Brachytherapy: Applications and Technique, 1st Edition

12. Role of Brachytherapy in Pediatrics

 

Thomas E. Merchant

Matthew J. Krasin

Brachytherapy is an art that is seldom practiced as a frontline treatment in pediatric patients owing to a number of factors that characterize the use of brachytherapy in general and the practice of pediatric radiation oncology that is focused on refining indications for radiation therapy and minimizing radiation dose to normal tissues. The practice of brachytherapy in children is governed by the education of those involved in treating rare pediatric tumors, availability of trained staff, sources, hardware and software, experience, guidelines, and, most of all, indications for tumors amenable to this modality. The successful use of brachytherapy techniques in adults and the inherent tissue-sparing abilities of this modality continue to direct pediatric investigators to develop applications for their patients or to consider brachytherapy as a part of multimodality management.

The purpose of this chapter is to provide an overview of the role of brachytherapy in pediatrics. To achieve this goal, it is essential to understand the diagnoses amenable to brachytherapy in children, the number of potential cases, published experiences, potential complications, treatment objectives for pediatric patients, and concerns surrounding the use of this generally invasive, high-dose local control modality in children.

In the first part of this chapter, we review the incidence of pediatric cancer and clinical factors such as age, presentation, and patterns of failure to outline malignancies and clinical scenarios for which brachytherapy might be indicated. We then review by diagnosis the published experiences for various tumor types including all the possible brachytherapy techniques. Technique-specific sections are limited to intraoperative high dose rate (IOHDR) brachytherapy and fractionated high dose rate (HDR) brachytherapy. We conclude discussing the vagaries of pediatric radiation oncology relative to the practice of brachytherapy institutionally and in the cooperative group trials setting. Case reports from our database are embedded in the chapter to highlight clinical scenarios, risks, and benefits.

Factors Influencing the Use of Brachytherapy in Children

Diagnosis

The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute began collecting data in 1973 in five states and two metropolitan areas expanding to include data from 14 population-based regions covering 26% of the US population. On the basis of SEER data collected from 1975 to 1995, there are 12,400 cases of childhood cancer each year in the United States affecting individuals 0 to 20 years of age. In decreasing order of incidence, these include leukemia (3,250), central nervous system tumors (2,200), lymphoma (1,700), carcinoma (1,050), soft tissue sarcoma (900), germ cell tumors (900), bone tumors (700), sympathetic nervous system (700), retinoblastoma (300), renal tumors (550), and hepatic tumors (135) (see Fig. 12.1). The number of diagnoses amenable to brachytherapy as a frontline treatment quickly dwindles to include patients with carcinoma, soft tissue sarcoma, bone tumors, and retinoblastoma that represent 2,950 cases or 24.6% of all patients. These numbers are further reduced considering that thyroid cancer (35.5%) and melanoma (30.9%) comprise most cases classified as carcinoma; 72% of patients with retinoblastoma have unilateral presentations and most are enucleated before referral to an oncology team; 57% of patients with bone sarcoma have radio-insensitive osteosarcoma and 78% have surgically resectable long-bone presentations; and finally, among patients with soft tissue sarcoma, only one third have rhabdomyosarcoma and most have histologically benign tumors that are not treated with adjuvant therapy.

Figure 12.1 Annual incidence of pediatric malignancies in the United States based on Surveillance, Epidemiology, and End Results (SEER) data 1975 to 1995. ALL, acute lymphoblastic leukemia; HD, Hodgkin disease; RMS, rhabdomyosarcoma; ES, Ewing sarcoma; NB, neurobastoma; WT, Wilms Tumor.

Overall Survival

The role of brachytherapy in pediatrics is defined by the high rate of disease control that characterizes childhood cancers. The following is the order of decreasing 5-year overall survival: Retinoblastoma (93%), renal tumors/Wilms tumor (92%/95%), Hodgkin disease/non-Hodgkin lymphoma (91%/72%) germ cell tumors (87%), acute lymphoblastic leukemia (ALL)/ acute myelogenous leukemia (AML) (77%/41%), brain tumors (65%), neuroblastoma (64%), hepatic tumors (59%), soft tissue sarcoma/rhabdomyosarcoma (64%), bone sarcomas osteosarcoma (OS)/Ewing sarcoma (ES) (63%/58%).

Age

Most childhood cancer is diagnosed at an early age when investigators are least interested in applying a high-dose radioactive treatment. Among the malignancies observed in children, the carcinomas, bone sarcomas, germ cell tumors and nonrhabdomyosarcoma soft tissue sarcomas tend to occur in older patients.

Patterns of Failure and Timing of Brachytherapy

Brachytherapy has been utilized as a salvage adjuvant therapy after prior surgical resection and even before external beam radiation therapy (EBRT) with some success. In this setting, local, regional and distant failures are of concern, depending on the tumor site and histology. For patients treated at diagnosis, particularly in children with sarcomas, brachytherapy is added as a high-dose adjuvant to reduce the incidence of local failure. Oncologists often note that local control in many of these settings does not effect the overall survival, as salvage surgery is available. Although this approach of radiation therapy avoidance is frequently utilized in the pediatric setting, both patients and caregivers should be educated about the relative risk of local disease recurrence in the absence of adjuvant radiation as well as the morbidity associated with a salvage surgical procedure.

Pediatric Malignancies

Wilms Tumor

Brachytherapy has been used at the time of recurrence for a variety of pediatric solid tumors including Wilms tumor.1 In frontline treatment setting, brachytherapy has been used for patients with bilateral Wilms tumor that presents a radiotherapeutic challenge. Investigators at the University of Pennsylvania devised a simple method of brachytherapy for patients with bilateral Wilms tumor and residual tumor after chemotherapy.2 Their procedure involved the placement of afterloading catheters for treatment with Cesium 137. Their technique was used in seven patients with resistant tumors, none of whom developed local recurrence after the procedure.3 Similarly, a novel approach combining endoscopic resection and brachytherapy for the treatment of recurrent intrapelvic Wilms tumor was used.

Neuroblastoma and Hepatoblastoma

It is difficult to imagine a setting in which brachytherapy might be used advantageously in a child with neuroblastoma because 70% of these patients present with metastatic disease, long-term survival is poor, and the inherent radiosensitivity of this tumor leads to a high rate of local control with low-dose irradiation. Most institutional series describing the application of brachytherapy in children with recurrent tumors include cases of neuroblastoma and some of the more uncommon pediatric solid tumors such as hepatoblastoma.4

Ewing Sarcoma

Ewing sarcoma generally affects older children and young adults and may arise at any location. Tumors involving the central axis (vertebral, rib, sternal, clavicle, pelvis, sacrum, and coccyx) are most common (45%) and pose the greatest challenge to the radiation oncologist. The highest rates of local failure are found among these sites and present an opportunity for brachytherapy to supplement external beam irradiation as a local control modality. There are numerous reports describing the use of low-dose interstitial or plaque brachytherapy, 5 pulsed or HDR afterloading, and IOHDR brachytherapy in the frontline treatment of these tumors or at the time of local failure in the setting of prior irradiation.

Investigators at the Osaka University employed perioperative fractionated HDR brachytherapy for malignant bone and soft tissue tumors and analyzed the influence of surgical margins in 14 patients with malignant bone and soft tissue tumors involving sites in the pelvis, upper and lower limbs, and neck. They prescribed, beginning on postoperative day 4, 40 to 50 Gy delivered in 7 to 10 fractions over 4 to 7 days. Local control rates were 75% at 1 year and 48% at 2 years. Disease control was achieved only in patients with microscopic or negative margins. Those with macroscopic residual were not controlled. They concluded that perioperative fractionated HDR brachytherapy is safe, well tolerated, and applicable to cases of marginal or wide resections.6

A similar approach was employed at the Ohio State University where children treated with HDR brachytherapy received 36 Gy in 12 fractions.7 One of two patients with Ewing sarcoma was controlled with this approach. Both patients underwent gross removal of all visible disease before implant.

IOHDR has been performed systematically by a number of groups.8,9 Investigators from Munster found that apart from longer operative procedures when intraoperative brachytherapy was applied (7.9 vs. 4.3 hours), patients treated with or without brachytherapy had similar rates of blood loss, treatment-related complications, and local control.9

In a multicenter report involving centers in Munster, Kiel, and Vienna, six patients with Ewing sarcoma were treated with HDR. The HDR treatment regimen consisted of brachytherapy given intraoperatively as a boost treatment after external beam therapy (50 to 55 Gy). The dose was 10 to 12 Gy applied in a single fraction. With a median follow-up of 21 months at the time of the report, there was no evidence of disease (NED) in the treated patients and perioperative and subacute morbidity was not increased.10

Investigators from Pamplona reported on a 17-year-old girl with a locally recurring puboischial ramus tumor treated successfully with HDR brachytherapy.11

We have treated two patients at the St. Jude Children's Research Hospital (SJCRH) with LDR brachytherapy for Ewing sarcoma family of tumors. Both remained locally controlled at 8 and 52 months, although the patient controlled at 8 months was found to have recurrent distant disease.

An example case of a patient diagnosed with extraosseous Ewing sarcoma of the chest wall is shown along with the accompanying LDR interstitial implant (see Fig. 12.2).

Figure 12.2 Preoperative T1-weighted image of a 16-year-old boy with extraosseous Ewing sarcoma of the chest wall. Orthogonal views of the low dose rate interstitial implant showing the 45 cGy per hour isodose line. Volumetric rendering of the 45 cGy per hour isosurface and adjacent anatomy.

 

Osteosarcoma

The radio insensitivity of this tumor leads investigators to avoid using radiation therapy in these patients. Nevertheless, for deep-seated and unresectable tumors of the head and neck, radiation has been called upon as a local control measure. Despite attempts with brachytherapy to increase the local dose in the cases of head and neck tumors, the results are poor and most patients experience local recurrence and die of their disease.12

Soft Tissue Sarcomas

Brachytherapy for pediatric patients has been popularized for those with adult-type soft tissue sarcomas in an effort to achieve a high-level standard of care and the excellent local control rates observed in adults. Many of the adult series include a few pediatric patients owing to the similarities among these patients and the fact that most presentations occur in the teenage or later years. The series of malignant peripheral nerve sheath tumors from the Mayo Clinic serves as an example. This series included patients aged 9 to 84 years and was instrumental in showing the impact of high-dose irradiation and the use of brachytherapy on local control and survival.13

One of the largest pediatric series is from SJCRH, which is unique for it is limited to children and to the adult-type soft tissue sarcomas. The study included 31 patients with a median age of 11 years and high-grade soft tissue sarcoma excluding rhabdomyosarcoma and Ewing sarcoma. Most patients, 27 of 31, were treated with brachytherapy as their initial course of management, whereas the remaining 4 were treated at the time of recurrence. The selection of isotope was largely driven by age; younger patients were more likely to receive treatment with iodine 125, whereas older patients were more likely to be treated with iridium 192. This series is also unique among pediatric series because 12 of the patients were treated with brachytherapy alone. The remaining 19 were treated with a combination of brachytherapy and EBRT because of involved margins of resection. Local control was excellent. Among the ten patients treated with brachytherapy alone, one patient developed metastatic disease and there were no local or regional failures among the remaining nine patients. Among the 17 patients treated with a combination of brachytherapy and EBRT, there was 1 local, 2 regional, and 3 distant failures. The report identified wound dehiscence, fibrosis/telangiectasia, pigment changes, and cellulitis as common side effects.14 In a prospective study of brachytherapy delivered either alone or in conjunction with EBRT, two of seven patients experienced grade 4 skin reactions adjacent to catheter sites in the subcutaneous tissue requiring local wound care and one patient had a postimplant infection. With a mean follow-up of 8 months, no local failures have occurred, although three of seven patients have experienced distant recurrence.

There are a number of smaller series reporting the use of brachytherapy in pediatric soft tissue sarcoma. Cherlow et al. treated 11 patients with brachytherapy including 9 with soft tissue sarcoma either as their primary treatment or at the time or recurrence.1 After a typical dose of 40 Gy using iridium 192, six patients, including four primary cases and two recurrent cases, were currently classified as NED without further local regional treatment at the time of the report. The median follow-up was 38 months.

In a multicenter report, 12 patients with soft tissue sarcoma were treated with high-dose rate and pulse dose rate (PDR) brachytherapy in Munster, Kiel, and Vienna on cooperative group studies. The HDR treatment regimen consisted of 15 to 43 Gy delivered in 3 to 16 fractions with PDR treatment regimen including 13 to 26 Gy delivered in fractions of 1 Gy per hour. In eight patients with soft tissue sarcoma, brachytherapy was part of the recurrence treatment regime; in four patients brachytherapy was part of the primary treatment alone or in combination with external beam therapy. With a median follow-up of 14 months, only three patients progressed locoregionally.10 Investigators showed how interstitial brachytherapy could be an effective method of delivering high doses of radiation to children with soft tissue sarcoma while sparing normal tissues. In a 14-year study conducted from 1971 and 1985, 12 children (median age 4.7 years) with localized residual soft tissue sarcoma were treated with interstitial brachytherapy. Eight children were treated as a part of their initial therapy and four were treated for recurrent or persistent disease. Treatment sites included the head and neck (n = 6), pelvis (n = 4), extremity (n = 1), and retroperitoneum (n = 1). A variety of nuclides were used and prescribed to a median dose of 39.6 Gy. Seven of eight children receiving interstitial brachytherapy as initial therapy remained locally controlled.15

Figure 12.3 Low dose rate interstitial implant preparation in a pediatric patient with soft tissue sarcoma of the thigh.

It needs to be mentioned that the number of catheters and volume of the implants required to cover the tumor bed in a soft tissue sarcoma case are relatively small compared with an adult patient, yet often large in the pediatric patient, making the implant less forgiving to variability in placement (see Fig. 12.3).

Rhabdomyosarcoma

Among the pediatric tumors that might be treated with brachytherapy, rhabdomyosarcoma comes to mind as the one that parallels the adult-type soft tissue sarcoma in form but differentiates itself by histogenesis and response to multiagent chemotherapy and lower doses of radiation therapy. The treatment paradigm for this disease includes radiotherapy avoidance, dose and volume reduction, and minimization of therapy, especially among those with favorable rhabdomyosarcoma that includes embryonal histology, localized extent of disease, favorable sites (cervix, uterus, vagina, and bladder), patient age, gender and resectability initially or based on response to induction chemotherapy. Brachytherapy is not incorporated in some cooperative group studies and included in others although without fully developed guidelines.16 Guidelines describe the same postoperative dose (e.g., 4,140 cGy) regardless of whether adjuvant external beam, interstitial LDR or HDR brachytherapy is used. The lack of clear guidelines limits the routine use of adjuvant brachytherapy, even by groups with significant experience in adults using this modality.

Reports that include rhabdomyosarcoma are limited. Nag et al. treated a series of patients with HDR brachytherapy with or without external beam irradiation in an effort to prevent severe late effects.17 Seven of 13 children had rhabdomyosarcoma and were treated with disease-appropriate chemotherapy in addition to radiation therapy that included fractionated 36 Gy HDR alone at a mean of 3.5 months from diagnosis or 10 to 12.5 Gy IOHDR brachytherapy and 27 Gy EBRT. Morbidity was scored as grade 1 in 46%, grade 2 in 15%, and grade 3 in 8% of patients.

One of the early St. Jude brachytherapy series reporting on 46 children with diverse tumors included 14 with rhabdomyosarcoma (n = 14). Patients with rhabdomyosarcoma undergoing LDR brachytherapy included seven with de novo primary site tumors and seven with recurrent disease or metastatic sites requiring implant. Among patients treated with brachytherapy at their primary site of disease during their initial course of therapy five of seven remain locally controlled with a median follow-up of 5 years.18

Patients with recurrent rhabdomyosarcoma tend to fare poorly if failure occurs within the previously irradiated volume leaving open the possibility that brachytherapy for failures may increase the rate of salvage (see Figs. 12.4 and 12.5).

Retinoblastoma

Guided by the long-term risks of EBRT, there is renewed interest in the use of episcleral plaque brachytherapy (EPBRT) after chemoreduction in patients with retinoblastoma.19,20 (see Fig. 12.6). Through the use of brachytherapy and other local ophthalmic measures, there is hope that eye preservation rates will increase.21 Current institutional series show wide-ranging uses of brachytherapy in these patients ranging from <3.7% of cases at one center to nearly 30% in a recent series from the Curie Institute.22,23Responses to brachytherapy are prompt (see Fig. 12.7).

Figure 12.4 Recurrent orbital rhabdomyosarcoma after external beam radiation therapy treated with exenteration and intracavity (moulage) brachytherapy. Images show step-wise surgery and preparation and placement of treatment device.

Figure 12.5 Anteroposterior and lateral radiographs showing seed placement within the orbit for previously described intracavity implant for recurrent orbital rhabdomyosarcoma after external beam radiation therapy.

 

Figure 12.6 Operative photograph showing an ocular oncologist preparing an eye for episcleral plaque brachytherapy. Anteroposterior radiograph showing notched episcleral plaque in situ.

Figure 12.7 Pre- and post-episcleral plaque fluorescein angiogram (3.5 days—42 Gy).

The usefulness of brachytherapy has been demonstrated in the multimodality management of retinoblastoma. Our own series showed that brachytherapy has a high rate of successful tumor control (96% lesion control rate) as a primary treatment or as a secondary therapy at the time of relapse. The usefulness of brachytherapy is enhanced if one considers its ability to delay or avoid EBRT. The median time to additional whole-eye measures in our series was 12 months.24 Brachytherapy for retinoblastoma evolved through the use of cobalt 60 and other sources to the standard of today which, reliably, is iodine 125. 25,26 Early series reporting the use of cobalt 60 identified high lesion control rates and low rates of complications predominantly for patients with retinoblastoma recurrent after external beam irradiation or other local ophthalmic measures.27,28 Indeed, early experience on the use of radioactive plaques included treatment of failure after external beam irradiation.29 Salvage plaque therapy can improve the overall eye preservation rate in most series as demonstrated by J Shields et al. who demonstrated tumor regression in 89% and recurrence in only 11% of patients.30 The series reported by Hernandez et al. increased the overall control rates.31 Among 34 eyes treated with EBRT alone, only 15 eyes were controlled primarily, whereas 10 eyes were salvaged by the use of plaque therapy at the time of failure, thereby increasing ocular control by 29.5%. This series also provided insight into a possible relationship among lesion control, radiation dose, and lesion size indicating that larger tumors required higher doses, opening the possibility that boost treatment with brachytherapy after external beam irradiation might be indicated in some.

The indications for brachytherapy are guided by lesion size. Guidelines from a 1993 article by C Shields et al. showed that tumors were well controlled when falling within the following measures of basal diameter, 1 to 16 mm (mean 7 mm), and thickness, 1 to 8 mm (mean 4 mm).32 A recent series from the Netherlands reports acceptable tumor sizes including lesions preferably smaller than 8 mm and thinner than 8 mm.33 Finally, the series from Ankara included iodine 125 plaque radiotherapy as a primary procedure for tumors with diameters ranging from 6 to 16 mm and thickness from 3 to 11 mm using doses of 3,500 to 5,000 to the tumor apex. They showed regression from 7 to 12 months.34 The lesion size averaged 6 mm in the series from the Curie Institute.23

It is important to note that the series by C Shields et al. did not exclude patients with localized seeding.32 Although treatment of patients with vitreous seeding may seem to be a contraindication, investigators from London have shown success with an innovative brachytherapy approach that ocular control was achievable in four of five patients treated with a customized plaque using iridium wire (40 Gy) and systemic therapy. The median follow-up was 26.2 months.35 The attachment of plaques requires great skill and, at times, improvisation.36 Among the most innovative brachytherapy applications is the 125I applicator known as “the claw” which is meant to bring the excellence of plaque dosimetry to the entire retina through the use of a device capable of whole-eye radiotherapy. The results from this technique look promising. Further evaluation by other centers is required to validate this method.37

The largest series for EPBRT has been reported from the oncology service at the Wills Eye Hospital of Thomas Jefferson University for patients treated between 1976 and 1999. There were 208 tumors in 141 children. The series included 60 lesions treated primarily with EPBRT and 148 lesions treated after prior therapy. The tumor control were 83% at 1 year and 79% at 5 years. Factors predictive of recurrence included vitreal and subretinal seeding and increasing patient age. The investigators reported the incidence of treatment-related complications measured at 5 years including nonproliferative retinopathy (27%), proliferative retinopathy (15%), maculopathy (25%), papillopathy (26%), cataract formation (31%), and glaucoma (11%). There were no cases of scleral necrosis.38 Other centers have shown good functional outcomes with complications (maculopathy) related to lesion location or other factors23,39 Murphree et al. reported that patients treated with carboplatin or with carboplatin, vincristine, and etoposide developed retinopathy uniformly when treated with EPBRT using 125I.40 Similarly, patients treated with systemic carboplatin were at increased risk for radiation retinopathy following 125I plaque therapy.

Although failure of plaque therapy may be technical in nature, Spraul et al. showed in a solitary patient that recurrent retinoblastoma may have arisen from radio-resistant well-differentiated cells after 125I plaque therapy.41 Innovations for recurrent tumors have included hyperthermia and EPBRT as reported for one patient by Liggett et al.42 Complications were reported in a series that also included patients with large melanoma.

Brachytherapy techniques to irradiate the postenucleation orbit has resulted in improved cosmesis and 100% local tumor control in patients with a variety of indications including scleral involvement, choroidal involvement, and tumor in the resected nerve.43,44 Recurrent retinoblastoma after orbital irradiation has been achieved using 125I embedded in a methylmethacrylate eye prosthesis where a relatively low dose (26.3 Gy) was prescribed to a depth of 2 mm.45

Craniopharyngioma

During the past 10 years, interstitial brachytherapy has fallen from favor in the treatment of malignant glioma in both adults and children. More aggressive and improved neurosurgery and the ease and availability of stereotactic radio surgery have largely been responsible for this change. Brachytherapy in the form of intracavitary 32P continues to play a role in the treatment of craniopharyngioma, a tumor that commonly presents with cystic and solid components.46,47,48,49 The most agreed upon indication for intracavitary 32P is the treatment of failure after external beam irradiation which occurs in <20% of irradiated cases: Craniopharyngioma represents approximately 3% of childhood brain tumors with approximately 100 cases diagnosed annually in the United States. More controversial is the use of 32P in newly diagnosed patients. 32P has been popularized more by neurosurgeons and parents focused on radiotherapy avoidance than by radiation oncologists. Requirements range from stereotactic needle cyst aspiration to craniotomy with reservoir placement, determination of cyst and isotope volumes, and calculation of cyst wall and normal tissue (optic chiasm and brainstem) dose based on five half-lives of the isotope.

One of the largest contemporary series is from the University of Pittsburgh that included 15 patients under the age of 16 years and 34 adult patients. Although cyst control rates were 76% when measured at 5 years, a reported 23% of patients had delayed worsening of vision and the overall control rate, considering the solid component, was poor.49 Prior reports from this same group have provided detailed information about preservation of vision, treatment-related complications, and cyst control.50 The mechanism of action includes destruction of cyst wall epithelium; however, because 32P does not address the solid component of the tumor, some investigators have proposed the addition of radiosurgery in conjunction with 32P.48,51 The largest series is from the Navy General Hospital in Beijing and includes 220 patients treated in 265 procedures using 32P and 90Y. There were no severe complications or deaths due to this procedure and progression appeared to occur in only 10% of patients.47

Special Considerations

Intraoperative Radiation Therapy

The feasibility and safety of IOHDR radiation therapy has been established for children with newly diagnosed and recurrent solid tumors. Advantages of this method include intraoperative inspection and margin evaluation as well as applicability in settings where intraoperative electron beam might have otherwise been considered.52

Nag et al. showed in six patients how single-dose IOHDR (10 to 12 Gy) in conjunction with combined modality therapy including low-dose (27 to 30.6 Gy) EBRT could be used safely and effectively in pediatric patients with soft tissue sarcoma to avoid growth abnormalities and organ dysfunction. In their series, there were two cases of major toxicity. One patient developed recurrent urinary tract infections and the other, ureteral stenosis requiring nephrectomy. With a median follow-up of 40 months, five of six patients remained locally controlled.

Zelefsky et al. initially reported 10 children with locally advanced or recurrent tumors in a phase I trial of IOHDR.53 Patients received a single dose of 12 Gy using a multichannel applicator, prescribed to a depth of 0.5 cm. One patient developed a perirectal abscess. The 2-year local recurrence-free survival estimate was 80%, with a median follow-up of 12 months. This series was updated in 1998 to include nine patients initially managed with IOHDR and seven patients with recurrent tumors including Ewing sarcoma, rhabdomyosarcoma, synovial cell sarcoma, Wilms tumor and a variety of other tumor types.54Complications ascribed to IOHDR included abscess, delayed wound healing, and cytopenia. With a median follow-up of 18 months, the actuarial rate of local control was 61%. This series was again updated in 2003 (Goodman 2003) to include a 10-year experience for 66 pediatric patients who underwent IOHDR through December 2002.55 The median age for this group was 7 years. Thirty-five patients (53%) were treated for recurrent disease, 24 (36%) had documented metastatic disease, and 29 patients (44%) received both EBRT and IOHDR. The 2-year estimated rates of local control were 56%, with a median follow-up of 12 months. Postoperative EBRT significantly improved 2-year local control (83% vs. 29%, p = 0.002). The actuarial 2-year late complication rate was 12%. This included small bowel obstruction, bronchoesophageal fistula and bone growth retardation. The authors concluded that IOHDR was an emerging treatment for pediatric solid tumors, primarily as an adjunct to EBRT; however, the role of IOHDR alone was questioned. Early effects were related to surgery, prior EBRT, and the use of chemotherapy.

In a follow-up of their prior report, Nag et al. showed how IOHDR could be used to decrease the dose of EBRT in children with soft tissue sarcomas and reduce morbidity without affecting local control.56 Their series included 13 pediatric patients treated with combined modality therapy. With a median follow-up of 47 months, the local control rate was 95%. Morbidity was observed in three patients (23%). One patient developed impaired orbital growth with mild ptosis, one required orthopaedic pinning of the femoral subcapital epiphysis and the construction of a neobladder secondary to urethral obstruction, and the third patient required reimplantation of her auto-transplanted kidney secondary to chronic urinary tract infection and ureteral reflux.

As a point of comparison, intraoperative electron radiation therapy (IOERT) has been used in children; one of the largest series is reported from Spain by Calvo et al.57 Through 1987, 33 children received intraoperative radiotherapy as part of a multidisciplinary tumor treatment including patients aged 2 to 17 years with Ewing sarcoma (n = 11), osteosarcoma (n = 8), soft tissue sarcomas (n = 5), Wilms tumor (n = 3), neuroblastoma (n = 3), and malignant pheochromocytoma (n = 1). Intraoperative radiotherapy was used in 26 previously untreated patients and in 7 cases of local failure (5 in previously irradiated areas). The intraoperative radiation field included the surgically exposed tumor or tumor bed, and the single doses ranged from 10 to 20 Gy, with 6 to 20 MeV electrons. Patients with osteosarcoma and recurrent tumor in a previously irradiated area did not receive postoperative external beam radiotherapy. With a median follow-up time of 10 months, 24 out of 33 patients were alive without local recurrence and 9 had died from tumor (5 with local disease progression).

In summary, the ability to confine the dose of radiation to the primary site and decrease the dose to normal tissues makes IOHDR an important adjunct to EBRT. The use of IOHDR in lieu of EBRT requires further investigation. IOHDR can be a safe and integral component in the management of pediatric solid tumors.

Complications

There is a great incentive in minimizing the radiation dose and treatment volume in children with cancer because their likelihood of survival is high and the potential impact of side effects may be great. Because the late effects of radiation therapy are poorly understood, even for children who might receive EBRT, it should come as no surprise that little is known about the long-term effects of brachytherapy. This unknown is detrimental to the expanded use of brachytherapy in children and could be overcome through careful longitudinal study and analysis of these patients.

Because brachytherapy tends to be a substitute for EBRT, the specter of side effects associated with radiation therapy in general (i.e., malignancy induction) has no specific bearing on its use. On the contrary, most will contend that side effects can be broadly reduced with brachytherapy because of enhanced conformity of the highest doses and avoidance of side effects related to tissues incidentally irradiated by beams that subtend normal tissue.

Of greatest concern is the potential for brachytherapy to result in structural and functional damage. The potential for early or extreme side effects may be obvious at the time of catheter or source placement on or near neurovascular structures or viscera and can be avoided. The potential for more insidious damage, such as deformity with functional deficit, may not be obvious. The latter is more likely to occur in a child treated with brachytherapy for an extremity sarcoma.

Brachytherapy tends to result in inhomogeneous dose distributions which when placed near to a growth center for bone may result in unpredictable deformity. This feature, combined with the added effects of volume loss associated with surgical resection, brachytherapy dosimetry, and, possibly, the supplemental use of external beam irradiation may result in noticeable effects of treatment and may, in some cases, require surgical intervention to maintain function.58

Although anecdotal, experience suggests that most parents and patients accept somatic side effects. As time passes, their concern about outward appearance is often tempered by their appreciation of local control for what was likely a high-risk malignancy and the thought and planning associated with the team approach that characterizes the use of brachytherapy in children.

References

1. Cherlow JM, Syed AM, Puthawala A, et al. Endocurietherapy in pediatric oncology. Am J Pediatr Hematol Oncol. 1990;12:155–159.

2. Thoms WW Jr, Goldwein JW, D'Angio G. A technique for the use of afterloading 137Cs brachytherapy in renal-sparing irradiation of bilateral Wilms tumor. Int J Radiat Oncol Biol Phys. 1997;39(5):1121–1124.

3. Cooper CS, Jaffe WI, Huff DS, et al. The role of renal salvage procedures for bilateral Wilms tumor: A 15-year review. J Urol. 2000;163:265–268.

4. Healey EA, Shamberger RC, Grier HE, et al. A 10-year experience of pediatric brachytherapy. Int J Radiat Oncol Biol Phys. 1995;32:451–455.

5. Gunduz K, Shields JA, Shields CL, et al. Ewing sarcoma metastatic to the iris. Am J Ophthalmol. 1997;124:550–552.

6. Koizumi M, Inoue T, Yamazaki H, et al. Perioperative fractionated high-dose rate brachytherapy for malignant bone and soft tissue tumors. Int J Radiat Oncol Biol Phys. 1999;43: 989–993.

7. Nag S, Tippin D, Ruymann FB. Long-term morbidity in children treated with fractionated high-side-rate brachytherapy for soft tissue sarcomas. J Pediatr Hematol Oncol. 2003;25: 448–452.

8. Schuck A, Willich N, Rube C, et al. Intraoperative high-dose-rate brachytherapy after preoperative radiochemotherapy in the treatment of Ewing's sarcoma. Front Radiat Ther Oncol. 1997;31:153–156.

9. Ozaki T, Hillmann A, Rube C, et al. The impact of intraoperative brachytherapy on surgery of Ewing's sarcoma. J Cancer Res Clin Oncol. 1997;123:53–56.

10. Potter R, Knocke TH, Kovacs G, et al. Brachytherapy in the combined modality treatment of pediatric malignancies. Principles and preliminary experience with treatment of soft tissue sarcoma (recurrence) and Ewing's sarcoma. Klin Padiatr. 1995;207(4):164–173.

11. Martinez-Monge R, Perez-Ochoa A, San Julian M, et al. Bone HDR brachytherapy in a patient with recurrent Ewing's sarcoma of the acetabulum: alternative to aggressive surgery. Brachytherapy. 2003;2:114–116.

12. Clark JL, Unni KK, Dahlin DC, et al. Osteosarcoma of the jaw. Cancer. 1983;51:2311–2316.

13. Wong WW, Hirose T, Scheithauer BW, et al. Malignant peripheral nerve sheath tumor: Analysis of treatment outcome. Int J Radiat Oncol Biol Phys. 1998;42:351–3560.

14. Merchant TE, Parsh N, del Valle PL, et al. Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys. 2000;46:427–432.

15. Curran WJ Jr, Littman P, Raney RB. Interstitial radiation therapy in the treatment of childhood soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 1988;14:169–174.

16. Donaldson SS, Asmar L, Breneman J, et al. Hyperfractionated radiation in children with rhabdomyosarcoma—results of an Intergroup Rhabdomyosarcoma Pilot Study. Int J Radiat Oncol Biol Phys. 1995;32:903–911.

17. Nag S, Olson T, Ruymann F, et al. High-dose-rate brachytherapy in childhood sarcomas: a local control strategy preserving bone growth and function.Med Pediatr Oncol. 1995;25: 463–469.

18. Fontanesi J, Rao BN, Fleming ID, et al. Pediatric brachytherapy. The St. Jude Children's Research Hospital experience. Cancer. 1994;74:733–739.

19. Shields CL, Meadows AT, Leahey AM, et al. Continuing challenges in the management of retinoblastoma with chemotherapy. Retina. 2004;24:849–862.

20. De Potter P. Current treatment of retinoblastoma. Curr Opin Ophthalmol. 2002;13:331–336.

21. Dondey JC, Staffieri S, McKenzie J, et al. Retinoblastoma in Victoria, 1976–2000: changing management trends and outcomes. Clin Experiment Ophthalmol. 2004;32:354–359.

22. Lee V, Hungerford JL, Bunce C, et al. Globe conserving treatment of the only eye in bilateral retinoblastoma. Br J Ophthalmol. 2003;87:1374–1380.

23. Desjardins L, Chefchaouni MC, Lumbroso L, et al. Functional results after treatment of retinoblastoma. J AAPOS. 2002;6:108–111.

24. Merchant TE, Gould CJ, Wilson MW, et al. Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer. 2004;43:134–139.

25. Shields JA, Giblin ME, Shields CL, et al. Episcleral plaque radiotherapy for retinoblastoma. Ophthalmology. 1989;96:530–537.

26. Messmer EP, Sauerwein W, Heinrich T, et al. New and recurrent tumor foci following local treatment as well as external beam radiation in eyes of patients with hereditary retinoblastoma. Graefes Arch Clin Exp Ophthalmol. 1990;228:426–431.

27. Buys RJ, Abramson DH, Ellsworth RM, et al. Radiation regression patterns after cobalt plaque insertion for retinoblastoma. Arch Ophthalmol. 1983;101:1206–1208.

28. Fass D, McCormick B, Abramson D, et al. Cobalt60 plaques in recurrent retinoblastoma. Int J Radiat Oncol Biol Phys. 1991;21:625–627.

29. Desjardins L, Levy C, Labib A, et al. An experience of the use of radioactive plaques after failure of external beam radiation in the treatment of retinoblastoma. Ophthalmic Paediatr Genet. 1993;14:39–42.

30. Shields JA, Shields CL, De Potter P, et al. Plaque radiotherapy for residual or recurrent retinoblastoma in 91 cases. J Pediatr Ophthalmol Strabismus. 1994;31:242–245.

31. Hernandez JC, Brady LW, Shields JA, et al. External beam radiation for retinoblastoma: results, patterns of failure, and a proposal for treatment guidelines. Int J Radiat Oncol Biol Phys. 1996;35:125–132.

32. Shields CL, Shields JA, Minelli S, et al. Regression of retinoblastoma after plaque radiotherapy. Am J Ophthalmol. 1993;115:181–187.

33. Imhof SM, Moll AC, Schouten-van Meeteren AY. Intraocular retinoblastoma: New therapeutic options. Ned Tijdschr Geneeskd. 2001;145:2165–2170.

34. Kiratli H, Bilgic S, Atahan IL. Plaque radiotherapy in the management of retinoblastoma. Turk J Pediatr. 1998;40:393–397.

35. Madreperla SA, Hungerford JL, Doughty D, et al. Treatment of retinoblastoma vitreous base seeding. Ophthalmology. 1998;105:120–124.

36. Abdel-Dayem HK, Trese MT. A technique for suturing peripapillary radioactive plaques. Am J Ophthalmol. 1999;127:224–226.

37. Stannard C, Sealy R, Hering E, et al. Localized whole eye radiotherapy for retinoblastoma using a (125)I applicator, “claws”. Int J Radiat Oncol Biol Phys. 2001;51:399–409.

38. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: Long-term tumor control and treatment complications in 208 tumors. Ophthalmology. 2001;108:2116–2121.

39. Archer DB, Amoaku WM, Kelly G. Choroidoretinal neovascularisation following radon seed treatment of retinoblastoma in two patients. Br J Ophthalmol. 1993;77:95–99.

40. Murphree AL, Villablanca JG, Deegan WF 3rd, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol. 1996;114:1348–1356.

41. Spraul CW, Lim JI, Lambert SR, et al. Retinoblastoma recurrence after iodine 125 plaque application. Retina. 1996;16:135–138.

42. Liggett PE, Ma C, Astrahan M, et al. Combined localized current field hyperthermia and irradiation for intraocular tumors. Ophthalmology 1991;98:1830–1835; discussion 1836.

43. Sealy R, Stannard C, Shackleton D. Improved cosmesis in retinoblastoma patients treated with iodine-125 orbital irradiation. Ophthalmic Paediatr Genet. 1987;8:95–99.

44. Stannard C, Sealy R, Hering E, et al. Postenucleation orbits in retinoblastoma: Treatment with 125I brachytherapy. Int J Radiat Oncol Biol Phys. 2002;54:1446–1454.

45. Bentel GC, Halperin EC, Buckley EG. 125I embedded in an orbital prosthesis for retreatment of recurrent retinoblastoma. Med Dosim. 1993;18:1–5.

46. Wycis HT, Robbins R, Spiegeladolf M, et al. Studies in stereoencephalotomy III; treatment of a cystic craniopharyngioma by injection of radioactive P32. Confin Neurol. 1954;14:193–202.

47. Liu Z, Tian Z, Yu X, et al. Stereotactic intratumour irradiation with nuclide for craniopharyngiomas. Chin Med J (Engl). 1996;109:219–222.

48. Yu X, Liu Z, Li S. Combined treatment with stereotactic intracavitary irradiation and gamma knife surgery for craniopharyngiomas. Stereotact Funct Neurosurg. 2000;75:117–122.

49. Hasegawa T, Kondziolka D, Hadjipanayis CG, et al. Management of cystic craniopharyngiomas with phosphorus-32 intracavitary irradiation. Neurosurgery. 2004;54:813–820; discussion 820–2.

50. Pollock BE, Lunsford LD, Kondziolka D, et al. Phosphorus-32 intracavitary irradiation of cystic craniopharyngiomas: Current technique and long-term results. Int J Radiat Oncol Biol Phys. 1995;33:437–446.

51. Shapiro B, Fig LM, Gross MD. Intracavitary therapy of craniopharyngiomas. Q J Nucl Med. 1999;43:367–374.

52. Nag S, Martinez-Monge R, Ruymann FB, et al. Feasibility of intraoperative high-dose rate brachytherapy to boost low dose external beam radiation therapy to treat pediatric soft tissue sarcomas. Med Pediatr Oncol. 1998;31:79–85.

53. Zelefsky MJ, LaQuaglia MP, Ghavimi F, et al. Preliminary results of phase I/II study of high-dose-rate intraoperative radiation therapy for pediatric tumors. J Surg Oncol. 1996;62:267–272.

54. Merchant TE, Zelefsky MJ, Sheldon JM, et al. High-dose rate intraoperative radiation therapy for pediatric solid tumors. Med Pediatr Oncol. 1998;30:34–39.

55. Goodman KA, Wolden SL, LaQuaglia MP, et al. Intraoperative high-dose-rate brachytherapy for pediatric solid tumors: A 10-year experience. Brachytherapy. 2003;2:139–146.

56. Nag S, Tippin D, Ruymann FB. Intraoperative high-dose-rate brachytherapy for the treatment of pediatric tumors: The Ohio State University experience. Int J Radiat Oncol Biol Phys. 2001;51:729–735.

57. Calvo FA, Sierrasesumaga L, Martin I, et al. Intraoperative radiotherapy in the multidisciplinary treatment of pediatric tumors. A preliminary report on initial results. Acta Oncol. 1989;28:257–260.

58. Fletcher DT, Warner WC, Neel MD, et al. Valgus and varus deformity after wide-local excision, brachytherapy and external beam irradiation in two children with lower extremity synovial cell sarcoma: Case report. BMC Cancer. 2004;4:57.



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