Intraoperative phosphorus-32 brachytherapy plaque for multiply recurrent high-risk epidural neuroblastoma

Case report

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Achieving local control is a crucial component in the management of neuroblastoma, but this may be complicated in the setting of prior radiation treatment, especially when the therapeutic target is in proximity to critical structures such as the spinal cord. The authors describe a pediatric patient with multiply recurrent neuroblastoma and prior high-dose radiation therapy to the spine who presented with progressive epidural disease. The patient was managed with resection and intraoperative high-dose-rate brachytherapy using a phosphorus-32 (32P) plaque previously developed for the treatment of brain and spine lesions.

Abbreviations used in this paper:GTR = gross-total resection; 123I = iodine-123; 192Ir = iridium-192; MIBG = metaiodobenzylguanidine; 32P = phosphorus-32.

Abstract

Achieving local control is a crucial component in the management of neuroblastoma, but this may be complicated in the setting of prior radiation treatment, especially when the therapeutic target is in proximity to critical structures such as the spinal cord. The authors describe a pediatric patient with multiply recurrent neuroblastoma and prior high-dose radiation therapy to the spine who presented with progressive epidural disease. The patient was managed with resection and intraoperative high-dose-rate brachytherapy using a phosphorus-32 (32P) plaque previously developed for the treatment of brain and spine lesions.

Neuroblastoma is the most common extracranial solid tumor in children and the most common malignancy in infants younger than 1 year old.1 The outcome for patients with recurrent high-risk neuroblastoma is very poor,5 and effective curative treatments have not been established in the setting of resistant neuroblastoma. Intraoperative electron beam therapy8,10,16,19,20 or brachytherapy7,13–15,17,21 for pediatric solid tumors has been used in many institutions to increase the likelihood of durable local control. Rich et al.18 recently described the outcomes for 44 patients with recurrent or persistent primary high-risk neuroblastoma treated with resection and intraoperative radiation therapy with iridium-192 (192Ir) high-dose-rate afterloader brachytherapy using the Harrison-Anderson-Mick (HAM) radiation applicator. During a median follow-up of 10.5 months, no operative or postoperative deaths were observed, and local control was approximately 50% with a median overall survival of 19 months.

Intraoperative brachytherapy has the advantage of direct placement of the radioactive source at a tumor site and rapid dose falloff with distance to permit localization of conformal dose to the site with relative sparing of nearby normal tissues. However, with 192Ir, a 50% reduction in dose requires a separation of approximately 8 mm from the source.3 At sites close to previously treated areas, this distance may be inadequate for sufficient sparing of normal tissue. Recently, an intraoperative brachytherapy applicator incorporating phosphorus-32 (32P) in a flexible film was developed.4 The benefit of this applicator is a sharp dose falloff, with a decrease to < 5% of the prescription dose within 3–4 mm (Fig. 1).

Fig. 1.
Fig. 1.

Percent depth dose (PDD) curve for an intraoperative 32P brachytherapy plaque, with measurements for radiation dose at a depth relative to prescription dose (10 Gy to 1-mm depth).

Case Report

History

A 6-year-old girl with multiply recurrent high-risk neuroblastoma was referred to our radiation oncology and neurosurgical services because of progressive disease in her thoracic spine resulting in spinal cord compression. She had been in her usual state of good health (41 months earlier, February 2009) when she experienced symptoms of constipation, abdominal pain, and low-grade fever. Her workup included an abdominal CT scan, which revealed a retroperitoneal mass and prominent lymph nodes. A biopsy revealed neuroblastoma—poorly differentiated, stroma poor, mitosis-karyorrhexis index > 100 (unfavorable histology), and N-myc nonamplified. Bone marrow studies were positive for neuroblastoma. Bone scan was negative for disease. Metaiodobenzylguanidine (MIBG) was positive in the abdomen only. A chronological summary of systemic, radiation, and surgical therapies with corresponding diagnostic evaluations is provided in Fig. 2. In brief, the patient underwent multiple tumor resections for both primary and recurrent disease; 38 cycles of chemotherapy and radioimmunotherapy, and external beam radiation therapy to her abdomen, femurs, and left supraclavicular lymph nodes; and stereotactic hypofractionated image-guided radiation therapy to spine metastases at C5–7 and T4–7, with treatment to her spine in November 2011 (Month 32 after diagnosis).

Fig. 2.
Fig. 2.

Timeline of diagnostic and therapeutic interventions prior to thoracic epidural recurrence and evaluation by a multidisciplinary pediatric oncology tumor board.

Follow-up MRI of the spine in August 2012 (Month 41 after diagnosis) revealed an interval increase in the epidural soft tissue at the T3–7 level, resulting in cord impingement and early cord compression (Fig. 3) A known ventral epidural tumor at the level of C5–7 was unchanged, with no evidence of spinal cord compression at that level. It was believed that additional local therapy in the thoracic spine would be necessary to prevent impending neurological damage due to cord compression, but it was less than 1 year after she had completed a course of hypofractionated external beam radiation therapy to the site, putting her at increased risk of spinal cord injury and/or myelitis. Thus, she was referred to the neurosurgical service/multidisciplinary pediatric oncology tumor board for consideration of decompression with radiation therapy at the time of surgery.

Fig. 3.
Fig. 3.

Presurgical planning sagittal (left) and axial (right) T2-weighted MR images showing an epidural mass extending from T-3 to T-7, compressing and displacing the spinal cord.

Her case was discussed in the multidisciplinary pediatric oncology tumor board, and it was believed that gross-total resection (GTR) was achievable, but that microscopic residual disease was probably unavoidable at the dural margins. Accordingly, intraoperative plaque brachytherapy was planned. Magnetic resonance imaging studies were reviewed to determine whether adequate CSF clearance could be achieved by assessing the CSF space above and below the site of epidural disease (Fig. 4). It was believed to be at least 4 mm, allowing adequate dose falloff to < 5% of the prescribed dose of 10 Gy at a depth of 1 mm (as shown in Fig. 1).

Fig. 4.
Fig. 4.

Axial T2-weighted MRI sequences, proximal (left) and distal (right) to the site of compression, showing the measurement of CSF thickness from the interior surface of the dura mater to the surface of the cord.

Operation

She was taken to the operating room in September 2012 (Month 42 following diagnosis) for thoracic laminectomies of levels T3–6 together with excision of extradural tumor, utilizing intraoperative fluoroscopy for localization. The tumor was ventral and lateral to the cord and was separated from the dura mater with microdissectors. Dural integrity was maintained. The cord returned to the center of the spinal canal, and the normal contours of the dura were restored, as the mass effect from the tumor was alleviated. No gross epidural tumor was visible, and meticulous hemostasis was maintained before beginning the intraoperative brachytherapy.

For the intraoperative brachytherapy, a 1 × 6–cm 32P plaque was applied to the exposed dorsal and dorsolateral T3–4 dura under sterile conditions. A photograph of a similar 32P plaque insertion is featured in Fig. 5. A total dose of 10 Gy was prescribed to a depth of 1 mm. The dose rate at treatment depth was calculated to be 71.6 cGy/minute, and treatment was delivered over the course of 13 minutes and 58 seconds. At the end of the treatment, the plaque was removed and placed in a shielded container, and the surgical cavity was surveyed to ensure that no residual radioactivity was detected. The area was irrigated with antibiotics, the fascia was closed with interrupted vicryl sutures, and the skin was closed with a running nylon suture. The patient was transferred to the postanesthesia care unit in stable condition.

Fig. 5.
Fig. 5.

Photograph of a flexible 32P plaque placed on the dura following resection of the epidural tumor.

Postoperative Course

Postoperative MRI showed resection of the lesion, expected postoperative changes, and decompression of the underlying spinal cord. There was no evidence of residual disease, confirming GTR (Fig. 6). Pathology submitted at the time of surgery confirmed the presence of viable malignant metastatic neuroblastoma. There were no wound complications, and the patient recovered quickly and continued with her fifth cycle of cyclophosphamide and topotecan. While asymptomatic neutropenia and thrombocytopenia developed, there were no acute toxicities associated with intraoperative therapy and no wound complications in the postoperative period.

Fig. 6.
Fig. 6.

Postoperative sagittal (left) and axial (right) T2-weighted MR images showing GTR of the lesion with expected postoperative changes and decompression of the underlying spinal cord.

Three months after surgery, MRI in December 2012 (Month 45 following diagnosis) showed no evidence of recurrence in her thoracic spine, and an iodine-123 (123I)–MIBG scan showed no activity in her thoracic spine and no progression outside the area treated with resection and intraoperative 32P brachytherapy (Fig. 7).

Fig. 7.
Fig. 7.

Follow-up sagittal (left) and axial (right) T2-weighted MR images showing stable postoperative changes and no evidence of recurrent disease.

She completed her eighth cycle of cyclophosphamide and topotecan and was clinically well until May 2013 (Month 50 following diagnosis) when she was found to have progressive disease on CT, 123I-MIBG, and MRI studies. The new areas of disease included the lungs, liver, and spine at the C6–T1 levels. However, there was no evidence of recurrence in the area treated with resection and intraoperative 32P brachytherapy. She subsequently started cyclophosphamide, carboplatin, and doxorubicin chemotherapy. Ten months following surgery (Month 52 after diagnosis), repeat spine MRI again showed no evidence of local recurrence in the area treated with resection and 32P brachytherapy, and no clinical signs of recurrence were noted at 11 months postsurgery.

Discussion

The standard of care for high-risk neuroblastoma is maximal safe resection after neoadjuvant chemotherapy, followed by postoperative radiation therapy.9,11,12 For patients with recurrent or refractory neuroblastoma, a number of therapies exist including salvage surgery, chemotherapy, and/or radiation therapy, as well as targeted radionuclide delivery via MIBG, newer retinoid compounds, and immunotherapy;1 however, the cure rate is low in patients whose aggressive up-front therapy has failed.

Intraoperative radiation therapy offers an option for patients who have had prior radiation and in whom there is concern for toxicity from additional radiation treatment. As the radiation is delivered locally and does not encompass the same degree of healthy tissue as in external beam radiation therapy, there is a significant reduction in the incidence and degree of toxicity to normal tissue. The dose of brachytherapy radiation decreases with the square of the distance from the applicator, leading to rapid dose falloff. High doses can be delivered in a single fraction, potentially resulting in a significantly increased radiobiological treatment effect.2,6

Specifically in the setting of neuroblastoma, most institutions have used intraoperative electron beam radiation therapy;8,10,16,19,20 the use of intraoperative brachytherapy has been reported at a smaller number of institutions.7,18 While intraoperative brachytherapy with flexible applicators is highly versatile, allowing ease of access to and conformal placement in anatomical locations that a bulky electron cone applicator may not be able to reach, the dose falloff with 192Ir, while rapid, may not allow sparing of sensitive structures such as the spinal cord when the dura (only 3–4 mm away) must be effectively treated. In this setting, a brachytherapy applicator with significant falloff in only a few millimeters is required.

The use of an intraoperative 32P brachytherapy plaque has been described.4 32P is a pure β-emitter (Emax = 1.71 MeV, T1/2 = 14.28 days) with a maximum electron range of approximately 7 mm in water). The RIC-100 conformal 32P source (RI Consultants) consists of 32P bound chemically to a flexible and transparent polymer layer and coated with silicone. Given a depth of approximately 3 mm from the dural surface to the surface of the cord, a standard prescription of 10 Gy at 1 mm will result in a maximum cord dose of approximately 1.6 Gy (Fig. 1). The dose at the dural surface would be approximately 25.5 Gy; the dose delivered at a depth of 4 mm from the surface is approximately 5% of the prescribed dose at 1 mm and < 1% of the prescribed dose at 5 mm (4 mm from the prescribed treatment depth).

The use of a 32P plaque in the intraoperative setting dramatically simplifies treatment; the size and shape of the plaque are determined preoperatively, but the film can be folded (or partially shielded) to account for smaller target volumes. It is very flexible, allowing for easy fit into tight spaces and is easily conformed to the target surface. No additional planning time is needed, and treatment duration is very short (generally on the order of 10–15 minutes), minimizing the prolongation of anesthesia and/or the immobilization generally needed for intraoperative treatment.

The primary limitation of the plaque relates to the same property that gives it such a dosimetric advantage for its use near critical structures; the rapid dose falloff means that the plaque is ineffective in the treatment of gross residual disease or microscopic disease extending more than a few millimeters. As such, the decision to use the 32P plaque should be based in part on the surgeon's confidence that GTR can be achieved. For adequate dose falloff, the dura should not be violated to prevent loss of CSF; dural compromise is considered a contraindication to proceeding with intraoperative 32P brachytherapy.

Conclusions

This is the first reported case in which intraoperative 32P brachytherapy has been used in the pediatric population. We demonstrated that brachytherapy was safely delivered with no immediate toxicity and effective local control to date. The dosimetric advantages and relative ease of use of 32P brachytherapy allow it to be an effective modality for delivering intraoperative radiation, and this therapy warrants consideration for further use in selected cases.

Disclosure

Dr. Yamada is a consultant for Varian Medical Systems and is a member of the Speakers Bureau for the Institute for Medical Education. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Acquisition of data: Tong, Folkert. Analysis and interpretation of data: all authors. Drafting the article: Tong, Folkert. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Wolden. Statistical analysis: Tong, Folkert. Administrative/technical/material support: Tong, Folkert. Study supervision: Wolden, Greenfield, Yamada.

This work was presented in part as a poster discussion at the 2013 American Brachytherapy Society Annual Meeting held in New Orleans, Louisiana, on April 18–20, 2013.

References

  • 1

    Brodeur GMMaris JMNeuroblastoma. Pizzo PPoplack D: Principles and Practice of Pediatric Oncology ed 4PhiladelphiaLippincott Williams and Wilkins2002. 865937

  • 2

    Brown JMKoong AC: High-dose single-fraction radiotherapy: exploiting a new biology?. Int J Radiat Oncol Biol Phys 71:3243252008

  • 3

    DeLaney TFChen GTMauceri TCMunro JJHornicek FJPedlow FX: Intraoperative dural irradiation by customized 192iridium and 90yttrium brachytherapy plaques. Int J Radiat Oncol Biol Phys 57:2392452003

  • 4

    Folkert MRBilsky MHCohen GNZaider MDauer LTCox BW: Intraoperative 32P high-dose rate brachytherapy of the dura for recurrent primary and metastatic intracranial and spinal tumors. Neurosurgery 71:100310112012

  • 5

    Garaventa AParodi SDe Bernardi BDau DManzitti CConte M: Outcome of children with neuroblastoma after progression or relaps. A retrospective study of the Italian neuroblastoma registry. Eur J Cancer 45:283528422009

  • 6

    Garcia-Barros MParis FCordon-Cardo CLyden DRafii SHaimovitz-Friedman A: Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:115511592003

  • 7

    Goodman KAWolden SLLaQuaglia MPAlektiar KD'Souza DZelefsky MJ: Intraoperative high-dose-rate brachytherapy for pediatric solid tumors: a 10-year experience. Brachytherapy 2:1391462003

  • 8

    Haas-Kogan DAFisch BMWara WMSwift PSFarmer DLHarrison MR: Intraoperative radiation therapy for high-risk pediatric neuroblastoma. Int J Radiat Oncol Biol Phys 47:9859922000

  • 9

    Haas-Kogan DASwift PSSelch MHaase GMSeeger RCGerbing RB: Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56:28392003

  • 10

    Haase GMMeagher DP JrMcNeely LKDaniel WEPoole MABlake M: Electron beam intraoperative radiation therapy for pediatric neoplasms. Cancer 74:7407471994

  • 11

    Matthay KKReynolds CPSeeger RCShimada HAdkins ESHaas-Kogan D: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 27:100710132009

  • 12

    Matthay KKVillablanca JGSeeger RCStram DOHarris RERamsay NK: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:116511731999

  • 13

    Merchant TEZelefsky MJSheldon JMLaQuaglia MBHarrison LB: High-dose rate intraoperative radiation therapy for pediatric solid tumors. Med Pediatr Oncol 30:34391998

  • 14

    Nag STippin DRuymann FB: Intraoperative high-dose-rate brachytherapy for the treatment of pediatric tumors: the Ohio State University experience. Int J Radiat Oncol Biol Phys 51:7297352001

  • 15

    Nag STippin DSmith SBauer CRuymann FB: Intraoperative electron beam treatment for pediatric malignancies: the Ohio State University experience. Med Pediatr Oncol 40:3603662003

  • 16

    Oertel SNiethammer AGKrempien RRoeder FEble MJBaer C: Combination of external-beam radiotherapy with intraoperative electron-beam therapy is effective in incompletely resected pediatric malignancies. Int J Radiat Oncol Biol Phys 64:2352412006

  • 17

    Puri DRWexler LHMeyers PALa Quaglia MPHealey JHWolden SL: The challenging role of radiation therapy for very young children with rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 65:117711842006

  • 18

    Rich BSMcEvoy MPLaQuaglia MPWolden SL: Local control, survival, and operative morbidity and mortality after reresection, and intraoperative radiation therapy for recurrent or persistent primary high-risk neuroblastoma. J Pediatr Surg 46:971022011

  • 19

    Schomberg PJGunderson LLMoir CRGilchrist GSSmithson WA: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79:225122561997

  • 20

    Stauder MCLaack NNMoir CRSchomberg PJ: Excellent local control and survival after intraoperative and external beam radiotherapy for pediatric solid tumors: long-term follow-up of the Mayo Clinic experience. J Pediatr Hematol Oncol 33:3503552011

  • 21

    Zelefsky MJLaQuaglia MPGhavimi FBass JHarrison LB: Preliminary results of phase I/II study of high-dose-rate intraoperative radiation therapy for pediatric tumors. J Surg Oncol 62:2672721996

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Article Information

Address correspondence to: Suzanne Wolden, M.D., Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 22, New York, NY 10065. email: woldens@mskcc.org.

Please include this information when citing this paper: published online January 31, 2014; DOI: 10.3171/2014.1.PEDS13121.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Percent depth dose (PDD) curve for an intraoperative 32P brachytherapy plaque, with measurements for radiation dose at a depth relative to prescription dose (10 Gy to 1-mm depth).

  • View in gallery

    Timeline of diagnostic and therapeutic interventions prior to thoracic epidural recurrence and evaluation by a multidisciplinary pediatric oncology tumor board.

  • View in gallery

    Presurgical planning sagittal (left) and axial (right) T2-weighted MR images showing an epidural mass extending from T-3 to T-7, compressing and displacing the spinal cord.

  • View in gallery

    Axial T2-weighted MRI sequences, proximal (left) and distal (right) to the site of compression, showing the measurement of CSF thickness from the interior surface of the dura mater to the surface of the cord.

  • View in gallery

    Photograph of a flexible 32P plaque placed on the dura following resection of the epidural tumor.

  • View in gallery

    Postoperative sagittal (left) and axial (right) T2-weighted MR images showing GTR of the lesion with expected postoperative changes and decompression of the underlying spinal cord.

  • View in gallery

    Follow-up sagittal (left) and axial (right) T2-weighted MR images showing stable postoperative changes and no evidence of recurrent disease.

References

1

Brodeur GMMaris JMNeuroblastoma. Pizzo PPoplack D: Principles and Practice of Pediatric Oncology ed 4PhiladelphiaLippincott Williams and Wilkins2002. 865937

2

Brown JMKoong AC: High-dose single-fraction radiotherapy: exploiting a new biology?. Int J Radiat Oncol Biol Phys 71:3243252008

3

DeLaney TFChen GTMauceri TCMunro JJHornicek FJPedlow FX: Intraoperative dural irradiation by customized 192iridium and 90yttrium brachytherapy plaques. Int J Radiat Oncol Biol Phys 57:2392452003

4

Folkert MRBilsky MHCohen GNZaider MDauer LTCox BW: Intraoperative 32P high-dose rate brachytherapy of the dura for recurrent primary and metastatic intracranial and spinal tumors. Neurosurgery 71:100310112012

5

Garaventa AParodi SDe Bernardi BDau DManzitti CConte M: Outcome of children with neuroblastoma after progression or relaps. A retrospective study of the Italian neuroblastoma registry. Eur J Cancer 45:283528422009

6

Garcia-Barros MParis FCordon-Cardo CLyden DRafii SHaimovitz-Friedman A: Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:115511592003

7

Goodman KAWolden SLLaQuaglia MPAlektiar KD'Souza DZelefsky MJ: Intraoperative high-dose-rate brachytherapy for pediatric solid tumors: a 10-year experience. Brachytherapy 2:1391462003

8

Haas-Kogan DAFisch BMWara WMSwift PSFarmer DLHarrison MR: Intraoperative radiation therapy for high-risk pediatric neuroblastoma. Int J Radiat Oncol Biol Phys 47:9859922000

9

Haas-Kogan DASwift PSSelch MHaase GMSeeger RCGerbing RB: Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56:28392003

10

Haase GMMeagher DP JrMcNeely LKDaniel WEPoole MABlake M: Electron beam intraoperative radiation therapy for pediatric neoplasms. Cancer 74:7407471994

11

Matthay KKReynolds CPSeeger RCShimada HAdkins ESHaas-Kogan D: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 27:100710132009

12

Matthay KKVillablanca JGSeeger RCStram DOHarris RERamsay NK: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:116511731999

13

Merchant TEZelefsky MJSheldon JMLaQuaglia MBHarrison LB: High-dose rate intraoperative radiation therapy for pediatric solid tumors. Med Pediatr Oncol 30:34391998

14

Nag STippin DRuymann FB: Intraoperative high-dose-rate brachytherapy for the treatment of pediatric tumors: the Ohio State University experience. Int J Radiat Oncol Biol Phys 51:7297352001

15

Nag STippin DSmith SBauer CRuymann FB: Intraoperative electron beam treatment for pediatric malignancies: the Ohio State University experience. Med Pediatr Oncol 40:3603662003

16

Oertel SNiethammer AGKrempien RRoeder FEble MJBaer C: Combination of external-beam radiotherapy with intraoperative electron-beam therapy is effective in incompletely resected pediatric malignancies. Int J Radiat Oncol Biol Phys 64:2352412006

17

Puri DRWexler LHMeyers PALa Quaglia MPHealey JHWolden SL: The challenging role of radiation therapy for very young children with rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 65:117711842006

18

Rich BSMcEvoy MPLaQuaglia MPWolden SL: Local control, survival, and operative morbidity and mortality after reresection, and intraoperative radiation therapy for recurrent or persistent primary high-risk neuroblastoma. J Pediatr Surg 46:971022011

19

Schomberg PJGunderson LLMoir CRGilchrist GSSmithson WA: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79:225122561997

20

Stauder MCLaack NNMoir CRSchomberg PJ: Excellent local control and survival after intraoperative and external beam radiotherapy for pediatric solid tumors: long-term follow-up of the Mayo Clinic experience. J Pediatr Hematol Oncol 33:3503552011

21

Zelefsky MJLaQuaglia MPGhavimi FBass JHarrison LB: Preliminary results of phase I/II study of high-dose-rate intraoperative radiation therapy for pediatric tumors. J Surg Oncol 62:2672721996

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