Multimodal conservative local treatment based on combined brachytherapy and external beam radiation therapy for paediatric pelvic and perineal rhabdomyosarcoma

Highlights

• •EBRT + BT achieved 78 % local control in pediatric pelvic/perineal RMS.
• •Organ preservation is feasible with favorable functional outcomes.
• •Multimodal approach should be tailored by risk factors: nodes, extension, dissemination.
• •Close collaboration enabled customized conservative RT strategies.

Abstract

Purpose

In pediatric pelvic or perineal rhabdomyosarcoma, organ preservation rates are high following neoadjuvant chemotherapy. We assessed the impact of combining external beam radiation therapy (EBRT) and brachytherapy (BT) on local control and functional outcomes.

Methods

We retrospectively analyzed records of all children who received both EBRT and a BT boost in our department from 2005 to 2023. Data collected included tumor relapse, local control, survival and late toxicity rates. Treatment was administered as part of a multimodal conservative radio-surgical approach.

Results

Eighteen patients were identified, with a median age of 4 years (range, 2.9 – 8.6 years). According to the Intergroup Rhabdomyosarcoma Study (IRS) risk groups, 10 patients were classified as IRS-III and 8 as IRS-IV. Seven patients had metastases at diagnosis. The median number of chemotherapy cycles prior to local treatment was 8 (range, 5–10). Nine patients (50 %) underwent prior conservative surgery, followed by radiation therapy consisting of both BT and EBRT. This combination was indicated for at least one the following reasons: nodal invasion (n = 11, 61 %), risk of peritoneal dissemination (n = 3, 17 %) and/or local extension (n = 7, 39 %). The median prescribed dose was 20 Gy (range 12–30 Gy) for BT and 50.4 Gy (range, 18.8–55 Gy) for EBRT. Two patients were treated with HDR BT, while the remaining received LDR (n = 4) or PDR (n = 12).The median follow-up period was 4.6 years (range, 2.9–6.6 years). At the last follow-up, failure free-survival was 67 %, local control was 78 % and overall survival was 83 %. Four patients experienced grade II late urinary toxicities, including dysuria or incontinence in two patients. One patient required secondary cystectomy, and another received botulinum toxin injections in the bladder neck.

Conclusion

Organ preservation with favorable functional outcome can be achieved in pelvic and perineal rhabdomyosarcoma by combining BT and EBRT, with or without prior surgery. This approach requires close collaboration to develop customized radiation therapy plans. Extended follow-up is necessary to assess long-term functional outcomes.

Introduction

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. It is a rare, high-grade malignant tumor with myogenic differentiation, occurring with an annual incidence of four cases per million in children aged 0–19 years, leading to approximately 400 new cases annually in Europe [1].

The International Society of Pediatric Oncology (SIOP) recently described prognostic factors for localized RMS, including molecular subtype, primary tumor site, nodal involvement, patient age, tumor size, and post-surgical stage, which have been in use since the RMS 2005 protocol [2]. This risk-stratification system, which highlights the significant impact of molecular subtypes over histology, is also adopted by the Clinical Oncology Group (COG). The most well-known translocations involve FOX01 with either PAX 3 or PAX 7, which are exclusively associated with the alveolar RMS subtype [[3], [4], [5]].

In a curative setting, treatments such as chemotherapy, surgery and/or radiotherapy are typically combined to control both the primary tumor and distant disease. The standard treatment sequence, as defined in the RMS 2005 protocol, includes a combination of ifosfamide, vincristine, and dactinomycin, with or without doxorubicin, followed by surgery, radiotherapy, or both. For patients at high risk of recurrence, maintenance therapy with vinorelbine and cyclophosphamide is recommended [6].

For high-risk tumors, it is estimated that up to one-third of patients relapse within five to nine months post-treatment, with two-thirds experiencing loco-regional relapse and 20–25 % developing metastases due to undetected residual disease [6,7]. In cases where a multimodal approach is feasible, long-term follow-up studies (over 10 years) indicate that 75 % of patients achieve satisfactory bladder function [8]. These insights emphasize the need for new strategies or the combination of local therapies to enhance tumor control while reducing long-term side effects. In specific tumor sites such as the genito-urinary region, brachytherapy (BT) combined with conservative surgery has shown high rates of organ preservation [1]. BT offers the advantage of dose escalation while sparing surrounding tissues, a critical concern in pediatric tumors. When a tumor’s loco-regional spread limits complete BT access, the combination of external beam radiation therapy (EBRT) with brachytherapy enables comprehensive treatment across the affected volume, providing dose escalation to residual disease and improving local tumor control. Here, we present a pediatric cohort treated with conservative local therapy through surgery combined with BT and EBRT at our institution.

Materials and Methods

Patients

We conducted a retrospective analysis of all consecutive children who received both BT and EBRT with curative intent for pelvic rhabdomyosarcoma at Gustave Roussy, Villejuif, France, between 2005 and 2023. Written informed consent was obtained from parents. Each case was validated by an interdisciplinary tumour board before treatment initiation. Prior to local treatment, patients underwent chemotherapy according to their risk group and to current protocols. The local treatment approach was adapted based on chemotherapy response, integrating clinical and imaging data.

Rhabdomyosarcomas were classified according to the SIOP group criteria, which account for tumor site, clinical group (localized, regional or distant disease at diagnosis), primary tumor size, nodal status, age, IRS stage and fusion status. Baseline tumor characteristics and all treatments type were recorded. This retrospective study received formal approval from the local ethics committee.

Treatment

Upfront chemotherapy, following the RMS 2005 protocol, was administered, followed by surgical assessment (with or without surgical resection and ovarian or testicular transposition), then BT and EBRT. EBRT was indicated for one or more of the following reasons: positive lymph nodes, tumor size, or location (if BT alone could not provide sufficient dosimetric coverage). Chemotherapy continued for up to nine cycles post-radiotherapy followed by maintenance chemotherapy if indicated.

Surgery

Surgical resection and BT catheter implantation were performed simultaneously at Kremlin-Bicêtre, University Hospital. For tumors located in the anterior bladder wall and extending above the trigone, a partial cystectomy was conducted, preserving the bladder neck and ensuring free upper margins. If the trigone was involved, the surgeon performed a resection of the mucosa and tumor without removing muscle tissue. Since 2015, temporary bilateral ovarian or unilateral testicular transposition could be performed during the same procedure to reduce radiation exposure, along with bilateral ureteral reimplantation if tumor extension observed during surgery warranted it.

In cases of partial cystectomy or partial prostatectomy, urethral preservation was consistently prioritized to minimize genitourinary toxicities, with no intent to achieve microscopically-free margins around the prostate and/or bladder neck. Elective lymphadenectomy or iliac and lomboaortic dissection was performed when imaging reevaluation suggested lymph node involvement.

Brachytherapy

Low-dose rate (LDR) brachytherapy was used until 2014, after which it was replaced by pulse-dose rate (PDR) brachytherapy. MRI, including at minimum T2 axial, sagittal, and coronal sequences, was performed prior to surgery and BT. Implantation was carried out during surgery, with two loops placed to encompass the volume of interest (prostate and/or urethra and/or bladder neck) before transitioning from LDR to PDR. With PDR brachytherapy, the two loops were replaced by at least four single interstitial catheters inserted via a transperineal approach. This change was done to avoid source blockade because of the loop curvature. The implantation was guided by MRI data and clinical evaluation during surgery to fully encompass the residual tumor bed while minimizing long-term side effects. Plastic tubes were then sutured to the bladder wall and perineum to maintain positional stability throughout the entire BT course. After a one-week recovery period, children were transferred to the BT department at the Gustave Roussy Institute. An example of implantation is shown Fig. 1.

Fig. 1.

Surgical insertion of interstitial catheters.

BT treatment planning for LDR treatments was based on 2D orthogonal X-ray radiographs and dose points, while for PDR treatments, it was based on 3D computed tomography (CT) scans and MRI. CT scan and MRI were acquired with the patient in the supine position and catheters in situ, with a slice thickness of 1.5 mm. Images were transferred to the Oncentra treatment planning system (Nucletron, Veenendaal, The Netherlands). Target volumes and organs at risk (OARs) were delineated, either directly on MRI or after MRI/CT fusion, depending on the ability to accurately reconstruct catheters on MRI. Catheters were then digitized, and computerized dosimetry was performed.

The clinical target volume (CTV) contour was delineated on post-operative MRI to encompass the visible residual disease. For bladder-prostate RMS, the CTV always included the tumor residuum, as well as the prostate and bladder neck. For gynecologic tumor locations, the CTV encompassed the residual tumor volume as identified on postoperative MRI. OARs including the bladder, sigmoid colon, rectum, intestines, urethra, uterine corpus and transposed ovaries or testicle were carefully delineated.

Two patients (aged 18 and 23 years) were treated with HDR-BT because their prostate volumes were comparable to those of adults, allowing management similar to standard adult cases. The CTV, corresponding to the whole prostate, was determined per procedure using endorectal ultrasound. HDR-BT with Iridium-192 was used for treatment.

Prescribed BT doses are summarized in Table 3. For LDR and PDR, total physical doses ranged from 12 to 30 Gy depending on the EBRT contribution and target volume. For the two HDR cases, the prescribed physical dose was 12 Gy delivered in a single session. The dose was prescribed at 100 % reference isodose (corresponding to 85 % of the minimal dose rate between planes, following the Paris system rules). The total combined EBRT + BT dose corresponded to approximately 55–60 Gy EQD2 to the tumor bed.

Table 3.

External beam radiotherapy and brachytherapy.

Patient	External beam radiotherapy										Brachytherapy		TOTAL EBRT + BT
	Technique	Volume 1	Dose (Gy)	Dose/ fraction (Gy)	Boost (simultanous/ sequential)	Volume 2	Dose (Gy)	Dose/ fraction (Gy)	Cumulated dose (Gy)	RTE indications	Technique	Dose (Gy)	Cumulated EQD2 dose (Gy)
1	3D	T + N	36	1.8	Sequential	T + N	5.4	1.8	41.4	N+	LDR	25.8	64.5
2	3D	T	44.8	1.6	−	−	−	−	44.8	tumor volume	LDR	20	61.8
3	3D	Abdomen	30	1.5	−	−	−	−	30	peritoneal extension	LDR	30	56.4
4	3D/IMRT boost	Abdomen	30	1.5	Sequential	T + N	12.6	1.8	42.6	N + and peritoneal extension	PDR	20.16	60.9
5	IMRT	T + N	41.4	1.8	−	−	−	−	41.4	tumor volume, N+	PDR	20.16	60.5
6	IMRT	T + N	41.4	1.8	SIB	under-dosed residue on BT	46	2	46	tumor volume, N+	PDR	20.16	65.8
7	IMRT	T	41.4	1.8	SIB	under-dosed residue on BT	50.6	2.2	50.6	tumor volume	PDR	20.16	71.2
8	IMRT	Abdomen	24	1.5	Sequential	T + N	14.4	1.8	38.4	tumor volume, N + and risk of peritoneal extension	PDR	20.16	56.9
9	3D	T	41.4	1.8	−	−	−	−	41.4	tumor volume	LDR	20	59.2
10	3D	T	28.8	1.8	−	−	−	−	28.8	tumor volume	PDR	21.4	49.3
11	IMRT	T	30.6	1.8	−	−	−	−	30.6	tumor volume	PDR	25.2	54.8
12	IMRT	T + N	41.4	1.8	Sequential	N+	12.6	1.8	54	N+	PDR	20.16	72.9
13	IMRT	T + N + Bone	41.4	1.8	−	−	−	−	41.4	N+	HDR	12	62.7
14	IMRT	T + N	45	1.8	SIB	ischio-rectal residue	55	2.2	55	tumor volume, N+	PDR	20.16	75.7
15	PROTON	T	41.4	1.8	−	−	−	−	41.4	tumor volume	HDR	12	62.7
16	IMRT	T	41.4	1.8	SIB	T + N	50.6	2.2	50.4	N+	PDR	20.16	71.2
17	IMRT	T	41.4	1.8	−	−	−	−	41.4	tumor volume, N+	PDR	20.16	60.5
18	IMRT	T	41.4	1.8	−	−	−	−	41.4	tumor volume, N+	PDR	20.16	60.5

Abbreviations: T, Tumour bed; N, nodes; N+, positives nodes; IMRT, intensity modulated radiation therapy; SIB, simultaneous integrated boost; LDR, low dose rate; PDR, pulsed dose rate; HDR, high dose rate; EQD2: Equivalent Dose in 2-Gy Fractions.

With PDR technique, dose optimization was achieved by adjusting dwell times and active catheter positions to enhance target volume coverage while minimizing doses to OARs, without applying specific dose/volume constraints. The goal was to prevent the 100 % isodose from overlapping with the anterior rectal wall. For girls, another dosimetric constraint was to minimize the vaginal wall receiving the 150 % isodose. Dose optimization in HDR followed the same principles as PDR planning (adjustment of dwell times by position), while respecting the GEC-ESTRO dose constraints for HDR prostate boost.

For LDR brachytherapy, irradiation was delivered in continuous using Iridium-192 wires sources For PDR brachytherapy, Iridium-192 stepping source was used, with total doses administered through hourly pulses of 0.42 Gy, maintaining a daily dose of 10 Gy based on LDR historical experience. Tumors and OAR doses were reported after conversion to equivalent dose per 2 Gy fractions (EQD2), applying a α/β ratio of 10 Gy for the CTV and 3 Gy for OARs.

During treatment, standard precautions for PDR-BT were implemented, consistent with previously reported protocols for bladder-prostate RMS treatments [9]. Parents received information on radioprotection guidelines and were not permitted to stay in the brachytherapy department overnight. Dedicated brachytherapy technologists conducted daily examinations to ensure there was no catheter or applicator displacement. In cases of uncertainty, CT scans were performed to check applicator positioning. A pediatrician visited the patient daily, or more frequently if needed, to prescribe analgesics and, if required, soft-conscious sedation to ensure patient comfort.

External beam radiation therapy

EBRT was delivered using photon-based Intensity Modulated Radiotherapy (IMRT, VMAT or Tomotherapy), 3D photon beams, or proton beam therapy (Double Scattering). Plans were created to ensure that ≥95 % of the planning target volume (PTV) received ≥95 % of the prescribed dose. A photon linear accelerator delivered daily fractions of 1.8 Gy, five days per week. Among the patients, five were treated with a 3D technique (opposed lateral fields), twelve with arctherapy (including three patients treated with tomotherapy), and one patient with proton beam therapy. Eight patients were treated at their original centers, outside Gustave Roussy. For each patient, dose distribution metrics within the PTV adhered to ICRU 50, 62, 83 guidelines, and target volume definition followed the RMS2005 protocol. The EBRT volumes encompassed the initial tumor extension with a 10 mm margin, along with regional lymph nodes if initially invaded, treated to 41.4 Gy, with an additional 9 Gy boost to persistently pathologic lymph nodes (total dose of 50.4 Gy). In cases of peritoneal dissemination, a dose 24 or 30 Gy was administered. Prescribed doses ranged from 28.8 to 55 Gy. Eleven patients received concomitant chemotherapy during EBRT.

Follow-up

Following radiation treatment, patients were monitored per pediatric protocols. Physical examinations and MRIs were performed every 3 months during the first 2 years and every 6 months for up to 5 years. All toxicities observed during treatment and follow-up were documented, distinguishing acute and late toxicities by a 3-month cut-off post-radiation therapy, and retrospectively classified using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Functional outcomes were assessed through clinical examination and interviews with the parents. Because of the young age of most patients, no validated questionnaires were used. Complementary urological evaluations, such as uroflowmetry or cystoscopy, were performed on a case-by-case basis when symptoms were reported. Functional assessment focused primarily on local toxicities, including urinary symptoms, erectile and sexual function, cutaneous, abdominal, and growth issues. Treatment failures were categorized according to the initial site of relapse.

Statistical analysis

Data were anonymized by assigning each patient a neutral identifier. Survival rates were calculated from the date of diagnosis to the event of interest. Kaplan-Meier curves were used to estimate overall survival (OS), progression free-survival (PFS), and failure-free survival (FFS). Five-year OS, PFS and LFFS were estimated with 95 % confidence interval (95 % CI). Multivariate analyses (Cox model) for prognostic factors were conducted for variables with a p-value < 0.2 in univariate analysis (log −ank test). The multivariate model was refined using the Akaike Information Criterion (AIC). Locoregional late side effects occurring more than 3 months after local treatment, with a grade ≥ 2, were analyzed. Statistical significance was defined as p < 0.05. All analyses were conducted using R software, version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patients and tumours characteristics

Between 2005 and 2023, 18 patients underwent combined BT and EBRT. Tumour localization was bladder-prostate (BP) for 12 patients, pararectal for three, peri-anal for two and vulvar for one patient.

The median age at diagnosis was 4 years (IQR 2.9–8.6). There were 16 boys and 2 girls. Most patients had embryonal histology (n = 14, 78 %). Sixteen tumors (89 %) measured 5 cm or greater (Table 1). Eleven patients presented with lymph node, all with pelvic nodes, while four had retroperitoneal and two had inguinal node involvement. Two patients had hydronephrosis due to ureteral invasion, requiring nephrostomy and/or a double J catheter before systemic therapy. Seven patients presented with metastasis at diagnosis: one with peritoneal dissemination, two with pulmonary metastases only, two with bone metastases only, two with both pulmonary and bone metastases. Eight patients were referred from overseas, and seven were referred from other centers. According to the Intergroup Rhabdomyosarcoma Study (IRS) classification, 10 tumors were categorized as IRS III and eight as IRS IV (for risk group classification, see Supplementary materials).

Table 1.

Baseline Characteristics, Stratification factors and group classification.

Characteristics	N = 18
Age at diagnosis − median − range	4 1.6–22.8
Age at the start of RT − median − range	5 2.8–23.3
Sex − no. (%)
M	16 (89)
F	2 (11)
Tumor location
Vesico-prostatic	12 (67)
Para-rectal	5 (28)
Vulva	1 (5)
Tumor histological type
Embryonal	14 (78)
Alveolar	4 (22)
Transcripts PAX3/PAX7-FOXO1
Positive	2 (12)
Negative	8 (44)
Unknown	8 (44)
Tumor size
≤ 5 cm	16 (89)
> 5 cm	2 (11)
Nodal status
N0	7 (39)
N1	11 (51)
Metastastic status
M0	11 (51)
M1	7 (39)
Group risk
Standard	1 (5)
High	10 (56)
Very high	7 (39)

Treatment characteristics

All patients received chemotherapy according to their initial risk group. Following at least six cycles (median: 8; IQR: 5–10) of chemotherapy with various regimens, the combination of BT and EBRT was planned due to nodal invasion (11 patients), risk of peritoneal dissemination (3 patients) and/or local extension (7 patients, including 5 with peri-rectal/anal tumors) (Table 2).

Table 2.

Chemotherapy type and timing.

Patient	Type of chemotherapy and number of cycles
	neoadjuvant	concomitant	adjuvant	maintenance treatment
1	4 IVADO, 2 IVA	1 IV	2 IV	V&C 6 months
2	3 IVA, 1 IVADO, 2 6Carboplatine-Adriamycine	Vinorelbine	5 VAC	V&C 6 months
3	4 IVADO + AVASTIN, 5 IVA	0	0	V&C + AVASTIN 1 year
4	1 IVA, 5IVADO, 4IVA	0	0	V&C 1 year
5	2IVA-VCR, 4IVA	1 IV	2 IV	V&C 6 months
6	10 IVA	Vinorelbine	−	V&C 6 months
7	2 VAC,7IVA	Vinorelbine	−	V&C 6 months
8	2 VAC, 4IVA	1 IV	2 IV(A)	V&C 6 months
9	4 IVADO + AVASTIN et 2 VAC	0	3 VAC	V&C + AVASTIN 1 year
10	1VAC, 4IVA	1IV	3IV(A)	V&C 6 months
11	9 IVA	0	0	0
12	3 lines of chemotherapy*	VCR-Irinotecan	0	0
13	1 AC, 4 IVADO, 3 IVA	1 IV	0	V&C 1 year
14	5 IVA, 4 IVADO	0	0	V&C 1 year
15	8 IVA	1 IV	0	0
16	4 IVADO, 3 IVA	0	0	0
17	1 IVA, 3 CyVADO, 1 IVADO, 4 CyVA, 3 VIT	2 VIT	0	VIT
18	9IVA	0	0	0

CyVA: Cyclophosphamide + Vincristine + Actinomycine.

N/E: Navelbine + Endoxan.

V&C: Vinorelbine + Cyclophosphamide / VCR: Vincristine.

VAC: Vincristine + Actinomycine + Cyclophosphamide.

VIT: Vincristine + Irinotecan + Temozolomide.

IVA: Ifosfamide + Vincristine + Actinomycine / IVADO: IVA + Doxorubicine.

* IVA then maintenance.

V&C.

1st relapse: Cisplatine + Adriamycine.

2nd relapse: Vincristine + Irinotecan + Temozolomide.

Four patients underwent incomplete resection before any systemic treatment, leading to their diagnosis. One patient, who had received two lines of systemic therapy without local treatment, was referred for loco-regional relapse at the start of a third line of treatment. A total of 16 patients were treated according to the RMS 2005 protocol, and two according to the Bernie protocol. Nine children had local surgical tumorectomy after chemotherapy, while the remaining nine received combined BT and EBRT without surgical tumor removal.

All patients showed a partial response to chemotherapy before the local procedure, with three achieving a complete response on resected specimens. There was no case of complete surgical resection. Eleven patients received concomitant chemotherapy during EBRT, and thirteen received maintenance therapy.

Radiation therapy parameters

LDR brachytherapy was administered to 4 patients, PDR to 12 patients, and high-dose rate (HDR) BT to 2 patients. The BT doses ranged from 12 to 30 Gy, with a median of 20 Gy. EBRT doses ranged from 28.8 Gy to 55 Gy, with a median of 50.4 Gy. Three patients received abdominal irradiation with EBRT doses of 24 to 30 Gy (daily fractions of 1.5 Gy) (Table 3). The median total volume treated with BT was 43 cm³ (IQR 9–57.5). When transposition was performed, the D50% for the testicles or ovaries did not exceed 2.8 Gy separately.

Eight patients received an EBRT boost, with doses ranging from 4.6 to 12.6 Gy (median: 9.6 Gy), targeting either the residual tumor, residual lymph nodes, or both. EBRT focused exclusively on the tumor bed in 8 cases, with doses ranging from 28.8 to 44.8 Gy. BT was administered before EBRT in 13 of the 19 procedures.

An example of implantation is shown Fig. 1.

Local control and survival

The median follow-up from diagnosis was 4.6 years (IQR 2.9–6.6). At the last follow-up, six relapses were observed, occurring at a median interval of 22 months from diagnosis (IQR 17–33). Three patients experienced local recurrences only: one had relapses within the boost radiation fields of both BT (para-rectal) and EBRT (inguinal) while on third-line systemic treatment, the second recurrence occurred at the edge of the EBRT field in the ischio-rectal fossa outside the CTV, and the third was pelvic, centered on the prostate.

One patient presented with both local (retro-vesical) and peritoneal dissemination. Two patients, both metastatic at diagnosis, experienced metastatic failures only (cutaneous and breast nodes). Overall survival was 83 % at the last follow-up, with all deaths attributed to the disease.

Acute toxicities

Following the combination of BT and EBRT, two patients experienced grade I urinary toxicities (dysuria and hematuria), and one child had grade II pollakiuria. Three patients reported grade I diarrhea, while one patient experienced grade II diarrhea. Seven patients developed radiation dermatitis, including one case of grade III (potentially exacerbated by concomitant chemotherapy). No complications were observed during the implantation or removal of interstitial catheters. The toxicities are reported in Table 4.

Table 4.

Toxicity.

Event	Acute		Late
	Grade 1–2	Grade 3	Grade 1–2	Grade 3
Dermatitis	6 (33.3 %)	1 (5.6 %)	0	0
Dysuria-hematuria	2 (11.1 %)	0	2 (11.1 %)	0
Pollakiuria	1 (5.6 %)	0	0	0
Incontinence	0	0	2 (11.1 %)	0
Diarrhea	4 (22.2 %)	0	0	0
Gonadal insufficiency	0	0	1 (5.6 %)	0

Number of patients (n, %).

Late toxicities

At the last follow-up, late toxicity was available for all patients. Four patients (22 %) experienced grade ≥ II late toxicities, with urinary complications being the most common. One patient required an enterocystoplasty due to grade III incontinence and hematuria, while another patient with incontinence received a botulinum toxin injection at the bladder neck. Two patients reported grade II dysuria and/or incontinence.

One patient had a transient grade II diarrhea that resolved spontaneously, along with gonadal insufficiency. There were no reported cases of sexual dysfunction or growth disorders, although most patients were likely too young to assess these complications (median age at last follow-up: 10 years).

Discussion

Although complete remission is achieved in over 90 % of children with non-metastatic rhabdomyosarcoma, nearly one-third are estimated to experience recurrences, with two-third are of these recurrences occurring at the primary site or in regional lymph nodes [10]. Data from the Intergroup Rhabdomyosarcoma Study Group (IRSG) indicate that histological subtype and tumor location significantly impact survival, with a poorer prognosis in cases of alveolar RMS and peri-anal/peri-rectal tumors. Additional factors associated with a significantly decreased survival rate include a primary tumor size over 5 cm, positive regional lymph node involvement, and age over 10 years [1,11,12].

Optimization of multimodal treatment protocols has increased overall survival (OS) for high-risk bladder-prostate rhabdomyosarcoma (BP-RMS) to over 80 % [13]. In the RMS 2005 trial, BT was the primary form of irradiation, with 41.7 % of patients receiving BT as part of their local treatment. Several retrospective studies indicate that BT enables more conformal and localized dose delivery [6,9,14,15]. In the present study, the decision to combine BT and EBRT was based on lymph node involvement or primary tumor extension, aiming to deliver higher doses to the primary site while minimizing irradiation of organs in young patients who have not yet achieved full organ maturation (increasing the therapeutic index). In this cohort, all patients had residual tumor before irradiation, necessitating a dose of 60 Gy.

In the IRS IV trial, 559 patients with group III tumors were randomized to receive either 50.5 Gy conventionally fractionated RT or 59.4 Gy hyperfractionatied RT. Analysis based on the treatment received showed a 5-year FFS rate of 73 % and OS rate of 77 %, with no significant difference between the two groups [16]. In our study, with a median follow-up of 4.6 years, the FFS rate was 67 % and OS rate was 83 %. This difference may be attributed to the inclusion of patients with more unfavourable profiles, including some with metastases at diagnosis. All three reported deaths occured in patients who were already metastatic at diagnosis and later developed distant relapse.

In our study, four patients were initially referred following tumorectomy that revealed an RMS. Overall, nine patients had a post-chemotherapy tumorectomy, while the remaining nine did not undergo surgery due to concerns about excessive mutilation. The feasibility of combining conservative surgery with BT, as an alternative to total cystectomy or EBRT, has previously been explored in our center within a bladder neck/prostate rhabdomyosarcoma cohort. In that cohort, endoscopic or surgical interventions were performed in 15 % of patients, with 78 % achieving normal daytime urinary continence. This multimodal strategy demonstrated efficacy, with local control and OS rates exceeding 90 %, and three of seven local relapses managed successfully with salvage treatment [17], aligning with results from other retrospective studies as well as our own findings [18,19]. In our cohort, we observed four local relapses, three of which occurred within the radiation therapy fields.

Comprehensive information about the initial tumor stage, size, extension, and the extent of residual disease after neoadjuvant chemotherapy is crucial for planning the optimal combination of local treatments. In pediatric patients, striking the right balance between maximizing tumor control and minimizing treatment-related toxicities is particularly important. The combination of BT and EBRT is generally used in children with regional lymph node involvement, as alveolar RMS carries a higher risk, although radiotherapy is delivered regardless of histology. A standard dose of 41.4 Gy is prescribed when no lymph nodes remain enlarged after initial chemotherapy. If lymph nodes are still enlarged at the start of radiotherapy, an additional boost is administered.

Long-term sequelae from local treatment modalities are a major concern in the pediatric population. Retrospective studies suggest improved rates of bladder preservation in recent years, with up to 60 % of patients with partial cystectomy in IRS III studies achieving good bladder function at 3 years, and 40 % at 6 years [[20], [21], [22]]. In our cohort, late urinary complications were the most common, with two patients requiring symptomatic treatment: one received botulinum toxin injection for incontinence at age 15 and another underwent enterocystoplasty at age 16 due to incontinence and hematuria. This latter patient also experienced late grade II transient diarrhea, and gonadal insufficiency (no gonadal transposition had been performed). These two significant interventions and side-effects occurred over ten years post-treatment and were associated with 3D radiation plans. At the last follow-up, two additional children presented with grade II urinary symptoms, but no other long-term abdominal or cutaneous toxicities were observed in our cohort.

In pediatric patients, assessing urological complications is particularly challenging due to age-related factors. For instance, continence is typically achieved around six years of age, making early evaluation impossible. Furthermore, treatment-related toxicities may not be consistently reported by oncologists, surgeons, or families. Because most patients are managed in external centers and return there for follow-up, long-term data collection is often incomplete, underscoring the need for systematic questionnaires or a centralized database. Evaluation of late toxicities, such as erectile dysfunction, was feasible in only a few cases due to the young median age at last follow-up. Nevertheless, previous retrospective studies in patients treated with surgery followed by BT report erectile dysfunction rates ranging from 0 to 10 % [17,[23], [24], [25]].

The IRS-IV study found no differences in outcomes between conventional and hyperfractionated RT, establishing 1.8 Gy per fraction as the standard [26]. The impact of dose escalation on local control has yet to be evaluated in a randomized clinical trial. This question is currently being explored in the FaR-RMS (Frontline and Relapsed Rhabdomyosarcoma) trial, which investigates the effects of novel systemic therapies, the impact of maintenance therapy duration on outcomes, and whether adjustments to dose, extent and timing of radiotherapy can improve quality of life and outcomes. This trial will also examine the role of local therapy in managing metastatic disease. Meanwhile, the BERNIE study demonstrated that radical treatment of the primary site significantly improves survival in patients with metastatic disease.

This study has several limitations. First, it is a single-center cohort, mainly due to the necessity for exceptionally close coordination among highly specialized surgeons, radiation oncologists, and brachytherapists to perform these procedures. The sequence and approach to local treatment must be determined by a multidisciplinary tumor board and tailored to the tumor's anatomy and patient-specific factors, with BT and EBRT doses adjusted based on the radiation tolerance of adjacent tissues.

Second, our cohort was heterogeneous, including bladder-prostate, vulvar, pararectal, and perianal rhabdomyosarcomas. Although this heterogeneity limits the statistical interpretation of outcomes, it reflects the diversity encountered in real-world clinical practice and reinforces the technical relevance of our experience. Perianal tumors, in particular, are known to represent an unfavorable site, with an increased risk of local and nodal relapse. This risk may be mitigated by the combined use of BT and EBRT, which provides comprehensive local coverage and dose escalation. The inclusion of such high-risk cases may partly account for the overall survival rate of 83 % observed in our series.

Additionally, half of the patients were younger than six years old at the last follow-up, further limiting definitive assessment of urological complications. Nonetheless, the observed rates are consistent with those reported in previous studies.

In conclusion, combining BT and EBRT allows effective local control while preserving organ function in selected pediatric pelvic and perineal rhabdomyosarcomas. This multimodal approach appears feasible and safe when carefully tailored to tumor site and response to chemotherapy. However, given the small and heterogeneous nature of current single-center experiences, these results should be interpreted cautiously. Broader collaborative and multi-institutional efforts are needed to refine patient selection, harmonize dosimetric practices, and better characterize long-term functional outcomes.

CRediT authorship contribution statement

Xavier Musset: Writing – original draft, Writing – review & editing, Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Software, Visualization. Sophie Espenel: Writing – review & editing. Jeanne Riverain: Writing – review & editing. Elaine Limkin: Writing – review & editing. Florent Guerin: . Véronique Minard: . Isabelle Dumas: . Noura Sellami: . Valentine Martin: . Stéphanie Bolle: Writing – review & editing. Mario Terlizzi: Writing – review & editing, Supervision, Project administration, Conceptualization, Methodology, Resources, Validation, Data curation, Visualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article: