Mgmt vulva and vagina cancers

MANAGEMENT OF VULVAR AND VAGINAL
CANCERS
DR. ASHUTOSH MUKHERJI

• The labia majora are
the most common site
of vulvar carcinoma
involvement and
account for about 50%
of cases.
• The labia minora
account for 15% to
20% of vulvar
carcinoma cases.
• The clitoris and
Bartholin glands are
less frequently
involved.
• Lesions are multifocal
in about 5% of cases.
3

• Constitutes
– 5% of all the malignancies of female genital tract
– 0.6% of female cancer
• Estimated new cases and deaths from vulval cancer
in the United States in 2015
– New cases: 5150
– Deaths: 1080
• Rare malignancy (28th) in the United States and
accounts for 0.3% of all new cancers.
• The disease spreads by both local extension and
lympho-vascular embolization.
4

• A disease of older women.
• Delayed diagnosis is typical, despite vulva being an
external organ.
• Vulvar cancer is most frequently diagnosed among
women aged 75-84.
• Median Age at Diagnosis is 68 years.
5

• Since last 60-70 years, radical vulvectomy and
inguino-femoral node dissection has been standard
treatment for squamous cell carcinomas of the vulva.
[4]
• Lymph-node involvement represents the most
important prognostic factor for recurrence and
survival [5].
• The 5-year disease-specific survival in patients with
negative inguino-femoral lymph nodes is 70-93%
but in node positive disease is 25–41%.
6

• Lymphatic metastases from lateralized lesions do not
cross over without ipsilateral metastatic disease
while spread from midline lesions can be identified in
either or both groins.
• Pelvic lymph node dissection routinely performed in
patients with a node positive groin dissection
• In recent years there has been a shift towards less
morbid surgery with an increasing role of adjuvant
irradiation and now recently even pre-operative
irradiation or chemo-radiation.
7

8
SEER 9 Incidence & U.S. Mortality 1975-2012, All Races, Females.
Rates are Age-Adjusted

TYPES OF VULVAR CANCER
Basloid or warty type
• multifocal
• In younger
• Related to HPV infection
• Vulvar Intraepithelial
Neoplasia
• Cigarette smoking
10
Keratinizing type
• Unifocal
• In older
• Not related to HPV
• In area adjacent to lichen
sclerosis and Squamous
hyperplasia(80%)
• VIN uncommon -
Differentiated type

Etiology - HPV
• Approximately, 40% vulvar cancers are HPV (Human Papilloma
Virus) Positive.
• Of these HPV positive invasive vulvar cancers – 85% are
attributed to HPV 16.
• Prophylactic HPV vaccines have the potential to decrease the
incidence of invasive vulvar cancer by about one-third overall,
and to be even more effective in younger women.
Smith JS et al.
Human Papillomavirus Type-Distribution in Vulvar and Vaginal Cancers and Their
Associated Precursors
Obstet Gynecol. 2009; 113:917-24
11

• The International Society for the Study of
Vulvovaginal Disease (ISSVD) in 2004 officially
divided VIN into two types:
– VIN Usual Type – HPV infection related (warty/ basaloid
/mixed)
– VIN Differentiated Type - unrelated to HPV infection
• The older classification of VIN 1, 2, and 3 was based
on the degree of histologic abnormality, but there is
no evidence that the VIN 1 to 3 morphologic
spectrum reflects a biologic continuum, or that VIN 1
is a cancer precursor
12

• Differentiated VIN had a higher risk of malignancy
(85.7%) than
– usual VIN (25.8%),
– lichen sclerosus (27.7%) or
– Squamous hyperplasia (31.7%).
13
Eva et al.
Differentiated type VIN has a high-risk association with vulval
squamous cell carcinoma
Int J Gynecol Cancer 2009;19:741-744

• Possible signs of vulvar cancer include bleeding or
itching.
– A lump or growth on the vulva.
– Changes in the vulvar skin, such as color changes or
growths that look like a wart or ulcer.
– Itching in the vulvar area, that does not go away.
– Bleeding
– Tenderness in the vulvar area.
14

15
• If the groin nodes
are enlarged the
odds of finding
cancer is 59% -
76%
• If the groin nodes
are not enlarged
the odds 25-35%
(16-24%)
• If there is cancer
in the groin nodes
the odds of cancer
in the pelvic
nodes is 28 - 30%

• Until the 1980’s, the standard therapeutic approach was radical
surgery, including complete en bloc resection of the vulva and
regional lymph nodes.
• In tumors clinically confined to the vulva or perineum, radical
local excision with a margin of at least 1 cm has generally
replaced radical vulvectomy.
• separate incision has replaced en bloc inguinal node dissection;
ipsilateral inguinal node dissection has replaced bilateral
dissection for laterally localized tumors; and femoral lymph
node dissection has been omitted in many cases.
24

Modern Treatment
• Early Stage: Radical Local Excision
• More Advanced: Modified Radical Excision with
Sentinel Node Biopsy
• Advanced Stage: Radiation plus Chemotherapy
(chemoradiation) possibly followed by limited
surgery.
• Sentinel Node Biopsy:
– Node metastases identified in 26% of sentinel node
procedures, and these went on to full inguinofemoral
lymphadenectomy. Those with negative sentinel nodes
had no further therapy.
25

INDICATORS OF POOR PROGNOSIS
• Advanced disease stage
• Inguino-femoral nodal disease with or without pelvic
lymph nodes.
• Two or more nodes
• Extracapsular spread
• Large size of the metastases (> 10 mm).
27

Indications for Chemoradiation
• Anorectal, urethral, or bladder involvement (in an effort to
avoid colostomy and urostomy)
• Disease that is fixed to the bone
• Gross inguinal or femoral node involvement (regardless of
whether a debulking lymphadenectomy was performed)
28
Based on studies such as by Heaps et
al on resection margins (higher risk
below 8mm)
GOG Protocol 36 on tumor size and
LVSI (larger than 4 cm and lympho-
vascular invasion associated with 21%
risk of local recurrence compared to
9% without).

Adjuvant irradiation / chemo-radiation for
perineum
• Indications based on GOG studies
• Advanced lesions (T3, T4) have been found to benefit more
from doses higher than 60 Gy with improvement in local
control from 62% to 80%.
• Re-excision may not be sufficient in view of the negative
prognostic implications of many risk factors,
• In cases with close margins along with factors such as depth
of invasion >5 mm and/or positive lympho-vascular space
invasion; adjuvant radiation should be considered.
• Recommended dose 45-50 Gy.
29

Elective irradiation / chemo-radiation for groin nodes
• Standard treatment of vulvar cancer with a clinically negative
groin has been radical vulvectomy or wide local tumor
excision with bilateral inguino-femoral node dissection.
• But less than 20% patients will have pathologically proven
nodal disease and would have unnecessarily undergone nodal
dissection and its attendant morbidities.
• A reasonable alternative could be elective groin irradiation.
An early report from the University of Florida treated patients
with N0-1 nodes with elective bilateral groin irradiation to 45
Gy in 5 weeks and observed no groin failures or treatment
complications.
30

Radiation Instead of Surgery for Lymph Nodes
• About 20-35% of patients will be found to have
spread to the groin lymph nodes.
• Small study (University of Florida) compared surgery
with radiation to the groin and there were more
relapse in the radiation group (18% versus 0%) so the
study was discontinued.
• Women with positive groin nodes were randomized
between pelvic node surgery or radiation.
• Radiation was superior with better survival (51%/6y
versus 41%) with lower vulva cancer mortality (29%
versus 51%) and less chronic lymphedema (16% s
22%).
31

• GOG 37 created indications for adjuvant radiotherapy and in view
of the high morbidity associated with radical inguinal node
dissection;
• GOG 88 compared radical vulvectomy and elective inguinal node
radiotherapy with standard superficial and deep inguinal node
dissection.
• This trial was however stopped after the interim analysis revealed
an unacceptably higher rate of nodal failure and death in the
radiotherapy arm.
32

• Caused by under-dosing of the nodal bed from single anterior
field used and dose prescribed to a depth of 3cm, whereas
pelvic CT imaging shows that average depth of femoral nodes
is about 6 cm. In contrast GOG 37 used AP-PA fields.
• Thus presently elective irradiation of groin nodes is not
recommended outside a trial protocol and that also only in
low risk cases and with adequate CT based treatment
planning to completely cover the nodal bed.
33

Neoadjuvant chemo-radiotherapy
• 5-FU or cisplatin alone or in combination with or without
mitomycin-C have been most commonly used in vulvar cancer. A
GOG study in patients with advanced vulvar cancer examined
outcomes of preoperative chemo-radiotherapy in reducing extent
of surgery.
• Nearly half the patients (46.5%) had no visible vulvar disease at the
time of planned surgery, and only 2.8% had residual unresectable
disease. Similar series have been reported from University of
California and Loma Linda University.
• This approach would be desirable for midline tumors in which
excising any residual disease could still affect clitoral or sphincter
function, despite tumor regression. 34

Definitive Chemo-radiation
• Is still debatable whether definitive chemo-radiation is better than
preoperative chemo-radiation and surgery mainly because of the
paucity of large randomized trials
• There is now encouraging evidence for definitive chemo-radiation
to allow organ preservation in place of extensive mutilating surgery
for locally advanced vulvar cancer.
• Elderly patients or those medically unfit for radical surgery can also
be successfully treated with radiation therapy alone.
• Several sizable series from the United States and Europe have
noted long term survival rates of between 20% and 45% in
advanced cases.
35
Moore DH, Thomas GM, Montana GS, et al. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the
Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys, 1998; 42:79-85.
Cunningham MJ, Goyer RP, Gibbons SK, et al. Primary radiation, cisplatin, and 5-fluorouracil for advanced squamous carcinoma
of the vulva. Gynecol Oncol, 1997; 66: 258-61.

Radiation for recurrent disease
• These cases can be salvaged occasionally with external beam
radiation, sometimes in combination with radiation implants.
• Failure in the groin is almost never salvaged whereas perineal
failures can be successfully managed depending on the extent of
disease.
• Factors indicating better prognosis even in recurrent disease
include smaller primary recurrence (5 cm or less), size of the groin
recurrence (2 cm or less), lack of perineal skin involvement, lack
of tissue necrosis, and higher radiation doses.
• Aggressive treatment of recurrent vulvar cancer should only be
reserved for patients with localized disease and with a reasonable
performance status.
36

PALLIATIVE RADIOTHERAPY
• Is indicated for advanced local disease, metastatic spread, or
significant co-morbidities in patients
• To palliate symptoms such as bleeding, ulceration, necrosis,
pain, and malodourous discharge.
• Palliative regimens such as 2,500 cGy in 10 fractions are
usually recommended.
37

RADIOTHERAPY TECHNIQUE AND PLANNING
• When treating the vulva alone, an appositional perineal field
is used with the patient in the lithotomy position.
• The beam energy used should cover the required depth.
• If the tumor cannot be adequately encompassed, an anterior-
posterior photon field is used with the patient in the frog-leg
position to minimize dose to the inner thighs.
• A bolus is used to ensure full dose to the mucosa and skin
where indicated.
38

RADIOTHERAPY TECHNIQUE AND PLANNING
• In preoperative RT, portals include the groin, perineum, and
low pelvic lymph nodes;
• In the adjuvant setting, AP-PA fields are used to cover both the
vulvar and nodal bed in one treatment portal. The CTV should
include entire operative bed, and for close or positive margins,
a margin of approximately 2 cm from the bed.
• If this results in irradiation of significant normal perineal tissue,
a central shield is placed in the AP-PA fields and a direct
perineal field used to treat the vulva.
• When electrons are used for the perineal field, care needs to be
taken as overlap of divergent beams can create hot spots, a
critical area being the medial divergence of the
anterior/posterior photon beam into the perineal field. 39

40
WIDE AP AND
NARROW PA FIELDS
MATCHED AP-PA WITH
LATERAL INGUINAL
ELECTRON FIELDS

• Patients should be simulated and treated with consistent
bladder and rectal filling if possible (i.e., comfortably full
bladder and empty rectum).
• If the vagina is involved, the simulation can be performed
with both a full and empty bladder to create an internal target
volume (ITV) for the vaginal region.
41

• For lesions involving the vagina (proximal to the hymenal
ring), the CTV should include a 3-cm margin on the GTV. For
any uncertainty regarding the proximal extent of tumor or if
LVI is present, the entire vaginal length should be included in
the CTV.
• Post-dissection nodal CTV includes surgical clips, seroma,
femoral vessels plus appropriate margins, scar, and
subcutaneous tissues in between CTV extends at least 2cm
along the urethra
42

• For lesions involving the anus or anal canal, bladder, or
rectum, the CTV margin should extend at least 2 cm into the
anorectum (or bladder).
• For periurethral lesions, the CTV margin should extend at least
2 cm along the urethra. If disease extends to the mid- or
proximal urethra, the entire urethra and bladder neck should
be included in the CTV.
• For periclitoral lesions, the CTV should include at least a 2-cm
margin on the GTV. In many cases, the CTV should cover the
suspensory ligament of the clitoris, which extends to the
pubic bone.
43

44
Clinical Situation Recommended dose schedule
Adjuvant RT to inguino-femoral nodes 4500 - 5000 cGy with fractions of 180 - 200 cGy
Adjuvant RT to perineum
4500 - 5000 cGy with fractions of 180 - 200 cGy;
T3 or T4 lesions may be considered for doses over
60 Gy or with ECE, + margin
Elective RT to inguino-femoral nodes 4500 - 5000 cGy with fractions of 180 - 200 cGy
Definitive chemo-RT 6200 to 6400 cGy in 200cGy fractions
Pre-operative chemo-RT
4000 – 5000 cGy in fractions of 180-200 cGy (lesser
fraction size if concurrent chemo given).
Palliative radiotherapy 2500 cGy in 10 fractions

BRACHYTHERAPY
• Interstitial implantation treatment option for patients with
locally advanced or recurrent vulvar disease or in medically
inoperable patients;
• Is especially useful for lesions near the clitoris or urethra where
surgery would definitely result in loss of organ function.
• The potential morbidities include fistula formation and
ulceration due to non-uniform dose distribution and hot spots.
• CT planning prevents this by proper anatomical assessment of
needle placement as well as dosimetric analysis.
50
Erickson B, Gillin MT. Interstitial implantation of gynecologic malignancies. J
Surg Oncol, 1997; 66: 285-95.

55
Clinical
Situation
RCOG recommendation FIGO recommendation
Early stage
disease
Surgery considered complete therapy.
Role of lymph node dissection debatable.
Sentinel node dissection considered
adequate to decide on further nodal
dissection. (Category B)
Surgery is primary modality with sentinel
nodal dissection considered adequate to
assess nodal disease.
Stage III
disease with
groin nodes
Surgery is the cornerstone of therapy for
the groin nodes in women with vulval
cancer. (Category A)
Individual women who cannot be
optimised to surgery can be treated with
primary radiotherapy.
Surgery primary modality of therapy. Nodal
dissection may be limited to inguino-femoral
dissection. Pelvic lymphadenectomy is
associated with increased morbidity. (Level 1)
Adjuvant RT to
inguino-
femoral nodes
-
Substantial clinical benefit of adjuvant
radiotherapy especially for patients with two
or more lymph-node metastases or extra-
capsular extension. (Level 1)
Adjuvant RT to
perineum
-
Current recommendations include close or
positive margins, depth of invasion more than
5 mm, lympho-vascular invasion, or an
infiltrative pattern of growth

56
Clinical Situation RCOG recommendation FIGO recommendation
Elective RT to
inguino-femoral
nodes
-
Elective irradiation of groin nodes not recommended outside
trial protocol and only in low risk cases with adequate CT
based treatment planning. This may be useful and less morbid
substitute for bilateral groin dissection in low risk patients but
cannot be strongly advocated at this time without further
prospective evaluation
Definitive chemo-
RT
Individual women who cannot be
optimized to surgery can be treated
with primary radiotherapy.
Reported in many single institution series with high response
rates. Role vis-à-vis pre-operative chemo-RT is still debatable.
Those patients not fit for surgery can also be considered for
radical RT. (Level 2b)
Pre-operative
chemo-RT
-
May be considered in trial protocols. GOG study has shown
benefit in reducing extent of surgical resection.
Recurrent disease
Primary and recurrent vulval cancer
does respond to chemotherapy but
responses are variable and toxicity may
be a problem in this population of
patients. (Category C)
Better prognosis even in recurrent disease include smaller
primary recurrence (5 cm or less), size of the groin recurrence
(2 cm or less), lack of perineal skin involvement, lack of tissue
necrosis, and higher radiation doses. Aggressive treatment of
recurrent vulvar cancer only for patients with localized disease
and reasonable performance status.
Palliative
radiotherapy
-
For advanced local disease, metastatic spread, or significant
co-morbidities in patients to palliate symptoms such as
bleeding, ulceration, necrosis, pain, and malodourous
discharge

• Primary carcinomas of the vagina represent 1–2% of
malignant neoplasms of the female genital tract.
• In the United States, it is estimated that there will be 3,170
new cases diagnosed in 2014, and 880 deaths from the
disease
• Like cervical cancer, squamous cell histology accounts for 70–
80% of cases.
• 84% of carcinomas involving the vagina were secondary,
usually from the cervix (32%); endometrium(18%); colon and
rectum (9%); ovary (6%); or vulva (6%).
58

• more than 50% of patients are diagnosed in the seventh,
eighth, and ninth decades of life.
• The mean age of the patients is approximately 67 years,
although the disease occasionally is seen in the third and
fourth decades of life. About 80% of patients are older than
50 years.
59

• Over 90% of high-grade VAIN 2–3 lesions and 70% of vaginal
cancers are associated with HPV infections. The true
malignant potential of vaginal intraepithelial neoplasia (VAIN)
is unclear because after diagnosis, the condition is usually
treated.
• HPVs 16 and 18 are associated with over 60% of high-grade
VAIN and 40% of low-grade VAIN
• Role of prophylactic HPV vaccines is unknown
• Prior pelvic radiation therapy has been considered a possible
cause of some vaginal carcinomas.
• Chronic local irritation from long-term use of a pessary may
be associated with vaginal cancer.
• Estimated risk of clear cell adenocarcinoma in DES exposed
offspring was 1:1,000 or less, and 70% of cases were stage I at
diagnosis
60

• Most lesions of vaginal cancer occur in the upper vagina.
• Definitive diagnosis is by biopsy of the suspected lesion.
Cervical and vulvar cancer primaries should be excluded, and
may require multiple biopsies of these areas.
• Examination of the perianal area to rule out a synchronous
anal cancer should be performed.
• If a lesion is not visualized in the presence of abnormal
cytologic results, colposcopy of the cervix and vagina must be
performed with acetic acid followed by Lugol’s iodine stain
(Schiller’s test).
61

TREATMENT
• A variety of non-radiotherapy treatment options are available
for therapy of VaIN including: excision (Grade B), CO2 ablation
(Grade B), and topical 5-fluorouracil (5-FU) chemotherapy
(Grade B) with recurrence rates after the first treatment
ranging from approximately 0% to 60% depending on the
series.
• Brachytherapy has been used in the treatment of VaIN with
EQD2 doses of 70-80 Gy2.
• Radiation therapy is the treatment of choice for most patients
with invasive squamous cell carcinoma (Grade B).
• Surgery has a limited role in part because of the close
proximity of the bladder and rectum.
63

• Surgery is mainly limited to disease for stage I patients
involving the upper posterior vagina.
• In patients with an intact uterus, upper vaginectomy to
achieve at least 1-cm margins, and pelvic lymphadenectomy
may be performed (Grade C) (FIGO 2006).
• In patients with a prior hysterectomy, radical upper
vaginectomy and pelvic lymphadenectomy may be an option
(Grade C) (FIGO 2006).
• In patients with Stage IVA disease, especially if a recto-vaginal
or vesico-vaginal fistula is present, primary pelvic exenteration
with pelvic lymphadenectomy or pre-operative radiation is an
option. If the lower third of the vagina is involved, bilateral
groin dissection should be considered (Grade C) (FIGO 2006).
• In patients with a central recurrence after radiation therapy,
pelvic exenteration may be necessary (Grade C) (FIGO 2006).
64

• MD Anderson Data (1970 – 2000): 193 patients;
treated with RT
• At 5 years, disease-specific survival (DSS) rates were
– 85% for the 50 patients with stage I,
– 78% for the 97 patients with stage II, and
– 58% for the 46 patients with stage III–IVA disease.
65

67
MD ANDERSON GUIDELINES ON VAGINAL RADIOTHERAPY
BASED ON LOCATION AND SIZE

68
SMALL VOLUME FIELD
LARGE VOLUME FIELD

• For stages I–IIA (IIA = FIGO II), a “small treatment volume”
four-field technique with the superior edge at the bottom of
the SI joints is recommended
• For stages IIB–IVA (IIB = FIGO II with parametrial involvement)
a “large treatment volume” four-field technique is
recommended.
• Shrinking field techniques, and three-dimensional conformal
radiotherapy (3D-CRT) can be used to dose escalate if
brachytherapy is not feasible.
• For posterior vaginal tumors, an EBRT boost is recommended
to minimize the risk of rectal complications from an interstitial
or intracavitary brachytherapy boost (Grade C).
69

• Margins of 15–20 mm from vessel to field edge are
reasonable when designing pelvic fields.
• CT simulation with vessel contouring as a surrogate for lymph
node localization provides more precise and individualized
field delineation (Finlay et al 2006).
• The open or “frog leg” position is useful when treating the
inguinal area to minimize skin reactions from skin folds.
• A small radio-opaque marker seed inserted in the distal
portion of the tumor may help when designing the treatment
fields.
• Elective irradiation of the inguinal nodes is recommended for
tumors involving the lower third of the vagina (Grade B), and
the rates of inguinal failure are less than 1% with this practice
70

• If the inguinal lymph nodes are involved, the modified
segmental boost technique can minimize dose inhomogeneity
compared to traditional techniques (Grade D)
71

72
ANTERIOR
ANTERIOR OBLIQUE
POSTERIOR
DOSE DISTR.
SEGMENTAL BOOST FIELDS

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