We report a recurrence of ERMS in a 36-month-old girl with stage I, low-risk, vaginal ERMS, even after standard treatment with chemotherapy and complete surgery. She had FFS and OS rates of only 28 and 39 months. The management of pediatric genitourinary RMS has evolved from pelvic exenteration in the 1970s and early 1980s to a multimodal treatment involving conservative surgery, chemotherapy, and RT in an effort to preserve genitourinary organs and reduce treatment morbidity. The rate of hysterectomy decreased from 48% in IRS-I/II to 22% in IRS-III/IV, with an increase in the use of RT from 23% in IRS-II to 45% in IRS-IV. Approximately half of RMSs in the female genital tract arise in the vagina, and a majority is of the embryonal subtype, all of which have a favorable prognosis.[1, 9, 12, 13] With the goals of limiting late effects resulting from treatment and preserving organ function, the approach to local treatment has changed radically over the last 30 years.
However, local therapy in children and adolescents with vaginal RMS remains a challenge. The predominant context of treatment failure in patients with initially localized RMS has been local recurrence. In IRS-II, of patients who achieved complete remission with chemotherapy and surgery, almost 20% of patients with Group I to III disease had local or regional relapses, and 30% of patients with Group IV disease had local or regional relapses.[8] Local or regional relapses accounted for 70–80% of all relapses among children with Group I to III disease and 46% of all relapses among patients with Group IV disease.[8]
Both surgery and RT are the primary measures taken to establish local control, but each has its risks and benefits. Surgical removal of the entire tumor should be considered initially, but only if functional and cosmetic impairment will not result.[16] RT is an effective method for achieving local control of the tumor in patients with microscopic or gross residual disease after biopsy, initial surgical resection, or chemotherapy. RT is recommended to enhance local control in all patients with RMS except those who had embryonal/fusion-negative clinical group I tumors. Brachytherapy, using either intracavitary or interstitial implants, is one method of local control and has been used in selected situations for children with ERMS, especially for patients with primary tumors at a vaginal site.[14, 17–19] The COG-STS recommended that RT be administered to patients with residual viable vaginal tumors beginning at week 12.[20] For patients aged 3 years and younger, reduced radiation doses may be appropriate if delayed surgery can provide negative margins. However, for patients who are unable to undergo surgical resection, higher doses of RT remain appropriate.[21] Many retrospective analyses have found that in patients with locally relapsed disease, not receiving RT was an important factor in tumor recurrence. However, these studies included intermediate- to high-risk RMS patients.[20, 22–24]. In a pooled analysis, fifty-one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery.[25] When making the decision to eliminate RT, the risk of local recurrence must be considered.[24] Moreover, for girls with genitourinary primary tumors who will receive pelvic irradiation, ovarian transposition (oophoropexy) before radiation therapy should be considered unless dose estimations suggest that ovarian function is likely to be preserved. Alternatively, ovarian tissue preservation is under investigation and can be considered. When RT is indicated, modalities that limit sequelae, such as brachytherapy, should be considered.[25]
Surgery is the most common treatment option considered for children with vaginal RMS. For prepubertal girls and adolescents, radical surgery did not confer a survival benefit compared to local tumor excision.[26] Conservative surgical intervention for vaginal RMS, with primary chemotherapy and RT (external beam or brachytherapy) for residual disease (Group II or III), leads to excellent 5-year survival rates.[1, 24, 27] Complete excision for localized disease is recommended as long as functional and/or cosmetic results are acceptable. The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but it is an alternative approach if easily accomplished without loss of form or function. Children aged 3 years or younger who are diagnosed with RMS pose a therapeutic challenge because of their increased risk of surgery-related morbidity.[28]
If complete resection is not feasible, it is better to undergo an initial diagnostic biopsy followed by neoadjuvant chemotherapy and then definitive local therapy with either surgery or RT. Moreover, there is little evidence that debulking surgery improves outcomes compared with resection alone; therefore, debulking surgery is not recommended for patients with RMS.[29] In a retrospective study of 73 selected patients, second-look procedures (also called delayed primary excision) identified viable tumors that remained after initial chemotherapy; 65 of these patients had also received RT. Patients with viable tumors had shorter FFS rates than those without viable tumors, but there was no effect on OS.[28] Thus, delaying surgery until after chemotherapy is preferred.
Chemotherapy is the most common treatment modality for vaginal ERMS.[30, 31] The choice of regimen depends on the estimated risk of disease recurrence. Approximately 25% of newly diagnosed patients are, by definition, low risk. Certain subgroups of low-risk patients have achieved survival rates higher than 90% when treated with a two-drug chemotherapy regimen that includes vincristine and dactinomycin (VA) plus RT for residual tumor.[32] In the report by Raney et al.,[33] the estimated 5-year FFS rate was 89% (95% CI, 84–92%) for low-risk RMS. In their study, Group I ERMS patients needed no RT. High-dose cyclophosphamide causes severe myelosuppression, infectious complications, and infertility in virtually all males and many females. In patients with Group I-III tumors, 43% of deaths are from toxicity.[1] The COG-ARST0331 trial evaluated the minimization of acute and long-term toxicities of therapy for two subsets of low-risk patients. The study enrolled 271 newly diagnosed patients with low-risk RMS, with a shorter duration chemotherapy regimen that included four cycles of VAC chemotherapy followed by 10 weeks of therapy with vincristine and dactinomycin.[34] The 3-year FFS rate was 89%, and the OS rate was 98%. These findings suggest that a shorter duration of therapy does not compromise the outcomes of these patients. The 5-year FFS outcome improved for these patients, from 70% for IRS-III patients with VA therapy to 84% for IRS-IV patients with the addition of intensive cyclophosphamide.[34] Neoadjuvant chemotherapy combined with radical surgery has achieved a favorable prognosis in cervical RMS[35] and vaginal RMS.[36, 37]
Numerous studies have discussed the molecular mechanism in ERMS to explore the pathogenesis of the disease, distinction of subtypes, and potential targeted therapies.[38] On the basis of methylation patterns, RMS is clustered into four distinct subtypes.[39] The IHC expression pattern of endogenous markers has emerged as a promising tool to predict the response to neoadjuvant chemotherapy for RMS. [40] A five-gene expression signature score shows a significant correlation with overall and FFS among cases from COG D9803.[41] However, these findings are awaiting further translation or validation in clinical trials. No available practical molecular testing or targeted therapy is officially used in RMS patients except for the association of alveolar RMS with translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), which lead to the generation of fusion genes.