ruggiero A, Riccardi R. Hepatic veno-occlusive disease: a chemotherapy-related toxicity in children with malignancies. Paediatr Drugs 2010; 12:277-284. [PMID: 20799757 DOI: 10.2165/11531840-000000000-00000] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.
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8
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Ho VT, Revta C, Richardson PG. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. Bone Marrow Transplant 2007; 41:229-37. [PMID: 17994121 DOI: 10.1038/sj.bmt.1705899] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), remains one of the most serious and common complications after myeloablative hematopoietic stem cell transplantation (HSCT). Clinical diagnosis of hepatic VOD is based on the clinical triad of (1) painful hepatomegaly, (2) hyperbilirubinemia and (3) unexplained fluid retention. While milder cases usually resolve spontaneously, severe VOD is associated with a grim prognosis. Defibrotide (DF), a polydisperse mixture of single-stranded oligonucleotide with antithrombotic and fibrinolytic effects on microvascular endothelium, has emerged as an effective and safe therapy for patients with severe VOD. Multiple studies, including a recent large international multicenter phase II clinical trial, have demonstrated 30-60% complete remission rates with DF, even among patients with severe VOD and multiorgan failure. This article will review our current understanding of hepatic VOD, and update the clinical trial experience with DF and other potential therapies for this feared transplant complication.
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Affiliation(s)
- V T Ho
- Department of Adult Oncology, Center for Hematologic Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Abstract
Our goal is to provide a detailed review of veno-occlusive disease (VOD), Budd-Chiari syndrome (BCS), and congestive hepatopathy (CH), all of which results in hepatic venous outflow obstruction. This is the first article in which all three syndromes have been reviewed, enabling the reader to compare the characteristics of these disorders. The histological findings in VOD, BCS, and CH are almost identical: sinusoidal congestion and cell necrosis mostly in perivenular areas of hepatic acini which eventually leads to bridging fibrosis between adjacent central veins. Tender hepatomegaly with jaundice and ascites is common to all three conditions. However, the clinical presentation depends mostly on the extent and rapidity of the outflow obstruction. Although the etiology and treatment are completely different in VOD, BCS, and CH; the similarities in clinical manifestations and liver histology may suggest a common mechanism of hepatic injury and adaptation in response to increased sinusoidal pressure.
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Affiliation(s)
- Ulas-Darda Bayraktar
- Department of Internal Medicine, Interfaith Medical Center, 229 Parkville Ave Apt# 4B, Brooklyn, NY 11230, United States.
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Elli M, Pinarli FG, Dagdemir A, Acar S. Veno-occlusive disease of the liver in a child after chemotherapy for brain tumor. Pediatr Blood Cancer 2006; 46:521-3. [PMID: 16317738 DOI: 10.1002/pbc.20338] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Veno-occlusive disease (VOD) of the liver is a life-threatening state generally occurring as a complication of bone marrow transplantation or chemotherapy for Wilms' tumor. Veno-occlusive disease after standard dose chemotherapy in malignancies other than Wilms' tumor is rare and only a few cases have been published in children. We report a 19 month-old-girl with medulloblastoma who experienced fatal VOD of liver after only one course of chemotherapy including carboplatin, vincristine and CCNU for medulloblastoma. As our knowledge, this is the first report of VOD after standard dose chemotherapy for brain tumor in childhood.
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Affiliation(s)
- Murat Elli
- Department of Pediatric Oncology, Ondokuz Mayis University, Medical Faculty, Samsun, Turkey
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Ibrahim RB, Peres E, Dansey R, Abidi MH, Abella EM, Klein J. Anti-thrombin III in the management of hematopoietic stem-cell transplantation-associated toxicity. Ann Pharmacother 2004; 38:1053-9. [PMID: 15113990 DOI: 10.1345/aph.1d235] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)-conditioning regimens. DATA SOURCES Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). STUDY SELECTION AND DATA EXTRACTION Case reports, small case series, case-control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). DATA SYNTHESIS Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. CONCLUSIONS Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.
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Affiliation(s)
- Rami B Ibrahim
- Karmanos Cancer Institute, Harper University Hospital, The Detroit Medical Center, 3990 John R, Detroit, MI 48201-2020, USA.
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D'Antiga L, Baker A, Pritchard J, Pryor D, Mieli-Vergani G. Veno-occlusive disease with multi-organ involvement following actinomycin-D. Eur J Cancer 2001; 37:1141-8. [PMID: 11378345 DOI: 10.1016/s0959-8049(01)00097-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Actinomycin-D (Act-D) is a rare cause of veno-occlusive disease (VOD). Between 1993 and 1998, we managed 6 patients, all male, median age 19 months (range 6-48 months) who received Act-D for Wilms' tumour (n=4), clear cell sarcoma (n=1) or rhabdomyosarcoma (n=1). VOD presented with a median platelet count of 12 x 10(9)/l, INR 3.8, fibrinogen 16 mg/l, fibrinogen degradation products (FDPs) > or =80 microg/l, aspartate aminotransferase (AST) 6922 IU/l, bilirubin 47 micromol/l. In 3 cases, transient liver dysfunction and thrombocytopenia without neutropenia had been observed after a previous course of Act-D. All six children developed encephalopathy, hepatomegaly, ascites, reversed portal flow and renal impairment. All received mechanical ventilation and two required haemofiltration. The treatment was supportive. Severe Adult Respiratory Distress Syndrome developed in 3 patients, all of whom died. 3 patients recovered. The outcome of VOD with multi-organ failure is poor. Intravascular coagulopathy precedes and characterises severe VOD during Act-D treatment.
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Affiliation(s)
- L D'Antiga
- Department of Child Health, King's College Hospital, Denmark Hill, SE5 9RS, London, UK
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Bearman SI. Avoiding hepatic veno-occlusive disease: what do we know and where are we going? Bone Marrow Transplant 2001; 27:1113-20. [PMID: 11551020 DOI: 10.1038/sj.bmt.1703014] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hepatic venocclusive disease (VOD) is a common toxicity associated with myeloablative chemotherapy or chemoradiotherapy used to prepare patients for stem cell transplantation. A sizable proportion of patients who develop VOD die. It is clear that injury to endothelial cells and hepatocytes in zone 3 of the liver acinus is the initial event in the pathogenesis of VOD. What are less clear are the mechanisms of injury and whether this knowledge can be exploited. This manuscript will briefly review some recent data and discuss how that information has influenced clinical practice.
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Affiliation(s)
- S I Bearman
- Bone Marrow Transplant Program, University of Colorado Health Sciences Center, Denver 80262, USA
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