Matthay 1999.

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 Induction regimen: 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. External radiotherapy: Following induction regimen patients with gross residual disease received surgery and radiotherapy. Number of patients not reported. Surgery: Timing of surgery: after cycle 4 of induction chemotherapy. Therapeutic MIBG‐I131: No Immunotherapy: No Retinoic acid: 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. Supportive care: 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)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation was performed by permuted‐block design; no further information provided.
Allocation concealment (selection bias)	Unclear risk	Randomisation was performed by permuted‐block design; no further information provided.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and personnel were not blinded. However, it should be noted that due to the nature of the interventions blinding of participants and personnel was virtually impossible.
Blinding of outcome assessment (detection bias) Event‐free survival	Low risk	Outcome assessors were blinded*.
Blinding of outcome assessment (detection bias) Overall survival	Low risk	Outcome assessors were blinded. In the additional follow‐up study no information on blinding of outcome assessors was provided, but since this is not applicable for overall survival we judged this as a low risk of bias.
Blinding of outcome assessment (detection bias) Adverse effects	Low risk	Outcome assessors were blinded*.
Incomplete outcome data (attrition bias) Event‐free survival	Unclear risk	It was not clear if all participants were included in the analysis.
Incomplete outcome data (attrition bias) Overall survival	Unclear risk	It was not clear if all participants were included in the analysis.
Incomplete outcome data (attrition bias) Adverse effects except treatment‐related death	Unclear risk	It was not clear if all participants were included in the analysis.
Incomplete outcome data (attrition bias) Treatment‐related death	High risk	Not all participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	There was no protocol mentioned in the manuscript (and we did not search for it), but all expected outcomes were reported.
Other bias	Unclear risk	Difference in length of follow‐up between treatment arms: unclear (not reported) Inappropriate influence of funders: unclear (no information provided).