Jon Pritchard

Pretreatment prognostic factors for children with hepatoblastoma — results from the International Society of Paediatric Oncology (SIOP) Study SIOPEL 1

The aim of this study was to investigate the prognostic significance of pretreatment patient and tumour characteristics for overall (OS) and event-free (EFS) survival in 154 children affected by hepatoblastoma (HB) in the first prospective liver tumour study run by the International Society of Paediatric Oncology. The pretreatment characteristics studied were age, alpha-fetoprotein, platelet count, histology; from radiology: intrahepatic tumour extension (PRETEXT), lung metastases, enlarged hilar lymph nodes, vena cava or extrahepatic vena porta tumour extension and tumour focality. Five-year OS was 75% (95% confidence interval (CI) 68-82%) and EFS 66% (95% CI 59-74%). Both were univariately associated with PRETEXT and the presence of metastases. Additionally tumour focality and enlargement of hilar lymph nodes at diagnosis were univariately associated with EFS. In multivariate analysis, PRETEXT was the only predictor of OS; PRETEXT and metastases were predictors of EFS. There is a need to investigate further these factors to confirm their validity.

Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group.

PURPOSE To improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy, as well as to collect information on the epidemiology, natural history, and prognostic factors. PATIENTS AND METHODS Forty children with hepatocellular carcinoma (HCC) were registered onto the Group for Epithelial Liver Tumors International Society of Pediatric Oncologys first study from January 1990 to February 1994. The outcome could be analyzed in 39 of those patients. Disease was often advanced at the time of diagnosis; metastases were identified in 31% of the children and extrahepatic tumor extension, vascular invasion, or both in 39%. Multifocal tumors were common (56%). Thirty-three percent of tumors were associated with hepatic cirrhosis. All but two patients received preoperative chemotherapy (cisplatin and doxorubicin). RESULTS Partial response was observed in 18 (49%) of 37 patients; there was no response or progression in the remainder. Complete tumor resection was achieved in 14 patients (36%). Twenty patients (51%) never became operable. Overall survival at 5 years was 28%, and event-free survival was 17%. Most deaths resulted from tumor progression (26 of 28). Presence of metastases and pretreatment extent of disease system grouping at diagnosis had an adverse influence on overall survival in multivariate analysis. CONCLUSION Survival for pediatric HCC patients is significantly inferior to that for children with hepatoblastoma. Complete tumor excision remains the only realistic chance of cure, although it is often prevented by advanced disease. The presence of metastases is the most potent predictor of poor prognosis. A prospective worldwide cooperation in the field of pediatric HCC should be encouraged to look for novel therapeutic concepts.

Cisplatin, Doxorubicin, and Delayed Surgery for Childhood Hepatoblastoma: A Successful Approach—Results of the First Prospective Study of the International Society of Pediatric Oncology

PURPOSE Hepatoblastoma (HB) is a rare malignant liver tumor which occurs almost exclusively in childhood. In the 1970s, survival was approximately 20% to 30%. Since the introduction of cisplatin (PLA) and doxorubicin (DO) into the chemotherapy regimens used to treat these patients, the survival rate has improved dramatically. In most recent studies, primary surgery preceded chemotherapy. In this study by the liver group of the International Society of Pediatric Oncology the aim was to improve survival and reduce operative morbidity and mortality by using preoperative chemotherapy. PATIENTS AND METHODS After biopsy and assessment of pretreatment extent of disease all patients were treated with continuous 24-hour intravenous infusion of PLA 80 mg/m(2) followed by DO 60 mg/m(2) over 48 hours (PLADO). After four courses of this chemotherapy, patients were reassessed. Where possible, the primary tumor was resected and treatment completed with two more courses of chemotherapy. RESULTS One hundred fifty-four patients were registered in the study, and 138 received preoperative chemotherapy. One hundred thirteen (82%) showed a partial response with tumor shrinkage and serial decrease of serum alpha-fetoprotein levels. One hundred fifteen patients had delayed surgery, and 106 (including six with liver transplants) had complete resection of primary tumor. Five-year event-free survival was 66%, and overall survival was 75%. CONCLUSION This study demonstrates that international collaboration on a large scale is feasible. The toxicity of chemotherapy and morbidity of surgery were acceptable and the overall survival gratifyingly high. We now regard PLADO chemotherapy and delayed surgery to be the best available treatment for children with HB. Other treatment programs should be measured against this standard.

High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group

High dose myeloablative chemotherapy (“megatherapy”), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma.

Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis

1but the biological basis for this link is unknown. We report two cases of Langerhans-cell histiocytosis arising in the context of precursor T-lymphoblastic leukaemia/lymphoma. The Langerhans-cell histiocytosis cells and the precursor T-lymphoblastic leukaemia/lymphoma cells had identical rearrangements of the gene for T-cell receptor � , confirming a clonal relation between the two neoplastic diseases. In April, 1996, a 5-year-old boy presented with a mediastinal mass and a white-cell count of 2·9� 10 9 /L. Bone-marrow aspiration showed precursor T-cell acute lymphoblastic leukaemia; cerebrospinal fluid was negative. He had a complete response to the BerlinFrankfurt-Munster middle-risk schedule. However, from August, 1998, to October, 1998, he developed multiple penile lesions and a biopsy sample showed Langerhans-cell histiocytosis. Between 1998 and 2002 he received several chemotherapeutic regimens and radiotherapy (total dose 44·8 Gy), without a sustained complete response. Regimens included: etoposide and prednisolone; combinations of topical chlormethine, indometacin, betamethasone-depot, vinblastine, thalidomide, etanercept, and intralesional methylprednisolone; mercaptopurine, vinblastine, and 500 mg/m 2 metho

Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: The SIOPEL group experience

AIM OF THE STUDY To investigate the characteristics of patients with hepatoblastoma and low serum alpha-fetoprotein (AFP) at diagnosis. PATIENTS AND METHODS Inclusion of all 21 patients accrued onto SIOPEL trials, whose serum AFP was <100ng/ml at diagnosis. Slides of all 15 patients with available histological material were centrally reviewed. RESULTS Median age: 10 months. Disease extension at diagnosis: PRETEXT group: II (3 patients), III (10 patients) and IV (8 patients). Extra-hepatic extension: 8 patients. Multifocal tumour: 8 patients. Histology at review: wholly epithelial subtype: 11/15 patients including nine with a small-cell undifferentiated histology. OUTCOME only 9 patients achieved a partial response and 16 died. Median survival: 4.4 months. Two-year overall survival: 24% (confidence interval 10-45%). CONCLUSION This study clearly identifies patients with hepatoblastoma and low serum AFP at diagnosis as a high-risk subgroup with extensive disease at diagnosis, poor response to chemotherapy and a poor outcome.

Hepatoblastoma presenting with lung metastases

The prognosis of children who are affected by hepatoblastoma (HB) that presents with lung metastases has always been considered very poor. In light of the overall improvement in the survival of HB patients since the introduction of cisplatin (CDDP) in the therapeutic armament of this tumor, the question has been raised whether patients with metastatic HB also would benefit from this drug. The purpose of the current study was to address this issue by analyzing the treatment outcome of those patients presenting with metastases who entered into the first HB study on childhood liver tumors conducted by the International Society of Paediatric Oncology (SIOPEL 1).

Neuroblastoma: A review of 21 cases presenting with spinal cord compression

The records of 21 children with neuroblastoma presenting with spinal cord compression, encountered over 17 years, were reviewed. Thirteen patients (61%) survive, free of neuroblastoma, at intervals ranging from nine months to 192 months (median, 78 months) from the time of diagnosis. The explanation for this relatively high survival rate was sought in an analysis of the cases which took into account age, site, extent of disease, and histology. The most significant features to emerge were the unusually high proportion of children under 12 months of age at presentation (11 of 21) most of whom survive (9 of 11) and the low incidence (3 of 21) of detectable metastases at the time of diagnosis. The absence of a paraspinal mass was an unfavourable prognostic features (1 of 6 survives) whilst if a paraspinal mass was present, its anatomical level did not influence survival. In particular, children with retroperitoneal tumors fared no worse (survival, 6 of 7) than those with primary tumors at other sites (survival, 6 of 8). Morbidity was high (6 of 13), principally in infants with spinal cord compression from birth. Survival was also related to the histologic maturity of the tumor, even in the presence of metastases. Recommendations for management are made.

The effects of radiation therapy for hodgkin's disease in a child with ataxia telangiectasia. A clinical, biological and pathologic study

Stage I lymphocyte‐predominant Hodgkins disease was diagnosed in a 44‐month‐old girl. Although immune deficiency was suspected and IgA deficiency demonstrated, the diagnosis of an ataxia‐telangiectasia (AT)‐like syndrome was not confirmed until eight weeks later when results of studies on the radiosensitivity of cultured skin fibroblasts were available. The child had none of the usual physical stigmata of AT. Severe acute radiation damage followed the treatment of this child with standard doses of radiation therapy. Clinical, pathologic, and radiobiologic correlations are drawn. The diagnosis of a malignant lymphoma disorder in children under the age of five should alert clinicians to the possibility of immune deficiency and, even in the absence of classical physical signs, to AT in particular. Suggestions for the management of future similar cases are put forward.

Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: A report from the European Neuroblastoma Study Group “Survey”

BACKGROUND AND PROCEDURE Most deaths from neuroblastoma occur within 2 years of diagnosis but there have been several anecdotal reports of relapse and death after much longer periods of follow up. In order to investigate and quantify the risk of late events we analysed data for patients registered with the European Neuroblastoma Study Group between 1982 and 1990. Out of a total of 1,277 children registered, 427 were alive with follow-up beyond 5 years from diagnosis (median follow-up of 8.8 years, range 5-14 years). Of these 406 were in remission with no prior recurrence, 16 were in remission having experienced a relapse prior to 5 years, and 5 were alive with progressive disease. RESULTS For the 406 patients in remission with no prior relapse the 10 year progression free survival (PFS) was 96% (CI 94-98). For those aged over 1 year with stage 4 disease at diagnosis 10 year PFS was 88% (CI 79-96) compared to 98% (CI 97-99) for other patients combined, P< 0.001. In a multivariate analysis of all 422 patients in remission at 5 years, significant risk factors for subsequent relapse were age > 1 yr with stage 4 disease at diagnosis (relative risk 10.5, P < 0.001) and prior relapse (RR 4.2, P= 0.01). CONCLUSIONS The results of this study emphasise the importance of longterm follow-up of patients and the need for late monitoring of clinical trials in children with neuroblastoma. They also provide a baseline for comparison with future and hopefully more effective treatment programmes.