Accelerated Hyper Fractionated Radiotherapy in Localized Ewing ’ s Sarcoma with or without Surgery : What ’ s New ? A Phase II Study

Background and aim of work: We aimed from this study to determine the response and local relapse free survival (RFS) of pediatric patients with localized Ewing’s sarcoma treated with accelerated hyper-fractionated RT. Patient and methods: This study was a nonrandomized uncontrolled phase II study and was conducted at clinical oncology department and south Egypt cancer institute; it involved 28 patients with histologically confirmed Ewing’s sarcoma; all of them were subjected to PET/CT whenever possible or MRI with contrast of the primary site, MSCT chest, bone scan, and LDH to ensure absence of metastasis followed by the protocol of accelerated hyper fractionated RT. Results: The overall response rate (ORR) was 92.9% by MRI with significant effect of the type of response on local RFS (P < 0.002). The median local RFS of 28 patients with localized Ewing’s sarcoma was 30 ± 8.599 months with 95% CI = 13.147 46.853; the 3-year local control was 35%. Conclusion: Accelerated hyper fractionated RT didn’t achieve better results than standard fractionation RT, but it is recommended to be done on a large sample size, and multiple centers, and continued follow up is also recommended to evaluate 5-year LRFS, 5-year OS.


Introduction
Ewing's sarcoma is the 2 nd most common primary malignant bone tumor in Several factors affect the choice of local treatment as patient age, site, size, and local extension of tumor; however surgical resection is better than definitive RT for local control [1], namely marginal resection or wide local excision while debulking followed by RT doesn't add any benefit over definitive RT [2].
Definitive RT is employed only for inoperable tumors with a dose of 54 -55.8 Gy given to the tumor with 2 cm safety margin including all surgical and biopsy scars [3].
According to Schuck A et al. [4] fractionation of RT doesn't affect the local control more than the quality of RT given, so it is advisable to be given by IMRT, stereotactic RT, or proton RT [2].
Post operative RT (PORT) is indicated whenever incomplete surgical excision [5], positive/close margin, or poor histologic response to chemotherapy exists; however the role of PORT is debatable in those patients with good histologic response to chemotherapy; Stephanie F et al. tried through their an observational study of the Euro-E.W.I.N.G group to solve this argument and declared that surgery plus PORT compared to surgery alone was associated with statistically significant reduction in local relapse leading to an 8-year local relapse incidence of 11.9% [6] and this benefit was marked for those with tumor volumes ≥ 200 ml and 100% necrosis following chemotherapy.
Regarding to tumor size and RT dose; despite of being predictive of local control in localized Ewing's sarcoma, CESS study [7] failed to detect a significant advantage of hyper fractionated RT over the standard fractionation and RT dose of 55.8 Gy.
Data from university of Florida [8] suggested that hyper fractionated RT was associated with lower early and late tissue toxicities.
We aimed from this study to determine the response and local relapse free survival (RFS) of pediatric patients with localized Ewing's sarcoma treated with accelerated hyper-fractionated RT.

Patients and Methods
This study was a nonrandomized uncontrolled phase II study and was conducted at clinical oncology department, Assiut university hospital and south Egypt cancer institute, Assiut university where children with histologically confirmed Ewing's sarcoma, localized, whether RT given as definitive therapy or postoperative for the presence of residual disease, age ≤ 18 years, any gender, informed consent was taken from their relatives, and the study was approved by the institutional ethics committee of faculty of medicine, Assiut University.
All patients were subjected to the followings prior to RT: -Preoperative chemotherapy in the form of alternating VACA/IE (Children's Oncology Group Study INT-0091) administered every 3 weeks for 12 weeks with doses of vincristine 2 mg/m 2 (max. 2 mg) i.v. on day 1, doxorubicin 75 mg/m 2 i.v.day 1, cyclophosphamide 1200 mg/m 2 i.v. with mesna uroprotection on day 1, dactinomycin 1.25 mg/m 2 i.v. on day 1 to be substituted for doxorubicin after 375 mg/m 2 of doxorubicin was received this regimen combination was given alternating with ifosfamide 1800 mg/m 2 i.v. on days 1 -5 with mesna uroprotection and etoposide 100 mg/m 2 i.v. on days 1 -5, VACA/IE was continued during radiotherapy but with omission of doxorubicin.
-Surgery was planned to be done on week 12 and it was wide local excision if possible with radiotherapy planned to be given for those with incomplete excision or definitively for those with just incisional or tru-cut needle biopsy.
-PET/CT whenever possible (as it was done in some patients) or MRI with contrast of the primary site, MSCT chest, bone scan, and LDH to ensure absence of metastasis.

Radiation Treatment Protocol
RT was given in two phases without any time separation, the dose for phase I was 44.8 Gy given over 28 fractions over two weeks in two fractions daily and fraction size of 1.6 Gy and the two fractions were at least 6 hours apart, CTV = pre chemotherapy GTV (bone and soft tissue) + 2 cm safety margin (in both longitudinal and lateral axes) (Figure 1).
The dose for phase II was 19.2 Gy given over 12 fractions over 6 days, CTV = pre chemotherapy bone GTV + residual soft tissue with 1 -2 cm safety margins in both longitudinal and lateral axes.Treatment was delivered regularly using 6 -15 MV energy and LINAC primus machine.Unfortunately, no other demographic or clinical characteristics had a prognostic impact on LRFS; but it may be logic to have no impact of age, sex, PS, presentation, biopsy type, CD 99, pretreatment MRI.
In this study; site of the tumor had no significant effect and this was contrary to Karski EE et al. also no significant of surgery on LRFS which wasn't comparable to Ricardo G et al. [11] that detected a 5-year event free survival of 30.8% for patients received definitive RT, 64.1% for surgery plus RT and 71.7% for surgery alone.
3-year LC in our study was 35% which was comparable to DuBois SG [1] that denoted high incidence of local relapses in those received definitive RT and in ours; the local control was low as no complete surgical excision was done.
Definitive RT without surgery especially in tumors ≥ 8 cm demonstrated inferior local control (P = 0.033) and progression free survival (P = 0.016) [12] and this was clear in our study as tumors ≥ 8 cm represented 60.7% The median LRFS and 3-year Local control in our study was lower to previous studies that utilized definitive RT with standard fractionation which implied inferiority of accelerated hyper fractionation, but this conclusion couldn't be confirmed because of small sample size, cases came only from single center and no complete surgical excision was done.

Conclusion
Accelerated hyper fractionated RT didn't achieve better results than standard fractionation but it is better to be done on a large sample size, and multiple centers, and continued follow up is recommended to evaluate 5-year LRFS, and 5-year OS.

Figure 1 .
Figure 1.Treatment portals for phase I RT of Ewing's sarcoma of upper end of humerus.

Figure 2 .
Figure 2. Local RFS among 28 patients with localized Ewing's sarcoma treated with accelerated hyper fractionated RT.

Table 1 .
Demographic and clinical characteristics of 28 patients with localized Ewing's sarcoma and their significant effects on RFS.

Table 2 .
Type of response among 28 patients with Ewing's sarcoma and their significance.