Study characteristics

Methods

The R2Pulm trial was an international, randomised, superiority trial comparing two consolidation regimens in a two‐parallel‐group design. The R2Pulm randomised trial was part of the Euro‐E.W.I.N.G. 99 study (ClinicalTrials.gov identifier: NCT00020566), recruiting people with Ewing sarcoma at diagnosis. From May 2010, people were also recruited in the same R2Pulm randomised trial conducted through the EWING 2008 study (ClinicalTrials.gov identifier: NCT00987636)

Enrolment took place in 144 centres from 14 countries between December 2015 and February 2000.

Randomisation was completed after four to six combed vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) courses. It was balanced and stratified according to co‐operative group, sex, age (younger than 25 years), and local treatment (surgery after induction chemotherapy with or without postoperative radiotherapy versus initial surgery versus combined surgery after induction chemotherapy followed by radiotherapy versus radiotherapy only).

Central randomisation software was used in all data centres, ensuring the concealment of the next participant allocation. The Gesellschaft fur Paediatrische Onkologie und Haematologie data centre used permuted blocks of four. In the European Organisation for Research and Treatment of Cancer, Children’s Cancer and Leukaemia Group, and French data centres, randomisation was also balanced by the treating centre using dynamic allocation of treatment (minimisation with a random factor set at 0.8).

Participants

Eligible participants were younger than 50 years of age. Therefore, we only included data if described separately for our included population (younger than 30 years of age). In descriptive data and analyses, this study classified the following age categories: < 12 years; 12 to 18 years; 18 to 25 years, and > 25 years. 

There were 267 participants younger than 25 years of age, and diagnosed with Ewing sarcoma with pulmonary or pleural metastases, without other distant metastases included in this study.

Age:

Not reported specifically for eligible patients

• the whole study group: median age 14.2 years (range, 1.0 to 47.8 years)

• intervention group: median 13.9 years (range 1.7 to 47.8 years)

• control group: median 14.6 years (range 1.0 to 44.1 years)

Gender:

Not reported specifically for eligible participants

• the whole study group: 59% male

• intervention group: 60% male

• control group: 57% male

Known risk factors for people with metastatic disease:

• Tumour volume: not reported for eligible participants

  • the whole study group: 60% ≥ 200 mL

  • equal in both treatment arms: 60% ≥ 200 mL

• Sites of metastases (lungs, bone, bone marrow, or combination, were not reported for eligible participants

  • the whole study group: 12% single pulmonary nodules and 88% multiple pulmonary nodules;

  • intervention group 89% multiple nodes

  • control group 86% multiple nodes

  • there were no bone or bone marrow metastases

Interventions

For all participants, induction chemotherapy consisted of six VIDE chemotherapy courses and 1 combined vincristine, actinomycin D, and Ifosfamide (VAI) course.

After induction, the allocated consolidation treatment was:

• control group: seven courses of VAI followed by WLI for the control arm (N = 134)

• intervention group: one course of combined high‐dose busulfan and melphalan (BuMel) chemotherapy with autologous stem‐cell transplantation (N = 133)

Participants aged younger than 12 years: chemotherapy and WLI (N = 44) versus BuMel and AHCT (N = 48)

Participants aged 12 to 18 years: chemotherapy and WLI (N = 66) versus BuMel and AHCT (N = 62)

Participants aged 18 to 25 years: chemotherapy and WLI (N = 24) versus BuMel and AHCT (N = 23)

Local therapy was tailored to participant and tumour characteristics, and included complete surgical removal of the tumour wherever feasible, radiotherapy, or a combination of both.

In the BuMel (intervention) group

• 115 participants (80%) underwent resection after chemotherapy, with or without late radiotherapy

• 29 people received other local treatment: 4 had a resection at diagnosis, and 22 received radiotherapy alone

In the conventional chemotherapy with WLI (control) group,

• 120 participants (84%)

• 23 people with other local treatment: 3 underwent resection after chemotherapy and early RT, 1 underwent resection at diagnosis, and 16 received radiotherapy alone

Autologous haematopoietic stem‐cell harvesting was completed according to local practices, at the earliest, after VIDE course 2

No actually received cumulative doses of the different chemotherapeutics were described. As described in the Ewing 2008 protocol the courses consisted of: 

VIDE courses (6 for each group)

• Vincristine: 1.5 mg/m², 6 cycles = cumulative dose of 9 mg/m²

• Ifosfamide: 9000 mg/m², 6 cycles = cumulative dose of 54,000 mg/m²

• Doxorubicin: 60 mg/m², 6 cycles = cumulative dose of 360 mg/m²

• Etoposide: 450 mg/m²; 6 cycles = cumulative dose of 2700 mg/m²

VAI courses (1 for intervention group, 8 for control group)

Intervention group:

• Vincristine 1.5 mg/m², 1 cycle = cumulative dose of 1.5 mg/m²

• Actinomycin D: 1.5 mg/m², 1 cycle = cumulative dose of 1.5 mg/m²

• Ifosfamide: 6000mg/m², 1 cycle = cumulative dose of 6000 mg/m²

Control group:

• Vincristine 1.5 mg/m²,  8 cycles = cumulative dose of 12 mg/m²

• Actinomycin D: 1.5 mg/m², 8 cycles = cumulative dose of 12 mg/m²

• Ifosfamide: 6000mg/m², 8 cycles = cumulative dose of 48,000 mg/m²

BuMel course

Busulfan: 

• Adults: 12.8 mg/kg

• Children and adolescents: < 9 kg = 16 mg/kg; 9 kg ≤ 16 kg = 19.2 mg/kg; 16 kg to 23 kg = 17.6 mg/kg; 23 kg to 34 kg = 15.2 mg/kg; > 34 kg = 12.8 mg/kg

Melphalan: 140 mg/m²  

Outcomes

Event‐free survival (defined as the time from randomisation to the time of the first event assessed by the investigator, defined as progression, relapse, second malignancy, or death, whatever the cause).

Notes

No information provided on follow‐up for the eligible participants (for the whole study group median 8.1 years (range 0 to 15.5 years), similar in the intervention group versus the conventional chemotherapy with WLI group).

Overall survival and toxicity data were assessed in the study, but not separately for the eligible participants for this review. The study authors were unable to provide us with additional data.

The study was supported by FP7‐EURO EWING Consortium; Association Enfants et Sante, Societe Française de Lutte Contre les Cancers et les Leucemies de l’Enfant et de l’Adolescent, Unicancer; Cancer Research UK (CRUK/02/ 014), National Institute for Health Research, University College London Hospitals, Biomedical Research Centre; Deutsche Krebshilfe (70‐2551‐Jue3 and 108128), and Bundesministerium fur Bildung und Forschung (BMBF 01GM0869; BMBF/Era‐Net 01KT1310); National Cancer Institute, Bethesda, MD (U10CA098413, U10CA098543, U10CA180886, and U10CA180899); and The Swedish Childhood Cancer Fund.

Authors' disclosures of potential conflict of interest are described. Study authors were sponsored by pharma.

No other potential conflicts of interest were reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central randomisation software was used, ensuring random sequence generation. 

Allocation concealment (selection bias)

Low risk

Central randomisation software was used, ensuring the concealment of the next participant allocation. 

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding to therapy could not be achieved because of obvious treatment differences.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information on blinding of outcome assessors of EFS was provided.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No data provided specifically for the participants eligible for this review, but out of 287 participants in the total study group, 11 in the intervention group, and 7 in the control group were lost to follow‐up. Even if all of these participants lost to follow‐up were ≤ 25 years old, the risk of attrition bias for EFS would still be low, as a maximum of 11/133 (8%) of the intervention group and 7/134 (5%) of the control group would be lost to follow‐up.

Selective reporting (reporting bias)

Low risk

Study protocol was available, and all of the study’s prespecified (primary and secondary) outcomes of interest were reported as pre‐specified. For this review, all outcomes that one would expect to be reported were defined as overall survival and toxicity. All expected outcomes were reported (although not eligible for inclusion in the review).

Other bias

High risk

Block randomisation in unblinded trials: yes

Baseline imbalance in treatment arms related to outcome (i.e. age, tumour volume): no

Important known prognostic characteristics were equally distributed: age was not reported separately for eligible participants, but the median age for the whole study group was similar in both treatment groups. Primary tumour volume was not reported separately for eligible participants, but for the whole study group; it was similar in both treatment groups. Therefore we judged this to be a low risk of bias.

Difference in length of follow‐up between treatment arms: no

No specific follow‐up was described for eligible age groups. In the whole cohort, both treatment groups had an equal follow‐up duration of 8.1 years (0 to 15.5 years). We judged this to be a low risk of bias.

Other potential biases: unclear (no information available separately for the participants eligible for this review, but in the total group, out of 543 eligible people, only 287 were enrolled in the trial for randomisation: 98 people/parents refused enrolment, 71 people were not enrolled because the physician refused, 63 people were not enrolled for miscellaneous reasons, and 24 people were not enrolled for unknown reasons). We judged this to be a high risk of bias.