Rhabdomyosarcoma (RMS) mainly occurs in the head and neck area, and the parameningeal site accounts for 15%–20% of all RMS [1]. According to the Intergroup RMS Study III [2], parameningeal rhabdomyosarcoma (PM-RMS) constitutes 41% of head and neck-based RMS.

PM-RMS refers to tumors occurring in the nasal cavity, paranasal sinuses, infratemporal fossa, pterygoid palatine fossa, nasopharynx, and the mastoid or middle ear. The PM-RMS, originating in the skull base, is invasive, and sometimes it can develop into neoplastic meningitis [1]. Hence, the parameningeal site has a poor prognosis compared with other locations of RMS [1,3].

The current treatment guidelines for RMS emphasize the importance of a multimodal approach [4]. However, surgical resection with an adequate margin is difficult because of its deep location, which is close to several important structures, such as the brain, cranial nerve, and many vessels. Therefore, radiotherapy (RT) with chemotherapy is considered a mainstay of treatment in PM-RMS.

In PM-RMS, the location of the tumor is known to be correlated with the prognosis. In particular, PM-RMS in the paranasal sinus, infratemporal fossa, or pterygopalatine fossa showed an unfavorable outcome according to a recent report by Merks et al. [5]. In addition, alveolar histology was shown to be related to poor prognosis, compared with embryonal histology according to a report by Turner and Richmon [6].

Early initiation of RT with chemotherapy is generally recommended if there is a possibility of meningeal (intracranial) involvement in cases with skull base bony erosion (SBBE), cranial nerve palsy (CNP), and intracranial extension (ICE) [7]. In particular, ICE is considered to the most important adverse prognostic factor [1] and the early application of RT (0–4 weeks) is often considered in ICE or CNP cases. However, the recommended optimal timing for RT is still variable, according to clinical protocols [7-9].

The current guideline for RT is a dosage of 1.8 Gy/day, up to a total of 50.4 Gy, using a 1.5–2 cm margin around the tumor [4]. Michalski et al. [10] argued that a dose of at least 47.5 Gy was associated with lower rates of local failure. In contrast, Puri et al. [11] reported that a comparable local control (2-year local control [LC], 84%) was achieved with a reduced dose of 36 Gy external beam RT in very young patients (≤36 months). The Intergroup Rhabdomyosarcoma Study V also used a reduced dose radiation (36.0–50.4 Gy) in very young patients. In this point of view, a radiation dose reduction can be considered in patients with young age or a low-risk of relapse [12].

Studies about the treatment of PM-RMS are rare and difficult because of the low incidence of this disease [13]. Thus, most studies about PM-RMS have been designed to use retrospectively collected data.

This study aimed to investigate RT outcomes and its clinically related prognostic factors. Delaying RT or inadequate RT for those with high risk features may reduce survival and LC. Therefore, we additionally evaluated an adequate dose and timing of the RT.

The parameningeal site is considered to be an adverse prognostic factor in RMS [5]. However, the current study showed a substantial level of LC (3-year, 77.7%) in the PM-RMS patients. All the patients in this study received RT as an initial treatment. In this regard, the administration of RT as an initial treatment is important to achieve a higher LC in PM-RMS. However, this higher LC was not extended to OS gain (3-year, 51.4%). The most common cause of treatment failure was distant metastasis. Moreover, all patients, who developed distant failure during the follow-up periods, eventually died.

In a recent study, Merks et al. [5] reported that age, meningeal invasion (cranial neuropathy ± SBBE ± ICE), tumor site, and tumor size were significant prognostic factors for PM-RMS. This study also showed that ICE was a significant prognostic factor for LC. However, age, tumor size, and tumor site did not significantly influence the treatment outcome. This discrepancy might be related to the smaller sample size of the current study.

An adequate application of RT is crucial in the PM-MRS. The RT timing and dose are important factors with regard to the effectiveness of the RT [10-12].

The timing of RT tended to be determined by the risk of intracranial (meningeal) involvement. However, it could be related to other factors, such as a young age, use of surgery or treatment toxicity [5]. The recommended timing of RT is variable according to protocols [2,7,8,14]. In general, it is recommended that patients with risk factors for progression receive RT at an early stage. However, in IRS-VI, the recommended RT timing was related to the degree of risk as follows: patients with low risk, 13 weeks; intermediate risk, 4 weeks; and high risk, 20 weeks. In the current study, a delayed RT (>22 weeks) was related to poor local control (40.0% of local failure) (Table 3). Moreover, the poor outcome of the delayed RT group was not clearly related with the burden of pre-existing risk factors, such as ICE and SBBE (Table 3). Surgical resection was not associated with delayed RT (Table 3) or decreased local control (p = 0.706). The small number of patients who were treated with surgery may be the reason for these statistically nonsignificant results. Delayed RT was related to prolonged chemotherapy administration or chemotherapy complications. The rarity of this disease might also contribute to the heterogeneity of tumors and treatment characteristics. Physicians with limited experience of this disease might have difficulty in administering prompt or appropriate treatment after diagnosis. The poor prognosis might be related to treatment delay, which resulted in a decrease in the RT effectiveness. In this regard, the administration of the RT in time is a desirable goal to achieve a better response from RT.

The radiation dose did not affect LC in this study (Table 3). This result supported the results of Puri et al. [11] Especially in young patients, a dose reduction can be considered as a treatment option to reduce radiation-induced toxicities, such as growth hormone deficiency, or growth delay, or bony deformity [15]. In regard to the reduction of the RT-induced late toxicity, the use of proton therapy or the shrinking field RT can also be considered as a treatment option [16].

This study showed a substantial rate of LC (5-year LC, 77.7%) in the PM-RMS. The modern RT techniques improve the target dose coverage (i.e., three-dimensional conformal RT [17] or intensity modulated RT [18]). The current risk-based approach [9] and tailored multimodal treatment [19] might also contribute to the improvement in treatment outcome.

The current study had several limitations. The initial response to chemotherapy is also known to have prognostic significance [13]. Nevertheless, an early response evaluation was impossible due to a lack of imaging studies after initial chemotherapy. In addition, this study did not deal with treatment-induced toxicity, which might compromise the survival rate. Also, it was difficult to estimate the effect on local control of high dose RT in patients with meningeal involvement. To clarify the effect of the RT, a prospective long-term follow-up study is warranted. Finally, because of the rarity of PM-RMS there were a relatively small number of patients. Our data is not sufficient to evaluate a real effect of RT because of small sample size. Especially, the number of patients who treated with reduced dose irradiation was only 4. Therefore, it is difficult to conclude that dose of RT did not influence the treatment outcome. Also, the results that tumor size was not related to prognosis might be affected by the small sample size of this study. The statistical power of this study tended to be lower than that of other large-scale studies. Nevertheless, this study’s findings could provide important clinical information about Korean PM-RMS patients. A well-designed, multi-institutional study is warranted to evaluate this rare disease.

In conclusion, RT can allow for a high rate of LC for the PM-RMS patients. An adequate use of RT is an essential part of treatment for the PM-RMS. However, the benefit of LC did not extend to survival outcome because of the high rate of systemic failure. Therefore, further studies should be attempted to achieve better treatment outcomes of PM-RMS. A more effective treatment is still warranted to improve the clinical outcome of PM-RMS.