Long-term functional follow-up of pediatric extremity sarcoma patients treated with brachytherapy

Abstract

BACKGROUND

Pediatric sarcomas of the extremities are most often treated with a combination of surgery, chemotherapy, and radiotherapy. Due to the limited anatomical dimensions in children, limb-sparing surgery with adequate surgical margins may be challenging. In addition, external beam radiotherapy near growth zones can result in abnormal or compromised development. However, the steep dose gradient of brachytherapy may deliver a sufficient radiation dose to the tumor or tumor bed while sparing surrounding tissues to a greater extent than external beam radiation techniques.

AIM

To assess functional outcomes and the long-term effects of brachytherapy on extremity function in pediatric patients treated at our institution.

METHODS

A retrospective cohort of patients was identified through internal hospital records. Patients were recruited during routine follow-up appointments, during which they were interviewed and completed patient-reported outcome measures.

RESULTS

Three patients treated with brachytherapy were included in the analysis. No recurrences were observed during follow-up, which ranged from 5-9 years. Two patients were treated at or near a physis, and both developed limb-length discrepancy, which was symptomatic in one patient with lower extremity involvement. Two of the three patients experienced progressive functional impairment that worsened with growth because of unyielding cicatricial tissue, with more pronounced impairment in the patient with lower extremity involvement. Extensive soft-tissue resection was performed in two patients, both of whom reported decreased endurance in the affected limb. Despite surgery and radiation adjacent to major peripheral nerves, no patients reported neural deficits.

CONCLUSION

Brachytherapy is a viable alternative to external beam radiotherapy for pediatric extremity sarcomas and may provide favorable functional outcomes; in our cohort, no patients experienced local recurrence. However, ongoing skeletal growth presents challenges in achieving optimal long-term functional outcomes. Close collaboration with oncology late-effects clinics and pediatric orthopedic surgeons may be beneficial, as postoperative sequelae in patients treated with brachytherapy may resemble growth-related musculoskeletal abnormalities.

Key Words: Brachytherapy; Orthopedic; Sarcoma; Pediatric outcome; Late effects

Core Tip: Brachytherapy is a viable alternative to external beam radiotherapy for pediatric extremity sarcomas and may provide acceptable functional outcomes. However, it does not eliminate growth-related complications, and ongoing skeletal growth presents challenges in achieving optimal long-term functional outcomes. Close cooperation with oncology late-effects clinics and continued evaluation by pediatric orthopedic surgeons may help optimize long-term care.

INTRODUCTION

Sarcomas are rare, aggressive tumors that affect all age groups, accounting for approximately 1% of adult malignancies and more than 10% of pediatric malignancies. Approximately 87% of sarcomas are soft-tissue or extraosseous sarcomas, whereas the remaining 13% are bone sarcomas[1-4]. The etiology is often unknown, and most sarcomas occur sporadically. Although sarcomas can occur at any age, certain subtypes, such as rhabdomyosarcoma, are more common in pediatric populations[2]. The diagnosis and treatment of sarcomas are challenging and often require a multidisciplinary approach involving surgeons, pediatricians, oncologists, radiologists, and pathologists to achieve curative outcomes while minimizing morbidity. Surgery remains the first-line treatment for sarcomas whenever feasible to achieve local control, although wide excisions or amputation does not guarantee cure. Treatment is often combined with radiotherapy to improve local control and preserve function[5-7].

Therefore, most of these tumors are treated with a combination of surgery, chemotherapy, and radiotherapy. To achieve complete eradication of malignant cells, the radiation dose must be carefully balanced against minimizing exposure to healthy tissue and critical structures. This is particularly important in pediatric patients, in whom irradiation of large volumes of normal tissues may result in significant adverse effects, including impaired or abnormal bone growth due to radiation exposure of the osseous growth plates (physes), deformity, scoliosis secondary to soft tissue fibrosis, and radiation-induced secondary malignancies[5,8].

Brachytherapy is a type of internal or externally applied radiation therapy used to treat cancer by placing radioactive sources inside or next to a tumor. This method allows for a high, targeted dose of radiation to destroy cancer cells while minimizing damage to surrounding healthy tissue. The treatment involves insertion of multiple catheters into the tumor bed (Figure 1A-C), followed by delivery of a small radioactive stepping source through the catheters using a computer-controlled afterloader[5,9]. Depending on the dose rate and radiation source, a full dose is delivered over a few minutes (high dose rate brachytherapy) or in hourly pulses over a few days (pulse dose rate brachytherapy)[10]. For very young children, it may be necessary to keep the patient sedated throughout the procedure. Even with radiation-resistant tumors such as sarcomas, radiation therapy still improves local control[11].

Figure 1 Patient A. A-C: Perioperative pictures and dose plan; D: Left lower arm, extra-osseous Ewing’s sarcoma, 5 years post-op (dorsal cotton swab due to recent blood draw).

Therefore, brachytherapy offers many potential benefits to pediatric patients[10]. The inverse-square relationship between radioactive source distance and dose rate generates a steep dose gradient, which allows delivery of high doses of radiation to the tumor or tumor bed while sparing surrounding tissue. Treatment duration with brachytherapy is short compared with external beam radiotherapy, which is clinically relevant for pediatric patients, as other radiation regimens require general anesthesia for each treatment session. With brachytherapy, there is no entrance dose and very limited exit dose, thereby reducing the total irradiated tissue volume compared with external beam therapy and limiting the risk for radiation-induced secondary cancer.

Although brachytherapy offers theoretical dosimetric advantages in pediatric extremity sarcomas, current evidence remains limited regarding its long-term effects during maturation. Existing studies predominantly emphasize local control and survival outcomes, while longitudinal pediatric-specific functional surveillance data remain sparse[12-14].

Purpose

To assess the functional outcome and long-term effects on extremity function following brachytherapy treatment in pediatric patients having received brachytherapy at our institution.

MATERIALS AND METHODS

Institutional review board approval was obtained. Inclusion criteria were age < 18 years at the time of treatment with brachytherapy. Exclusion criteria were death or refusal to participate. A potential cohort of four consecutive patients treated between 2010 and 2020 was retrospectively identified through internal departmental records for whom brachytherapy was recommended and cross-referenced with the pediatric clinic for late effects, which performs follow-up on all such pediatric patients. The four patients were contacted during routine yearly follow-up and offered enrollment in the study over the course of a year. One patient who was previously considered for brachytherapy underwent proton-beam therapy instead of the brachytherapy intervention and was thus excluded.

This left a total of three pediatric patients (A, B, and C) who had received brachytherapy since its introduction at our institution, available for long-term follow-up. The prescribed dose of brachytherapy was 30-36 Gy to 98% of the target (tumor bed), in accordance with the Paris system[10,15]. Patient A, who had a tumor near the wrist, also received 25 Gy in 15 fractions as external beam radiotherapy prior to surgery and brachytherapy. All patients received preoperative chemotherapy.

Patients’ legal guardians signed consent forms for participation and allowed access to patients’ electronic medical records. Patients completed validated Patient-Reported Outcome Measures in the form of Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), pediatric Toronto Extremity Salvage Score (pTESS) arm, and pTESS leg, where applicable. The pTESS score is rated from 0 to 100, with a score of 0 being severe disability and 100 being no disability. QuickDASH scoring is inversely scaled, with a score of 0 indicating no disability and 100 indicating severe disability. Furthermore, patients and their parents were given the option to comment on issues they felt Patient-Reported Outcome Measures did not assess.

RESULTS

Three patients were included in the study. No recurrences were observed during follow-up, which ranged from 5-9 years, with an average of 7.2 years. Two patients were diagnosed with alveolar rhabdomyosarcoma, and one had an (extraosseous) Ewing’s sarcoma. Tumors were located in the volar wrist (patient A, Figure 1), biceps brachii muscle (patient B, Figure 2), and gastrocnemius muscle (patient C, Figure 3). Patients A and C were treated at or near a physis, and both experienced limb-length discrepancy, although patient A also received external beam therapy at the same site. Patients B and C had extensive muscular resection during treatment.

Figure 2 Patient B. A: Right upper arm, alveolar rhabdomyosarcoma, 7 years post-op, close-up; B: Right upper arm, alveolar rhabdomyosarcoma, 7 years post-op, range of motion.

Figure 3 Patient C. A: Right lower leg, alveolar rhabdomyosarcoma, 9 years post-op, standing on flat foot; B: Right lower leg, alveolar rhabdomyosarcoma, 9 years post-op, standing on toes; C: Right lower leg, alveolar rhabdomyosarcoma, 8 years post-op, flexed knee showing lack of muscle and limb length discrepancy.

No complications were recorded in the electronic medical record within the first year of follow-up. Patients B and C had experienced progressive functional deterioration that was inversely correlated with growth due to contracture or unyielding cicatricial tissue at late follow-up. Of these, only Patient C had limb-length discrepancy. Both patients B and C reported complaints related to joints distal to the operated and irradiated site, with more severe functional impairment in Patient C, who had lower extremity involvement. No patients reported neural deficits, and sensory and motor function were preserved, despite having received surgery and considerable radiation adjacent to significant peripheral nerves. The average pTESS arm score was 100, QuickDASH 2.3 and the pTESS leg score was 88.5.

Corrective surgery

Patient C had undergone corrective surgery before follow-up. The procedure consisted of Achilles tendon lengthening to address contracture. Patient B was referred for evaluation for corrective surgery during routine follow-up. However, surgery was not pursued because of the risk of nerve injury and because the patient was largely unbothered by the reduced range of elbow extension.

Late complications

Patient A’s only complaint was scar hyperpigmentation, which increased scar visibility. Patient B reported early-onset fatigue during running or play due to limited arm extension and an abnormal resting limb position. The patient did not find the fatigue bothersome during daily activities or interactions with peers but was distressed by the resulting limitations when competing with a younger sibling. Patient C reported more pronounced fatigue and pain in the affected limb; uninterrupted walking for more than 1 hour resulted in pain severe enough to require assistance with ambulation (Table 1).

Table 1 Overview of patient characteristics.

Patient	A	B	C
Patient age at diagnosis (years)	5	0.6	0.3
Patient age at follow-up (years)	10	8	9.5
Follow-up time (years)	5	7.4	9.2
Diagnosis	Ewing’s Sarcoma, extra-osseous	Alveolar rhabdomyosarcoma	Alveolar rhabdomyosarcoma
Preoperative chemo	Yes	Yes	Yes
Open biopsy	2	1	1
Initial surgeries	1	1	2
Corrective surgeries	0	0	1
Brachytherapy dose (Gy)	30	32	36
External beam dose (Gy)	25	0	0
Recurrence	No	No	No
Limb-length discrepancy	Yes	No	Yes
Contractures	No	Yes	Yes
Fatigue in extremity	No	Yes	Yes
Neurovascular intact?	Yes	Yes	Yes
Complications	Hyperpigmentation	Progressive extension defect in the elbow	Achilles tendon contracture
pTESS arm	100	100	N/A
pTESS leg	N/A	N/A	88.5
Quickdash	2.3	2.3	N/A

pTESS: Pediatric Toronto Extremity Salvage Score; N/A: Not applicable.

DISCUSSION

Numerous techniques are available for radiotherapy delivery, with external beam radiation therapy being the most widely used, typically delivered using photons or, when available, protons. Each modality has distinct advantages and limitations. Brachytherapy may help overcome some of these limitations. One advantage of brachytherapy is its relatively short treatment duration, typically requiring only a few days of therapy, although this often necessitates prolonged sedation in pediatric patients. Following extubation, ventilatory weaning may be required because of the duration of sedation. In contrast, external beam radiation therapy is typically administered in daily fractions over 5-6 weeks, with each session potentially requiring repeated sedation. Therefore, brachytherapy may be preferable for children who are unable to remain still during external beam radiotherapy.

The decision to use brachytherapy remains somewhat institution-specific, as it requires specialized infrastructure, technical expertise, and multidisciplinary collaboration to perform[16]. In all three cases, brachytherapy was chosen based on a multidisciplinary discussion of the local tumor response to chemotherapy, position, and residual tumor dimensions relative to compartmental aspects of surgical resection and expected performance of external beam radiotherapy (including protons) vs brachytherapy.

Sarcomas are rare, and the use of brachytherapy in their treatment is even less common. Given the small sample size, it is difficult to overly generalize results, especially given the heterogeneity, rarity, and localization of sarcomas. We believe several implications can be extrapolated. Brachytherapy attempts to mitigate the risk of growth retardation; two-thirds of our patients developed clinical length shortening of the affected limb compared with the unaffected side, but of those, one patient also received external beam radiation therapy to the same site. Two-thirds experienced progressive inhibition of function as they grew. The patient with the least functional impairment was treated in the upper extremity, in an area primarily comprised of tendinous structures, while the others received extensive muscular excisions. Importantly, their decreased function emerged slowly as the unyielding fibrotic or cicatricial tissue interfered with the normal or impaired limb lengthening. The results suggest vigilance in following up on limb function until skeletal maturity. Another important implication of our findings is the necessity for multidisciplinary survivorship care. Current survivorship frameworks, including at our institution, often remain oncology-centered. Our study suggests that surveillance may allow earlier identification of progressive functional impairment before severe disability develops. This multidisciplinary approach may be particularly important in younger patients who have substantial skeletal growth remaining at the time of treatment. Given the steep dose gradient of brachytherapy, radiation delivered across a physis may cause uneven growth inhibition, resulting in progressive angular deformity rather than simple limb-length discrepancy. Such cases warrant close follow-up to enable early detection and timely corrective or preventive intervention[17]. Care should be taken when considering the underlying growth plates. Long bones grow from a proximal and distal physis, and the ratio of extremity growth in length from each physis varies from bone to bone and by age. The greater the remaining growth potential, the more important it is to spare the affected area, and prolonged follow-up is recommended.

Two-thirds of our patients developed clinical length shortening. One patient required additional surgical intervention of the affected limb in the form of a tenotomy to address Achilles tendon shortening; however, the relative contributions of brachytherapy, extent of surgical excision, chemotherapy, or their combined effects remains unclear. All patients received treatment in close proximity to neural structures, but none reported sensory changes. In addition, gross motor function was retained.

CONCLUSION

In conclusion, brachytherapy represents a viable alternative to external beam radiotherapy for pediatric sarcomas of the extremities, with potentially good functional results. In our cohort, no local recurrence was observed. However, although the small sample size makes it difficult to definitively attribute these complications to brachytherapy alone, brachytherapy does not appear to eliminate late growth complications, and ongoing skeletal growth presents challenges in achieving optimal functional outcomes. Closer cooperation with oncology late-effects clinics and pediatric orthopedic surgeons is recommended, as patients’ post-treatment conditions may resemble growth abnormalities that can be corrected or mitigated through orthopedic intervention if identified early.