Evidence
Patients with completely resected tumors at diagnosis have a favorable prognosis with chemotherapy alone, i.e. avoiding radiotherapy. In the international pooled analysis, 33 Group I patients were not irradiated and the 10-year EFS was 79% with an OS of 97%.4 The analysis of Group II patients is more difficult as some patients did receive RT and others did not. In general for RMS, the omission of RT for patients with Group II tumors is associated with an increased risk of local failure and lower EFS.10, 11 In the IRS-III trial, Group II patients did receive RT with 41.4 Gy, whereas in COG D960212 and COG ART033113 patients with Group IIA or III vaginal RMS had initial omission of RT if in CR after chemotherapy with or without surgery, but later in the ARST0531 trial, 36 Gy was utilized. In the EpSSG study, patients with unfavourable features (age ≥ 10 years and/or tumor size > 5cm) achieving CR and all patients with PR received RT.4
Local control of FGU-RMS appears to be additionally influenced by the total cumulative dose of alkylating agents and may impact the amount of local therapy that is required for optimal treatment. Prior to 2004, the COG cumulative cyclophosphamide equivalent doses were higher (24.4-30.8 g/m2) and RT was infrequently used in Group II and III vaginal RMS tumors.8 This resulted in local recurrence rates of 26% which were higher than local recurrence rates (14%) for similar tumors at other sites. RT was withheld in accordance with the paradigm utilized in European studies due to the high rate of morbidity associated with pelvic RT in young female patients. After 2004, COG used a lower cumulative cyclophosphamide dose (4.8 g/m2) in an effort to preserve fertility but there were no changes made in the local control paradigm which still discouraged resection and RT. This lower cyclophosphamide dose treatment regimen had a 43% local failure rate. However, the use of RT in these patients decreased local failure rates from 53% to 17%.14 The OS was still excellent for patients with local recurrences since the majority could be salvaged but at the cost of increased chemotherapy, surgical resection and RT. Local recurrences were grossly excised in 73% of patients. Subsequently, COG ARST1431 is treating patients with Group III FGU-RMS on intermediate risk protocols with a higher cumulative cyclophosphamide dose (8.4 g/m2) in an attempt to decrease local recurrence as seen on the prior ARST0331. In the large international pooled analysis of FGU-RMS, cooperative group trials that used cumulative cyclophosphamide doses 24.4-30.8 g/m2 (in COG trials) or cumulative ifosfamide doses of 24-54 g/m2 (in European trials) were associated with a CR rate of 95% and local recurrence rate of 24%, with similar rates across cooperative study groups.
All suspicious lesions identified either by imaging or during vaginoscopy require biopsy to confirm resolution of viable tumor. The biopsy is important because an abnormal lesion does not always equate to residual viable tumor. Mature rhabdomyoblasts usually persist following chemotherapy and RT causing an end of therapy mass that can be present on imaging or examination, however, these cells do not predispose to local failure and therefore do not require resection or additional therapy.15
There is a role for surgical resection of gross disease provided the tenets of complete gross resection with organ preservation utilizing conservative procedures can be maintained. As mentioned previously in the large multinational study of patients with both vaginal and uterine RMS approximately 31% of patients were operated on before the initiation of chemotherapy to resect the tumor grossly.4 Another 28% had a surgical resection at some point during initial therapy, for a total of 59% of patients. Surgery was conservative in 41% of all patients and radical in 18%. During all primary therapy the frequency of conservative resection (36-53%) was equally distributed across all multinational study groups and included procedures such as enucleation, partial vaginectomy and partial cervix excision. Fifty-seven percent of patients in the pooled international analysis achieved CR with chemotherapy and biopsy or conservative resection. Radical excision was also equally distributed (8-22%) among cooperative groups and included procedures such as hysterectomies and vaginectomies.4 However, an important caveat is that primary tumor location was the main factor associated with the frequency of radical surgery (12/26 [46%] for patients with uterus corpus vs. 25/160 [16%], and 6/51 [12%] for those with vagina and cervix, respectively). Therefore, although much of the resection data presented reflects both vaginal and uterine RMS tumors, it is clear that the need and frequency of radical resections is lower in vaginal tumors compared to uterine tumors that have an inferior EFS and OS. This further supports the good outcomes associated with conservative operative procedures for vaginal RMS tumors. Further supporting this conclusion is a recent review of FGU-RMS using the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) database that determined the OS was not improved in patients that had a radical procedure vs a more conservative resection (88% vs 95% respectively).16