Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience.

BACKGROUND: Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. PROCEDURE: The trial protocol included induction chemotherapy (randomized "Standard" OPEC/OJEC vs. "Rapid" COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. RESULTS: Median follow-up was 12.9 (6.9-16.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate <80 ml/min/1.73 m(2), but no cases of chronic renal failure were documented. Endocrine complications (28.1% of children) included mainly hypogonadism and delayed growth. Four children developed second malignancies, three of them 5 years after diagnosis: one osteosarcoma, one carcinoma of the parotid gland and one ependymoma. There were no hematological malignancies or deaths in remission. CONCLUSIONS: This study analyzed a wide cohort of high-risk neuroblastoma survivors from a multi-institutional randomized trial and established the profile of long-term toxicity within the setting of an international clinical trial.

High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial.

BACKGROUND: The current standard treatment for patients with high-risk neuroblastoma includes initial induction chemotherapy with a 21-day interval between induction treatments. We aimed to assess whether an intensive chemotherapy protocol that had a 10-day interval between treatments would improve event-free survival (EFS) in patients aged 1 year or over with high-risk neuroblastoma. METHODS: Between Oct 30, 1990, and March 18, 1999, patients with stage 4 neuroblastoma who had not received previous chemotherapy were enrolled from 29 centres in Europe. Patients were randomly assigned to rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC) or standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC). Both regimens used the same total cumulative doses of each drug (except vincristine), but the dose intensity of the rapid regimen was 1.8-times higher than that of the standard regimen. The standard regimen was given every 21 days if patients showed haematological recovery, whereas the rapid regimen was given every 10 days irrespective of haematological recovery. Response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC). In responders, surgical excision of the primary tumour was attempted, followed by myeloablation (with 200 mg/m2 of melphalan) and haemopoietic stem-cell rescue. Primary endpoints were 3-year, 5-year, and 10-year EFS. Data were analysed by intention to treat. This trial is registered on the clinical trials site of the US National Cancer Institute website, number NCT00365755, and also as EU-20592 and CCLG-NB-1990-11. FINDINGS: 262 patients, of median age 2.95 years (range 1.03-20.97), were randomly assigned-132 patients to standard and 130 patients to rapid treatment. 111 patients in the standard group and 109 patients in the rapid group completed chemotherapy. Chemotherapy doses were recorded for 123 patients in the standard group and 126 patients in the rapid group. 97 of 123 (79%) patients in the standard group and 84 of 126 (67%) patients in the rapid group received at least 90% of the scheduled chemotherapy, and the relative dose intensity was 1.94 compared with the standard regimen. 3-year EFS was 24.2% for patients in the standard group and 31.0% for those in the rapid group (hazard ratio [HR] 0.86 [95% CI 0.66-1.14], p=0.30. 5-year EFS was 18.2% in the standard group and 30.2% in the rapid group, representing a difference of 12.0% (1.8 to 22.3), p=0.022. 10-year EFS was 18.2% in the standard group and 27.1% in the rapid group, representing a difference of 8.9% (-1.2 to 19.0), p=0.085. Myeloablation was given a median of 55 days earlier in patients assigned rapid treatment than those assigned standard treatment. Infective complications (numbers of patients with febrile neutropenia and septicaemia, and if given, time on antibiotic and antifungal treatment) and time in hospital were greater with rapid treatment. Occurrence of fungal infection was the same in both regimens. INTERPRETATION: Dose intensity can be increased with a rapid induction regimen in patients with high-risk neuroblastoma. There was no significant difference in OS between the rapid and standard regimens at 5 years and 10 years. However, an increasing difference in EFS after 3 years suggests that the efficacy of the rapid regimen is better than the standard regimen. A rapid induction regimen enables myeloablation to be given much earlier, which might contribute to a better outcome.

Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms' tumour: results of a randomised trial (UKW3) by the UK Children's Cancer Study Group.

PURPOSE: To determine if patients receiving preoperative chemotherapy with vincristine and actinomycin D for non-metastatic Wilms' tumour have a more advantageous stage distribution and so need less treatment compared to patients who have immediate nephrectomy, without adversely affecting outcome. METHODS: Between 1991 and 2001, a total of 205 patients with newly diagnosed non-metastatic renal tumours, of which 186 had Wilms' histologies, were randomly assigned either to immediate surgery or to 6 weeks preoperative chemotherapy and then delayed surgery. Both groups of children received postoperative chemotherapy according to tumour stage and histology determined at the time of nephrectomy. RESULTS: There was a significant improvement in the stage distribution for patients with Wilms' histologies receiving delayed surgery compared to those having immediate nephrectomy (stage I: 65.2% versus 54.3%; stage II: 23.9% versus 14.9%; stage III: 9.8% versus 29.8%, chi2 test for trend=7.02, p=0.008). This improvement resulted in 20% fewer children receiving radiotherapy or doxorubicin yet event-free and overall survivals at 5 years of 79.6% and 89.0%, respectively, were similar in the two groups. CONCLUSION: Six weeks of preoperative chemotherapy with vincristine and actinomycin D results in a significant shift towards a more advantageous stage distribution and hence reduction in therapy, while maintaining excellent event free and overall survival in children with non-metastatic Wilms' tumour. Around 20% of survivors were therefore spared the late-effects of doxorubicin or radiotherapy. Our results suggest that all children with non-metastatic Wilms' tumour should receive chemotherapy prior to tumour resection.

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

BACKGROUND: 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. PROCEDURE: In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. RESULTS: Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test). CONCLUSIONS: In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials.

Factors influencing early failure of central venous catheters in children with cancer.

BACKGROUND: The authors report the results of a prospective, multicenter, multidisciplinary study of central venous catheters (CVCs) in pediatric oncology patients analyzing factors involved in early failure. METHODS: Information was collected from parent-held records on the fate of 824 devices inserted over a 20-month period, 415 of which were no longer in situ. RESULTS: Within the first 7 weeks after insertion, there were 66 failures, all occurring in external lines. Accidental dislodgement was the principal reason for CVC failure (44 of 66, 67%). Detailed analysis of the reason for failure of this large subgroup showed 11 factors individually associated with early dislodgement, of which, 4 were independently associated with failure by multivariate analysis. These 4 variables were the use of multilumen catheters, the absence of a skin exit site suture, platelet transfusion at the time of insertion, and patient age less than 2 years. CONCLUSIONS: This study confirms the multiple influences on successful CVC usage. Our analysis supports the principle of only using multilumen lines when clinically essential. The findings also support the inception of randomized studies of fixation, particularly in infants.

Localized non-Hodgkin's lymphoma with B-cell histology: cure without cyclophosphamide? A report of the United Kingdom Children's Cancer Study Group on studies NHL 8501 and NHL 9001 (1985-1996).

We have examined the outcome for children treated on two consecutive United Kingdom Children's Cancer Study Group studies of localized B-cell non-Hodgkin's lymphoma (NHL). The first study (NHL 8501; 1985-1989) included cyclophosphamide in the treatment regimen at a total cumulative dose of 4 g/m2 whereas the regimen in the succeeding study (NHL 9001; 1990-1996) did not include cyclophosphamide. Ninety children with confirmed B-cell NHL were treated in the two studies (NHL 8501, n = 33 and NHL9001, n = 57). With a median follow-up of 7.5 years, overall survival for localized B-cell NHL did not differ between the two regimens with observed 3-year survivals of 94%[95% confidence interval (CI) 80-98%] and 89% (95% CI 79-95%) respectively (P = 0.47). There was also no difference in the event-free survival between children treated on regimen NHL 8501 and NHL 9001 [91% (95% CI 76-97%) vs 84% (95% CI 73-92%) after 3 years; P = 0.34]. Although the difference in the number of failed remissions between NHL 8501 and 9001 (0/33 vs 6/57) approached statistical significance (P = 0.08, Fisher's exact test), there was no overall statistical difference between the treatment failures on either regimen (P = 0.34). Substantial long-term survival can be achieved for many children with localized B-cell NHL without the use of cyclophosphamide. Further studies are needed to identify whether all clinical or histopathological subgroups will benefit equally from the omission of cyclophosphamide.

Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study.

PURPOSE: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2. PATIENTS AND METHODS: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. RESULTS: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P =.0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P =.0928). Multivariate analysis identified use of chemotherapy (P =.0248) and time to complete RT (P =.0100) as having significant effect on EFS. CONCLUSION: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.

ChlVPP chemotherapy in children with stage IV Hodgkin's disease: results of the UKCCSG HD 8201 and HD 9201 studies.

We reviewed the results of two consecutive United Kingdom Childrens' Cancer Study Group (UKCCSG) studies of children with stage IV Hodgkin's Disease (HD) treated between January 1982 and December 1999. Among 697 children with HD, 67 were diagnosed to be stage IV. The median age at diagnosis was 12.7 years (range 4.4-16.2). Thirty-five (52%) were boys. Thirty-nine patients (58%) had B symptoms at diagnosis. All were treated with 6-8 cycles of ChlVPP chemotherapy regimen (Chlorambucil, Vinblastine, Procarbazine and prednisolone) and only 12 had radiotherapy. The overall survival (OS) at 5 and 10 years was 80.8% and 77.2%, respectively, whilst the event-free survival (EFS) at the same time intervals was 55.2% and 48.8% respectively. Twenty-eight patients (41.79%) relapsed/progressed, 18 (64%) survived after further chemotherapy with or without high-dose therapy and stem cell rescue. Twelve patients died, seven of HD, three from infections and one from secondary acute myeloblastic leukaemia (AML). Although the EFS in this study was lower than other studies, 64% of relapsed patients were salvaged with second-line therapy. It is also anticipated that survivors treated with this non-anthracycline-containing regimen will have less long-term toxicity.

Isolated parenchymal lung involvement in children with stage IV Hodgkin's disease: results of the UKCCSG HD8201 and HD9201 studies.

We retrospectively reviewed the case notes of 27 patients who were diagnosed with stage IV Hodgkin's disease (HD) because of isolated parenchymal pulmonary involvement on chest radiograph and computerized tomography scan (excluding subcategory E). Ten were boys and 15 had B symptoms. Median age at diagnosis was 13.6 years (range 6.1-16.2). All received 6-8 cycles of ChlVPP (chlorambucil, vinblastine, procarbazine and prednisolone) and two had additional whole lung irradiation (12 Gy). Ten patients (37%) relapsed or progressed. Seven survive following second-line therapy while three died, two of HD and one of secondary acute myeloid leukaemia 4 years from diagnosis. At the time of analysis, the median follow-up of patients was 56 months (range 9-127). The event-free survival (EFS) was 58.4% (95% CI 38.5-75.8%) at both 5 and 10 years from diagnosis, and the overall survival (OS) was 84.2% (95% CI 61.8-94.6%) at both 5 and 10 years from diagnosis. We conclude that the outcome for HD patients defined as stage IV, because of isolated parenchymal lung involvement, is encouraging and compares favourably with other extra lymphatic organ involvement. Combination chemotherapy is effective in achieving long-term remission and whole lung irradiation is unnecessary.

Anaplastic large cell lymphoma in childhood: analysis of 72 patients treated on The United Kingdom Children's Cancer Study Group chemotherapy regimens.

From June 1990 to June 1998, 72 patients with anaplastic large cell lymphoma (ALCL) were treated with short intensive multi-agent regimens [non-Hodgkin's lymphoma (NHL) 9000 and 9602]. Diagnosis was based on morphological and immunophenotypic criteria. Treatment for stage I disease consisted of eight courses (2 x vincristine, doxorubicin, prednisolone; 2 x methotrexate; 2 x cytarabine, thioguanine; and 2 x methotrexate etoposide). For stage II, III and non-central nervous system (CNS) stage IV, two COPADM (cyclophosphamide, doxorubicin, prednisolone, methotrexate, vincristine), two CYM (cytarabine methotrexate) and a COPADM was given. For CNS-positive disease, treatment was intensified and contained methotrexate 8 g/m(2) and cytarabine 3 g/m(2). Fifty-nine patients (82%) achieved a remission. Thirteen of these relapsed, with a median time to relapse from the start of treatment of 5 months (range 3-14). Relapse included a new site in 9/13 patients. The probabilities of overall and event free survival at 5 years were 65% (53-76%) and 59% (47-70%), respectively, with a median follow up of 4.3 years. Mediastinal and visceral involvement at presentation were found to be predictive of an increased risk of failure.