The patient was subsequently able to complete her remaining 4 cycles of chemotherapy. Audiometric evaluation revealed grade 2 ototoxicity, resulting in a 50% reduction in the cisplatin dose for her third cycle. In addition, there was a 25% dose reduction of cyclophosphamide due to delayed hematopoietic recovery and vincristine was omitted due to persistent hyperbilirubinemia (40 μmol/L). Grade 3 ototoxicity resulted in a 75% dose reduction of cisplatin for the fourth cycle with full-dose administration of cyclophosphamide and vincristine. Prophylactic defibrotide (25 mg/kg/d) was administered during the third and fourth maintenance cycles and ursodeoxycholic acid was continued throughout the duration of therapy. During cycles 5 and 6, cisplatin was completely omitted due to grade 4 ototoxicity and cyclophosphamide and vincristine were administered at full dose. There was no further recurrence of HSOS. The patient remained in clinical and radiologic remission for 8 months following the completion of therapy. Subsequent surveillance magnetic resonance imaging revealed disease recurrence in the right ventricular frontal horn.
The incidence of HSOS after HSCT in children has been reported by a number of groups and ranges between 11% and 60%, with a mean incidence of 25%.8 Risk factors in HSCT recipients include younger age (<6.7 y), previous liver irradiation, previous Gemtuzumab ozogamicin, prior hepatic disease, busulfan-containing conditioning regimens, and total body irradiation, with a higher risk for the latter 2 when administered in conjunction with cyclophosphamide. An increased risk is seen after HSCT for neuroblastoma, familial hemophagocytic lymphohistiocytosis, and osteopetrosis.8 The incidence of HSOS after therapy for Wilms tumor ranges from 1.2% to 8%9 with actinomycin-D identified as the primary etiological agent. Additional risk factors in this group include young age, previous abdominal radiotherapy, right-sided tumors, and lower body weight.10–12 HSOS has also been reported during treatment for childhood rhabdomyosarcoma9,13–19 with an incidence of 1.2% to 5.3%.14,18 Identified risk factors in this population include VAC (vincristine, actinomycin-D, and cyclophosphamide) chemotherapy and age <36 months. There is a single report of HSOS occurring in a 2-year-old boy with recurrent yolk sac tumor receiving VAC chemotherapy20 and a report of HSOS after 2 doses of actinomycin-D in a 14-year-old girl with a paraspinal primitive neuroectodermal tumor who had received prior combination chemotherapy with etoposide, ifosfamide, cyclophosphamide, doxorubicin, vincristine, and external beam radiation partly involving the liver.20 In addition, HSOS is a well-reported complication of oral 6-thioguanine during acute lymphoblastic leukemia (ALL) therapy,21,22 while there have been anecdotal reports of HSOS during induction therapy for pediatric ALL23,24 and induction therapy for primary CNS lymphoma.25
Although the incidence of HSOS in children undergoing HSCT, treatment for Wilms tumor, rhabdomyosarcoma, and ALL, has been established within large co-operative group trials, there are no reports within such trials of HSOS in children undergoing therapy for medulloblastoma.26–29 Outside of the large co-operative group trials, there have only been 2 prior case reports of HSOS following standard-dose chemotherapy for medulloblastoma.30,31 One patient was a 19-month-old girl who developed fatal HSOS after 8 days of a vincristine, carboplatin, and lomustine based regimen, despite supportive measures and treatment with low-molecular weight heparin.30 The second was a 14-year-old boy who initially received 36 Gy craniospinal radiation with a 20 Gy boost to the posterior fossa with concurrent weekly vincristine and developed severe HSOS 4 days after completion of the first cycle of a vincristine, carboplatin, and cyclophosphamide based regimen. He was treated with 1 week of oral ursodeoxycholic acid and 3 days of parenteral N-acetylcysteine, with resolution of the HSOS. To prevent recurrence, the patient subsequently received a reduction in the frequency of cyclophosphamide, with administration every second cycle.31 Our case further highlights the occurrence of HSOS outside the traditional settings discussed above. HSOS may have been precipitated in our patient by a number of factors including cyclophosphamide, young age, and scatter to the liver from her prior craniospinal radiotherapy. Notably, the only feature common to all 3 cases was the administration of vincristine, which also forms part of therapy for Wilms tumor, rhabdomyosarcoma, and ALL. This suggests that vincristine may not be an innocent bystander, but could have a potentiating role in the development of HSOS.
Severity of HSOS is one of the key factors influencing the outcome of patients, with mortality in excess of 85% in severe disease,5 however, assessment of severity is difficult as it is generally retrospectively defined. Three grades of increasing severity have been classified: mild (resolution of symptoms, decrease of serum bilirubin <34.2 μmol/L, with or without specific treatment), moderate (clinical signs and symptoms of progressive disease, including ascites and/or pleural effusion but no multiorgan failure), and severe (multiorgan failure needing oxygen or mechanical ventilation and/or renal failure and/or encephalopathy).1 In addition to supportive care measures, a number of therapeutic strategies have attempted to improve outcome including N-acetylcysteine,24,31,32 high-dose methylprednisolone,16,33 recombinant human tissue plasminogen activator alone34,35 and in combination with heparin,9,36,37 antithrombin III,23,38 and prostaglandin E1 in combination with heparin39 and thrombomodulin,40 although the data for their use is limited. There is increasing evidence, however, for the use of defibrotide, a polydisperse oligonucleotide with local antithrombotic, anti-ischemic, and anti-inflammatory activity. The therapeutic potential of defibrotide has largely been studied in patients who developed HSOS after HSCT. Our case reports successful treatment with defibrotide for HSOS after standard-dose chemotherapy for childhood medulloblastoma, with the dose of 25 mg/kg/d based on the recommendations from the outcome of a recent dose-finding trial.41
In summary, our case highlights the occurrence of HSOS in a child receiving standard-dose chemotherapy for medulloblastoma after craniospinal radiotherapy. A diagnosis of HSOS should not be excluded based on the absence of classic risk factors and disease settings, with early consideration given in the presence of premature, unexplained thrombocytopenia after chemotherapy. Defibrotide was an effective therapeutic strategy in our case.
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