Local Treatment of Children Suffering From Parameningeal Rhabdomyosarcoma: A Retrospective Single-Center Study From China

Abstract

Background

Treatment for parameningeal rhabdomyosarcoma (PM-RMS) has been a challenge since local control is difficult. The goal of this study was to analyse the impact of different local treatment approaches on childhood PM-RMS patients and help dispel the doubt that whether secondary radical surgery (SRS) should be encouraged in the management of PM-RMS.

Methods

A total of 17 children with PM-RMS who received unified systemic chemotherapy and individualized local therapy such as radiotherapy (RT) and/or SRS were included in this retrospective study. The overall survival (OS) and event free survival (EFS) were compared between groups adopting different local strategies.

Results

The 3-year OS and EFS of our PM-RMS patients was 75.5% and 56.5% respectively. The OS and EFS of patients who received SRS were both significantly lower than that of the non-SRS group (3-year OS: 50.0% vs 90.0%, P = .031; 3-year EFS: 33.3% vs 60.6%, P = .020). The OS and EFS of the patients who received RT was higher than that of the patients of the non-RT group (3-year OS: 85.6% vs 0%, P = .001; 3-year EFS: 64.0% vs 0%, P = .011).

Conclusion

This study illustrates that SRS was associated with poor prognosis of PM-RMS and should not be routinely performed. Optimized RT strategies along with more intensive chemotherapy may be alternative options to improve the survival of patients with PM-RMS. Multi-center, large sample and prospective studies are needed to further validate these findings.

Introduction

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of children and accounts for 3.5 to 4.5% of all childhood tumors.^1,2 RMS may occur at any anatomical position since it originates from immature striated muscle which exists anywhere in human body. ¹ After decades of efforts, clinicians have developed relatively mature multimodal therapeutic protocols to increase the 5-year overall survival (OS) rate of children with RMS from 25% before 1970 to nearly 80%∼90% nowadays.^3,4 However, patients with high-risk factors such as unfavorable locations could not share the equal fortune. Parameningeal rhabdomyosarcoma (PM-RMS) is a specific group of RMS arising from parameningeal regions including nasal cavity, paranasal sinuses, infratemporal fossa, nasopharynx, or mastoid/middle ear. PM-RMS accounts for about 20% of all RMS cases and outcome of these patients is worse than those of other locations. ⁵ The reported 5-year OS of PM-RMS varied from 45.7% to 73%.^6,7 Disease recurrence at the primary site and distant metastases are the leading cause of death in PM-RMS.^6,8

It is reported that about 37.5% of PM-RMS patients may experience local failure (LF) ⁹ and the estimated 3-year survival after LF was 17%. ¹⁰ Local treatment plays an important role in controlling local lesions and preventing recurrence of RMS. However, the optimal local treatment strategy for PM-RMS patients is still under debate. In regard of the anatomic complexity and concerns about functional and cosmetic impairments, complete resection with negative margins is often difficult to achieved in the initial surgery approach. Therefore a second-look operation is available if residual disease is suspected after induction chemotherapy. ¹¹ At present, there is limited data for secondary radical surgery (SRS) in PM-RMS.

The aim of this study was to analyse the impact of different local treatment approaches on childhood PM-RMS patients and help dispel the doubt that whether SRS should be encouraged in the management of PM-RMS.

Methods

Study Population and Setting

We retrospectively reviewed the records of patients with childhood rhabdomyosarcoma at the pediatric department of the Sun Yat-sen Memorial Hospital from January 2013 to December 2018. The study was approved by the ethics committee of Sun Yat-sen Memorial Hospital. The reporting of this study conforms to STROBE guidelines. ¹²

The inclusion criteria were listed as follow: (a) children diagnosed with RMS, pathologically confirmed by typical morphology, H&E staining and myogenin immunohistochemistry; (b) primary tumor sites revealed by imageological examination located at parameningeal regions such as nasal cavity, paranasal sinuses, infratemporal fossa, nasopharynx, or mastoid/middle ear; (c) clinical risk groups were stratified according to TNM staging, the Intergroup Rhabdomyosarcoma Study (IRS) grouping, the pathological subtype, age at diagnosis, primary tumor site, regional lymph node involvement and the central nervous system (CNS) violation (Table 1); ¹³ (d) treatment followed the protocol named RMS-CQ-2009 proposed by the Chinese Children Cancer Group (CCCG) of Rhabdomyosarcoma (Table 2).

Table 1.

Risk Classification of Rhabdomyosarcoma.

Risk	TNM staging	IRS grouping	Pathological subtype	Age	Primary site	Regional lymph node involvement	CNS violation
LR group A	1	I-II	ERMS	Any	Any	N0	No
	1	III	ERMS	Any	Orbit	N0	No
	2	I	ERMS	Any	Any	N0 or Nx	No
LR group B	1	II	ERMS	Any	Any	N1	No
	1	III	ERMS	Any	Orbit	N1	No
	1	III	ERMS	Any	Non-orbit	N0、N1 or Nx	No
	2	II	ERMS	Any	Any	N0 or Nx	No
	3	I-II	ERMS	Any	Any	N0、N1 or Nx	No
IR group	2-3	III	ERMS	Any	Any	Any	No
	4	IV	ERMS	<10 years	Any	Any	No
	1-3	I-III	ARMS	Any	Any	Any	No
HR group A	4	IV	ERMS	≥10 years	Any	Any	No
	4	IV	ARMS	Any	Any	Any	No
HR group B	4	IV	Any	Any	Any	Any	Yes

LR, low-risk; IR, intermediate-risk; HR, high-risk; ERMS: Embryonal rhabdomyosarcoma, ARMS: Alveolar rhabdomyosarcoma.

Table 2.

RMS-CQ-2009 Protocol.

Chemotherapy

All patients received systemic chemotherapy (CT). CT was always conducted immediately after primary surgery or as an upfront treatment in inoperable or metastatic patients. CT regimens consisted of vincristine (VCR, abbreviated as V), actinomycin D (ACTD, abbreviated as A) and cyclophosphamide (CTX, abbreviated as C). The protocol was composed of alternating VAC, V, A, VA, VC regimen (Table 2), in which ACTD was omitted during radiotherapy. Treatment courses varied from 12 weeks to 41 weeks according to different RMS risk groups.

Radiotherapy

Radiotherapy (RT) was not required for low-risk group embryonic RMS subjects with no residual tumors (Group I). For patients with residual tumor (group II and Group III), radiotherapy was initiated in the 3^rd week (low-risk group A), the 5^th week (low-risk group A), the 12^th week (intermediate-risk and high-risk group A) and the 15^th week (high-risk group B) respectively. Emergency radiotherapy was performed in those patients whose meningeal tumor directly invaded the brain tissue and oppressed the cranial nerve palsy or spinal cord.

Surgery

Complete surgical excision was initially conducted if it would not cause major functional or cosmetic deficits. In cases that could not be completely resected, initial biopsy followed by chemotherapy and definitive local control measures was carried out. The time point of SRS was arranged after the 12th week or the 24th week of chemotherapy. SRS was defined as extensive excision of primary tumor along with the lymph nodes in the regional lymphatic drainage area after chemotherapy. Rapid biopsies were performed intraoperatively to achieve negative margins as far as possible.

Statistical Analysis

EFS was defined as the time from the date of initial treatment to the first occurrence of disease progression, disease relapse, or death. For those not experiencing one of these events, EFS was censored at last contact. Estimates of OS and EFS as time-to-event distributions were calculated using the Kaplan-Meier method, and distributions were compared using log-rank tests. A P value of <.05 was considered statistically significant.

Results

Patient Characteristics

A total of 17 patients were included in the study. Patient characteristics are listed in Table 3. The male patients (n = 11,64.7%) outnumbered the female (n = 6, 35.3%). The median age was 4.2 years (the range was .9-13 years). The embryonal variant was the most frequent pathological subtype as it constituted 94.1% (n = 16) of all cases. The common primary sites were middle ear/mastoid (n = 5, 29.4%), infratemporal fossa (n = 5, 29.4%) and parapharyngeal area (n = 5, 29.4%). Eleven (64.7%) of them were TNM Stage 3 or IRS Group III, and three (17.6%) of them were TNM Stage 4 or IRS Group IV. For risk stratification, fifteen of them were intermediate-risk (IR) and two were high-risk (HR).

Table 3.

Characteristics of the 17 Patients With Parameningeal Rhabdomyosarcoma.

Patient	Gender	Age (y)	Primary tumor localization	Histology	TNM stage	IRS group	Risk	Treatment	Replase	Outcome
1	Male	0.9	Middle ear	ERMS	T2bN1M0	III	IR	CT + SRS + RT	Yes	Dead
2	Male	2.1	Nasal cavity	ARMS	T1bNxM0	III	IR	CT + RT	Yes	Alive
3	Female	4.5	Infratemporal fossa	ERMS	T2aN1M0	III	IR	CT + SRS + RT	Yes	Alive
4	Male	8.6	Parapharyngeal area	ERMS	T2bN0M0	III	IR	CT + RT	No	Dead
5	Female	8.0	Infratemporal fossa	ERMS	T2aN1M1	IV	HR	CT + SRS	Yes	Dead
6	Male	4.2	Middle ear	ERMS	T2aN0M0	I	IR	CT + RT	No	Alive
7	Female	2.8	Infratemporal fossa	ERMS	T2bN1M1	IV	IR	CT + RT	No	Alive
8	Male	6.7	Middle ear	ERMS	T2aNxM0	II	IR	CT + SRS	Yes	Dead
9	Female	1.8	Parapharyngeal area	ERMS	T2aN0M0	II	IR	CT + RT	No	Alive
10	Male	4.2	Paranasal sinuse	ERMS	T2bN1M0	III	IR	CT + RT	No	Alive
11	Male	8.4	Infratemporal fossa	ERMS	T2bN1M0	III	IR	CT + RT	Yes	Alive
12	Male	3.9	Parapharyngeal area	ERMS	T2bNxM0	III	IR	CT + RT	No	Alive
13	Female	3.6	Parapharyngeal area	ERMS	T2aN1M0	III	IR	CT + RT	Yes	Alive
14	Male	3.3	Mastoid	ERMS	T2aN1M0	III	IR	CT + RT	No	Alive
15	Male	13.0	Parapharyngeal area	ERMS	T2bN1M0	III	IR	CT + SRS + RT	No	Alive
16	Female	4.2	Middle ear	ERMS	T2bN1M1	IV	HR	CT + RT	No	Alive
17	Male	2.9	Infratemporal fossa	ERMS	T2bN1M0	III	IR	CT + SRS + RT	No	Alive

ERMS, embryonal rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; IR, intermediate-risk; HR, high-risk; CT, chemotherapy; SRS, secondary radical surgery; RT: Radiotherapy.

Treatment Outcome

The median follow-up was 56.9 months overall. The 3-year OS and 3-year EFS was 75.5% (95% CI: 54.5%-96.5%) and 56.5% (95% CI: 31.8%-81.2%) respectively. A total of 4 (23.5%) patients died (Patient 1, 4, 5, 8) and disease relapse was noted in 7 (41.2%) patients (Patient 1, 2, 3, 5, 8, 11, 13). Specifically (Table 4), 27.3% (3/11) of the patients who received CT + RT treatments underwent relapses and 9.1% (1/11) of them died. Two patients receive CT + SRS treatments and all of them (100%) relapsed and died. Among the 4 patients who receive CT + SRS + RT treatment, 2 (50%) relapsed and 1 (25%) died. The 3-year OS of patients in CT + RT group, CT + RT + SRS group and CT + SRS group were 90.0% (71.4%-100%), 75.0% (32.5%-100%), 0% (0%-0%) respectively, while the 3-year EFS were 70.7% (30.4%-90.8%), 50.0% (1.0%-99.0%), 0% (0%-0%) respectively. The 3-year OS and EFS of the patients who received SRS were both lower than those who did not receive SRS treatment (3-year OS: 50.0% (95% CI: 10.0%-90.0%) vs 90.0% (95% CI: 71.4%-100.0%), P = .031; 3-year EFS: 33.3% (95% CI:43.3%-70.9%) vs 60.6% (95% CI: 30.4%-90.8%), P = .020). The survival rate of PM-RMS patients who received RT was significantly higher than those who did not received RT (3-year OS: 85.6% (95% CI: 67.0%-100.0%) vs 0% (95% CI: 0%-0%), P = .001; 3-year EFS: (64.0% (95% CI: 38.3%-89.6%) vs 0% (95% CI: 0%-0%), P = .011). The survival curve of different treatment strategies are shown in Figure 1.

Table 4.

Prognosis of Different Treatments.

	All patient N (%)	Relapse n (%)	Death n (%)	3- year OS (95%CI)	3-year EFS (95% CI)
CT + RT	11 (58.8%)	3 (27.3%)	1 (9.1%)	90.0% (71.4%-100%)	70.7% (30.4%-90.8%)
CT + SRS	2 (11.8%)	2 (100%)	2 (100%)	0% (0%-0%)	0% (0%-0%)
CT + SRS + RT	4 (23.5%)	2 (50.0%)	1 (25.0%)	75.0% (32.5%-100%)	50% (1%-99%)
Total	17 (100%)	7 (41.2%)	4 (23.5%)	75.5% (54.5%-96.5%)	56.5% (31.8%-81.2%)

Figure 1.

The survival curve of PM-RMS patients. (A) OS of children with different treatments; (B) EFS of children with different treatments; CT: Chemotherapy; SRS: Secondary radical surgery; RT: Radiotherapy.

Discussion

RMS is a highly heterogeneous tumor with diverse primary sites, differing pathologic classifications, complex clinical features and varying outcomes. Compared to other locations, PM-RMS is endowed with more unfavorable features concerned with poor prognosis. This is attributed to not only delayed diagnosis, as PM-RMS patients can be asymptomatic and manifest with less distinctive symptoms, but also complexity of its anatomy, proximity to the cranial cavity and potential dissemination via the cerebrospinal fluid (CSF). In our research, the 3-year OS and EFS was 75.5% and 56.5% respectively. This result is similar to that in the IRS studies and the Associazione Italiana di Ematologiae Oncologia Pediatrica (AIEOP) studies.^14,15 There were many factors that affected the prognosis of PM-RMS, including treatment programs, stage, primary site, age, etc. Rahman, H.A., et al claimed that late presentation and advanced local disease decreased OS and EFS, with a significant difference of the 3-year OS in metastatic patients and non-metastatic patients (35.8% vs 65.9%). ¹⁶ The IRS-II through -IV studies showed that the 5-year OS of patients with tumors in paranasal sinuses or pterygopalatine/infratemporal fossa with meningeal involvement was 57% while OS in those with tumors the middle ear/mastoid, nasopharynx/nasal cavity, or parapharyngeal space without meningeal involvement was 92%. ¹⁴ They also identified age 1-9 years at diagnosis as independent favorable factors. However, it’s reported histology did not predict outcome for PM-RMS independently.^14,15,17 In our cohort, the majority (82.3%) of patients did not have distant metastasis at diagnosis and the median age was 4.2 years old, 88.2% of them within the range of 1-9 years old. Only 29.4% of the primary tumors located in the unfavorable parameningeal sites. Without regard to the differences in treatment options, the above characteristics may contribute to the relatively better outcome in our study.

Local treatment is essential for RMS management. Since complete resection of the tumor is closely associated with the clinical stage and prognosis of the disease, ¹⁸ radical surgery with negative margins if possible is advisable for RMS. There were numerous researchers recommended SRS providing residual diseases was suspected after induction chemotherapy,^6,15,19–22 but limited researches focused on the effect of SRS in childhood PM-RMS patients. In our study, stratified analysis demonstrated that the survival rate of children with PM-RMS treated with SRS was significantly lower than that of those without SRS. This could be attributed to the difficulties to obtain disease-negative margin in parameningeal areas especially for pediatric patients and increased risks of metastasis by iatrogenic spreading. In a recent study, the recurrence and metastasis rates of pediatric patients with RMS who received combined skull-maxillofacial resection reached 43.8%, with 31.3% of mortality. ²³ On the other hand, SRS in itself may not contribute to prolong the survival of RMS patients. Result from COG D9803 study showed that the local control outcome of group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) who received secondary excision with reduced radiation dose was similar to historic results with radiation therapy alone. ²¹ Another study concerning nonmetastatic adult head and neck RMS also demonstrated SRS did not have significant impact on OS. ²⁴ Therefore we suggest SRS should not be routinely performed in pediatric patients with PM-RMS. Surgical resection must be prudently discussed by a multidisciplinary team and cautiously applied in selective cases such as recurrent disease salvage and small tumors without dural involvement. ²⁵

RT is another effective means of local treatment for RMS. Postoperative RT is recommended for patients with rhabdomyosarcoma having microscopic disease. ²⁶ It’s believed that cure of PM-RMS remains unlikely without systematic use of RT. ⁷ Both data from COG and International Society of Pediatric Oncology (SIOP) studies revealed that omission or delay of RT significantly increased local recurrence rate even in infant and children younger than 3 years old.^7,26,27 Results of our research represented that the survival rate of patients treated with RT was significantly higher than those without radiotherapy, confirming the importance of RT for the treatment of PM-RMS.^5,28 Despite concerns about the acute toxicity and late effects of its use in young children, progressive radiotherapy technologies such as intensity-modulated radiotherapy (IMRT) and proton radiotherapy (PT) are well-tolerated with mild-moderate toxicity.^29,30 Specifically, PT has apparent radiation physical advantages for pediatric PM-RMS patients owing to superior normal tissue sparing with equivalent tumor control rate compared to traditional photon radiotherapy.^30–33

Treatment for RMS is a joint effort involving systemic chemotherapy and local therapy. Systemic chemotherapy has significantly increased the OS of children with RMS in the past decades. It’s reported that that poor response to induction chemotherapy was associated with an increased risk of local failure in PM-RMS. ⁹ There is still a need to explore new effective treatments and protocols for patients with PM-RMS. Several studies have shown intensive induction chemotherapy improved local control rates as well as survival rates and may allow for a response-based radiotherapy approach which could decrease treatment-related morbidity.^34,35 Experience from a tertiary cancer care center from India revealed that patients with PM-RMS who received >20 weeks of intended chemotherapy schedule and had complete response to first-line treatment were found to have superior failure-free survival. ³⁶ Recently the Children’s Oncology Group (COG) reported a dose-intensive multiagent regimen, including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, and irinotecan could improve outcome of patients with high-risk RMS. ³⁷ Thus intensive chemotherapy with new agent combinations based on standard (VAC) regimen may be recommended in PM-RMS patients.

There are several limitations to this preliminary study, with the most prominent limitation being sample size. We are also aware of the limitations in the monocentric sample source. Though surgery operations of these cases were performed by experienced neurosurgical and maxillofacial surgeons, whose professions kept in an advanced level of China, multi-center, large sample and prospective studies are needed to further verify these results.

Conclusion

The present study suggested that SRS should not be routinely performed in PM-RMS. Optimized RT strategies along with more intensive chemotherapy may be alternative options to improve the survival of patients with PM-RMS. Multi-center, large sample and prospective studies are needed to further validate these findings.

Appendix.

Abbreviations

PM-RMS

parameningeal rhabdomyosarcoma

SRS

secondary radical surgery

RT

radiotherapy

OS

overall survival

EFS

event free survival

RMS

rhabdomyosarcoma

IRS

Intergroup Rhabdomyosarcoma Study

CNS

central nervous system

CCCG

Chinese Children Cancer Group

CT

chemotherapy

VCR, V

vincristine

ACTD, A

actinomycin D

CTX, C

cyclophosphamide

SPSS

Statistical Package for the Social Sciences

ERMS

embryonal rhabdomyosarcoma

ARMS

alveolar rhabdomyosarcoma

CSF

cerebrospinal fluid

COG

Children’s Oncology Group

LF

local failure

IMRT

intensity-modulated radiotherapy

PT

proton radiotherapy

Ethical Statement

Ethical Approval

The study was approved by the ethics committee of Sun Yat-sen Memorial Hospital (approval number: SYSKY-2023-1136-01).

Informed Consent

This is a retrospective observational study. An exemption from informed consent was obtained from the ethics committee of Sun Yat-sen Memorial Hospital.

ORCID iD

Xiaomin Peng https://orcid.org/0000-0002-0376-9400

Data Availability Statement

Data is available upon request at the corresponding author.