]
The E6 and E7 oncoproteins of HPV induce carcinogenesis
by inactivating tumor suppressor genes. Approximately
90?95% of vulvar cancers are squamous
cell carcinoma (SCC), while the rest are tumors such
as melanoma, basal cell carcinoma and sarcoma.
[,,] VIN (Vulvar Intraepithelial Neoplasia) is the
precursor lesion of vulvar SCCs and accordingly the
disease is divided into 2 main categories: HPV dependent
(dVIN) and independent type (uVIN). The
HPV-dependent variant is observed in younger populations and is significantly correlated with smoking.
Despite a 5% progression rate to invasive SCC,
it constitutes roughly 40% of vulvar SCC cases.[,]
The HPV-independent type is caused by chronic diseases
such as lichen sclerosus and lichen planus. The
risk of malignant transformation is greater than that
of uVIN. The keratinizing subtype constitutes 60-
80% of vulvar squamous cell carcinoma cases, while
the remaining subtypes are warty and basaloid SCC.
The warty and basaloid subtypes manifest at earlier
ages and are linked to HPV, whereas the keratinized
type appears at older ages and typically occurs independently
of HPV.[,] The predominant symptom
of the disease is pruritus; however, hemorrhage,
discharge, dysuria, discomfort, and mass-related
symptoms may also be present. In cases of suspected
vulvar cancer, a pelvic examination, speculum examination,
and colposcopy of the vulva and vagina
should be performed; the definitive diagnostic procedure
for the disease is biopsy.[] The conventional
management for vulvar squamous cell carcinoma is
surgical excision, adjuvant radiotherapy and/or chemotherapy
may be recommended if there are factors
that increase the risk of recurrence as a result of surgical
pathology.[,,] This review aims to provide
information about the indication, field, technique
and doses of radiotherapy in vulvar SCC.
RADIOTHERAPY IN VULVAR SQUAMOUS CELL
CARCINOMA
Once vulvar cancer is diagnosed, the disease should
be staged. Staging can be done according to TNM
system or FIGO system.[,] Tumor size, stromal
invasion, involvement of adjacent pelvic structures,
lymph node metastasis status and presence of distant
metastasis are taken into account in disease staging.
During staging, the assessment of neighboring pelvic
structures (rectum, anus, urethra, vagina) is crucial.
Ultrasound and pelvic MRI are proficient in assessing
the local progression of the tumor and the inguinofemoral
lymph nodes. The use of T2WI, DWI and
DCE-MR modalities is recommended. FDG PET/
CT may be used when there is a suspicion of distant
metastases in advanced illness or involvement of inguinofemoral
lymph nodes.[,]
The principal intervention for vulvar squamous cell
carcinoma is radical local excision.[,]
While the objective in surgery for many years
was to secure a minimum of 8 mm negative margin, new studies have diminished the significance of
this threshold, emphasizing instead the necessity of
obtaining tumor-negative surgical margins.[-]
Treatment is indicated for inguinal lymph nodes with
> T1a malignancies. Midline tumors necessitate bilateral
inguinal surgical assessment. Sentinel lymph
node assessment is advised for patients with tumors
less than 4 cm, unifocal, and clinically negative lymph
nodes. Inguinofemoral lymphadenectomy is advised
for patients with tumors measuring ≥4 cm and/or
exhibiting multifocality. During lymphadenectomy,
both superficial and deep femoral lymph nodes must
be removed. Should metastases be identified in the
ipsilateral lymph nodes, contralateral lymphadenectomy
may be conducted. Radiotherapy for vulvar
squamous cell carcinoma will be analyzed in two categories:
Primary and postoperative radiotherapy.
Primary Radiotherapy in Vulvar Squamous Cell
Carcinoma
Neoadjuvant and definitive radiation are regarded
as primary forms of radiotherapy. The GOG 101
and GOG 205 phase 2 studies are significant investigations
assessing neoadjuvant radiation in locally
advanced vulvar carcinoma. In these experiments,
three-dimensional radiotherapy (3DRT) was employed
as the radiation method. In GOG 101, 73
patients with stage 3?4 vulvar squamous cell carcinoma
had split-course radiation in conjunction
with simultaneous administration of cisplatin and
5-fluorouracil.[] Following radiotherapy, patients
received extensive tumor resection and inguinofemoral
lymphadenectomy. Radiotherapy dose was 47.6
Gy/1.7 Gy. On chemotherapy administration days, 2
fractions were given daily. In clinical N2-3 patients,
the radiation field encompasses the primary vulvar
tumor, inguinofemoral lymph nodes, and lower pelvic
nodes, whereas in other stages it just includes
the primary vulvar tumor. Post-chemoradiotherapy,
48% of patients exhibited no detectable malignancy.
Of these patients, 3 did not undergo surgery and it
was determined that 70% of the patients who went
to surgery had no residual microscopic disease. Urinary
and/or gastrointestinal continence could not be
maintained in only 3 patients. Cutaneous toxicity and
problems related to surgical wounds were the predominant
treatment toxicities. The study indicated
that neoadjuvant chemoradiotherapy is an effective
treatment that diminishes the necessity for pelvic exenteration
in advanced vulvar squamous cell carcinoma.
In the GOG 205 study, patients with locally advanced T3-4 vulvar squamous cell carcinoma, which
was inoperable with routine radical vulvectomy, received
chemoradiotherapy followed by excision of
remaining tumor.[] Cisplatin was administered
weekly as concomitant chemotherapy. The dose of
radiotherapy was 57.6 Gy/1.8 Gy. In contrast to GOG
101, a divided course regimen was not favored in radiotherapy.
A radical vulvectomy was conducted 6 to
8 weeks post-chemoradiotherapy. The overall clinical
response rate was 64%, whereas the pathological
complete response rate was 50%. The predominant
adverse effects included leukopenia, discomfort, and
radiation dermatitis. The study concluded that concurrent
radiation and cisplatin for locally advanced
vulvar SCC is a treatment approach characterized by
a good response rate and acceptable toxicity levels.
The NCDB review compared definitive chemoradiotherapy
with radiation in 1352 unresectable
patients.[] The median dose of radiation administered
was 59.4 Gy. In the chemoradiotherapy cohort,
65.2% underwent single-agent chemotherapy, whereas
30.6% received multiple-agent chemotherapy. The
analysis revealed that the 5-year overall survival rate
was considerably greater in the chemoradiotherapy
group (49.9% compared to 27.4%). A prospective
study by Montana involved surgery following preoperative
chemoradiotherapy in individuals with vulvar
cancer classified as N2-3.[] The GOG 101 regimen
was implemented in the chemotherapy and radiation
procedure. Surgery was conducted 3 to 8 weeks following
the chemoradiotherapy regimen. During the
procedure, excision of the residual vulvar lesion and
bilateral inguinofemoral dissection were conducted.
Following chemoradiotherapy, the resectability rate
of the lymph nodes was determined to be 95%, the
local control rate for the lymph nodes was 97%, and
the local control rate for the primary tumor was
76%. Preoperative chemoradiotherapy is an effective
treatment approach that yields a high rate of resectability
and local control in locally advanced vulvar
cancer. In the phase 2 study, definitive chemoradiotherapy
was administered to 52 patients with locally
advanced vulvar carcinoma.[] Capecitabine was
administered in conjunction with chemotherapy.
64.8 Gy was designated for the tumor and 50.4 Gy
for the elective lymph nodes. The predominant > G2
acute adverse events were skin/mucosal reactions
(54%) and discomfort (37%). The predominant > G2
late adverse effect was skin/mucosal reaction (10%).
Following 12 weeks of treatment, the local clinical
complete response rate was 62%, while the regional control rate was 75%. The 5-year progression-free
survival (PFS) rate was 45%, while the overall survival
(OS) rate was 52%. The study highlighted that
capecitabine-based chemoradiotherapy for vulvar
cancer should be considered an alternative to major
surgery, demonstrating satisfactory locoregional
control and survival rates. In the prospective study
conducted by Beriwal, preoperative chemoradiotherapy
was applied to 18 vulvar cancer patients with the
intensity modulated radiotherapy (IMRT) technique.
[] 5-FU and cisplatin were administered concurrently.
A hybrid hyperfractionated regimen was employed
in split-course radiotherapy. The median dose
of radiation administered was 46.4 Gy. In the cohort
of patients who underwent surgery following treatment,
the rate of pathological complete response was
64%. The 2-year cause-specific survival rate was 75%,
whereas the overall survival rate was 70%. A significant
observation was that no patient experienced
grade 3 or higher acute or late adverse effects attributable
to radiation. It was concluded that preoperative
chemoradiotherapy with IMRT technique is an effective
and highly tolerable treatment modality in vulvar
cancer. The retrospective study by Rishi assessed
the outcomes of high-dose radiation administered to
26 vulvar cancer patients with the IMRT technique.
[] The majority of patients underwent platinumbased
concomitant chemotherapy. The median dosage
was 65.4 Gy. A complete response was achieved
in 80.7% of patients. The one year local, regional, and
distant control rates were 72.4%, 85.4%, and 86%, respectively.
The overall survival rates at 1 and 2 years
were established at 91% and 62%, respectively. Grade
3 late soft tissue toxicity/dermatitis was noted in 5
patients, 3 of whom had previously undergone radiotherapy
to the pelvic area. Grade 4 dermatitis was not
seen in any patient. A tumor dosage above 66 Gy and
prior pelvic irradiation were identified as predictive
variables for Grade 3-4 toxicity. It was emphasized
that the high dose given with IMRT in vulvar cancer
is a treatment with a successful control rate and acceptable
toxicity. The retrospective study by Richman
assessed the outcomes of dose escalation in patients
undergoing neoadjuvant or definitive chemoradiotherapy
with the IMRT technique.[]
In the study, the median dose was 66 Gy for those
receiving definitive treatment and 59.4 Gy for those receiving
preoperative treatment. The study's results indicated
that dose escalation using IMRT is a tolerated
treatment associated with a high complete response
rate. Mahantshetty's retrospective study assessed the outcomes of high dose rate interstitial brachytherapy
in vulvar cancer among 38 patients.[] Among the 38
patients, 29 patients received definitive brachytherapy,
6 patients received postoperative brachytherapy and 3
patients received salvage brachytherapy. Brachytherapy
boost was administered to 29 patients, whereas single
brachytherapy was administered to 9 patients. The median
EQD2 dose was 23,3 Gy10 for patients receiving a
brachytherapy boost, compared to a median EQD2 dose
of 38,4 Gy10 for those undergoing single brachytherapy.
A clinical complete response was observed in 30
patients during the 3-month control evaluation following
treatment. At a median follow-up of 30 months, 29
patients (76.3%) were disease-free. The overall survival
rate at five years was 82%, with disease-free survival at
51% and local control at 77%. Interstitial brachytherapy
for vulvar cancer is recognized as a tolerable treatment
that provides effective control and survival rates.
A Cochrane systematic review evaluated the effectiveness
of preoperative chemoradiotherapy in patients with
advanced vulvar SCC.[] Skin toxicity was observed in
all patients. Common side effects include wound infection,
lymphedema, and lymphocele. The operability rate
ranged from 63% to 92%. Preoperative chemoradiotherapy
is recognized for its role in reducing tumor size and
enhancing operability. However, the efficacy of neoadjuvant
chemotherapy in patients eligible for radical vulvectomy
and bilateral inguinal lymph node dissection
remains unproven. The studies included in the review
comprised patients who received treatment with older
radiotherapy techniques. In the review by Tagliaferi, it
was mentioned that there was no survival advantage in
the patient group receiving chemoradiotherapy in locally
advanced vulvar cancer compared to the primary
surgery group, but the risk of incomplete data and bias
in the literature was expressed.[] Furthermore, it was
noted that the existing literature primarily comprises
retrospective studies and those utilizing outdated radiotherapy
techniques. Modern radiotherapy techniques,
such as IMRT, enable treatments characterized by low
toxicity and high complete response rates. The studies
indicate that definitive/neoadjuvant radiotherapy, administered
concurrently with cisplatin or capecitabinebased
chemotherapy in patients with advanced vulvar
cancer who are inoperable due to tumor or patient-related
factors, demonstrates a high locoregional control rate
and acceptable long-term side effects. According to the
European Society of Gynaecological Oncology (ESGO)
guideline, primary chemoradiotherapy is the main treatment
option for unresectable disease and should be considered
if morbid surgery requiring stoma insertion is necessary. The guideline recommends that treatment
response evaluation after chemoradiotherapy should be
performed 12 weeks after the end of treatment.[9] The
National Comprehensive Cancer Network (NCCN)
guideline also indicates to primary chemoradiotherapy
as the main treatment option for unresectable disease.
[27] Radiotherapy may be administered as external radiotherapy
alone, brachytherapy alone, or a combination
of both modalities, contingent upon the clinic's available
facilities.[,,,-] Important studies on preoperative
and definitive chemoradiotherapy in vulvar cancer
and their findings are shown in Table 1.
Table 1 Important studies on preoperative and definitive chemoradiotherapy in vulvar cancer and their findings
Adjuvant Radiotherapy in Vulvar Squamous
Cell Carcinoma
Adjuvant treatments have been brought to the agenda
due to the high rate of locoregional recurrence after surgery
in vulvar cancer.[,] Adjuvant treatments aim
to minimize the risk of local and regional recurrence.
Bhatla's review indicates that margin status and lymph
node status are the primary factors influencing the decision
regarding adjuvant treatment in vulvar cancer.[]
In a retrospective study conducted by Parthasarathy on
208 patients, the effectiveness of adjuvant radiotherapy
was evaluated in patients with postoperative single inguinal
node positivity.[] The analysis revealed that
5-year disease-specific survival was significantly greater
with adjuvant radiotherapy, at 77% compared to 61.2%.
Survival rates have been observed to improve with the
use of adjuvant radiotherapy in patients who have undergone
excision of 12 or fewer lymph nodes. Kunos
conducted a randomized controlled trial involving 114
patients, categorizing those with operated lymph nodes
into two groups: Radiotherapy and ipsilateral pelvic
node resection.[] Radiotherapy included the pelvic
and inguinal nodes, with a prescribed dose of 45-50
Gy. The study found that adjuvant radiotherapy significantly
reduced local recurrences and cancer-related
deaths, with late toxicities remaining comparable. The
multicenter retrospective AGO-CaRE-1 study demonstrated
that adjuvant radiotherapy was associated with
an increase in 3-year progression-free survival (PFS)
and overall survival (OS) in patients with pathological
lymph node positivity.[] In the subgroup analysis of
the patient group in the AGO-CaRE-1 study, 360 patients
with positive pathological lymph nodes were evaluated.[] Vulvar recurrence was significantly lower in
the group that received radiotherapy to the vulva and
groin/pelvis compared to the group that received radiotherapy
to the groin/pelvis alone and the group that
received no radiotherapy. The recurrence-reducing effect of local radiotherapy is independent of the status
of the resection margin. The effect of radiotherapy on
the vulva in reducing local recurrence was significantly
greater in HPV-positive tumors compared to HPV-negative
tumors. In the multicentric phase 2 GROINSS-V 2
study involving 1535 patients, local excision combined
with sentinel node biopsy was conducted on early-stage
vulvar cancer patients who were clinically lymph nodenegative.[] Inguinofemoral radiotherapy was administered
to patients exhibiting sentinel node positivity.
During the study, the protocol was amended to include
inguinofemoral lymphadenectomy (IFL) when macrometastasis
(>2 mm) was detected in the sentinel lymph
node. In patients receiving radiotherapy with micrometastases
(≤ 2 mm) in the sentinel tumor, the isolated
groin recurrence rate at 2 years was 1.6%. The presence of
macrometastasis in sentinel tumors resulted in a 2-year
isolated groin recurrence rate of 22% for patients receiving
radiotherapy, compared to 6.9% for those undergoing
IFL. Radiotherapy is associated with lower morbidity
compared to IFL. Radiotherapy is acknowledged as a
minimally invasive and safe treatment modality for IFL
in the presence of sentinel micrometastases.
In a database-based retrospective study, the effectiveness
of adjuvant treatment in 2779 inguinal nodepositive
vulvar cancer cases was evaluated.[] Patients
were categorized into two groups: Those with one positive
lymph node and those with more than one positive
lymph node. Adjuvant radiotherapy was shown to
enhance survival in both groups. The incorporation of
chemotherapy into adjuvant radiotherapy demonstrated
a survival benefit for patients with two or more positive
lymph nodes; however, this benefit was not observed in
patients with a single positive lymph node. A database
analysis involving 1,797 patients assessed the effectiveness
of adjuvant chemotherapy in those who received adjuvant
radiotherapy due to node positivity.[] The study
concluded that adjuvant chemotherapy significantly decreased
mortality risk in this patient population.
Postoperative radiotherapy is advised for cases with
close surgical margins, tumor invasion depth exceeding
5 mm, lymphovascular invasion positivity, single lymph
node metastasis with size under 2 mm, as indicated by the
data from the studies. Postoperative chemoradiotherapy
is indicated for patients with positive surgical margins,
single lymph node metastasis greater than 2 mm, two or more lymph node metastases, or extracapsular extension
in lymph node metastases. It is stated that postoperative
radiotherapy should start within 6-8 weeks as soon as the
wound healing process is completed.[,,] According
to ESGO guideline, radiotherapy should be performed
with intensity-modulated radiotherapy techniques.[] The
radiotherapy field image of a vulvar cancer patient who
applied postoperative radiotherapy was shown in Figure 1.
Fig. 1. Radiotherapy field image of a vulvar cancer patient who applied postoperative radiotherapy.
Radiotherapy Technique, Field, Dose/Fraction
Regimes in Vulvar Cancer
In the context of vulvar cancer radiotherapy, the prescribed
dose to the primary surgical bed (with clear
margins) and uninvolved lymph nodes is 45?50.4 Gy
delivered in 25-28 fractions.
In case of a close or positive margin, a dose of 54-60
Gy is defined to the primary site. In case of positive and
gross residual disease with ECE negative lymph nodes,
a radiation dose of 50?55 Gy may be administered to
the affected lymph node. A dose of 54-64 Gy is recommended
for lymph nodes with extracapsular extension
(ECE) positivity. In the presence of gross residual or
unresectable lymph node, a dose of 60-70 Gy is defined
for the relevant lymph node. In the presence of gross
primary disease, a dose of 60-70 Gy should be defined
for the primary region.[,] The primary tumor, the
vulva, and the bilateral inguinofemoral region are all
included in the classical radiotherapy field. Depending
on the primary tumor and lymph node involvement,
pelvic lymph nodes may be included. The lymph node
that is one level above the most involved cranial lymph
node should be treated if the pelvic lymph nodes are involved.
The response rate is high and the toxicity rate is
tolerable in the studies, which is why it is recommended
to use modern planning methods such as IMRT as
an external radiotherapy technique.[-,]
Chemotherapy Regimens in Chemoradiotherapy
Chemoradiotherapy is a critical treatment option for
vulvar cancer, particularly in cases of locally advanced
disease and high-risk early-stage disease. The initial treatment
option for chemotherapy that is administered concurrently
with radiotherapy is cisplatin-based regimens.
The protocol that is most frequently recommended
is to administer cisplatin at a weekly dose of 40 mg/
m2 during radiotherapy.[,] Carboplatin (AUC 2
weekly) is recommended as an alternative option for
patients who are intolerant to cisplatin. The efficacy
of the cisplatin-gemcitabine combination has been
demonstrated in recent studies, particularly in locally
advanced disease, and it has since assumed its place
among the current treatment options.[]
During chemoradiotherapy, it is crucial to manage
toxicity. Weekly complete blood count monitoring,
close monitoring of liver and renal functions and
appropriate hydration support should be provided for
the monitoring and management of hematologic toxicity.
Dose modifications may be necessary in patients
with Grade 3-4 toxicity. Close follow-up and supportive
treatment should be applied especially for mucositis
and skin reactions. The treatment process must
be completed as planned and interruptions should be
avoided, as the local control rates are adversely affected
as the treatment period extends.[]
