Proton Radiotherapy for Pediatric Ewing's Sarcomas: Initial Clinical Outcomes of 29 Patients

Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

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Presenter: B. Rombi
Presenter's Affiliation: Trento, Italy
Type of Session: Scientific

Background

  • Ewing’s sarcoma represents the second most common bone tumor in children; the Ewing’s family of tumors includes osseous Ewing’s sarcoma, extraosseous Ewing’s sarcoma, peripheral neuroendocrine tumors (PNET), and Askin’s tumors (PNET of chest wall).
  • The median age of presentation is 14 years (usual range 8- 25 years), with males being affected more often than females.
  • Ewing’s sarcomas are most commonly diagnosed in the lower extremities, followed by pelvis, upper extremities, and spine.
  • 75 – 80% of patients present with localized disease. Even in these situations, Ewing’s sarcoma requires aggressive treatment both to the primary site and systemically. All patients thus require a multidisciplinary treatment approach, consisting of induction chemotherapy, followed by surgical resection when feasible. Post-operative radiation is generally offered in situations of positive surgical margins, gross residual disease, or poor histologic response to chemotherapy. Radiation may be offered as definitive treatment in cases of unresectable tumors, most commonly of the skull, face, pelvis, or spine.
  • Patients with gross disease require radiotherapy doses approaching 60 Gy, while those with microscopic disease require 50 Gy.
  • This treatment approach may be associated with significant morbidity, the nature of which may depend on the primary tumor site. Radiotherapy to immature bones may result in premature epiphysis closure, leading to gait difficulties. Radiotherapy and surgery may contribute to lymphedema, joint fibrosis, and risk of fracture.
  • Patients treated for Ewing’s sarcoma have also been observed to be at high risk for development of second malignant neoplasms, with genetic factors, radiotherapy, and chemotherapy likely contributing to this increased risk.
  • The physical properties of proton radiotherapy may allow reduction of radiation dose delivered to normal tissues. Depending on tumor site, this improved specificity in dose delivery may allow reduction of risk of late effects; in addition, theoretical data has demonstrated potential reduction in risk of development of second malignancy with proton versus photon radiation (Yock, ASTRO, 2008).
  • In light of these potential benefits, children with Ewing’s sarcomas have been treated with proton radiotherapy at the Burr Proton Facility in Boston, Massachusetts. Here, the preliminary clinical outcomes for this cohort are reported.

Materials and Methods

  • 29 children with Ewing’s sarcoma treated at the Francis H. Burr Proton Facility between April 2003 and April 2009 and were included in this study.
    • Of these, 13 were male and 16 female.
    • Median age was 10.8 years (range 1.8 – 21.0 years)
  • Tumor locations included pelvis in 4 cases, trunk in 15 (14 involving the vertebrae), head and neck region in 6, and the cranium in 6. No patients had tumors of the extremities.
  • All patients were treated with standard chemotherapy, with or without surgery:
    • 10 patients received definitive radiation
    • 19 received adjuvant radiation
    • 2 received salvage radiation
  • Proton radiotherapy dose ranged from 45 – 59.5 CGE (median 54 CGE), with treatment volumes delineated as follows:
    • GTV1: pre-chemotherapy disease extent based on CT scan, MRI, and/or PET scan
    • CTV1: 1-2 cm expansion from GTV1, anatomically constrained
    • GTV2: post-chemotherapy soft tissue disease and original sites of bony disease
    • CTV2: 1-2 cm expansion from GTV2
    • 45 Gy was delivered to the CTV1, with dose to CTV2 ranging from 0 – 15.4 Gy
  • Medical records were retrospectively reviewed for assessment of local control, progression-free survival, and overall survival.
  • Median follow-up was 21.7 months (range 30 days – 6 years from start of radiation therapy).

Results

  • At the last follow-up, 79% of patients (n = 23) were alive without evidence of disease (2 had received salvage for failures), 7% (n = 2) were alive with disease, 10% (n = 3) died of metastatic disease, and 3% (n = 1) died of a second malignancy.
  • The crude rate of local control was 93.1% at year 1, and 88% at year 3.
  • Rate of progression-free survival was 79.3%.
  • Overall survival was 89.6%.
  • Proton therapy was tolerated well in the acute setting, with skin reactions being the most common reported acute toxicity. Other acute toxicities included fatigue, nausea/diarrhea, hoarseness, and kerato-conjunctivitis.
  • Late effects included the following:
    • Scoliosis/kyphoses (n = 4). Three of four cases were felt to be most likely attributable to surgical laminectomy.
    • Mild limb length discrepancy (n = 1), requiring no intervention
    • Radiation induced skin changes (n = 4)
    • Hypothyroidism (n = 1)
    • Unilateral high frequency hearing loss (n = 1) G
    • Growth hormone deficiency (n = 1)
    • Ptosis with chronic corneal erosion in a patient who received radiotherapy for Ewing's sarcoma of the orbit.
    • Secondary malignancies (n = 4)
      • 3 cases of acute myeloid leukemia
      • 1 case of myelodysplastic syndrome
      • Median time to second cancer diagnosis was 27 months

Author's Conclusions

  • The authors conclude that proton therapy for pediatric Ewing’s sarcoma may be well-tolerated without unacceptable adverse events.
  • They note that follow-up is short within the study reported here, but also note that treatment failures typically occur within 2 years and that the outcomes compare favorably with the literature.
  • They state that longer follow-up time is needed for full assessment of both clinical outcomes and late effects.

Clinical/Scientific Implications

  • The study presented here is interesting, and is certainly one of the first and only reports evaluating clinical outcomes after treatment with proton radiotherapy for pediatric Ewing’s sarcoma.
  • As the authors point out, follow-up is relatively short; however, some patients have been studied for as long as 6 years, yielding enough data for preliminary assessment of some late effects. Certainly, increased follow-up will be of utmost importance for further understanding of late effects following treatment.
  • Within this study, local control and overall survival rates appear to be at least similar to those reported in the literature, as the authors point out. Although full assessment is not feasible in the absence of randomized data, the outcomes here may in fact be superior to those reported elsewhere, particularly because the study population represents a group of patients with high-risk disease. Longer follow-up and future studies involving larger groups of patients will hopefully help to elucidate outcomes benefits that may be available from use of proton therapy.
  • Within this study, 4 of 29 patients developed second malignant neoplasms. All were hematologic, the risk of which is recognized to increase dramatically after treatment with alkylating agents such as etoposide. The development of these second tumors may thus not be related to radiotherapy type or technique. The rate of second tumor development in this population does seem higher than expected, however, based on other reports in the literature, and further observation of larger populations may help to elucidate the clinical impact of proton radiation on development of second cancers.
  • Despite the limitations of small study size and retrospective nature, this study represents a valuable contribution to the literature, with presentation and analysis of preliminary data regarding use of proton radiotherapy in treatment of pediatric Ewing’s sarcomas of the axial skeleton and skull base.



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