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High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma

  1. Bilgehan Yalçin1,*,
  2. Leontien CM Kremer2,
  3. Huib N Caron2,
  4. Elvira C van Dalen2

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 22 AUG 2013

Assessed as up-to-date: 24 DEC 2012

DOI: 10.1002/14651858.CD006301.pub3


How to Cite

Yalçin B, Kremer LCM, Caron HN, van Dalen EC. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006301. DOI: 10.1002/14651858.CD006301.pub3.

Author Information

  1. 1

    Hacettepe University Faculty of Medicine, Pediatric Oncology, Ankara, Turkey

  2. 2

    Emma Children's Hospital / Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands

*Bilgehan Yalçin, Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey. yalcinb@hacettepe.edu.tr. bilgehanyalcin@yahoo.com.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 22 AUG 2013

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Characteristics of included studies [ordered by study ID]
Berthold 2005

MethodsRandomisation was performed centrally by computer-generated sequence with a block size of 8. The stratification criteria were MYCN alone (amplified vs not amplified vs unknown), concentration of serum LDH at diagnosis (raised vs not raised vs unknown), and age (1 to < 2 years vs > 2 years at diagnosis).

Randomisation was performed at a median of 39 days (range 7 to 224 days) after diagnosis. Patients were randomised to myeloablative therapy or conventional chemotherapy


Participants295 children with high-risk neuroblastoma.

High-risk neuroblastoma was defined as: stage IV disease in patients older than 1 year or as MYCN-amplified tumours in patients with stage I, II, III or IV-S disease or with stage IV disease and aged younger than 1 year. Staging was done in accordance with the International Neuroblastoma Staging System criteria (Brodeur 1993).

Age: 22 patients < 1 year and 273 patients > 1 year

Sex: not reported

Stage of disease: I (n = 2), II (n = 6), III (n = 19), IV-S (n = 5) and IV (n = 263)

Primary disease or recurrence: not reported

Histology: not reported

Bone metastases: yes n = 179, no n = 116 (including 84 stage IV patients)

Immunocytologic analysis of bone marrow at diagnosis: not reported

MYCN amplification: yes n = 114, no n = 176, unclear n = 5

Serum LDH level (cut-off values not mentioned): raised n = 262, not raised n = 29, not reported n = 4

Induction regimen:

Data for all randomised patients were not available; these are data for 212 of the 295 patients. According to protocol, they received 3 N5 cycles with 40 mg/m2 cisplatin a day and 100 mg/m2 etoposide a day, both given as continuous infusion over 96 hours on days 1 to 4, and 3 mg/m2 vindesine given intravenously over 1 hour on day 1; and 3 N6 cycles with 1.5 mg/m2 vincristine a day given intravenously over 1 hour on days 1 and 8, 200 mg/m2 dacarbazine a day given intravenously over 1 hour on days 1 to 5, 1.5 g/m2 ifosfamide a day given as continuous infusion over 120 hours on days 1 to 5, and 30 mg/m2 doxorubicin a day given intravenously over 4 hours on days 6 and 7. In a pilot setting, 3 patients received cycles with slightly higher doses of etoposide (125 mg/m2 a day given as continuous infusion over 96 hours on days 1 to 4) and a different infusion time for doxorubicin (48 hours continuous infusion instead of 2 infusions of 4 hours each). Actually received cumulative doses were not reported. The N5 and N6 cycles were alternated; the total duration of the induction regimen was 5 to 7 months.

External radiotherapy:

Patients with contrast medium or MIBG uptake in the primary tumour at the end of induction chemotherapy had local radiotherapy to the primary residual tumour. Data for all randomised patients were not available; these are data for 212 of the 295 patients. Yes (36-40 Gy to residual tumour) n = 24, no n = 188.

Surgery:

Timing of surgery varied during induction chemotherapy regimen: at diagnosis or after 2nd, 4th or 6th cycles of chemotherapy.

Therapeutic MIBG-I131:

Patients with clear uptake of 123-iodine MIBG in metastatic lesions at the end of induction chemotherapy received MIBG therapy. Data for all randomised patients were not available; these are data for 212 of the 295 patients. Yes n = 28.

Immunotherapy:

For 1 year was started 4 to 6 weeks after the end of the conventional chemotherapy or after recovery of the haemopoiesis after megatherapy. Six infusion cycles (one cycle every 2 months) of 20 mg/m2 ch14.18 (chimeric monoclonal antibody against GD2) a day given intravenously over 8 to 12 hours on days 1 to 5 of every cycle. Yes n = 146.

Retinoic acid:

After November 2002, instead of immunotherapy: 160 mg/m2/day, oral on days 1 to 14, followed by a break for 14 days, for 6 months. After 3 months’ break, retinoic acid was resumed for another 3 months. Yes n = 35.

Supportive care:

Prophylactic antibiotics not reported, growth factors not reported, granulocyte infusions not reported, other: drugs were given to control pain and allergic reactions during immunotherapy (n = not reported).

Response before randomisation:

Complete remission or very good partial remission n = 163, partial remission n = 87, stable disease (or mixed remission) n = 13, progressive disease (or death) n = 25, not reported n = 1, not applicable n = 6. Response was assessed by use of the International Neuroblastoma Remission Criteria (Brodeur 1993)


InterventionsData for all randomised patients were not available; data were available for 212 of the 295 patients.

Myeloablative therapy (n = 149):

According to protocol: melphalan 45 mg/m2 a day given intravenously over 30 minutes on days 8 to 5 before transplantation, etoposide 40 mg/kg a day given intravenously over 4 hours on day 4 before transplantation, carboplatin 500 mg/m2 a day given intravenously over 1 hour on days 4 to 2 before transplantation. Actually received cumulative doses not mentioned. Note: some dose and drug adjustments were made in 6 patients because of hearing loss: 3 received cyclophosphamide instead of carboplatin and 3 received no carboplatin. In 9 children, melphalan was combined with busulfan. Use of total body irradiation was not reported.                         

Source of stem cells: autologous peripheral blood

Timing of cell harvest: between 2nd and 5th induction regimen

Timing of stem cell rescue: after 6th induction chemotherapy cycle

Number of cells infused: 1-2 X 106/kg CD 34(+) cells was recommended

Contamination with tumour cells: not mentioned

Purging:  yes n = 96, no n = 1, not mentioned n = 13

Conventional therapy (n = 146):

According to protocol: 4 N7 cycles: cyclophosphamide, 150 mg/m2 a day, orally, with mesna 50 mg/m2 3 times a day on days 1 to 8. Actually received cumulative doses not mentioned


OutcomesEvent-free survival (defined as time until disease progression or relapse, a second neoplastic disease, or death from any cause, whichever occurred first, or until the last examination).

Overall survival (defined as death from any cause or until the last examination if the patient survived).

Adverse effects, i.e. second malignancies and treatment-related deaths (according to World Health Organization criteria)


NotesLength of follow up not reported (median follow up for all cases alive at the censoring date was 3.57 years (range 1.01 to 7.02))

Matthay 1999

MethodsRandomisation 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


Participants379 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)


InterventionsMyeloablative 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 


OutcomesEvent-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)


NotesLength 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)

Pritchard 2005

MethodsRandomisation was performed at the co-ordinating data centre by means of a minimisation technique using stages (III or IV) and individual participating centres as stratification factors.

Time of randomisation not reported (the decision to randomise was made 5 to 9 months after diagnosis).

Patients were randomised to myeloablative therapy or no further treatment


Participants65 children with high-risk neuroblastoma.

High-risk neuroblastoma was defined as: age > 6 months, stage III or IV. Staging was done using the Evans staging criteria (Evans 1971).

Age: 5 patients < 1 year and 60 patients > 1 year

Sex: 34 males and 31 females

Stage of disease: I (n = 0), II (n = 0), III (n = 13), IVS (n = 0) and IV (n = 52)

Primary disease or recurrence: not reported

Histology: not reported

Bone metastases: yes n = 40/52 stage IV patients, unclear n = 12/52 stage IV patients

Immunocytologic analysis of bone marrow at diagnosis: not reported

MYCN amplification: not reported

Serum LDH level: not reported

Induction regimen:

According to protocol all patients received vincristine 1.5 mg/m2 on day 1, cyclophosphamide 600 mg/m2 on day 1, cisplatin 60 mg/m2 on day 2, and teniposide 150 mg/m2 on day 4 repeated every 21 days or as soon as possible afterwards if recovery of neutrophil and platelet counts was slow. Cumulative doses not reported.

External radiotherapy:

No

Surgery:

Surgery was performed before randomisation took place.

Therapeutic MIBG-I131:

No

Immunotherapy:

No

Retinoic acid:

No

Supportive care:

Prophylactic antibiotics not mentioned, growth factors no, granulocyte infusions not mentioned, other: nutritional supplementation (n = not reported).

Response before randomisation:

Complete remission n = 36, good partial remission n = 29. This study was carried out and completed prior to the publication of the International Neuroblastoma Remission Criteria, but the definitions used in this study were agreed unanimously by the trialists as they were considered to be "standard practice" at the time of the study. Complete remission was defined as disappearance of primary tumour as judged by abdominal imaging and of secondary deposits and normal urine catecholamine metabolite levels. Good partial remission was defined as (a) shrinkage of primary tumour by more than 50% in each of three dimensions, (b) reduction of urine catecholamine metabolite levels by more than 50% of the original values and (c) disappearance of secondary deposits including bone marrow involvement. In both types of response, however, isotope bone scan appearances need not have normalised as long as there was improvement at all sites reported as abnormal on the scan performed at diagnosis, with no new lesions


InterventionsMyeloablative therapy (n = 32):

According to protocol: melphalan 180 mg/ m2, i.v. bolus, 4 to 8 weeks after surgery or final course of chemotherapy (whichever came first). Cumulative doses not reported. Total body irradiation not reported.

Source of stem cells: bone marrow

Timing of cell harvest: the day before melphalan

Timing of stem cell rescue: after induction regimens

Contamination with tumour cells: not reported

Number of cells infused: 4.6 X 108 nucleated cells of bone marrow per kg (range 1.8 to 14.2)

Purging: no

Conventional therapy (n = 33):

No further treatment


OutcomesEvent-free survival (defined as the time to relapse or death prior to relapse from randomisation).

Overall survival (defined as the time to death from any cause from randomisation)


NotesLength of follow up not mentioned (median follow up for 21 surviving children was 14.3 years from randomisation (range 8.8 to 17.1 years))

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adkins 2004Patients also included in Matthay 1999

Berthold 1990Not a RCT

Castel 2001Not a RCT

Castel 2002Not a RCT

Dini 1989All patients underwent BMT

Dini 1991aAll patients underwent BMT

Dini 1991bAll patients underwent BMT

Garaventa 1993Not a RCT; all patients underwent BMT

Haas-Kogan 2003Patients also included in Matthay 1999

Hartmann 1985All patients underwent BMT

Kaneko 1999Not a RCT

Klingebiel 1994All patients underwent transplant

Ladenstein 1991Not a RCT; all patients underwent BMT

Ladenstein 1996Not a RCT; all patients with stage IV underwent BMT

Madon 1985Randomisation between chemotherapy and chemotherapy + immunotherapy

Matthay 1995Not a RCT

Matthay 1996Review of different study protocols

Matthay 1998Not a RCT

Mugishima 1999Not a RCT; review

Ohnuma 1995Not a RCT

Olgun 2008Not a RCT (even though this was stated in the abstract)

Paolucci 1989Not a RCT

Philip 1991All patients underwent BMT

Pinkerton 1991Preliminary results of Pritchard 2005

Saarinen 1996Not a RCT

Sawaguchi 1989Not a RCT

Sawaguchi 1990Not a RCT

Schmidt 2005Patients also included in Matthay 1999

Seeger 1991All patients underwent BMT

Seeger 2000Patients also included in Matthay 1999

Shuster 1991Not a RCT

Stram 1994Not a RCT

Stram 1996Not a RCT

Zucker 1991All patients underwent BMT

 
Characteristics of studies awaiting assessment [ordered by study ID]
Hero 2010

MethodsNo information on method of randomisation provided

Participants295 children with high-risk neuroblastoma (defined as stage 4 or MYCN amplified).

No information was provided on age, sex, stage of disease, primary disease or recurrence, histology, presence of bone metastases, immunocytologic analysis of bone marrow at diagnosis, MYCN amplification, serum LDH level, treatment details, response before randomisation

InterventionsMyeloablative therapy (n=143) versus conventional therapy, i.e. 4 cycles of oral cyclophosphamide (n=119). For 33 patients no information was provided

OutcomesRelapses occurred statistically significantly (P < 0.001) later in the transplant group (74 out of 143 (52%) patients; median 21 months (range 8 to 85 months)) than in the control group (83 out of 119 (70%) patients; median 16 months (range 7 to 60 months, median 16 months)).  

Patients died up to nine years after diagnosis: in the transplant group at a median of 30 months; in the control group at a median of 20 months (P < 0.001).

Early complications (the abstract did not report if these were statistically significant differences): (a) pneumonia n = 10 in the transplant group versus n = 1 in the control group, (b) other severe infectious complications n = 8 in the transplant group, (c) veno-occlusive disease n = 8 in the transplant group, (d) renal failure n = 3 in the transplant group, (e) treatment related death n = 5 in the transplant group versus n = 0 in the control group.

Secondary malignant disease: 1 in each treatment group (both leukaemia cases; no further information provided).

Major late effects in 109 patients surviving 5 years or longer, i.e. n = 68 in the transplant group versus n = 41 in the control group (it was unclear if this were all patients who survived 5 years or longer): (a) hearing loss 72% versus 51% (P = 0.04), (b) tubular damage 18% versus 12% (NS), (c) hypothyroidism 19% versus 2% (P = 0.02), (d) focal nodular hyperplasia of the liver 10% versus 0 % (P = 0.04), (e) impaired growth 10% versus 0% (P = 0.04).

In conclusion: myeloablative therapy proofed effective with respect to long-term outcome, but is complicated by acute and long-term toxicity

NotesThis study has not been published in full text (October 2012), but has been presented at the ANR conference 2010.

It provides additional follow-up of the Berthold 2005 study.

Length of follow-up was up to 12 years (median observation time 8.4 years)

 
Comparison 1. Myeloablative therapy versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Event-free survival without additional follow-up data3739Hazard Ratio (Random, 95% CI)0.78 [0.67, 0.90]

    1.1 Event-free survival including secondary malignant disease as an event without additional follow-up data
2674Hazard Ratio (Random, 95% CI)0.79 [0.67, 0.92]

    1.2 Event-free survival not including secondary malignant disease as an event without additional follow-up data
165Hazard Ratio (Random, 95% CI)0.73 [0.49, 1.07]

 2 Event-free survival including additional follow-up data of Matthay 19993739Hazard Ratio (Random, 95% CI)0.79 [0.70, 0.90]

    2.1 Event-free survival including additional follow-up data and secondary malignant disease as an event
2674Hazard Ratio (Random, 95% CI)0.80 [0.70, 0.92]

    2.2 Event-free survival including additional follow-up data and not including secondary malignant disease as an event
165Hazard Ratio (Random, 95% CI)0.73 [0.49, 1.07]

 3 Overall survival without additional follow-up data2360Hazard Ratio (Random, 95% CI)0.74 [0.57, 0.98]

 4 Overall survival including additional follow-up data of Matthay 19993739Hazard Ratio (Random, 95% CI)0.86 [0.73, 1.01]

 5 Adverse effects grade 3 or higher without additional follow-up data2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Treatment-related death
2574Risk Ratio (M-H, Random, 95% CI)2.53 [0.17, 37.12]

    5.2 Secondary malignant disease
2674Risk Ratio (M-H, Random, 95% CI)0.99 [0.14, 7.00]

    5.3 Serious infections
1379Risk Ratio (M-H, Random, 95% CI)1.02 [0.84, 1.23]

    5.4 Sepsis
1379Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.30]

    5.5 Renal effects
1379Risk Ratio (M-H, Random, 95% CI)2.28 [1.28, 4.04]

    5.6 Interstitial pneumonitis
1379Risk Ratio (M-H, Random, 95% CI)9.55 [2.26, 40.43]

    5.7 Veno-occlusive disease
1379Risk Ratio (M-H, Random, 95% CI)35.18 [2.13, 580.88]

 6 Adverse effects grade 3 or higher including additional follow-up of Matthay 19992Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Treatment-related death
2555Risk Ratio (M-H, Random, 95% CI)1.08 [0.65, 1.78]

    6.2 Secondary malignant disease
2674Risk Ratio (M-H, Random, 95% CI)1.48 [0.24, 9.01]

    6.3 Serious infections
1379Risk Ratio (M-H, Random, 95% CI)1.02 [0.84, 1.23]

    6.4 Sepsis
1379Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.30]

    6.5 Renal effects
1379Risk Ratio (M-H, Random, 95% CI)2.28 [1.28, 4.04]

    6.6 Interstitial pneumonitis
1379Risk Ratio (M-H, Random, 95% CI)9.55 [2.26, 40.43]

    6.7 Veno-occlusive disease
1379Risk Ratio (M-H, Random, 95% CI)35.18 [2.13, 580.88]

 
Table 1. Criteria for the assessment of risk of bias in included studies

Risk of bias itemType of biasImplementation

Allocation concealmentSelection biasAdequate: use of randomisation method that did not allow investigator and participant to know or influence the allocation of treatment before eligible participants entered the study.
Inadequate: use of alternate medical record numbers or unsealed envelopes as randomisation method, and/or there is information in the study indicating that investigators or participants could have influenced the allocation of treatment.
Unclear: randomisation stated but no information on method used is available

Blinding of care providersPerformance biasAdequate information about blinding must have been provided

Blinding of patientsPerformance biasAdequate information about blinding must have been provided

Blinding of outcome assessorsDetection biasAdequate information about blinding must have been provided

Intention-to-treat analysisAttrition biasYes: all participants are analysed in the treatment group to which they were randomised, regardless of whether or not they received the allocated intervention.
No: some participants (< 5%, 5% to 10%, 11% to 20%, > 20%) are not analysed in the treatment group to which they were randomised because they did not receive the study intervention, they withdrew from the study, or because of protocol violation.
Unclear: inability to determine if patients were analysed according to the intention-to-treat principle

Completeness of follow upAttrition biasPercentage of participants excluded or lost to follow up (< 5%, 5% to 10%, 11% to 20%, > 20%) should be stated

 
Table 2. Risk of bias in included studies

StudyAllocation concealmentBlinding of care providersBlinding of patientsBlinding of outcome assessorsIntention-to-treat analysisCompleteness of follow up

Berthold 2005YesNoNoEvent-free survival, adverse effects (i.e. treatment-related death/secondary malignant disease): unclearEvent-free survival, overall survival, adverse effects (i.e. treatment-related death/secondary malignant disease): yesEvent-free survival, overall survival, adverse effects (i.e. secondary malignant disease): unclear; adverse effects (i.e. treatment-related death): yes

Matthay 1999UnclearNoNoEvent-free survival, adverse effects (i.e. treatment-related death/secondary malignant disease/veno-occlusive disease/interstitial pneumonitis/renal effects/sepsis/serious infections): yes (in the additional follow-up study: unclear)Event-free survival, overall survival, adverse effects (i.e. treatment-related death/secondary malignant disease/veno-occlusive disease/interstitial pneumonitis/renal effects/sepsis/serious infections): yesEvent-free survival, overall survival, adverse effects (i.e. secondary malignant disease/veno-occlusive disease/interstitial pneumonitis/renal effects/sepsis/serious infections): unclear; adverse effects (i.e. treatment-related deaths): no (> 20% lost to follow up)

Pritchard 2005YesUnclearUnclearEvent-free survival: unclearEvent-free survival and overall survival: yesEvent-free survival and overall survival: unclear