High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008

Abstract

Purpose: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases.

Methods: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method.

Results: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm.

Conclusion: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Trial registration: ClinicalTrials.gov NCT00020566 NCT00987636.

FIG 1.

Trial profile. A total of 124 patients assessed for eligibility for the R2Pulm trial did not meet eligibility criteria because of lung or pleural metastases without metastases at another site; insufficient diagnosis criteria or diagnosis rejected (n = 7); persisting toxicity related to previous treatment and/or contraindication to planned treatment (n = 83), including contraindication to busulfan and melphalan (BuMel) because of planned radiotherapy to an axial site (n = 41); early radiotherapy (n = 18); psychological problems (n = 5); age younger than 4 or older than 50 years (n = 8); and Ewing sarcoma as a second malignancy (n = 3). Sixty-three patients meeting eligibility criteria were not enrolled because of other reasons. EE99, European Ewing Tumour Working Initiative of National Groups, 1999 study; HDC, high dose chemotherapy; WLR, whole-lung irradiation.

FIG 2.

(A and B) Event-free survival and (C) overall survival. (A) Kaplan-Meier estimates of event-free survival by treatment group on the intention-to-treat (ITT) population. At the time of this analysis (cutoff date, January 1, 2017), 144 events were reported: 78 in the vincristine, dactinomycin, and ifosfamide (VAI) plus whole-lung irradiation (WLI) group and 66 in the busulfan and melphalan (BuMel) group. (B) Forest plot of event-free survival according to subgroups. The hazard ratio (HR) of events by subgroup were estimated in a Cox model proportional hazard model on the ITT population, including all patients except (1) for the assessment of treatment effect according to primary tumor site: we excluded one patient with an unknown primary; (2) for the assessment of treatment effect according to primary tumor volume: we excluded four patients with missing data; (3) for the assessment of treatment effect according to the size of the largest pulmonary nodule: we excluded 19 patients with missing data; (4) for the assessment of treatment effect according to pulmonary nodule: we excluded five patients with missing data; French group: French Society of Pediatric Oncology/French Sarcoma Group/Unicancer. (C) Kaplan-Meier estimates of overall survival by treatment group on the ITT population. COG, Children’s Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; GPOH, Gesellschaft fuer Paediatrische Onkologie und Haematologie; UKCCLG, Children’s Cancer and Leukaemia Group.

FIG 3.

Adverse events. The panel on the left is a butterfly plot showing the proportion of patients experiencing an adverse event, whatever the grade (light red for the busulfan and melphalan [BuMel] arm and light blue for the vincristine, dactinomycin, and ifosfamide [VAI] plus whole-lung irradiation [WLI] arm) and a severe adverse event (dark red for the BuMel arm and dark blue for VAI plus WLI arm) according to the randomization group. The panel on the right displays the relative risk of a severe adverse event in patients with BuMel relative to patients with VAI plus WLI, with 95% CIs for a 2 × 2 table. The acute toxicity related to chemotherapy was assessed after each course, using a list of 22 selected items from the National Cancer Institute Common Terminology Criteria for Adverse Events (version 2.0). A modified list of items was used to evaluate toxicity after radiotherapy, using Radiation Therapy Oncology Group classification for eight types of specific toxicities. A free text area was available to document other adverse reactions. The toxicity items were then pooled by category: bladder toxicity, cardiac toxicity, GI toxicity, general deterioration, hematologic toxicity, infection, liver toxicity, lung toxicity, neurologic toxicity (including mood alteration), renal toxicity, and skin toxicity. The respiratory tract toxicity (larynx, pharynx, salivary gland) reported after radiotherapy was pooled within the category of GI toxicity because of small numbers and because they were usually associated. Details are provided in the Data Supplement. For each adverse event type, the analysis was based on the maximum grade observed over the whole maintenance treatment duration. A grade 4 hematologic toxicity and a grade 3 or higher nonhematologic toxicity were classified as severe toxicities. The categories of adverse events was ordered by decreasing value of the relative risk of severe toxicity. This analysis was performed on the safety set (127 patients taking VAI plus WLI and 117 patients taking BuMel), excluding patients who did not receive the treatment allocated by randomization (as-treated population), as well as patients with missing data for toxicity assessment. The number of chemotherapy courses followed by toxicity over the whole maintenance treatment duration is detailed in the Data Supplement.