|Methods||Randomisation was performed by permuted-block design using strata with and without metastatic disease. Randomisation was performed at week 8, before the 3rd cycle of chemotherapy for patients without disease progression at a median of 60 days after diagnosis. Patients were randomised to myeloablative therapy or conventional chemotherapy|
|Participants||379 children with high-risk neuroblastoma.|
High-risk neuroblastoma was defined as: stage IV neuroblastoma; stage III disease with one or more of the following: amplification of the MYCN oncogene, a serum ferritin level of at least 143 ng per millilitre, and unfavourable histopathological findings; stage II disease with amplification of MYCN (age > 1 year); stage I or II disease with bone metastases before therapy other than surgery; and stage IV disease with MYCN amplification for less than 1 year. Staging was done using the Evans staging criteria (Evans 1971). Unfavourable histopathological findings were based on the Shimada classification (Shimada 1984).
Age: 9 patients < 1 year and 370 patients > 1 year
Sex: not reported
Stage of disease: I (n = 0), II with MYCN amplification (n = 1), III (n = 44), IV-S (n = 0) and IV (n = 334)
Primary disease or recurrence: all primary disease
Histology: favourable n = 15, unfavourable n = 248, unclear n = 116
Bone metastases: yes n = 230, no n = 149 (including 104 stage IV patients)
Immunocytologic analysis of bone marrow at diagnosis: negative n = 66, positive n = 184, unclear n = 129
MYCN amplification: yes n = 104, no n = 179, unclear n = 96
Serum LDH level: not reported
According to protocol all patients received 5 courses at 28-day intervals of cisplatin 60 mg/m2 on day 0; doxorubicin 30 mg/m2 on day 2; etoposide 100 mg/m2on days 2 and 5; cyclophosphamide 1 gr/m2 on days 3 - 4. Actually received cumulative doses not reported.
Following induction regimen patients with gross residual disease received surgery and radiotherapy. Number of patients not reported.
Timing of surgery: after cycle 4 of induction chemotherapy.
50 children randomised to myeloablative therapy received 13-cis-retinoic acid (whereas 48 did not) and 52 children randomised to conventional chemotherapy received 13-cis-retinoic acid (whereas 53 did not). Treatment with 13-cis-retinoic acid was part of a second randomisation (see notes); not all patients included in the first randomisation were eligible for inclusion in the second one.
Prophylactic antibiotics not mentioned, growth factors: 250 mcg/m2/day intravenously in patients undergoing myeloablative therapy and 5 mcg/kg/day s.c. in patients undergoing maintenance therapy, granulocyte infusions not reported, other not reported.
Response before randomisation:
Complete remission n = 117, (very good) partial remission n = 147, stable disease or mixed response n = 34, progressive disease n = 52, not mentioned n = 29. Response was assessed by use of the International Neuroblastoma Remission Criteria (Brodeur 1988; Brodeur 1993)
|Interventions||Myeloablative therapy (n = 189):|
According to protocol: carboplatin 1000 mg/m2, 96-hour continuous infusion, day -8; etoposide 640 mg/m2, 96-hour continuous infusion, day -8; melphalan 140 mg/m2 and 70 mg/m2 bolus infusion, days -7 and -6. Cumulative doses not mentioned. Total body irradiation: 333 cGy/day, days -3, -2, -1. Actually received cumulative doses not reported.
Source of stem cells: bone marrow
Timing of cell harvest: between 3rd and 4th and 4th and 5th cycles of induction regimen
Timing of stem cell rescue: after 5th induction chemotherapy cycle
Number of cells infused: 2 X 108 mnc/kg, day 0 (median dose)
Contamination with tumour cells: no
Purging: yes (performed by sedimentation, filtration, immunomagnetic separation)
Conventional therapy (n = 190):
According to protocol: 3 cycles of cisplatin 160 mg/m2; etoposide 500 mg/m2; doxorubicin 40 mg/m2 96 hours continuous infusion; simultaneously with bolus ifosfamide 2500 mg/m2 + mesna 1500 mg/m2 days 0 to 3. Actually received cumulative doses were not reported
|Outcomes||Event-free survival (defined as the time from randomisation to disease progression, death from any cause and a second neoplasm, whichever occurred first).|
Overall survival (definition not reported).
Adverse effects, i.e. treatment-related death, secondary malignant disease, veno-occlusive disease, interstitial pneumonitis, renal effects, sepsis, serious infections (according to the common toxicity criteria of the National Cancer Institute)
|Notes||Length of follow up not reported.|
In this study a second randomisation was included to answer the question of whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) could further improve event-free survival.
Additional follow-up data of this study have been published (Matthay 2009): for response before randomisation slightly different numbers of patients were reported (i.e. complete remission n = 117, (very good) partial remission n = 148 (instead of 147), stable disease or mixed response n = 34, progressive disease n = 46 (instead of 52), not mentioned n = 34 (instead of 29). The length of follow-up was not reported, but the median follow-up of patients alive without an event was 7.7 years (range 130 days to 12.8 years). In this publication another definition of event-free survival was used (relapse was included as an event): the time from randomisation to disease progression, relapse, death from any cause and a second neoplasm, whichever occurred first)