Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases.

PURPOSE: To report on the treatment of patients with newly diagnosed neuroblastoma presenting with spinal cord compression (SCC). PATIENTS AND METHODS: Of 1,462 children with neuroblastoma registered between 1979 and 1998, 76 (5.2%) presented with signs/symptoms of SCC, including motor deficit in 75 patients (mild in 43, moderate in 22, severe [ie, paraplegia] in 10), pain in 47, sphincteric deficit in 30, and sensory loss in 11. Treatment of SCC consisted of radiotherapy in 11 patients, laminectomy in 32, and chemotherapy in 33. Laminectomy was more frequently performed in cases with favorable disease stages and in those with severe motor deficit, whereas chemotherapy was preferred in patients with advanced disease. RESULTS: Thirty-three patients achieved full neurologic recovery, 14 improved, 22 remained stable, and eight worsened, including three who become paraplegic. None of the 10 patients with grade 3 motor deficit, eight of whom were treated by laminectomy, recovered or improved. In the other 66 patients, the neurologic response to treatment was comparable for the three therapeutic modalities. All 11 patients treated by radiotherapy and 26 of 32 patients treated by laminectomy, but only two of 33 treated by chemotherapy, received additional therapy for SCC. Fifty-four of 76 patients are alive at time of the analysis, with follow-up of 4 to 209 months (median, 139 months). Twenty-six (44%) of 54 survivors have late sequelae, mainly scoliosis and sphincteric deficit. CONCLUSION: Radiotherapy, laminectomy, and chemotherapy showed comparable ability to relieve or improve SCC. However, patients treated with chemotherapy usually did not require additional therapy, whereas patients treated either with radiotherapy or laminectomy commonly did. No patient presenting with (or developing) severe motor deficit recovered or improved. Sequelae were documented in 44% of surviving patients.

Place of meta-[131I]iodobenzylguanidine in the treatment of neuroblastoma: the Genoa experience.

The aim of this paper is to focus on our previous experience with the treatment of Group 3 and 4 neuroblastoma patients and on the therapeutic use of [131I]MIBG, to better define the role of this radioactive drug in the treatment of neuroblastoma (NB). Analysis of the studies on Group 3 patients treated with chemotherapy and surgery showed that the progression-free survival (PFS) increased from 45% for patients treated before 1985 to 63% for patients treated in the period of 1985-1989 and to 78% for patients treated after 1989. [131I]MIBG administered in 17 Group 3 patients who did not achieve a radical excision of the primary resulted in 7 partial response (PR) and 5 minor response (MR), with 10 cases of long term survival. Results in Group 4 patients confirmed the good prognosis in the subset of children aged 6-12 months at diagnosis (PFS 86% at 5 years). In patients aged > 12 months at diagnosis intensive induction chemotherapy induced a higher response rate of 69% and PFS was 26% at 5 years. [131I]MIBG administered in advanced stage 4 patients induced a response in 50% of the cases (2 complete response [CR], 13 PR and 2 MR out of 34 children) and 8 children treated for residual primary (4 cases) or residual bone metastases (4 cases) are long term survivors. We conclude that [131I]MIBG is the treatment of choice in Group 3 patient with a residual primary tumor and could contribute to consolidate the response obtained in Group 4 patients.

Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Italian Cooperative Group for Neuroblastoma.

PURPOSE: To define factors that influence outcome in children with localized but unresectable neuroblastoma by retrospective investigation of response to therapy and outcome in 21 Italian institutions. PATIENTS AND METHODS: Of 145 assessable children diagnosed between 1979 and 1990, 77 were treated between 1979 and 1984 with three consecutive standard-dose (SD) protocols, and 68 between 1985 and 1990 with a high-dose (HD) protocol. All protocols included chemotherapy, followed by resection of primary tumor if feasible. If at least partial resection was achieved, consolidation therapy followed, except that from 1985 onward, patients considered disease-free following surgery received no further treatment. RESULTS: Ninety-four of 145 patients (65%) achieved a complete response (CR) or partial response (PR) with chemotherapy and 75 (52%) subsequently underwent complete resection of the primary tumor. Eighty-one patients are alive (73 without disease, eight with disease), 63 have died, and one is lost to follow-up. The 5-year overall survival (OS) rate is 55% and progression-free survival (PFS) rate 50%. Both OS and PFS correlated with response to chemotherapy, removal of primary tumor, HD therapy, and serum lactate dehydrogenase (LDH) levels. Infants (< 1 year), independent of primary tumor site, and children aged 1 to 15 years with a nonabdominal primary tumor, did better compared with children aged 1 to 15 years with an abdominal primary tumor (PFS, 72% and 64% v 30%; P < .001 and < .01, respectively). Outcome of this last group improved with the HD protocol (PFS, 40% v 23%; P = .01). CONCLUSION: In children with unresectable neuroblastoma, risk categories can be defined by age and primary tumor site. HD chemotherapy should be investigated for the poor-risk category age 1 to 15 years with an abdominal primary tumor.

Enhanced chromosomal fragility in neuroblastoma: correlation with poor prognosis.

In a previous study we demonstrated spontaneous fragility and hypersensitivity to fragile site induction by aphidicolin in lymphocytes from some neuroblastoma patients and their parents. Here we report data based on a total of 40 patients and 37 families. Possible correlations between higher sensitivity to aphidicolin and a variety of personal and clinical characteristics were verified. Patients with a poor prognosis generally proved to be more susceptible to fragile site induction.

Disseminated neuroblastoma (stage IV and IV-S) in the first year of life. Outcome related to age and stage. Italian Cooperative Group on Neuroblastoma.

BACKGROUND: Infants (age 0-11 months) with disseminated neuroblastoma are known to have a better prognosis than older children with the disease, but there is little information regarding factors that influence the outcome of the disease in these patients. METHODS: The authors report a series of 110 infants with disseminated neuroblastoma with disease diagnosed between March 1976 and February 1991 in 21 institutions participating in the Italian Cooperative Group on Neuroblastoma (ICGNB). Of the 110 infants, 34 had Stage IV disease, and 76 had Stage IV-S disease. RESULTS: The 5-year survival probability was 77% for all patients, 71% for those with Stage IV disease, and 81% for those with Stage IV-S disease. Of the 34 infants with Stage IV disease, the 9 who were 5 months or younger at the time of disease diagnosis are all alive (1 with active disease) at 7-143 months after diagnosis, whereas of the 25 infants who were 6-11 months of age at the time of disease diagnosis, 10 have died. Of the 76 infants with Stage IV-S disease, 12/64 who were 5 months of age or younger at the time of disease diagnosis died (mostly of massive hepatomegaly); 9 of these deaths occurred in infants with disease diagnosed before they were 2 months old, whereas 1 death occurred in the 12 infants with disease diagnosed when they were 6-11 months old. Four infants with Stage IV-S disease achieved complete disease remission and subsequently had relapse of disease. High levels of serum LDH and low urinary excretion of vanillylmandelic acid were associated with worse prognosis. CONCLUSIONS: The authors suggest that infants older than 6 months of age who have Stage IV disease require aggressive therapy. For infants with disease diagnosed before they are 2 months old, Stage IV-S disease may have a worse prognosis than Stage IV disease.

Association of cytogenetic abnormalities in a neuroblastoma and fragile sites expression.

A 15 month old boy with a stage IV right suprarenal gland neuroblastoma showed a number of raised biochemical parameters, whilst catecholamines and skeletal survey were normal. Treatment with peptichemio failed to give a clinical response. Histological evidence of neuroblastoma infiltration in the bone marrow aspirate was absent. Immunofluorescence on sedimented cells was negative using antibody UJ223.8, PI153/3 and H11; only UJ308 and to a lesser extent UJ13A gave positive results. After 21 days, however, the same cells in culture showed highly differentiated dendritic processes. Thirty-seven percent metaphases from bone marrow aspirate showed the following karyotype 45XY, del (1) (p32), and two markers. Mar1 = der (2) t (2; 2) (2qter----2q14::2p24----2qter). Mar2 = der (15) t (15; 2) (15qter----15p11::2p11----2pter). Treatment with methotrexate reduced the aberrant mitoses rate to 2%. N-myc in situ hybridisation showed significant signal on both markers confirming the cytogenetic interpretation. Peripheral blood lymphocytes at 72 h showed a higher level of breaks per cell than control. After treatment with aphidicolin (APC) or methotrexate (MTX) for the last 24 h, to induce fragile sites, the incidence of breaks per cells was increased. Moreover 11.4% of APC-induced breaks were in 1p31-32 (mean of normal controls = 2.3%). The mother presented an increased sensitivity to the inducibility of fragile sites, while the father's lymphocytes showed values within the control range. The genetic changes produced by the abnormalities on chromosomes 1 and 2 might be related to tumour progression. Furthermore this is the first description of correlation between a high frequency of fragile site 1p31-32 induced by APC in the patient's lymphocytes and deletion of 1p32 in tumour cells. The interpretation of these findings and of other similar correlations needs further study.

Tumor response and toxicity after single high-dose versus standard five-day divided-dose dactinomycin in childhood rhabdomyosarcoma.

This report deals with a randomized prospective multicentric clinical trial in childhood rhabdomyosarcoma (RMS) conducted to evaluate the toxicity and the effectiveness of dactinomycin (ACT-D) administered as high, single doses v five-day, divided doses administered in combination with vincristine (VCR) and cyclophosphamide (CYC). Fifty-five group III evaluable patients (pts) less than 15 years of age with tumor size greater than 5 cm in diameter, without high-risk features of CNS involvement, and 15 group IV RMS pts were randomized to receive VAC as primary chemotherapy (CT): VCR, 1.5 mg/m2 intravenously (IV) days 1 and 8; CYC, 275 mg/m2 IV days 1 through 5; and ACT-D, 0.45 mg/m2 IV days 1 through 5 every 28 days for three cycles (33 pts), or VAC-M: CYC, 150 mg/m2 intramuscularly (IM) days 1 through 7; VCR, 2.0 mg/m2 IV day 8; and ACT-D, 1.7 mg/m2 IV day 8 every 21 days for four cycles (37 pts). Major responses (complete plus partial responses [PR]) were obtained in 67% of the VAC pts and in 70% of the VAC-M pts. Toxic effects were low, and no increased toxicity was observed in pts treated with high, single-dose ACT-D. These results confirm the effectiveness and feasibility of single, high doses of ACT-D with the advantage of requiring less pt hospitalization.

Cancer mortality among relatives of children with soft-tissue sarcoma: a national survey in Italy.

Information was obtained on the living status or cause of death of 2223 close relatives of 195 children with soft-tissue sarcomas (STS) diagnosed under age 15. Three-hundred nine relatives had died, from all causes, before STS diagnosis in the index child. The expected figure estimated from age- and sex-specific mortality rates in Italy was 293.3. Cancer was reported as cause of death in 76 relatives (75.1 expected). Seven grandmothers, 2 aunts, 1 uncle and 0 mothers died from breast cancer vs. 4.6, 0.9, 0.0 and 0.2 expected. Three siblings died from cancer (0.2 expected, P less than 0.01), i.e. STS, ependymoma and non-Hodgkin lymphoma. These results confirm and expand previous observations that STS in children are associated with other cancers, particularly childhood and breast cancer, in members of the same family.

Phase II trial of cisplatin and etoposide in children with advanced soft tissue sarcoma: a report from the Italian Cooperative Rhabdomyosarcoma Group.

A phase II multicenter evaluation of cisplatin (90 mg/m2, Day 1) and etoposide (150 mg/m2, Days 2, 3, and 4) in 4-week cycles was carried out in 21 relapsed children with rhabdomyosarcoma (RMS) and six with non-RMS soft tissue sarcomas (NRSTS). Clinical responses were evaluated after four cycles. There were three complete responses (CRs) and four partial responses (PRs) among the 21 patients with RMS and no responses among the patients with NRSTS. The durations of the three CRs and the four PRs were 11, 9, and 8 months, and 5, 2, 2, and 1 month, respectively. Bone marrow and renal toxicity was cumulative and predictable, but not life threatening. The response rate (CR + PR = 33.3%) to cisplatin and etoposide warrants testing as front-line therapy for RMS.

Therapeutic approach to primary malignant epithelial tumors of the liver in childhood: results of the Italian retrospective study and literature survey.

We analyzed the clinical features and treatment of 23 hepatoblastomas (HPBs) and 16 hepatocellular carcinomas (HPCs) occurring in patients less than 19 years old, admitted to the Italian retrospective multicentric study, conducted between 1983 and 1985, on childhood malignant hepatic tumors. The median ages of the patients with HPB and HPC at diagnosis were 22.34 months and 96.23 months, respectively, with a male/female ratio of 0.7 and 1.7, respectively. Fourteen HPBs (61%) and 5 HPCs (31%) achieved surgical complete remission (CR). Of these, 11 HPB and all 5 HPC are still in CR with a median follow-up of 36 months and 3.5 years, respectively. One HPB and 1 HPC became resectable after a primary course of cis-platinum alone in the case of HPB and used with VP-16 in the case of HPC. All of the 9 HPBs and 11 HPCs, who never achieved CR, died of disease at a median interval from diagnosis of 5 and 2 months, respectively. The published therapeutic approaches for these tumors were also reviewed.

The outcome of Wilms' tumor in infants. Italy 1970-79.

Thirty-four infants under 1 year of age with Wilms' tumor were diagnosed and treated in 14 Italian pediatric oncology units during 1970-79. The 3-year survival rates decreased with higher group unilateral tumors: 95% in group I Wilms' tumor, 75% in group II and 20% in group III. The survival rates for children with group I and II Wilms' tumor were similar for those who were treated with surgery and chemotherapy and those who also received postoperative radiotherapy. During 1975-79 fewer patients with group I Wilms' tumor received radiotherapy (1 of 11) than during 1970-74 (4 of 6, p less than 0.05). All these children are alive at this writing.