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.

Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89.

PURPOSE: To improve outcome for children with nonmetastatic rhabdomyosarcoma and to reduce systematic use of local therapy. PATIENTS AND METHODS: Five hundred three previously untreated patients aged from birth to 18 years, recruited between 1989 and 1995, were allocated to one of six treatment schedules by site and stage. RESULTS: Five-year overall survival (OS) and event-free survival (EFS) were 71% and 57%, respectively. Primary site, T-stage, and pathologic subtype were independent factors in predicting OS by multivariate analysis. Differences between EFS and OS reflected local treatment strategy and successful re-treatment for some patients after relapse. Patients with genitourinary nonbladder prostate tumors had the most favorable outcome (5-year OS, 94%): the majority were boys with paratesticular tumors treated successfully without alkylating agents. Patients with stage III disease treated with a novel six-drug combination showed improved survival compared with the Malignant Mesenchymal Tumor 84 study (MMT 84; 5-year OS, 60% v 42%, respectively). OS was not significantly better than that achieved in the previous MMT 84 study, but 49% of survivors were cured without significant local therapy. CONCLUSION: Selective avoidance of local therapy is justified in some patients, though further work is required to prospectively identify those for whom this is most applicable. Exclusion of alkylating agents is justified for the most favorable subset of patients. The value of the new six-drug chemotherapy combination is being evaluated further in a randomized study (MMT 95).

Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[(131)I]iodobenzylguanidine by neuroblastoma tumors.

PURPOSE: The suitability of neuroblastoma patients for therapy using radiolabeled meta-iodobenzylguanidine (MIBG) is determined by scintigraphy after the administration of a tracer dose of radioiodinated MIBG whose uptake is dependent upon the cellular expression of the noradrenaline transporter (NAT). As a possible alternative to gamma camera imaging, we developed a novel molecular assay of NAT expression. mRNA extracted from neuroblastoma biopsy samples, obtained retrospectively, was reverse transcribed, and NAT-specific cDNA was quantified by real-time PCR, referenced against the expression of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase. EXPERMENTAL DESIGN: Tumor specimens from 54 neuroblastoma patients were analyzed using real-time PCR, and NAT expression was compared with the corresponding diagnostic scintigrams. RESULTS: Forty-eight of 54 (89%) of tumors showed MIBG uptake by scintigraphy. NAT expression was found to be significantly associated with MIBG uptake (P < 0.0001, Fisher's exact test). None of the samples from the six tumors that failed to concentrate MIBG expressed detectable levels of the NAT (specificity = 1.0). However, of the 48 MIBG uptake-positive tumors, only 43 (90%) expressed NAT (sensitivity = 0.9). The real-time PCR test has a positive predictive value of 1.0 but a negative predictive value of 0.55. CONCLUSIONS: The results indicate that whereas this method has substantial ability to predict the capacity of neuroblastoma tumors to accumulate MIBG, confirmation is required in prospective studies to determine more accurately the predictive strength of the test and its role in the management of patients with neuroblastoma.

Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.

PURPOSE: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. PATIENTS AND METHODS: From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. RESULTS: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. CONCLUSION: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Pharmacokinetics of carboplatin and etoposide in infant neuroblastoma patients.

PURPOSE: Carboplatin and etoposide are commonly used chemotherapeutics for the treatment of many paediatric cancers. However, there are very limited published data concerning the pharmacokinetics of these agents in infants and very young children, for whom dose reductions are frequently implemented. METHODS: Etoposide (5 mg/kg; 2 h i.v. infusion) was co-administered with carboplatin (6.6 mg/kg; 1 h i.v. infusion) on each of 3 days of treatment and samples were taken between 0.5 and 4 h after the start of administration, from a total of 19 neuroblastoma patients aged <1 year at diagnosis and weighing <12 kg at treatment. Pharmacokinetic analysis was carried out using a non-linear mixed effects modelling approach. RESULTS: Two compartment structural models were selected for both carboplatin and etoposide analysis. Body weight (BW) was strongly associated with carboplatin clearance (Cl), with a slightly weaker relationship observed with etoposide Cl. Carboplatin Cl values ranged from 12.8 to 33.6 ml/min, with total AUC values of 4.2-9.3 mg/ml.min achieved over the 3 days of treatment. Cl values normalized to BW were significantly higher in patients <12 kg than in children >12 kg, with mean +/- SD values of 2.9 +/- 0.4 and 2.5 +/- 0.4 ml/min/kg, respectively (P < 0.05). Etoposide exhibited a median half-life of 4.6 h (range 4.1-6.6), a median AUC of 7.1 mg/ml.min (range 3.4-11.0) and a median Cl of 6.6 ml/min (range 3.2-13.0). CONCLUSION: Results suggest that prediction of absolute carboplatin Cl values may be difficult in infant patients <12 kg, with a small but significant difference in Cl values normalized to BW observed in this patient group. Etoposide pharmacokinetic data support previous findings that question the utility of modified dosing in infants. The current study demonstrates the feasibility of generating informative pharmacokinetic data in infants and young children.

Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98.

PURPOSE: Results are presented of the SIOP study MMT-98 for paediatric metastatic rhabdomyosarcoma (RMS), which evaluated intensive chemotherapy followed by low intensity 'maintenance' chemotherapy in standard risk patients (SRG). For poor risk patients (PRG), the value of a therapeutic window study, sequential high dose monotherapy to achieve a complete response (CR) followed by low dose maintenance chemotherapy was examined. PATIENTS AND METHODS: From November 1998 to 2005, 146 patients aged 6 months to 18 years with metastatic RMS were entered. Forty-five were SRG, i.e. age<10 years and no bone marrow or bone involvement. Treatment was a 6-drug regimen with local therapy of surgery and/or radiotherapy followed by maintenance of 9 courses of vincristine, actinomycin D and cyclophosphamide (VAC). One hundred and one patients were PRG, i.e. >10 years, or with bone marrow or bone metastases. An upfront window study, high dose monotherapy, local treatment and then VAC maintenance therapy were given. RESULTS: With a median follow-up of 1.52 years, the 3-year event-free survival (EFS) and overall survival (OS) for SRG were 54.92% and 62.14%, respectively, whilst for the PRG 16.17% and 23.17%. The corresponding adverse hazard ratio (HR) for the PRG was HR=2.65 (95% CI 1.63-4.31, p-value<0.001) for EFS and HR=2.51 (CI 1.53-4.11, p-value<0.001) for OS. CONCLUSION: SRG patients' EFS and OS were comparable to those of previous studies. For PRG patients there was no improvement in survival.

Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification.

PURPOSE: On the assumption that most infants with disseminated neuroblastoma without MYCN amplification (MYCNA) have a favorable prognosis, two concomitant prospective trials were started in which chemotherapy was limited to patients presenting life- or organ-threatening symptoms or overt metastases to skeleton, lung, or CNS. Surgery was to be performed only in the absence of surgical risk factors. PATIENTS AND METHODS: One hundred seventy infants with disseminated neuroblastoma without MYCNA, diagnosed between June 1999 and June 2004 in nine European countries were eligible for either of the two studies. Trial 99.2 included all stage 4S infants and those with stage 4 with a primary tumor infiltrating across the midline or positive skeletal scintigraphy who were to be observed in absence of symptoms. Trial 99.3 included infants with overt metastases to the skeleton, lung, and CNS to be treated with a minimum of four chemotherapy courses. RESULTS: The 125 infants treated on trial 99.2 had a 2-year overall survival (OS) of 97.6% with no difference between asymptomatic and symptomatic patients (97.7% v 97.3%), patients without or with unresectable primary tumors (96.8% v 100%), and patients without or with positive skeletal scintigraphy without radiologic abnormalities (97.2% v 100%). The 45 infants treated on trial 99.3 had a 2-year OS of 95.6%. No patients died of surgery- or chemotherapy-related complications. CONCLUSION: Infants with disseminated disease without MYCNA have excellent survival with minimal or no treatment. Asymptomatic infants with an unresectable primary tumor or positive skeletal scintigraphy without radiologic abnormalities may undergo observation alone.