Radiotherapy (RT) is considered a mainstay of treatment in parameningeal rhabdomyosarcoma (PM-RMS). We aim to determine the treatment outcomes and prognostic factors for PM-RMS patients who treated with RT. In addition, we tried to evaluate the adequate dose and timing of RT.
Twenty-two patients with PM-RMS from 1995 to 2013 were evaluated. Seven patients had intracranial extension (ICE) and 17 patients had skull base bony erosion (SBBE). Five patients showed distant metastases at the time of diagnosis. All patients underwent chemotherapy and RT. The median radiation dose was 50.4 Gy (range, 40.0 to 56.0 Gy).
The median follow-up was 28.7 months. Twelve patients (54.5%) experienced failure after treatment; 4 local, 2 regional, and 6 distant failures. The 5-year local control (LC) and overall survival (OS) were 77.7% and 38.5%, respectively. The 5-year OS rate was 50.8% for patients without distant metastases and 0% for patients with metastases (p < 0.001). Radiation dose (<50 Gy vs. ≥50 Gy) did not compromise the LC (p = 0.645). However, LC was affected by ICE (p = 0.031). Delayed administration (>22 weeks) of RT was related to a higher rate of local failure (40.0%).
RT resulted in a higher rate of local control in PM-RMS. However, it was not extended to survival outcome. A more effective treatment for PM-RMS is warranted.
Rhabdomyosarcoma (RMS) mainly occurs in the head and neck area, and the parameningeal site accounts for 15%–20% of all 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 [
The current treatment guidelines for RMS emphasize the importance of a multimodal approach [
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. [
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) [
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 [
Studies about the treatment of PM-RMS are rare and difficult because of the low incidence of this disease [
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.
In this study 22 patients were identified and evaluated with PM-RMS and received RT and chemotherapy at the Samsung Medical Center in Seoul, Korea from May 1995 to April 2013. A retrospective analysis was performed to assess treatment outcome and prognostic factors for these PM-RMS patients. This study was approved by the Samsung Medical Center Institutional Review Board. The preoperative staging of RMS was defined as follows: stage I, favorable site; stage II, unfavorable site (<5 cm), N0; stage III, unfavorable site, (> 5cm) or N1; stage IV, M1. Every PM-RMS was classified as an unfavorable site according to the criteria.
Seventeen patients (77.4%) underwent MRI and the other 5 patients (22.7%) underwent CT for diagnosis of meningeal involvement.
For the sequence of treatment, surgical resection or biopsy was initially performed. Chemotherapy followed by RT was administered subsequently.
According to the Intergroup Rhabdomyosarcoma Study (IRS)-III protocol, the chemotherapy regimen was composed of vincristine, adriamycin (or actinomycin D), cyclophosphamide, and cis-platinum (or cis-platinum plus etoposide). The IRS-IV chemotherapy protocol includes vincristine, dactinomycin, and cyclophosphamide (the most common); or vincristine, dactinomycin, and ifosfamide; or vincristine, ifosfamide, and etoposide.
For RT planning, the patients were fixed with a thermoplastic mask during a simulation computed tomography (CT) scanning. The CT images were used in all patients for treatment planning. For RT, a three-dimensional conformal radiotherapy technique was commonly used. However, an intensity-modulated RT was also used, if deemed necessary by the physicians. A total of 50.4 Gy was generally given to control the tumor. However, young patients (<10 years, n = 2), or patients with a favorable response to initial chemotherapy, were considered for a reduced dose RT (<50 Gy). The clinical target volume (CTV) was defined as 1.0–1.5 cm margin to gross tumor volume. The planning target volume was defined as an additional 0.5 cm margin to CTV. Brainstem, cochleas, optic nerves, optic chiasm, and lens were drawn as organs at risk.
Events were categorized according to local, regional (lymph nodal), and distant failure. Failure was defined as an increased size of a pre-existing tumor or newly developed disease at any site.
A Fisher’s exact test was used to find the clinical factors related to treatment outcomes. The Kaplan-Meier method and log-rank test were used for LC and survival analysis. LC and survival were defined as time from the diagnosis to local failure and death, respectively. Progression-free survival (PFS) was defined as time from the diagnosis to event (local, regional, and distant failure or death).
Surgical resection was performed before the RT in 4 patients (18.2%). Among the 4 patients who underwent surgery before RT, 2 patients underwent gross total resection and other 2 patients underwent partial resection (endoscopic sinus surgery). Among the 4 patients who underwent surgery, 2 patients had tumors less than 5 cm and 2 patients had tumors equal to or greater than 5 cm. All patients underwent chemotherapy and RT. The most commonly used chemotherapy regimen was the IRS-III regimen 35 (n = 12, 54.5%). The other 4 patients (18.2%) received IRS-IV regimen based chemotherapy. The median radiation dose was 50.4 Gy (range, 40.0 to 56.0 Gy).
The median follow-up time was 28.7 months. During the follow-up period, local, regional and distant failures occurred in 4 (18.2%), 2 (9.1%), and 6 (27.3%) patients. Overall, 12 patients (54.5%) showed disease progression (1 experienced both local failure and distant failure). Alveolar histology and ICE showed a tendency for higher local failure (p = 0.098 and p = 0.077, respectively, by Fisher exact test). No secondary malignancy was observed in the follow-up periods.
The 2- and 3-year LC rates were 84.2% and 77.7%, respectively (
The 2- and 3-year overall survival (OS) rates were 66.8% and 51.4%, respectively (
Surgical resection did not affect the PFS (p = 0.692) or OS (p = 0.593).
Patients were divided into two groups and evaluated according to the radiation dose; the first group (n = 18) was composed of patients treated with an equal and greater dose of the standard guideline (≥50 Gy). The second group (n = 4) was composed of patients who were treated with a reduced dose of radiation (<50 Gy). Half of the patients (n = 2), who were treated with reduced dose radiation (<50 Gy), were patients under the age of 10 years. The patients with ICE did not receive a higher dose of RT (ICE 5/7 vs. non-ICE 13/15, >50 Gy) than patients without ICE. The RT dose did not significantly compromise the LC rate (p = 0.501) (
Patients were divided according to the timing of the RT administration and evaluated at the following reference points: 4 weeks, 13 weeks, and 20 weeks from the time of diagnosis.
Causes of delay in administering RT (>22 weeks) varied. Among 5 patients who received delayed RT, 2 patients experienced complications (cardiomyositis/neutropenia) after chemotherapy. Two patients were transferred to our hospital after receiving several cycles of chemotherapy in other hospitals. The other patient was too young (3 years old) at the time of initial diagnosis; therefore, chemotherapy was administered preferentially and RT was delayed for 1 year.
Patients in the delayed RT group (n = 5) did not undergo surgery before RT. Four patients had stage III disease and 1 patient had stage IV disease. Even though a large portion of patients who delayed RT had metastases at the time of the initial diagnosis (60.0%) (
Among the 4 patients who underwent surgery, no patients experienced local failure and only 1 patient had ICE at diagnosis. A delay in administering RT (>22 weeks) did not occur as a consequence of performing surgery. All patients who underwent surgery before RT received RT within 15 weeks (
The parameningeal site is considered to be an adverse prognostic factor in RMS [
In a recent study, Merks et al. [
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 [
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 [
The radiation dose did not affect LC in this study (
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 [
The current study had several limitations. The initial response to chemotherapy is also known to have prognostic significance [
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.
No potential conflict of interest relevant to this article was reported.
Local control, progression-free survival, and overall survival.
Local control according to (A) intracranial extension and (B) skull base bony erosion.
Patient characteristics and treatments
Characteristic | No. (%) |
---|---|
Sex | |
Male | 7 (31.8) |
Female | 15 (68.2) |
Age (yr), median (range) | 19.5 (3-60) |
Histology | |
Embryonal | 9 (40.9) |
Alveolar | 9 (40.9) |
Pleomorphic | 1 (4.5) |
NOS | 3 (13.6) |
Risk factor | |
Cranial nerve palsy | 1 (4.5) |
Skull base bony erosion | 17 (77.3) |
Intracranial extension | 7 (31.8) |
Site | |
Nasopharynx | 7 (31.8) |
Nasal cavity | 6 (27.3) |
Paranasal sinus | 7 (31.8) |
Infratemporal fossa and PPF | 2 (9.1) |
Preoperative stage | |
Stage II (<5 cm and N0) | 2 (9.1) |
Stage III (≥5 cm or N1) | 15 (68.2) |
Stage IV (M1) | 5 (22.7) |
Treatment method | |
Surgery | 4 (18.2) |
Gross total resection | 2 (9.1) |
Partial resection | 2 (9.1) |
Chemotherapy | 22 (100) |
Radiotherapy | 22 (100) |
RT modality | |
3D-CRT | 17 (77.3) |
IMRT | 5 (22.7) |
RT field | |
Primary tumor | 19 (86.4) |
Primary tumor + regional LN | 3 (13.6) |
RT dose (Gy) | |
<50 | 4 (18.2) |
≥50 | 18 (81.8) |
NOS, not otherwise specified; PPF, pterygopalatine fossa; RT, radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; LN, lymph node.
Prognostic factor for local control in parameningeal rhabdomyosarcoma
Variable | No. (%) | Local control |
|
---|---|---|---|
3-yr(%) | p-value | ||
Age (yr) | 0.786 | ||
<10 | 5 (22.7) | 75.0 | |
≥10 | 17 (77.3) | 78.0 | |
Histology | 0.071 | ||
Alveolar | 9 (40.9) | 62.3 | |
Others | 13 (59.1) | 100 | |
Tumor site | 0.670 | ||
Nasopharynx and nasal cavity | 13 (59.1) | 80.8 | |
Paranasal sinus, infratemporal fossa, and PPF | 9 (40.9) | 75.0 | |
ICE | 0.036 | ||
Yes | 7 (31.8) | 44.4 | |
No | 15 (68.2) | 92.3 | |
SBBE | 0.206 | ||
Yes | 17 (77.3) | 69.8 | |
No | 5 (22.7) | 100 | |
CNP | 0.620 | ||
Yes | 1 (4.5) | 100 | |
No | 21 (95.5) | 76.4 | |
Tumor size (cm) | 0.455 | ||
<5 | 2 (9.1) | 74.9 | |
≥5 | 20 (90.9) | 100 | |
Disease extent | 0.400 | ||
M0 | 17 (77.3) | 80.2 | |
M1 | 5 (22.7) | 66.7 | |
Surgery | 0.280 | ||
Yes | 4 (18.2) | 100 | |
No | 18 (81.8) | 72.0 | |
RT dose (Gy) | 0.501 | ||
<50 | 4 (18.2) | 66.7 | |
≥50 | 18 (81.8) | 79.5 | |
Timing of RT (wk) | 0.200 | ||
4 (ref. 0-6) | 5 (22.7) | 66.7 | |
13 (ref. 7-15) | 10 (45.5) | 90.0 | |
20 (ref. 16-22) | 2 (9.1) | 100 | |
Delayed (ref. >22) | 5 (22.7) | 50.0 | |
RT modality | 0.229 | ||
3D-CRT | 17 (77.3) | 57.1 | |
IMRT | 5 (22.7) | 100 |
PPF, pterygopalatine fossa; ICE, intracranial extension; SBBE, skull base bony invasion; CNP, cranial nerve palsy; RT, radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.
Clinical risk factors and treatment outcomes according to the timing of radiotherapy
Timing of radiotherapy (wk) |
||||
---|---|---|---|---|
4 | 13 | 20 | Delayed | |
(ref. 0-6) | (ref. 7-15) | (ref. 16-22) | (ref. >22) | |
(n = 5) | (n = 10) | (n = 2) | (n = 5) | |
Risk factor | ||||
ICE | 4 (80) | 2 (20) | 0 (0) | 1 (20) |
SBBE | 4 (80) | 7 (70) | 2 (100) | 4 (80) |
Disease extent | ||||
Metastasis | 1 (20) | 1 (10) | 0 (0) | 3 (60) |
Operation | ||||
Surgery | 1 (20) | 3 (30) | 0 (0) | 0 (0) |
RT dose (Gy) | ||||
≥50 | 4 (80) | 8 (80) | 2 (100) | 4 (80) |
Treatment outcome | ||||
Local failure | 1 (20) | 1 (10) | 0 (0) | 2 (40) |
Overall progression | 2 (40) | 4 (40) | 0 (0) | 4 (80) |
Values are presented as number (%).
ICE, intracranial extension; SBBE, skull base bony erosion.