What is the impact of local control in Ewing sarcoma: analysis of the first Brazilian collaborative study group – EWING1

The study was approved by the institutional review board of Hospital de Clínicas de Porto Alegre through the Office of Research and Graduate Studies (IRB No. 00000921). All patients signed an informed consent form prior to their inclusion in the EWING1 trial from 2003 to 2010 (original trial, IRB No. 03363, date: October 15, 2003).

Patients with localized ES of bone treated between 2003 and 2010 according to the EWING1 trial were eligible for the study. Patients were allocated to low-risk (LRG) or high-risk (HRG) groups, where high-risk patients were defined as those with unresectable tumors, tumors of the pelvis, and lactate dehydrogenase (LDH) levels ≥ 1.5 times the upper limit of normal (x ULN). Tumor size was assessed on magnetic resonance imaging (MRI) and computed tomography (CT) scans before starting induction chemotherapy and categorized into ≤ 8 cm (small tumors) and > 8 cm (large tumors). Chemotherapy response was defined as good or poor according to the necrosis index (> 95% or ≤ 95%, respectively) [21, 22].

Patients were treated at 15 centers located in 6 states in Brazil, and one in Uruguay. Each center’s institutional review board approved the treatment protocols, and written informed consent was obtained for all patients at enrollment.

In the EWING1 trial, the induction chemotherapy consisted of two courses of ifosfamide/carboplatin/etoposide (ICE) and two courses of vincristine/doxorubicin/cyclophosphamide (VDC), followed by local control. After local treatment, LRG patients received 10 additional alternating cycles of ifosfamide/etoposide (IE) with VDC, while HRG patients received two additional cycles of ICE at the end of the consolidation therapy. Details of the treatment plan and timing of local control have been published previously [20].

Local control modality was defined based on the experience of treating physicians within each participating institution; however, the coordinating center established some criteria based on the patient and tumor characteristics to standardize the choice of local control. Patients with tumors that were amenable to resection with adequate margins, regardless of size, response to chemotherapy, or location, should be treated surgically. Cases with positive surgical margins, in which wide resection was not possible due to high morbidity, should receive PORT. The dose of PORT was defined as 45 Gy for marginal resections and 55.8 Gy for intralesional resections. The presence of necrotic tissue, even in the absence of viable ES cells, was considered incomplete resection and treated with 55.8 Gy. Patients with tumors of the ribs, with a pleural effusion contiguous to a primary lesion, should also receive PORT.

Definitive radiation was given to patients when wide resection could cause high morbidity or mutilation, and in unresectable tumors. Radiation was planned according to the X-ray, CT, and MRI when available. Radiotherapy was delivered to the original tumor volume with a 2-cm margin and a total dose of 55.8 Gy at 1.8 Gy/fraction started during week 11. At the end of treatment, it was established that patients would be followed up every 3 months during the first 2 years, then every 6 months for 5 years, and annually thereafter.

Recurrence was classified as local or systemic. For analysis purposes, any local recurrence was defined as local failure (LF) and systemic recurrence as distant failure (DF). Combined recurrences were included in the systemic group. The classification of the local control modality received by each patient was determined according to all interventions performed at the local tumor site up to and including the start of consolidation therapy. Local control was classified into one of three procedures: surgery, radiotherapy, or surgery plus radiotherapy. Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were defined as the time from the end of all local control measures until a respective event occurs or last patient contact, at which time the patient was censored. Patients who experienced disease progression, second malignant neoplasm, or death were scored as having experienced an event.

The outcome measures were OS, EFS, DFS, and cumulative incidence (CI) of LF and DF timed from the completion of local control therapy, as calculated by the Kaplan-Meier method. The CI of each type of event was calculated for each method of local control and compared by the log-rank test. Associations between categorical variables were analyzed using Pearson’s chi-square test. The Mann-Whitney test was used to compare medians for radiation dose. The association between local control modality and event risk was analyzed using univariate and multivariate Cox proportional-hazards regression models. The hazard ratio (HR) and 95% confidence interval (95% CI) were used as the measure of effect.

Data from 73 patients (45 males and 28 females, mean age of 12.8 years) with localized bone disease submitted to local control were selected from a total of 175 patients (96 with localized bone and extraosseous ES and 79 with metastatic bone and extraosseous ES) of the EWING1 trial. The median follow-up time of patients in this study was 4.5 years (range, 2.3 to 6.7 years). Forty-three tumors (58.9%) were located in the extremities, 10 (13.7%) in the pelvis, 10 (13.7%) in the chest wall, 6 (8.2%) in the spine, and 4 (5.5%) in other sites (p > 0.001). Thirty-eight (52.1%) patients were allocated as LRG and 35 (47.9%) patients as HRG (p < 0.001). Pelvic tumors were relatively more likely to receive radiotherapy than surgery alone. On the other hand, non-pelvic tumors were more frequently treated with surgery (p = 0.012). Tumor size ≤ 8 cm vs > 8 cm was not significantly associated with the local control modality performed (p = 0.12). The response to chemotherapy was poor (necrosis index ≤ 95%) in 56% and good (> 95%) in 44% of patients. Of 68 patients with complete LDH records, only 15 (22%) had LDH ≥ 1.5 x ULN and were more likely to have a surgical procedure (66.6%) than radiotherapy alone (33.3%) (p = 0.05). The median radiation dose was 50.4 Gy for both groups (range, 45.0 to 55.9 Gy).

Of 43 patients with tumors of the extremities, almost all underwent surgical treatment (n = 41, 95.4%), while only 2 (4.6%) received radiotherapy alone. Of 16 patients with tumors of the pelvis and spine, only 6 (37.5%) underwent surgery, while 10 (62.5%) received radiotherapy alone (p < 0.001) (Table 1).

The estimated 5-year EFS, OS, and DFS for all 73 patients was 62.1%, 63.3%, and 73.1%, respectively. The 5-year CI of LF and DF was 6.9% and 14.7%, respectively. Sixty-eight patients had complete information on local or distant recurrence. Only 4 had isolated LF, and 11 had DF combined or not with LF (Table 2; Figs. 1, 2, and 3).

The 5-year EFS was not statistically different according to tumor size ≤ 8 cm vs > 8 cm at presentation (61.1% vs 58.1%, HR = 1.07; P = 0.89), pelvic location (41.1% vs 66.7%, HR = 1.47; p = 0.44), LDH levels < 1.5 vs ≥ 1.5 x ULN (63.1% vs 51.3%, HR = 1.11; p = 0.83), or radiation dose (HR = 0.99; p = 0.56). LRG and HRG patients had EFS rates of 73.7% and 48.2% and LF rates of 5.6% and 8.3%, respectively (p = 0.16) (Table 2).

On multivariate analysis, definitive radiotherapy, age > 15 years and HRG were not associated with a higher risk of any event (Table 3).

The 5-year EFS was 30.8% for patients submitted to definitive radiotherapy (13 patients), 64.1% for surgery plus radiotherapy (13 patients), and 71.7% for surgery alone (47 patients) (p = 0.009). There was no significant difference in LF rates by local control modality (p = 0.61), and the LF rates were the same at 2 and 5 years of follow-up: 7.6% in the surgery group, 11% in the radiotherapy group, and 0% in the PORT group (p = 0.62). Considering all 15 patients with local or systemic recurrence, the CI of LF and DF at both 2 and 5 years was 11% for radiotherapy alone, 16.7% for surgery plus radiotherapy, and 25% for surgery alone (p = 0.64). The local disease control rate was 78%.