Ewing sarcoma (ES) of the jaw bones comprises a small fraction of ES at all sites. Due to their rarity, a specific policy for local treatment is lacking. The aim of this study was to evaluate the local therapy for ES and recommend measures to individualize treatment options. Patients with primary non-metastatic ES of the jaw bones treated between August 2005 and February 2015 were analyzed. All patients received primary induction chemotherapy, following which lesions amenable to resection based on specific radiological criteria were resected; those with unresectable lesions were offered definitive radiotherapy. The maxilla was the primary site in 13 patients and the mandible in eight. The median age of patients was 11.6 years (range 5–17 years). Overall, surgery was performed in 17 patients and definitive radiotherapy was used in four patients. Postoperative radiotherapy was administered to 12 patients and was avoided in five patients with 100% tumour necrosis. The 3-year overall survival, event-free survival, and local control were 68.1%, 63.6%, and 80.2%, respectively. Mandible primary and a histological response to chemotherapy were significant prognostic factors. The stratification of patients based on radiological criteria aids in selecting local therapy. In eligible patients, surgery with contemporary reconstruction results in optimal oncological and functional outcomes. Surgery also has the added advantage of identifying patients who may not need radiotherapy.
Ewing sarcoma (ES) of the jaw bones accounts for 1.8–5.2% of ES at all sites. Although the role and impact of primary chemotherapy is well established in ES, the management of local disease remains inconsistent. Lesions of the jaw represent a distinct surgical challenge, with the possibility of functional impairment and cosmetic inadequacy. Similarly, radiation for jaw lesions is restricted due to the proximity of critical structures, which may compromise the delivery of effective radiation therapy. As data specific for jaw ES are limited and varied treatments are offered, a definitive and uniform policy for local treatment is lacking. Generally, radiotherapy is reserved for large lesions that are considered unresectable. At the same time, due to concerns related to the surgical defect and the need for reconstruction, surgery is also relatively contraindicated. A randomized controlled trial comparing those with a similar extent of disease treated with surgery or radiotherapy may perhaps resolve this issue. However, this seems unlikely since ES of the mandible and maxilla is rare. Hence, the evaluation of a case series may help in determining the appropriate treatment. The case series presented herein includes updated data for a few patient cases that have been reported previously, in order to have a sufficient number of patients to evaluate treatment outcomes and to identify risk factors.
The aim of this study was primarily to evaluate the local therapy of ES and recommend measures to individualize treatment options in a given clinical scenario for patients with ES of the jaw.
Materials and methods
Patients with primary non-metastatic ES of the mandible or maxilla treated between August 2005 and February 2015 were selected from a prospectively maintained institutional database. All patients had undergone a comprehensive clinical evaluation and a core biopsy for confirmation of the diagnosis. Patients who underwent a surgical exploration elsewhere had their biopsy result reviewed at the study centre. Diagnosis was established based on histomorphology and immunohistochemical analysis. Translocation studies were performed in equivocal cases. All patients underwent investigations to exclude metastatic disease, including a whole-body technetium bone scan, chest computed tomography (CT) scan, bone marrow aspiration, and biopsy. A whole-body positron emission tomography (PET) scan was also performed in some patients ( n = 13). Every patient case was discussed at a multidisciplinary tumour board meeting for treatment planning.
CT or magnetic resonance imaging (MRI) was performed for all patients to evaluate the primary tumour and to assess the response to induction chemotherapy. A PET scan was performed for patients receiving definitive radiotherapy in order to assess the local response. A large volume tumour was defined as a neoplasm equal to or more than 5 cm in the greatest dimension, and a small volume tumour as one with a greatest dimension of less than 5 cm.
All patients were treated according to the institutional chemotherapy protocol for ES, which included two courses of VIE couplet (vincristine, ifosfamide, and etoposide), followed by two courses of VAC couplet (vincristine, doxorubicin, and cyclophosphamide) administered every 3 weeks as neoadjuvant/induction chemotherapy. Following local therapy to the primary tumour, maintenance therapy was administered, consisting of 10 courses of chemotherapy administered every 3 weeks (four courses of VAC, two courses of VIE, and four courses of VCD (vincristine, cyclophosphamide and actinomycin D) with actinomycin D substituted for doxorubicin after a total dose of 360 mg/m 2 ). Vincristine was administered weekly throughout the chemotherapy schedule.
An absence of specific criteria on imaging, together with the possibility of achieving negative surgical margins, formed the basis of the selection of patients for surgery ( Figs. 1–3 ). The tumour was considered unresectable if there was (1) deep infiltration of the infratemporal fossa or base of the skull, (2) involvement of the posterior ethmoid and sphenoid sinus, or (3) extensive soft tissue and skin infiltration.
Lesions amenable to surgery were resected. Patients with unresectable lesions were offered definitive radiotherapy. The surgical technique used has been described previously. The tumour response to chemotherapy and the tumour margins were evaluated in the resected specimen. The tumour response was classified as ‘good’ when there was no identifiable viable tumour or less than 5% identifiable residual tumour cells, and ‘poor’ if the surgical specimen contained more than 5% residual tumour cells. The margins were categorized as ‘tumour-positive’ or ‘tumour-negative’ depending on the presence or absence of tumour cells on gross or histological examination.
Postoperative radiotherapy was recommended for patients with positive surgical margins or a poor response to chemotherapy.
Patients were followed up every 3 months for 2 years, and then every 6 months for 3 years. Imaging was performed at completion of chemotherapy and then at least every 6 months during the first 3 years off therapy. Additional studies, including biopsy, were added when indicated by clinical and radiological evaluation. Patients not followed up at the hospital were contacted by telephone or mail. Follow-up was undertaken until August 2015. The functional outcomes of patients who underwent surgery were measured in terms of tooth alignment, chewing, swallowing, speech, diet, and facial symmetry, and gait for donor site morbidity. Questionnaires were completed and referrals made to an occupational therapist and dentist for objective assessment of functional outcomes. Facial symmetry was assessed subjectively by comparing the reconstructed site with the normal contralateral side.
Overall survival (OS), event-free survival (EFS), and local control (LC) were calculated by Kaplan–Meier method. OS was calculated from the date of diagnosis to the date of death from any cause. For patients receiving definitive radiotherapy, progression was defined as a clinical or radiological increase in the size of the primary tumour or appearance of a new metastatic lesion; complete response (CR) was defined as the disappearance of the lesion or no uptake on PET scan. EFS was calculated from the date of diagnosis to the date of relapse, progression, or death from any cause. LC was defined by any local relapse or progression, regardless of metastatic disease status at the time, to better characterize our ability to control gross disease. IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis.
During the study period, 628 patients with ES were treated, of whom 25 (4%) had tumours of the maxilla or mandible. Twenty-three of these patients had primary non-metastatic tumours and were treated with curative intent; two patients had recurrent/metastatic disease and were offered best supportive care. The latter two patients were excluded from the study. Of the 23 patients, two discontinued neoadjuvant chemotherapy before local therapy and died of progressive disease. The remaining 21 patients completed the planned treatment and were analyzed in this study ( Fig. 4 ). There were 11 males and 10 females, with a median age of 11.6 years (range 5–17 years). The maxilla was the most common site ( n = 13) as compared to the mandible ( n = 8). Regional lymph node metastasis was not present in any patient.
Local therapy was performed after neoadjuvant chemotherapy in all except one patient, who underwent functional endoscopic sinus surgery (FESS) before chemotherapy. Overall, surgery was performed in 17 patients and definitive radiotherapy was used in four patients. All mandible tumours were resectable as per the stipulated criteria, while 9/13 maxilla tumours were resectable. Surgery included hemimandibulectomy (six patients), extended hemimandibulectomy (one patient), and middle third mandibulectomy (one patient). A total maxillectomy was performed in seven patients, and one patient required a radical maxillectomy.
Restoration of the surgical defect was performed with a free fibular osteomuscular flap (FFOF) in 11 patients, free anterolateral thigh flap (FALTF) in one patient, a pectoralis major myofascial flap (PMMF) in one patient, and a split thickness skin graft (STSG) in two patients. Minor wound complications occurred in two patients and were managed conservatively. Compartment syndrome secondary to tight closure of the skin defect at the donor site occurred in one patient and required debridement; this led to a delay in initiating adjuvant treatment. There were no complications related to microvascular anastomosis or flap loss. There was no perioperative or postoperative mortality.
Surgical margins were negative in 14/17 patients. The three patients (including the patient who had FESS) with positive margins had a maxillary tumour of less than 5 cm in size. Postoperative radiotherapy was administered to 12 patients. Two of these had a small volume tumour but had positive margins after resection. The median radiation dose was 46.8 Gy (range 41–50 Gy). Five patients with evidence of 100% tumour necrosis in the specimen after neoadjuvant chemotherapy did not receive postoperative radiotherapy.
The radiation dose for definitive radiotherapy was 55.8 Gy. On completion of treatment following definitive radiotherapy, three patients had CR, while disease progression occurred in one patient.
Outcomes and survival
After a median follow-up of 36 months (range 7–123 months), 14 patients were alive without evidence of disease (NED), one was alive with disease (AWD), five had died of disease (DOD), and two patients had died of chemotherapy-related toxicity. The median time to death from disease relapse was 10 months (range 1–28 months). The 3-year OS, EFS, and LC for the entire cohort were 68.1%, 63.6%, and 80.2%, respectively.
On univariate analysis, age, sex, and tumour size were not significant predictors of the outcome ( Tables 1–3 ). Mandible tumours were associated with better EFS ( P = 0.02) and OS ( P = 0.04). The OS for patients who underwent surgery with or without radiotherapy was 73% and that for patients who underwent definitive radiotherapy was 50.1% ( P = 0.35); the EFS was 74.3% and 25%, respectively ( P = 0.03) and LC was 91.7% and 33.3% respectively ( P < 0.01). The histological response to chemotherapy was a significant predictor of both OS and EFS.
|3-year %||P -value||3-year %||P -value|
|Surgery ± radiotherapy||17||74.3||0.03||73||0.35|
|Histology response a|