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primary surgery. In this randomised controlled trial, 68 women with operable LAVC were
randomised to either primary radical surgery followed by radiation if more than one groin lymph
node contained metastatic disease, or to neoadjuvant chemoradiation followed by surgery.
Chemoradiation comprised 50 Gy neoadjuvant radiotherapy with concurrent infusional 5-FU 750
mg/m² days 1-5 and Mitomycin-C 15 mg/m² IV day 1, with two courses given three weeks apart. In
the primary surgery arm, 15 (15/37) patients underwent adjuvant radiation. Surgery was feasible in
24 out of 28 patients in the neoadjuvant arm. At a mean follow-up of 42 months, thirty recurrences
have been reported (13 in the neoadjuvant chemoradiation arm and 17 in the primary surgery arm).
The authors reported no statistically significant difference in the risk of death at 5 years between the
two therapeutic approaches (RR = 1.39, 95% CI = 0.94-2.06, p > 0.05). Furthermore, no statistically
significant difference in the risk of overall treatment related morbidity was found (RR = 1.18, 95%
CI = 0.71-1.96, p > 0.05). It should be noted that details regarding the extent of primary tumour and
the complexity of surgical procedures required in each group are not provided, and quality of life is
not reported.

Two other original studies243,244 enrolling at least 50 patients were identified. In a GOG phase II LoE 2+
study including 71 patients with unresectable vulvar disease, or disease requiring exenterations,
Moore et al.243 investigated the role of concurrent radiotherapy and cisplatin/infusional 5-FU
chemotherapy. A cCR occurred in 47% of patients. Among those patients who had surgery, 70% had
a pCR. Two of 71 patients had unresectable disease after chemoradiation, and three patients required
exenteration. After a median follow-up of 50 months, 40 patients were alive with no evidence of
disease and no recurrence (Table 10). Toxicity from chemoradiation was estimated acceptable,
although acute cutaneous reactions were almost universal. In the second identified study244, 58
patients referring for primary or recurrent disease received preoperative radiotherapy to a dose of 54
Gy (divided into two courses with an interval of two weeks). Concurrent preoperative chemotherapy
with 5-FU (750 mg/m² daily for 5 days) and Mitomycin-C (15 mg/m² single bolus) were given at the
start of each cycle. A cCR of both the vulvar and inguinal disease occurred in 27% of patients. A
pCR was confirmed in 13 patients (31%). After a median follow-up of 22 months, 28 patients were
alive with no evidence of disease and no recurrence (Table 10). Like the GOG phase II study243,
treatment side effects were estimated acceptable.

As part of a meta-analysis including 7 studies229,234,237,245-248 for a total of 70 patients, Stuckey et LoE 1-
al.249 investigated whether elderly patients are more likely to die of intercurrent disease or of
treatment complications. It should be noted that Stuckey et al.249 included patients receiving
preoperative or primary chemoradiation treatment with curative intent even if in the majority of
cases, this was given with neoadjuvant intent. Radiation doses ranged from 18 to 72 Gy and included
the vulvar, inguinal, and the pelvic regions. Chemotherapy included 5-FU with or without cisplatin
or Mitomycin-C (Table 11). Seventy-eight percent of patients younger than 65 years were without
evidence of disease after treatment versus 66% of patients aged 65 years and above. Three percent of
patients younger than 65 years of age died of intercurrent disease or treatment-related complications
versus 11% of patients aged 65 years and above. But these differences did not reach statistical
significance (p = 0.30 and p = 0.37, respectively). It should be noted that 1) the small sample size
from included studies and 2) the changes in radiation therapy techniques and chemotherapy could
make it difficult to statistically support the trend showing that elderly patients have lower survival
and higher intercurrent death.

Results from the 11 other identified studies233,242,245-247,250-255 are limited notably by the small number LoE 3
of patients evaluated (only 4 studies242,250,252,253 have accrued in excess of 20 patients) and by the
heterogeneity in the chemotherapy regimens used in the neoadjuvant setting along with radiation
therapy (Table 10). Although studies are small, chemoradiation as a neoadjuvant therapeutic approach
has been reported to produce high response rates and high rates of surgical resectability without
exenteration, regardless of chemotherapy regimen used. Overall, authors described high but

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