Jozsef Zsiros

Successful Treatment of Childhood High-Risk Hepatoblastoma With Dose-Intensive Multiagent Chemotherapy and Surgery: Final Results of the SIOPEL-3HR Study

PURPOSE The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. PATIENTS AND METHODS High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. RESULTS Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. CONCLUSION The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

Cisplatin versus Cisplatin plus Doxorubicin for Standard-Risk Hepatoblastoma

BACKGROUND Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection). RESULTS Between June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%). CONCLUSIONS As compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)

Impact of the Methotrexate Administration Dose on the Need for Intrathecal Treatment in Children and Adolescents With Anaplastic Large-Cell Lymphoma: Results of a Randomized Trial of the EICNHL Group

PURPOSE To compare the efficacy and safety of two methotrexate doses and administration schedules in children with anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS This randomized trial for children with ALCL was based on the Non-Hodgkins Lymphoma-Berlin-Frankfurt-Muenster 90 (NHL-BFM90) study protocol and compared six courses of methotrexate 1 g/m2 over 24 hours and an intrathecal injection (IT) followed by folinic acid rescue at 42 hours (MTX1 arm) with six courses of methotrexate 3 g/m2 over 3 hours followed by folinic acid rescue at 24 hours without IT (MTX3 arm). This trial involved most European pediatric/lymphoma study groups and a Japanese group. RESULTS Overall, 352 patients (96% ALK positive) were recruited between 1999 and 2005; 175 were randomly assigned to the MTX1 arm, and 177 were assigned to the MTX3 arm. Ninety-two percent of patients received protocol treatment. Median follow-up time is 3.7 years. Event-free survival (EFS) curves were superimposed with 2-year EFS rates (73.6% and 74.5% in the MTX1 and MTX3 arms, respectively; hazard ratio = 0.98; 91.76% CI, 0.69 to 1.38). Two-year overall survival rates were 90.1% and 94.9% in MTX1 and MTX3, respectively. Only two CNS relapses occurred (both in the MTX1 arm). Toxicity was assessed after 2,050 courses and included grade 4 hematologic toxicity after 79% and 64% of MTX1 and MTX3 courses, respectively (P < .0001); infection after 50% and 32% of courses, respectively (P < .0001); and grade 3 to 4 stomatitis after 21% and 6% of courses, respectively (P < .0001). CONCLUSION The results of the NHL-BFM90 study were reproduced in this large international trial. The methotrexate schedule of the NHL-BFM90 protocol including IT therapy can be safely replaced by a less toxic schedule of methotrexate 3 g/m2 in a 3-hour infusion without IT therapy.

Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study

Summary Background The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma. Methods SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1–A3: cisplatin 80 mg/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m2 per day in 24 h on days 1–3 and 22–24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m2 per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389. Findings We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91–100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67–88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65–87) and 3-year overall survival was 83% (73–93). 60 (97%) patients had grade 3–4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients). Interpretation The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding Cancer Research UK and Cancer Research Switzerland/Oncosuisse.

First line targeted radiotherapy, a new concept in the treatment of advanced stage neuroblastoma

33 previously untreated advanced stage neuroblastoma patients were treated with [131I]meta-iodobenzylguanidine (MIBG). The number of treatments varied between 2 and 7 per patient (mean 3). Toxicity was seldom severe. Only thrombocytopenia WHO-grade 4 was noticed. Response was documented before surgery for the primary tumour was performed. There was one complete response (CR), 18 partial responses (PR), 11 had stable disease (SD) and 3 had progressive disease (PD). After MIBG therapy and surgery, 12 of 33 patients achieved a CR. This approach is feasible, comparable to multidrug chemotherapy in efficacy and less toxic. Long term results are not known yet.

Whole-body MRI, including diffusion-weighted imaging, for staging lymphoma: Comparison with CT in a prospective multicenter study

To compare whole‐body magnetic resonance imaging (MRI), including diffusion‐weighted imaging (DWI), to computed tomography (CT) for staging newly diagnosed lymphoma.

Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma – A phase II trial of the childhood liver tumour strategy group (SIOPEL) ☆

PURPOSE To assess the clinical activity of irinotecan as single drug in children with refractory or recurrent hepatoblastoma. PATIENTS AND METHODS Four cycles of irinotecan were administered (20mg/m(2)/day intravenous (i.v.) infusion on days 1-5 and 8-12, every 21days) unless tumour progression occurred or resectability was achieved earlier. Tumour response was assessed according to modified SIOPEL and Response Evaluation Criteria In Solid Tumours (RECIST) criteria. Main end-points were best overall response rate (RR), early progression rate (EPR) and progression free survival (PFS). RESULTS Twenty-four eligible patients (median age 58.0months; 19 boys) were enrolled in the study (11 relapses, 13 refractory diseases). Of the 23 evaluable patients six had an overall partial response, 11 stable disease and six progressive disease, of which four were early progression (RR: 26%, EPR: 17%). In eight patients the residual tumour could be completely resected; seven patients became tumour free. At last follow-up 12 patients were alive (six with no evidence of disease, six with disease). PFS at 1year was 24%. Patients with relapse had a higher RR than patients with refractory disease (46% versus 8%) and patients with isolated lung lesions showed a better response than patients with other tumour localisations (50% versus 13%). The main grade 3-4 toxicities, diarrhoea and neutropenia, occurred in half of the patients. CONCLUSION Irinotecan has a significant anti-tumour activity and acceptable toxicity in patients with relapsed hepatoblastoma and therefore should be considered for the treatment of these patients. Exploration of the role of irinotecan in the initial treatment of hepatoblastoma is warranted.

Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study.

In an international study of systemic childhood ALCL, 12/463 patients had CNS involvement, three of which had isolated CNS disease. Comparative analysis of CNS positive and negative patients showed no difference in ALK positivity, immunophenotype, presence of B symptoms or other sites of disease. The lymphohistiocytic variant was over represented in the CNS positive group (36% vs. 5%). With multi‐agent chemotherapy, including high dose methotrexate, Ara‐C and intrathecal treatment, the event free and overall survival of the CNS positive group at 5 years were 50% (95%CI, 25–75%) and 74% (45–91%), respectively with a median follow up of 4.1 years. Pediatr Blood Cancer 2013;60:E118–E121.

MRI for staging lymphoma: Whole-body or less?

To assess whether whole‐body MRI detects more clinically relevant lesions (i.e., leading to a change in Ann Arbor stage) than an MRI protocol that only includes the head/neck and trunk (i.e., from cranial vertex to groin, excluding the arms) in patients with lymphoma.

Mutational analysis ofBax andBcl-2 in childhood acute lymphoblastic leukaemia

In childhood acute lymphoblastic leukaemia there are large interpatient variations in levels of the apoptosis‐regulating proteins Bax and Bcl‐2, but the molecular basis for this variation is unknown. Point‐mutations in bax have been reported in cell lines derived from haematological malignancies. Frameshift mutations, which result in reduced Bax levels, have also been found in colon cancer of the microsatellite mutator phenotype. Bcl‐2 overexpression, or gain of function mutations in the open reading frame (ORF) or in the translational repressor, the upstream ORF (uORF) of bcl‐2, might also be important in deregulating its function or expression. We have therefore analyzed 21 bone marrow aspirates from untreated childhood acute lymphoblastic leukaemia and 2 from myeloid leukaemia for mutations in bax and bcl‐2. DNA sequence analysis of the ORFs of bax and bcl‐2 and of the uORF of bcl‐2 revealed no mutations, despite the large range in expression levels. Thus, mutations within the (u)ORFs of bax and bcl‐2 that (in)activate or deregulate Bax and Bcl‐2 are infrequent in primary childhood acute leukaemia and do not play a major role in regulation of the encoded proteins in this disease. Int. J. Cancer (Pred. Oncol.) 79:273–277, 1998.© 1998 Wiley‐Liss, Inc.