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