Results of a Prospective Study Delivering Limited Margin Radiotherapy for Pediatric Patients with Ewing’s Sarcoma Family of Tumors
Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2009
Presenter: M.J. Krasin Presenter's Affiliation: St. Jude Children’s Research Hospital, Memphis, TN Type of Session: Scientific
The Ewing’s sarcoma represents the 2nd most common bone tumor in children, following osteosarcoma. The Ewing’s sarcoma family of tumors includes Ewing’s sarcoma of bone, extraosseous Ewing’s sarcoma, peripheral primitive neuroectodermal tumor (PNET), and Askin’s tumor (PNET of chest wall).
Research since the 1960s has demonstrated improved local control and survival with use of a multimodality treatment approach, incorporating surgery, chemotherapy, and radiotherapy.
Definitive radiotherapy and/or combinations of radiotherapy and surgery have been demonstrated to provide equivalent local control when compared to more radical surgery (POG 8346, CESS 81, CESS 86), and may allow limb-sparing.
Risks of radiation in the pediatric population are well-recognized, and include risk of second malignant neoplasm and long-term limits to function. Patients with Ewing’s sarcoma may be at particular risk for development of second malignant neoplasm than pediatric patients with some other diagnoses.
As a result, research attempting to reduce both radiation dose and volume delivered to pediatric patients is paramount in determining the optimal risk-benefit balance.
As improvements in imaging modalities, radiation treatment planning, patient positioning, and treatment delivery with image-guidance have continued to advance, opportunities to deliver targeted, conformal radiotherapy with increased accuracy have also gained potential.
Although radiotherapy for sarcomas is recognized to require relatively large margins compared to some other forms of cancer, these assumptions must be questioned in light of modern technologic advances.
The study described here was undertaken in order to investigate local tumor control with use of limited-margin radiotherapy and adaptive dosing in treatment of pediatric Ewing’s sarcoma family of tumors.
Materials and Methods
The study described here was designed as a phase II, prospective study with a primary endpoint of local control after radiotherapy with limited margins for Ewing’s sarcoma.
Secondary endpoints included radiotherapy-related side effects.
Eligible patients were pediatric patients undergoing either adjuvant or definitive radiotherapy for Ewing’s sarcoma family of tumors at St. Jude Children’s Research Hospital.
Patients received systemic chemotherapy as described in the Pediatric Oncology Group 9354 study, consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide.
All patients received radiotherapy with the following dose prescriptions:
For unresected patients, a dose of 45 Gray (Gy) was delivered to the clinical target volume (CTV), followed by a boost to the gross tumor volume (GTV). Boost consisted of 9 Gy for tumors less than 8 cm, and 19.8 Gy for tumors 8 cm or greater.
For patients having undergone marginal resection, a dose of 50.4 Gy was delivered to the CTV.
Patients were treated with combinations of 3-D conformal radiation (3D CRT), intensity modulated radiotherapy (IMRT), and/or brachytherapy.
External beam treatment volume margin delineation was performed using registered MRI as follows:
GTV encompassed the regions of soft-tissue involvement after chemotherapy, as well as the regions of bone initially involved (prior to chemotherapy).
CTV consisted of an anatomically-constrained 2 cm margin for the first 9 patients, and a 1 cm margin for subsequent patients.
PTV margins ranged from 0.3 – 0.7 cm.
A total of 30 patients were enrolled on this trial from February, 2003 – January, 2009.
16 patients were treated for localized disease, and 14 for metastatic.
Median patient age was 12.8 years (range 5.0 – 24.7).
Median follow-up was 32.5 months.
Median tumor dose was 55.8 Gy for all patients, and 64.6 Gy for those with tumors 8 cm or larger.
All patients received systemic chemotherapy.
The three-year local control rate was 95.5% (+/- 4.6%).
The three year event-free survival was 90.9% (+/- 9.1%) for nonmetastatic patients, and 63.6% (+/- 36.4%) for metastatic.
On multivariate analysis, local control did not depend on disease extent (p = 0.36), tumor site (p = 0.54), or degree of resection (p = 0.10), or tumor size (p = 0.36).
Tumor size approached significance as a predictive factor for worse event-free survival (p = 0.05).
Patients with tumors 8 cm or greater appeared more likely to present with metastatic disease than those with smaller tumors (p = 0.0009).
The authors conclude that treatment with limited margin radiotherapy provides favorable local control in Ewing’s sarcoma, even for large tumors.
They note that the outcomes of this method of planning and delivering radiotherapy involve use of MR-based planning, and that further investigation in the setting of a large, prospective study is warranted.
Much work in the field of pediatric radiotherapy has focused on reduction of radiation dose and volume.
Reducing delivery of radiation to pediatric tissue has potential to reduce risk of second malignant neoplasm, and to preserve function, both factors which may be particularly important in the Ewing’s sarcoma population.
In parallel with work seeking to reduce radiation volume and dose needed to treat pediatric malignancies, work in both adult and pediatric sarcomas has sought to move away from a paradigm of radical surgery and towards function-preserving surgery in combination with radiotherapy and chemotherapy.
Advances in technology allow increased accuracy in radiotherapy planning and delivery – these include MRI and PET based planning, use of technologies such as IMRT and proton radiotherapy, image-guided treatment delivery, and advances in patient positioning. As we gain access to these technologies, our prior treatment paradigms must be reconsidered.
The authors have demonstrated through the study described above that consideration of smaller treatment margins may allow excellent local control during treatment of Ewing’s sarcoma family of tumors.
On multivariate analysis, neither tumor size nor extent of resection were found to be prognostic factors for local failure, suggesting that use of higher radiotherapy doses for large tumors or residual tumors might to some degree compensate for large amounts of residual disease.
Although the work presented here is certainly hypothesis-generating, it is not definitive due to small patient numbers and a heterogeneous patient and treatment population. As the authors point out, further evaluation in the setting of a large trial would potentially be very valuable in promotion of understanding of situations in which limited margins and radiotherapy dose may be employed to spare normal tissue, as well as clinical situations requiring adaptive higher dosing to provide optimal local control.
Dec 22, 2011 - Cixutumumab is well tolerated in children with refractory solid tumors, but limited single-agent activity is seen in Ewing sarcoma, according to a study published online Dec. 19 in the Journal of Clinical Oncology.