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.
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.
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.
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.