]
The International Society for the Study of Vulvovaginal
Disease updated the terminology used to
characterize vulvar lesions as low-grade squamous intraepithelial
lesion or usual-type vulvar intraepithelial
neoplasia due to flat condyloma or human papilloma
virus (HPV) 6-11 infection, high-grade squamous intraepithelial
lesion or uVIN 2-3 due to carcinogenic strains of HPV, and differentiated-type VIN (dVIN)
associated with vulvar dermatologic conditions such
as lichen sclerosis.[] uVIN tends to occur in young
patients in the third to fifth decades of life, on the contrary,
dVIN typically occurs in older patients in the
sixth to eighth decades of life.[] Well-known risk factors
for the development of vulvar cancer include increasing
age, HPV infection, smoking, multiple sexual
partners, and immunosuppression.[]
Vulvar cancer mainly spreads through direct extension
to adjacent structures and the lymphatics, first
inguinofemoral followed by pelvic LNs. Prognosis is
strongly correlated with LN involvement and depth of
invasion (>5 mm). Positive or close (<8 mm) surgical
margin, International Federation of Gynecology and
Obstetrics (FIGO) stage, tumor size, tumor localization,
lymphovascular space invasion (LVSI), and presence
of HPV infection are also associated with treatment
outcomes.[-]
Due to the rarity of vulvar cancer, treatment strategies
mainly come from the results of limited number of
retrospective studies. Historically, radical surgery including
radical vulvectomy and bilateral inguinofemoral
LN dissection (IFLND) was the standard surgical approach
for patients diagnosed with vulvar cancer, regardless
of disease extent. However, due to morbidity,
psychological effects of exenterative surgery, and insufficient
locoregional control rates in patients with
locally advanced-stage disease, multimodal treatment
approaches have been developed to decrease treatmentrelated
morbidity. Radiotherapy (RT) has a major role
in the treatment of vulvar cancer; as a neoadjuvant
therapy to improve resectability and provide less radical
surgery, as a definitive therapy for an inoperable disease,
or as an adjuvant therapy to prevent local-regional recurrences.
In this review, we will discuss the rationale
of RT in neoadjuvant, definitive, and adjuvant settings.
Treatment of Early-Stage Disease (Stages I-II)
Surgery
Historically, en bloc radical vulvectomy with bilateral
IFLND referred to as "butterfly resection" was the standard
approach for vulvar cancer, regardless of disease
extent.[] However, this exenterative surgery has serious
postoperative morbidity and psychological sequelae.
IFLND alone has also 21-47% risk of lymphedema.
[,] In a Cochrane meta-analysis, it was shown that
radical vulvectomy and radical local excision with an
at least 1 cm tumor free margin had similar low rates
of recurrence and the triple incision technique was as
effective as butterfly resection with less morbidity.[]
Again, in a study comparing triple incision technique
to butterfly technique by Van der Velden et al.,[] no
difference was observed in overall survival (OS) and
disease-free survival rates, however, triple incision technique
was found to be an independent prognostic factor
for vulvar recurrences in patients with LN metastasis but
not for inguinal/pelvic recurrences. Burke et al.[] also
reported that contralateral groin recurrence was a rare
event after unilateral LN dissection in patients with welllateralized
tumors. Today, simple or radical partial vulvectomy
is recommended for T1 or small T2 ( ≤4 cm) tumors
and only ipsilateral inguinofemoral LN evaluation
is recommended in case of well-lateralized tumors.[]
Lymphatic Staging and Role of RT as Alternative
to IFLND
Vulvar cancer spreads from the vulva to the ipsilateral
superficial inguinofemoral LNs, followed by deep in guinofemoral LNs, and then to the pelvic LNs.[]
Involvement of contralateral inguinofemoral LNs or
pelvic LNs without the involvement of ipsilateral LNs
is a rare event, however, the risk of contralateral LN
metastases increase with the tumors approaching or
crossing the midline.[] The frequency of inguinal
LN metastases in surgical series ranges from 6% to
50% depending on the extent of the primary disease.
[,] Homesley et al.[] found that greater tumor
thickness, older age, LVSI, and tumor grade were risk
factors for LN involvement. In one study, perineural
invasion was also shown to be a strong risk factor for
LN metastasis.[] Ipsilateral LN evaluation is recommended
for well-lateralized (≥2 cm from the midline)
tumors deeper than 1 mm and contralateral LN evaluation
should be added for tumors approaching or crossing
the midline.[]
For lymphatic staging, sentinel LN biopsy (SLNB)
in clinically LN-negative early-stage vulvar cancer
has been tested in GROINSS-V-I and GOG 173 trials
as a conservative approach instead of IFLND.[-]
SLNB was found to be safe and effective with less lymphedema
and lower groin recurrence rates in patients
with tumor-free sentinel LNs.[,] The GOG 173
trial showed that the false-negative rate of SLNB was
only 2% with tumors <4 cm and it was 7.4% with tumors
≥4 cm.[] Today, SLNB is accepted as an alternative
option to IFLND for lymphatic staging in T1b or
T2 tumors.[]
GROINSS-V II/GOG 270 trial investigated whether
RT was a safe alternative for IFLND in vulvar cancer
patients with a metastatic sentinel LN.[,] In this
prospective multicenter Phase II trial, patients were
included with early-stage SCC of the vulva (diameter
<4 cm) without suspicious LNs at imaging, who had
primary surgery with SLNB. In case of a metastatic
sentinel LN in any size, 50 Gy conventionally fractionated
RT was given to the groin(s). In case of a negative
sentinel LN, patients were followed-up for ?2 years.
From December 2005 to October 2016, 1552 eligible
patients were registered. Sentinel LN metastasis was
found in 21% (324/1552) of patients. After 54 months
of inclusion, the trial was stopped due to increased
risk of groin recurrence (2.1% vs. 20%) in case of sentinel
LN >2 mm and/or with extracapsular extension
(ECE).[] The treatment protocol was amended with
patients with micrometastasis (≤2 mm) in sentinel LN
receiving RT from then on, and those with >2 mm in
sentinel LN undergoing IFLND (with adjuvant RT in
case of >1 LN and/or ECE). Isolated groin recurrences
in patients with a sentinel LN micrometastasis (≤2 mm) decreased to 3.2% with this new treatment protocol
and the combination of RT with SLNB was associated
with minimal toxicity: 4.2% Grade 3 toxicity
and no Grade 4 or 5 toxicity.[25] This study showed
that RT to the groin is a safe alternative to IFLND with
minimal toxicity in patients with micrometastasis in
sentinel LNs. However, RT alone with a dose of 50
Gy is not sufficient for macrometastases. The ongoing
GROINSS-V-III trial investigates the effectiveness and
safety of chemoradiotherapy (CRT) (56 Gy to the involved
site combined with weekly 40 mg/m2 cisplatin)
in patients with macrometastases in sentinel LNs.
Adjuvant Treatment
Adjuvant RT is commonly used to reduce the risk of recurrences
in vulvar cancer patients with high-risk features.
The indications of adjuvant RT should be considered
for primary tumor site and lymphatics separately.
In patients with negative LNs, indication for primary
tumor site RT depends on the adverse primary tumor
risk factors. The most accepted primary tumor risk factor
for recurrence is positive or closes surgical margins.
[26,27] Ignatov et al.[] observed that 5-year OS was
higher (67.6% vs. 29%) in patients with positive or close
(<1 cm) surgical margin who received adjuvant RT than
those who did not. Viswanathan et al.[] also reported
that vulvar relapses increased in patients with positive
or close (<5 mm) surgical margins, and adjuvant RT
reduced local recurrences from 35% to 21% in those
patients. Two retrospective studies also reported that
none of the patients with surgical margin larger than 8
mm had a vulvar recurrence, but 21-48% of those with
a surgical margin less than 8 mm had local recurrences.
[,] Based on the retrospective series, RT has been
generally recommended for patients with <8 mm surgical
margins. However, the need for a minimal margin
of 8 mm was not confirmed in the AGO-CaRE database
and recent retrospective studies.[-] The definition
of close surgical margin remains unclear, but the cutoff
value of 8 mm for surgical margin is widely accepted.
Although, 5 mm surgical margin is accepted adequate
by some. All patients with close or positive surgical
margins initially should be evaluated for reexcision. In
cases whom surgery cannot be performed (tumor close
to urethra, clitoris, anal sphincter, etc.), RT should be
considered. The recent National Comprehensive Cancer
Network (NCCN) recommends adjuvant RT for patients
with positive or close surgical margins and accepts
5-8 mm as the definition of close surgical margin.[]
The second important risk factor for the recommendation
of adjuvant RT to primary tumor site is the depth of tumor invasion. Depth of invasion correlates
not only with local recurrences but also with the risk
of LN metastasis and subsequently survival rates.[]
There are several studies investigating the cutoff value
for depth of invasion to predict recurrences.[,] Bogani
et al.[] showed increased rate of local recurrences
in patients with a stromal invasion >2 mm than those
with ≤2 mm. Zapardiel et al.[] also found the stromal
invasion of more than 5 mm as a poor prognostic factor
for recurrence and OS. In the light of these findings,
adjuvant RT for primary tumor site in patients with tumor
thickness >5 mm is widely recommended.[] Besides
that, NCCN also recommends adjuvant RT to the
primary tumor site for tumors with LVSI, large tumors
(>4 cm), and diffuse/spray pattern of invasion, since
several studies demonstrated these features as adverse
risk factors for recurrence.[,,]
LN involvement is one of the most important prognostic
factors in vulvar cancer. Farias-Eisner et al.[]
reported that 5-year OS rates were 45% and 98% in
patients with and without LN metastasis, respectively.
Gynecologic Oncology Group (GOG) 37 trial compared
pelvic LN dissection to pelvic RT after radical
vulvectomy and IFLND in patients with pathologically
positive inguinofemoral LNs.[] Within 74 months of
follow-up, patients receiving RT had improved 6-year
OS rate (41% vs. 51%) and decreased 6-year cancerspecific
death and groin recurrence rates (51% vs. 29%
and 24% vs. 5%, respectively).[] The subgroup of patients
who got the most benefit with adjuvant RT was
those with macrometastasis, ECE, or ≥2 LN metastases.
Although adjuvant RT in patients with ≥2 LN metastases
or ECE is not debatable, there are conflicting
results in the literature regarding the role of adjuvant
RT in patients with only one LN metastasis.[-]
The AGO-CaRE-1 study was conducted to investigate
the role of adjuvant RT in patients with positive LNs
and adjuvant RT was administered in 41% of patients
with LN metastasis[] and revealed that adjuvant RT
improved OS (57.7% vs. 51.4%) and progression-free
survival (39.6% vs. 25.9%) in the whole cohort. However,
this improvement was significant especially for
patients with ≥2 positive LNs, without any significant
survival benefit for patients with only one LN metastasis.[] Van der Velden et al.[] also recently supported
omitting RT to the groin in patients with a single
occult intracapsular LN metastasis due to the low
risk of groin recurrence and the excellent groin recurrence-
free survival without adjuvant RT. On the other
hand, the Surveillance, Epidemiology, and End Results
(SEER) database analysis revealed that adjuvant RT statistically significantly improved survival, especially
in patients with resected LNs less than 12 and single
LN metastasis.[] Of the 490 patients with Stage III,
node-positive vulvar cancer in this SEER analysis had
a single positive inguinal LN. The median number of
LNs resected was 13 (range: 1-34). Patients who received
adjuvant RT had a 5-year disease-specific survival
of 77.0% compared to 61.2% in those without RT
(P = 0.02). After stratifying the study group based on
the extent of lymphadenectomy, 5-year survival rates
with RT were 76.6% in patients with ≤12 LNs removed
which was statistically significantly higher than those
without RT in whom survival rate was 55.1%. In those
with more than 12 nodes resected, RT increased the
survival from 66.7% to 77.3%, though this difference
was not statistically significant.[] Serre et al.[] also
reported that 5-year OS rates were similar in patients
with one intracapsular LN metastasis, one extracapsular
LN metastasis, and two LN metastases, furthermore,
they suggested adjuvant RT to patients with LN
metastasis, irrespective of the number of involved LNs
in case of LVSI.
There are no randomized data comparing adjuvant
RT with CRT. Gill et al.[] supported the addition of
chemotherapy in adjuvant setting using the data from
National Cancer Data Base (NCDB). Among 1797 vulvar
cancer patients with positive LNs, 26.3% received
adjuvant chemotherapy in addition to adjuvant RT and
76.6% had 1-3 involved LNs. Adjuvant chemotherapy
increased OS (44 vs. 29.7 months) and reduced the risk
of death (HR = 0.62; 95% CI, 0.48-0.79; P < 0.001).[]
Based on all these retrospective studies, adjuvant RT is
strongly recommended for patients with LN metastasis
in SLNB or IFLND and CRT is strongly recommended
for patients with ≥2 positive LNs or a single LN with >2
mm metastasis after IFLND.[] Based on limited experience,
the most commonly used concurrent cytotoxic
agent is weekly cisplatin with a dose of 40 mg/m2.[]
Treatment of Locally Advanced-Stage Disease
(Stages III-IVA)
The locally advanced disease is defined as patients with
tumors extending to the adjacent structures (large [≥4
cm] T2 and all T3 tumors) or clinically positive groin
LNs (FIGO Stages III-IVA). In this phase, the disease is
considered unresectable or needs exenterative surgery
which leads to significant post-operative complications
and decreased quality of life. Thus, a multimodality
treatment has been explored to reduce surgery-related morbidity and improve organ preservation rates.[]
RT is commonly used in locally advanced-stage disease
as neoadjuvant or definitive treatment.
Neoadjuvant Treatment
Neoadjuvant RT/CRT can be used in patients with
locally advanced-stage disease who are considered inoperable
or required extensive surgery to improve the
resectability rate and reduce the extent of the surgery.
Pre-operative RT in locally advanced disease was first
shown to result in tumor debulking and reduce the extent
of surgery in a landmark study by Boronow.[]
In that particular study, 5-year OS rate was 75.6% and
pathologically complete response (CR) rate was 40%.
[] There is no randomized study in the literature
comparing concurrent CRT with RT alone in locally
advanced vulvar cancer, however, concurrent weekly
cisplatin or 5-FU alone or in combination is commonly
used in locally advanced disease as a radiosensitizer
based on Phase III trials which showed the benefit of
CRT compared to RT alone in cervical and anal cancers.[,] In the GOG 101 study, 73 vulvar cancer
patients with unresectable T3-4 tumors received preoperative
47.6 Gy RT in 28 fractions to the pelvis and
the inguinofemoral LNs with concurrent cisplatin
and 5-FU.[] The clinical and pathological CR rates
in that study were 48% and 31%, respectively. Only
2.8% of patients remained unresectable after CRT.[]
Another GOG study which accrued 46 vulvar cancer
patients with unresectable N2-3 disease reported CR
rates of 41% in LNs after the same CRT protocol with
the GOG 101 trial.[] In this study, local control rates
for LNs and primary tumor were 97% and 76%, respectively.
Although local control and resectability rates
were acceptable in these studies, a RT dose of 47.6 Gy
was not sufficient for macroscopic disease. Therefore,
GOG 205 trial investigated the effect of increasing RT
dose to 57.6 Gy in 32 fractions with concurrent weekly
cisplatin followed by surgery in patients with unresectable
T3-4 disease.[] The authors reported that
69% of all patients completed the treatment and clinical
and pathological CR rates increased to 64% and
78%, respectively.[50]
Definitive Treatment
Based on studies evaluating the effectiveness of neoadjuvant
RT/CRT, high pathologic CR rates led to a growing
acceptance of omitting surgery in locally advanced
tumors in case of clinical CR. In the recent NCDB analysis,
2046 patients with locally advanced vulvar cancer
who were treated with either definitive RT/CRT or pre-operative RT/CRT were analyzed.[] Within 21.9
months follow-up, 3-year OS was significantly higher
(57.1% vs. 41.7%) in pre-operative RT/CRT group than
primary RT/CRT group.[] However, on multivariate
analysis, OS associated with primary RT/CRT with
doses more than 55 Gy was not significantly different
from RT/CRT and surgery, and the use of concurrent
chemotherapy improved OS of primary RT with doses
more than 55 Gy compared with CRT and surgery. The
results of an ongoing GOG 279 trial investigating the
role of definitive CRT (a dose of 64 Gy with concurrent
cisplatin and gemcitabine) in T2-3, N0-3 vulvar
cancer patients are pending. For patients with locally
advanced-stage disease who underwent neoadjuvant
or definitive RT/CRT, it is recommended to clinically
evaluate the patients and perform biopsy within the
first 3 months after completion of RT/CRT.[] If the
patient has clinically and pathologically CR, observation
is the surveillance policy, but if there is a residual
tumor or LN metastasis, surgery or a boost dose of RT
should be considered.[]
RT
Simulation
Computed tomography (CT) simulation is critical
for appropriate treatment planning in vulvar cancer.
A "frog leg" position in a vacuum-evacuated device
is generally preferred to spare the skin in the medial
thigh. Full bladder and empty rectum are preferred
during simulation and treatment to minimize the dose
to the small bowel. Internal target volume should be
generated in case of locally advanced disease, especially
when vagina, urethra, and/or anus are involved. Bolus
over the groin is not routinely recommended, but it
should be used for large, superficial LNs, or in case of
skin involvement.[] If bolus is used, bolus should be
placed over scars with a margin of at least 3 cm. At the
time of simulation, patients should undergo scanning
both with and without bolus to avoid treatment interruption
in case that patients may develop a brisk skin
reaction and treatment can be continued without bolus
material.[]
Target Volume Delineation
Recently, consensus guideline has been published for
target delineation and treatment planning in vulvar
cancer.[] Magnetic resonance imaging (MRI) may
be useful for delineating the extent of the tumor in
definitive treatment. The GTV should encompass all gross lesions according to clinical examination and radiological
images. The entire vulva should be included
in the CTV, and CTV should be generated with a 1 cm
margin to GTV if GTV extends beyond the vulva. If
the primary tumor involves the vagina, 3 cm margins
to GTV should be included in the CTV and the entire
vaginal length should be included in the CTV in case of
any uncertainty about the proximal extent of the vaginal
extension. If the primary vulvar lesion involves the
anus, bladder, or urethra, gross disease plus at least 2
cm of anus, bladder, or urethra should be included in
the CTV. Satellite lesions, tumors with extensive LVSI,
or dermal lymphatic invasion should be included with
extra margins in the CTV. In post-operative settings,
CTV should cover the entire operative bed with a margin
of 2 cm. CTV to PTV margin should be 0.7-1.0 cm
depending on the patient stability procedure or the
treatment technique.
The GTV for LNs may be defined on either MRI
or CT and encompasses all gross LNs. Nodal CTV
should encompass nodal GTV. If the primary tumor
involves the distal vagina, bilateral external iliac, internal
iliac, obturator, and inguinofemoral LNs should be
included in the nodal CTV. Presacral LNs should also
be included in case of involvement of proximal half of
the posterior vaginal wall. The inguinofemoral LNs are
defined superiorly from where the external iliac artery
leaves the bony pelvis to become the femoral artery. The
inferior border is 2 cm below the saphenofemoral junction;
however, another commonly used landmark is the
level of the lesser trochanter. The ideal perivascular or
radial margin (a margin that incorporates the location
of all potential inguinal LNs) is not known. Based on a
recent study, anteromedial ≥35 mm, anterior ≥23 mm,
anterolateral ≥25 mm, and medial ≥22 mm margins
to inguinofemoral vessels are recommended to obtain
nodal CTV.[] LN recurrence is not seen posterior
or lateral to femoral vessels, thus addition of margins
to the vessels in those regions is not recommended.
Furthermore, if extensive lymphadenopathy or ECE
is noted, covering the entire operative bed should be
considered.
RT Dose
Dose recommendations are mainly based on these consensus
guideline and GOG 205 trial protocol.[,,]
Definitive CRT is the standard treatment in locally advanced
vulvar cancer. A boost dose should be given in
the gross disease at the primary site to improve local
control and the recommended dose range is 60 Gy-
>70 Gy. In post-operative cases, a minimum equivalent dose of 45-50 Gy is recommended for clear margins and
54-60 Gy for close or positive margins. Viswanathan et
al.[] demonstrated an increase of vulvar recurrence
rate in vulvar cancer patients with close or positive surgical
margin and a minimum dose of 56 Gy decreased
recurrence rate from 35% to 21% in patients with 0-5
mm of surgical margin. A NCDB data evaluating 3075
vulvar cancer patients with positive surgical margin
also reported the best survival rate with 54-59.9 Gy.[]
A similar approach is applied for LNs and clinically
and/or radiographically uninvolved inguinofemoral
LNs should be treated to a "microscopic dose" of 45-
50 Gy. Positive inguinofemoral LNs without ECE after
IFLND should be treated to a dose of 50-55 Gy, and 54-
64 Gy is recommended for LNs with ECE. Minimum
of 60-70 Gy should be delivered to inguinofemoral LNs
for gross residual or unresectable disease. Dose recommendations
and dose constraints for organs at risk are
detailed in Tables 1 and 2, respectively.
Table 1: Radiotherapy dose recommendations for
vulvar cancer
Table 2: Radiotherapy dose constraints for organs at risk
RT Technique
RT has a major role in the curative treatment of vulvar
cancer. Intensity-modulated RT (IMRT) provides
increased tumor control and reduces normal tissue
complications.[] Beriwal et al.[] comparing threedimensional
conformal RT (3DCRT) plans with IMRT plans in 15 vulvar cancer patients demonstrated that
mean bowel, bladder, and rectum doses were significantly
lower with IMRT plans. A few studies investigating
the role of CRT in the treatment of vulvar cancer
used IMRT as a RT technique and reported that
IMRT with concurrent chemotherapy is well tolerated,
with good pathologic response rates and clinical outcomes.[-] Bloemers et al.[] comparing 3DCRT,
sequential IMRT, IMRT with simultaneous integrated
boost (SIB), and IMRT with dose-escalated (increased)
SIB also reported that all IMRT techniques have lower
mean doses in organs at risk than 3DCRT techniques
without compromising the dosimetric coverage of the
target. The results of the ongoing GOG 279 trial using
the IMRT technique are pending. Based on these
findings in the literature, IMRT is recommended for
the treatment of vulvar cancer. The definitive treatment
planning belongs to a patient with Stage IB vulvar cancer
is shown in Figure 1.
Fig 1: The treatment planning belongs to a patient with Stage IB vulvar carcinoma who received 50.4 Gy in 28 fractions
to pelvic and inguinofemoral lymphatics, a boost dose of 10 Gy in five fractions to inguinal gross lymph node, and
a boost dose of 16.2 Gy in nine fractions to the primary vulvar lesion with concurrent weekly cisplatin. (a, b) Axial
images of computed tomography showing delineation of inguinofemoral lymphatics and the vulva for the first
phase of the treatment. (c, d) Axial images of computed tomography showing delineation of the primary vulvar
lesion and inguinal gross lymph node metastasis for the second phase of the treatment, respectively. (e, f) Axial
and coronal images of computed tomography showing dose color wash of the first phase of the treatment. Green
isodose line shows 95% dose color wash of the treatment planning for a total dose of 50.4 Gy. (g, h) Axial images
of computed tomography showing dose color wash of the second phase of the treatment. Yellow isodose line shows
95% dose color wash of the treatment planning for a total dose of 66.6 Gy and green isodose line shows 95% dose
color wash of the treatment planning for a total dose of 60.4 Gy.
Gy: Gray.
