Pediatr Blood Cancer 2007;49:649–655

Interstitial Brachytherapy for Childhood Soft Tissue Sarcoma

Siddhartha Laskar, MD,1* Gaurav Bahl, MD,1 Mary Ann Muckaden, MD,1 Ajay Puri, MS,2 Manish G. Agarwal, MS,2

Nikhilesh Patil, MD,1 Shyam K. Shrivastava, MD,1 and Ketayun A. Dinshaw, FRCR1

INTRODUCTION

Soft tissue sarcomas (STS) are a relatively uncommon and

heterogeneous group of neoplasms. These tumors are of mesen-

chymal origin and may occur within any organ or at any anatomic

location. They account for about 5% of all cancers in patients

younger than 20 years of age [1]. Majority of these malignancies are

treated with multimodality therapy comprising of surgery (Sx),

chemotherapy (CTh), and radiotherapy (RT) [1–4]. In the current

context of organ and function preservation, external beam radio-

therapy (EBRT) plays a pivotal role in the local control of these

tumors and is an integral component of most treatment protocols.

However, the goal of complete tumor eradication through the

delivery of escalating radiation doses must be balanced by the need

to minimize the dose to normal tissues. This is essential to avoid the

adverse effects of ionizing radiation on growth and development, as

well as the potential of second malignancy induction in the pediatric

population [8–10]. Hence, the doses of EBRT have to be reduced

while treating children although this may compromise local control.

Brachytherapy (BRT) is ideal for the pediatric patient. This

treatment approach delivers high doses of radiation to the tumor

volume in a very precise and localized manner while sparing the

nearby normal tissues. As a result, the radiation-related side effects

that are likely to occur when these children are treated with external

irradiation alone are greatly reduced [11,14]. Furthermore, the

overall treatment time is shortened while maintaining a comparable

high rate of local control. These benefits are particularly important

in the pediatric age group where limitation of the late toxicities of

treatment is of paramount concern. In an attempt to further define the

efficacy of BRT in the pediatric population, we reviewed our past

20-year experience with interstitial BRT in this age group of patients

treated at the Tata Memorial Hospital, Mumbai.

METHODS

Between September 1984 and December 2003, 50 children with

non-metastatic soft tissue sarcomas underwent conservative, organ,

and function-preserving surgery along with BRT with or without

EBRT, at the Tata Memorial Hospital, Mumbai, India. Patients were

in the age group of 1–18 years with a median age of 13 years at

presentation. There were 30 males and 20 female patients.

Approximately one-third (32%) of these children were being

treated for recurrent disease. The lower extremities were most

commonly involved (66%), followed by the upper extremities

(18%), the chest and abdominal walls (14%), and the head and neck

region (2%). The most common histological type was synovial

sarcoma (32%), followed by a diverse group of histologies including

Ewing sarcoma/PNET (16%), fibrosarcoma (12%), spindle cell

sarcoma (10%), rhabdomyosarcoma (10%), malignant peripheral

nerve sheath tumor (6%), fibromatosis (4%), and various other soft

tissue sarcomas (10%). Thirteen patients (26%) had Grade III

(high grade), 18 (36%) had Grade II (intermediate grade), and

11 (22%) had Grade I (low grade) tumors, while in 8 patients, the

grade was not specified. The surgical margins where positive in

6 (12%) of the patients. Twenty-six children (52%) had lesions

greater than 5 cm in maximum diameter. The tumor size was

determined from the gross pathologic description when available,

or else from the initial clinical description. The tumor grade,

histological subtype, and margins were obtained from microscopic

description by experienced pathologists. Table I contains the

pertinent clinical and pathological patient-related information.

All patients received treatment comprising of conservative

surgery in the form of wide local excision (WLE) of the tumor

followed by post-operative radiotherapy. Thirty patients (60%) were

treated with radical BRT alone while 20 (40%) received a

combination of BRT and external beam irradiation. The EBRT

dose ranged from 30 to 60 Gy (median 45 Gy), and the majority of

the patients were treated with simple parallel-opposed portals using

Background. To evaluate the efficacy of interstitial brachytherapy(BRT) in children undergoing combined modality treatment forsoft tissue sarcomas (STS). Procedure. From September 1984 toDecember 2003, 50 children (median age 13 years, range 1 to 18)with STS who received BRT as part of loco-regional treatment wereincluded. There were 30 males and 20 females, the majority (68%)had primary lesions, synovial sarcoma (32%) was the most commonhistological type, and 26% had high-grade lesions. Treatmentincluded wide local excision and BRT with or without externalbeam radiotherapy (EBRT). Thirty children (60%) received BRTalone. Results. After a median follow-up of 51 months, the localcontrol (LC), disease-free survival, and overall survival were 82%,68%, and 71%, respectively. LC was superior in patients with tumorsize �5 cm versus >5 cm (96% vs. 67%, P¼0.04), symptom

duration <2 months versus >2 months (100% vs. 73%, P¼0.05),and Grade I versus Grade II versus Grade III tumors (100% vs. 93%vs. 57%, P¼ 0.03). Children receiving a combination of BRT andEBRT had comparable LC to those receiving BRT alone (78% vs.84%, P¼0.89). There was no significant difference in LC forpatients receiving LDR versus HDR BRT (77% vs. 92%, P¼0.32,for BRT alone; and 67% vs. 100%, P¼0.17, for BRTþ EBRT).Conclusion. Interstitial BRT with or without EBRT appears to result insatisfactory outcome in children with STS. Radical BRT alone, whenused judiciously in select groups of children, results in excellentlocal control and functional outcomewith reduced treatment-relatedmorbidity. Pediatr Blood Cancer 2007;49:649–655.� 2007 Wiley-Liss, Inc.

Key words: interstitial brachytherapy; pediatric; radiotherapy; soft tissue sarcoma

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21118

——————1Department of Radiation Oncology, Tata Memorial Hospital,

Mumbai, India; 2Department of Surgery, Tata Memorial Hospital,

Mumbai, India

*Correspondence to: Siddhartha Laskar, Associate Professor,

Department of Radiation Oncology, Tata Memorial Hospital,

Dr. Ernest Borges Road, Parel, Mumbai 400012, India.

E-mail: laskars2000@yahoo.com

Received 28 May 2006; Accepted 30 October 2006

60 Cobalt g rays or 6 MV photons. While in 58% of the patients

(n¼ 29), BRTwas delivered at a low dose rate (LDR), the remaining

42% (n¼ 21) received high dose rate (HDR) BRT. Ten patients also

received adjuvant chemotherapy.

Brachytherapy Technique

All patients included in this study were treated with temporary

interstitial BRT using iridium-192. After WLE, the surgeon and the

radiation oncologist jointly demarcated the tumor bed using radio-

opaque surgical clips. Plastic after-loading catheters were intro-

duced into the tumor bed using 16-gauge stainless steel needles. The

implanted area generally included the tumor bed with a 2-cm radial

margin when the intent was to use BRT as a boost along with

EBRT, while the margin was increased to 3–4 cm if the plan was to

use radical BRT alone. The catheters were placed parallel to each

other at a distance of 1.0 to 1.5 cm intervals, and a single plane

arrangement was used for all patients. If required, gel-foam or thin

muscle flaps were interposed between the catheter plane and

neighboring critical structures. Finally, catheters were secured in

position using stainless steel buttons and plastic beads (Fig. 1). After

the procedure, the surgical incision was closed either by primary

closure or, if necessary, with the reconstruction of the surgical defect

with regional or micro-vascular free flaps. Orthogonal radiographs

were taken on the 4th to 5th post-operative day for dosimetry and

planning. Dose prescription was done using dose-point optimization

at 5 mm away from each catheter using the 85% isodose line (Fig. 2).

Treatment was started on the same day of dosimetry. The EBRT and

BRT doses were based on the intent of BRT (Radical vs. Boost) and

the BRT dose rate (HDR vs. LDR) (Table II). The BRT dose with

radical BRTwas 36 Gy in nine fractions at 4 Gy per fraction with two

fractions delivered daily with a minimum interfraction interval of

6 hr. When combined with EBRT, the total HDR BRT dose was

reduced to 21 Gy in seven fractions (earlier protocol) and 15 Gy in

five fractions (current protocol).

Statistical Analysis

Follow-up information was abstracted from patients’ hospital

records and from an existing database of patients undergoing BRT.

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. Tumor Characteristics

Histological grade Tumor depth Tumor size Site of primary tumor

Histologic type (WHO) n Gr I Gr II Gr III Superficial Deep �5 cm >5 cm

Upper

extremity

Lower

extremity

Trunk and

H&N

Fibromatosis 2 2 0 0 1 1 0 2 1 1 0

Fibrosarcoma 6 3 2 1 1 5 4 2 1 2 3

Malignant fibrous histiocytoma 1 0 0 1 0 1 0 1 1 0 0

Malignant hemangiopericytoma 1 0 1 0 0 1 0 1 0 0 1

Synovial sarcoma 16 3 9 4 5 11 8 8 2 13 1

Malignant peripheral nerve

sheath tumor

3 0 1 2 0 3 0 3 0 2 1

Epithelioid sarcoma 1 0 1 0 1 0 1 0 0 1 0

Pleomorphic sarcoma 1 0 0 1 0 1 0 1 0 0 1

Spindle cell sarcoma 5 1 3 1 2 3 4 1 1 3 1

Soft tissue primitive neuro

ectodermal tumor (PNET)

8 0 1 0 2 6 5 3 2 6 0

Rhabdomyosarcoma 5 2 0 2 1 4 2 3 1 4 0

Other 1 0 0 1 0 1 0 1 0 1 0

Total 50 11 18 13 13 37 24 26 9 33 8

Fig. 1. Tumor bed with stainless steel needles (A) and the site after closure of wound with the brachytherapy catheters in situ (B). [Color figure can

be viewed in the online issue, which is available at www.interscience.wiley.com.]

650 Laskar et al.

Because BRT is primarily a local treatment, disease control at the

site of the implant was the primary endpoint reviewed in this study.

Local failure was defined as recurrence or progression within or at

the margin of the irradiated field. Disease free survival (DFS) was

calculated from the date of registration to date of recurrence of

disease at any site. Overall survival (OS) was calculated from date of

registration to the date of death due to any cause. Local control (LC),

DFS, and OS rates were calculated using the Kaplan–Meier method

and prognostic factors were compared using the log-rank test.

Multiple-covariate analysis was performed using the stepwise

Cox’s proportional hazards regression model. Complications were

recorded as either acute or chronic if they occurred within 3 months

or greater than 3 months after the conclusion of treatment, res-

pectively. Events were scored according to the Radiation Therapy

Oncology Group (RTOG) late radiation morbidity scoring system.

RESULTS

After a median follow up of 51 months (range 1 to 128 months),

39 patients were alive without disease, 6 were alive with disease, and

5 children had died due to tumor progression. The 5-year local

control, DFS, and OS were 82%, 68%, and 71%, respectively

(Figs. 3 and 4A). Five children failed locally, four patients

developed distant metastasis, of whom three succumbed to the

metastatic disease, and two children had developed distant meta-

stasis as well as a local recurrence and both died of the local disease

progression. The most common site of distant metastases was the

lung. Table III illustrates the treatment results.

Prognostic Factors

Various prognostic factors were analyzed to establish their

influence on local control and survival of children with soft tissue

sarcoma treated using BRT. On univariate analysis, patients having a

maximum tumor diameter less than or equal to 5 cm, at the time of

diagnosis, were found to have a significantly better outcome as

compared to those with lesions greater than 5 cm in size. The LC

(Fig. 4B), DFS, and OS for these two groups were 96% versus 67%

(P¼ 0.04), 89% versus 44% (P¼ 0.01), and 93% versus 52%

(P¼ 0.07), respectively. Children with high-grade tumors

(Grade III) did worse compared to patients with low or intermediate

grade tumors (Grade I and Grade II). The LC (Fig. 4C), DFS, and OS

were all 100% for Grade I tumors, versus 57% (P¼ 0.03), 29%

(P¼ 0.03), and 36% (P¼ 0.12), respectively for Grade III sarcomas.

The duration of symptoms at the time of presentation also proved to

be a significant prognostic indicator in this patient population. All of

the 13 children who had been symptomatic for less than 2 months

before treatment was initiated, were alive and disease free at the time

of analysis, while children who had been symptomatic for a period

exceeding 2 months, had a LC rate of 73% (P¼ 0.05), a DFS of 51%

(P¼ 0.01), and an OS of 55% (P¼ 0.04). However, on multivariate

analysis, only the tumor size (HR¼ 5.88, 95% CI¼ 1.26–27.44,

P¼ 0.024) and grade (HR¼ 14.39, 95% CI¼ 2.84–39.53,

P¼ 0.004) retained statistical significance [Table IV].

Treatment Outcome

All patients received post-operative radiotherapy in the form of

either radical BRTalone (60%), or a combination of BRTand EBRT

(40%). There was no difference between these two groups of

patients in terms of local control (84% vs. 78%,P¼ 0.89) (Fig. 4D),

Disease-Free (84% vs. 45%, P¼ 0.11) or Overall Survival (95% vs.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 2. Orthogonal radiographs with dummy sources for dosimetry (A) and the resultant isodose distribution (B). [Color figure can be viewed in

the online issue, which is available at www.interscience.wiley.com.]

TABLE II. Brachytherapy Treatment Details

Radiotherapy

type

No. of

patients

BRT dose range

(median dose)

EBRT dose range

(median dose)

BRT alone

LDR 16 35–50Gy (39.7Gy) —

HDR 14 30–40Gy (36Gy) —

BRTþEBRT

LDR 13 25–40Gy (30Gy) 30–60Gy (50Gy)

HDR 07 15–36Gy (21Gy) 30.6–45Gy (45Gy)

Brachytherapy for Childhood Soft Tissue Sarcoma 651

55%, P¼ 0.10). In the subset of patients treated with a combination

of BRTand EBRT, the use of HDR (n¼ 7) versus LDR BRT (n¼ 13)

did not have a statistically significant influence on the treatment

outcome (LC: 100% vs. 67%, P¼ 0.17; DFS: 100% vs. 28%,

P¼ 0.05; OS 100% vs. 31%, P¼ 0.17). Furthermore, subset

analysis of the 30 patients who received RT in the form of radical

BRTalone did not demonstrate any difference in outcome with HDR

BRT compared to LDR BRT (LC: 92% vs. 77%,P¼ 0.1; DFS: 92%

vs. 77%, P¼ 0.33; OS: 100% vs. 90%, P¼ 0.34). Also worth

mention is that none of the 30 patients who received BRT alone

developed distant metastasis and only 1 patient had expired at the

end of the study period. Of the 20 patients who received a

combination of BRT and EBRT, 4 patients had developed distant

metastasis and died by the time this analysis was conducted.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 3. Kaplan–Meier Survival curves for DFS (A) and OS (B).

Fig. 4. Kaplan–Meier survival curves for local control (n¼ 50) (A), tumour size as a prognostic factor (�5 cm, n¼ 24; >5 cm, n¼ 26)

(B), tumour grade as a prognostic factor (Grade I, n¼ 11, Grade II, n¼ 18, Grade III, n¼ 13) (C), and local control for Brachytherapy alone (n¼ 30)

vs. BrachytherapyþExternal Beam Radiotherapy (n¼ 20) (D).

652 Laskar et al.

Complications

Patients tolerated the BRT procedure well and there were no

major acute complications directly related to the procedures. Minor

complaints like pain and swelling were treated symptomatically.

Primary closure of the surgical wound was achieved in 46 children, a

pedicle graft was required in 3 patients, and 1 child underwent a split

skin graft. Wound healing was impaired in three patients who

underwent primary closure of the surgical incision and in one child

who had undergone a pedicle graft. All four of these children

developed wound infection and dehiscence requiring an extended

hospital stay and antibiotic therapy. Twelve (60%) of the 20 patients

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE III. Prognostic Factors

Prognostic factor

5-year local control

(LC)

5-year disease free

survival (DFS)

5-year overall

survival (OS)

Sex

Male 80% 62% 60%

Female 83% (P¼ 0.99) 76% (P¼ 0.66) 92% (P¼ 0.28)

Age

�10 years 81% 81% 100%

>10 years 82% (P¼ 0.65) 63% (P¼ 0.67) 63% (P¼ 0.15)

Symptom duration

<2 months 100% 100% 100%

>2 months 73% (P¼ 0.05) 51% (P¼ 0.01) 55% (P¼ 0.04)

Tumor depth

Superficial 92% 92% 100%

Deep 78% (P¼ 0.41) 56% (P¼ 0.11) 65% (P¼ 0.08)

Size of tumor

�5 cm 96% 89% 93%

>5 cm 67% (P¼ 0.04) 44% (P¼ 0.01) 52% (P¼ 0.06)

Primary site

Extremities 82% 66% 69%

Axial/trunk 86% (P¼ 0.99) 86% (P¼ 0.65) 100% (P¼ 0.38)

Type of lesion

Primary 89% 71% 71%

Recurrent 67% (P¼ 0.09) 56% (P¼ 0.22) 68% (P¼ 0.57)

Tumour grade

Gr I 100% 100% 100%

Gr II 93% 75% 81%

Gr III 57% (P¼ 0.03) 29% (P¼ 0.03) 36% (P¼ 0.12)

Surgical margins

Negative 82% 68% 68%

Positive/close 80% (P¼ 0.74) 67% (P¼ 0.88) 100% (P¼ 0.45)

Treatment

BRT alone 84% 84% 95%

BRTþEBRT 78% (P¼ 0.89) 45% (P¼ 0.11) 55% (P¼ 0.10)

Radiotherapy type (BRTþEBRT)

LDR 67% 28% 31%

HDR 100% (P¼ 0.17) 100% (P¼ 0.05) 100% (P¼ 0.17)

Radiotherapy type (BRT alone)

LDR 77% 77% 90%

HDR 92% (P¼ 0.32) 92% (P¼ 0.33) 100% (P¼ 0.34)

Gr, grade; BRT, brachytherapy; EBRT, external beam radiotherapy; LDR, low dose rate; HDR, high dose

rate.

TABLE IV. Multiple-Covariate Cox Regression Analysis for Prognostic Factors

Variable

Local control Disease free survival

P-value HR 95.0% CI P-value HR 95.0% CI

Size of tumor >5 cm 0.024 5.88 1.26–27.44 0.042 3.69 1.06–13.03

Grade III (high grade) tumor 0.004 14.39 2.84–39.53 0.001 11.78 2.87–48.36

Recurrent tumor 0.657 1.76 0.14–21.45 0.517 1.92 0.27–13.67

Symptom duration >2 months 0.235 4.64 0.82–26.23 0.121 5.22 0.35–7.69

Brachytherapy alone 0.448 0.53 0.10–2.76 0.358 0.57 0.15–1.98

CI, confidence interval; HR, hazard ratio.

Brachytherapy for Childhood Soft Tissue Sarcoma 653

who received a combination of BRT and EBRT developed Grade 2

acute skin toxicity (dry desquamation) and 2 (10%) children

developed Grade 3 acute toxicity (moist desquamation). On the

other hand, only 4 patients (13%) of the 30 treated with BRT alone

developed Grade 2 acute toxicity to the skin. No other acute

toxicities were reported in this group of patients. Late sequel of

radiotherapy, in the form of woody subcutaneous fibrosis, was

evident in 10 patients. Seven (70%) of these patients had been

treated with a combination of BRTand EBRT. Two of these children

progressed to develop edema of the lower limb requiring supportive

care and two children developed stiffness and impaired mobility of

the knee joint, which was within the radiated field. The remaining

three children had received radical LDR BRT alone. All children

were treated symptomatically for their complaints.

DISCUSSION

Traditionally, the primary treatment for STS has been surgery,

and the success in achieving control dependent on the extent of the

surgical procedure [2–4]. While radical surgery and amputation

are associated with the maximum local control rates, they do not

assure cure, and result in loss of functional integrity and marked

psychological trauma to the patient. Hence, the preferred manage-

ment of these tumors is with multimodality therapy, combining

conservative, organ and function-sparing surgery, and post-

operative adjuvant RT with or without chemotherapy. The goals of

adjuvant RT are to enhance local control, preserve function, and

achieve acceptable cosmesis. However, with the high doses of

EBRT required for local control, the long-term consequences of

ionizing radiation on bone and soft tissue growth, normal organ

development, and the induction of second malignancies cannot be

ignored [5–10]. These adverse effects are a limiting factor for the

use of radiation therapy in young children, and more conformal

approaches are essential to reduce the dose to critical normal tissues.

BRT, when properly applied, is capable of achieving a high rate

of local control for patients with STS treated with an organ and

function preserving approach. However, the technique relies heavily

on preoperative diagnostic imaging, pre and intra-operative assess-

ment of tumor extent, and the extent of resection. Technical

expertise in performing the BRT procedure is an important factor

that could influence the final result in terms of disease control and

functional and cosmetic outcome. The value of BRT for soft tissue

sarcomas has been consistently demonstrated in adults [11–15].

Harrison et al. [15] have established the local control advantage of

BRT over wide local excision alone for adults with high-grade

tumors. However, there are limited data available in literature

regarding BRT for children, most of which is from series that

include relatively small numbers of patients with different tumor

types [16–20].

The objective of this study was to evaluate the efficacy

of interstitial BRT for children with soft tissue sarcomas,

and determine the prognostic factors influencing treatment out-

come. We report on a relatively large series of children with this

uncommon tumor treated at a single institute. Important prognostic

factors for STS reported in literature include tumor size, grade,

depth, site, primary or recurrent tumors, and surgical margins

among others. In our current series, tumor size and histological

grade were important factors influencing LC and DFS. The 5-year

LC, DFS, and OS for these children were 82%, 68%, and 71%,

respectively. BRT when used alone or in combination with EBRT

resulted in equivalent LC rates (84% vs. 78%, P¼ 0.89).

Furthermore, there was no difference in outcome for patients

treated with either LDR or HDR BRT. Gerbaulet et al. [21] have

reported similar results with BRT alone in a large series from the

Institut Gustave-Roussy. Merchant et al. [22] in a series of

31 children treated with BRT or a combination of BRT and EBRT,

reported 100% local control in the 12 children treated with LDR

BRT alone. Nag et al. [23] reported a series of 15 children treated

with fractionated HDR BRT. They reported a DFS of 80% after a

median follow-up of 10 years. Treatment-related sequel reported in

most of the series have ranged between 20 and 22% [21–23]. As

expected, the complication rates were higher amongst children

receiving a combination of BRT and EBRT. We report similar

complication rates in the current series.

In our series, small superficial tumors with low-grade histology

had excellent LC rates. Hence, young children with such tumors

may be treated with wide local excision alone, reserving BRT for

children with high risk of local recurrence, likelihood of high

morbidity with revision excision, or at the time of disease

recurrence. Rydholm et al. [24] have suggested that a subset of

patients with subcutaneous or intramuscular tumors could be

observed after an excision with negative margins. Geer et al. [25]

also reported that selected patients with tumor <5 cm undergoing

WLE with negative margins could be kept under observation with

the possibility of local recurrence of 10%.

In conclusion, this retrospective study suggests that interstitial

BRT with or without EBRT is an effective modality in the

conservative management of STS in children. Furthermore, results

with the use of HDR BRTappear to be equivalent to those with LDR

BRT. The high local control rate and minimal observed toxicity with

the use of radical BRT alone is encouraging. Future studies using

BRT in children should try to risk stratify patients into prognostic

groups based on clinico-pathological factors so that selected

patients can be treated with BRT alone and thus reduce the

treatment-related morbidity.

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