Transcript Carcinoma of the Cervix

Epidemiology
 for women aged 20 to 39 years, cervical cancer
remained the second leading cause of cancer deaths
after breast cancer, accounting for about 10% of cancer
deaths.
 Despite the declining death rates in developed
countries cervical cancer remains the leading cause of
cancer deaths among women in many medically
underserved countries, including many countries of
Latin America, Africa, Asia, and eastern Europe.
‫کاهش مرگ در اثر کانسر سرویکس‬
routine screening programs, including pelvic
examinations and cervical cytologic evaluation
2. the death rates from cervical cancer had begun to
decrease before the implementation of Papanicolaou
(Pap) screening, suggesting that other unknown
factors may have played some role.
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International incidences
 cultural attitudes
 screening programs
 liberal attitudes toward sexual behavior
‫اتیولوژی‬
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HPV
prostitutes
first coitus at a young age
multiple sexual partners
bear children at a young age
Promiscuous sexual behavior in male partners
a lower incidence of HPV infection in circumcised
than uncircumcised males, with a correspondingly
lower incidence of cervical cancer in their female
partners.
prophylactic HPV vaccine
 a prophylactic HPV vaccine for women between the
ages of 9 and 26 years; this quadrivalent vaccine has
been demonstrated to be highly effective in preventing
benign warts and neoplasia caused by the most
common HPV types (6, 11, 16, and 18).
‫علل عدم کاهش انسیدانس ادنوکارسینوما سرویکس‬
A. an increase in recognition of cases with glandular
elements as adenocarcinomas
B. cytologic screening methods may be less effective in
detecting adenocarcinomas at a preinvasive stage
‫ارتباط نقص امینی و کنسر سرویکس‬
 The relationship between immunosuppression
(particularly HIV-related immunosuppression) and
the risk of HPV-related disease is complex and
incompletely understood.
 Current data strongly suggest that HIV-related
immunosuppression is correlated with an increased
risk of cervical HPV infection.
 an inverse correlation between CD4+ level and the risk
of HPV infection, and patients with low CD4+ levels
tend to have higher HPV DNA levels.
 (HIV) infection also appears to be associated with a
higher prevalence of CIN and a faster rate of
progression to high-grade CIN.
 Iatrogenic immunosuppression is also associated with
an increased prevalence of CIN.
 risk of progression from CIN to invasive disease and
on the virulence of invasive cervical cancer is less
certain
 Antiretroviral therapy does not appear to affect HPV
levels, and rarely produces regression of CIN 2 or CIN
3 lesions, even with increases in CD4+ levels.
HIV-positive
 Overlapping risk factors tend to confound studies of
the association between HIV and HPV-related cancers.
However, because of the increased risk of HPV
infection in HIV-positive women, vigilant surveillance
with Pap smears, pelvic examinations, and colposcopy
(when indicated) should be part of the routine care of
these women.
Natural History and Pattern of
Spread
 Most arise at the junction between the primarily
columnar epithelium of the endocervix and the
squamous epithelium of the ectocervix.
 This junction is a site of continuous metaplastic
change, which is greatest in utero, at puberty, and
during first pregnancy, and declines after menopause.
The greatest risk of neoplastic transformation
coincides with periods of greatest metaplastic activity.
Virally induced atypical squamous metaplasia
developing in this region can progress to higher-grade
squamous intraepithelial lesions (SILs).
 The mean age of women with CIN is about 15 years
younger than that of women with invasive cancer,
suggesting a slow progression of CIN to invasive
carcinoma.
Natural History and Pattern of
Spread
 CIN 3 disease progressed in only 14%, whereas it
remained the same in 61% and disappeared in the
others
 spontaneous regression in 38% of high-grade HPVassociated SILs.
 mean times to development of carcinoma in situ of 58,
38, and 12 months for patients with mild, moderate, or
severe dysplasia, respectively, and predicted that 66%
of all cases of dysplasia would progress to carcinoma in
situ within 10 years.
Natural History and Pattern of
Spread
 exophytic growths
 endocervical lesions
 Tumor may become fixed to the pelvic wall by direct
extension or by coalescence of central tumor with
regional adenopathy.
 bladder mucosal invasion.
 Rectum invasion
Three groups of lymphatics
 The upper branches: follow the uterine artery, and
terminate in the uppermost hypogastric nodes.
 The middle branches drain to deeper hypogastric
(obturator) nodes.
 The lowest branches follow a posterior course to the
inferior and superior gluteal, common iliac, presacral,
and subaortic nodes.
 The incidence of pelvic and para-aortic node
involvement is correlated with tumor stage and with
other tumor characteristics, such as size, histologic
subtype, depth of invasion, and presence of LVSI
 stage I disease treated with radical hysterectomy, most
investigators report an incidence of positive pelvic
nodes of 15% to 20% and an incidence of para-aortic
nodes of 1% to 5%. Reported incidences are higher for
patients with stage I disease treated with radiation:
10% to 25% of such patients are reported to have
positive para-aortic nodes, reflecting the more
advanced stage I tumors that are usually selected for
treatment with radiation.
pattern of metastas
 Cervical cancer usually follows a relatively orderly
pattern of metastatic progression, initially to primaryechelon nodes in the pelvis and then to para-aortic
nodes and distant sites.
 Even patients with locoregionally advanced disease
rarely have detectable hematogenous metastases at
initial diagnosis of their cervical cancer.
 The most frequent sites of distant recurrence are lung,
extrapelvic nodes, liver, and bone
Cervical Intraepithelial Neoplasia
cervical cytologic findings (important
characteristics ):
 cellular immaturity
 cellular disorganization
 nuclear abnormalities
 increased mitotic activity.
degree of neoplasia
 extensiveness of the mitotic activity
 immature cell proliferation
 nuclear atypia
 If mitoses and immature cells are present only in the
lower third of the epithelium, the lesion is usually
designated CIN 1. Lesions involving only the lower and
middle thirds are designated as CIN 2, and those
involving the upper third are designated as CIN 3.
The term cervical intraepithelial neoplasia, refers only to
a lesion that may progress to invasive carcinoma.
Although CIN 1 and CIN 2 are sometimes referred to as
mild-to-moderate dysplasia, CIN is now preferred over
dysplasia.
The Bethesda system of classification, designed to
further standardize reporting of cervical cytologic
findings, was developed
Squamous intraepithelial lesions
SILs include
 Condyloma
 dysplasia,
 CIN
The Bethesda system divides SILs
 low grade
 high grade(higher likelihood of progressing to
invasive cancer)) CIN2,CIN3)
Bethesda system
 atypical squamous cells of undetermined significance
(ASCUS).
 most common abnormal Pap smear result in United
States laboratories,
 most cases of ASCUS reflect a benign process, about
5% to 10% are associated with an underlying HSIL, and
one third or more of HSILs are heralded by a finding of
ASCUS on a Pap smear.
three methods of management ASCUS or LSIL
 immediate colposcopy
 cytologic follow-up
 HPV DNA testing (ASCUS )
in patients with LSIL, the prevalence of high-risk HPV was
too high to permit useful triage based on HPV DNA
testing, but that in patients with ASCUS, HPV DNA testing
had a sensitivity in the detection of HSIL similar to that of
immediate colposcopy and reduced the number of referrals
for colposcopy by 50%.
Adenocarcinoma In Situ
 About 20% to 50% of women with cervical
adenocarcinoma in situ also have squamous CIN, and
adenocarcinoma in situ is often an incidental finding
in patients operated on for squamous carcinoma.
 is frequently multifocal, cone biopsy margins are
unreliable.
 Although some investigators have described a possible
precursor lesion termed endocervical glandular
dysplasia, the reproducibility and clinical value of this
designation are uncertain
Microinvasive Carcinoma
 definition of microinvasive carcinoma is based on the
maximum depth (no more than 5 mm) and linear
extent (no more than 7 mm) of involvement.
 This requires a cervical cone biopsy
 With the advent of cytologic screening, the
proportion of invasive carcinomas that invade less
than 5 mm has increased more than tenfold to about
20% in the United States
Microinvasive Carcinoma
 The importance of LVSI remains somewhat
controversial
 the risk of metastatic regional disease appears to be
exceedingly low for any tumor that invades less than 3
mm, even in the presence of LVSI.
 many think that the risk of regional spread from
tumors that have invaded 3 to 5 mm is sufficiently high
to warrant treatment of the parametria and regional
nodes.
Microinvasive adenocarcinoma
 measuring the depth of invasion can be difficult.
 a subset of patients with very small adenocarcinomas
have a low likelihood of lymph node metastases or
recurrence. In the absence of a consensus definition of
microinvasion for adenocarcinoma, decisions are
usually guided by specific descriptions of the depth
and extent of invasion and other features that have
been correlated with increased risk, such as high grade
and the presence of LVSI.
Invasive Squamous Cell Carcinoma
A number of systems have been used to grade and classify squamous
cell carcinomas, but none have consistently been demonstrated to
predict prognosis
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large cell keratinizing
large cell nonkeratinizing
small cell carcinoma (poorer prognosis)
Papillary variants of squamous carcinoma
1.well differentiated (occasionally confused with immature
condylomata)
2. very poorly differentiated (resembling high-grade transitional
carcinoma)
 Verrucous carcinoma (DDx benign condyloma )
 Sarcomatoid squamous carcinoma
Adenocarcinoma
 pure or mixed with squamous cell carcinoma
(adenosquamous carcinoma).
 80% of cervical adenocarcinomas are of the
endocervical type
 Minimal-deviation adenocarcinoma (adenoma
malignum) is a rare, extremely well-differentiated
adenocarcinoma that is sometimes associated with
Peutz-Jeghers syndrome.
Adenocarcinoma
Other rare variants of adenosquamous carcinoma include
 adenoid basal carcinoma (favorable prognosis)
 adenoid cystic carcinoma(aggressive behavior )
 endometrioid, serous, or clear cells; mixtures of these cell
types
Anaplastic Small Cell/Neuroendocrine Carcinoma
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Anaplastic small cell carcinoma resembles oat cell
carcinoma of the lung
 About 30% to 50% of anaplastic small cell carcinomas
display neuroendocrine features.
 Widespread hematogenous metastases
Other Rare Neoplasms
 A variety of neoplasms may infiltrate the cervix from
adjacent sites, and this makes differential diagnosis
difficult. Although endometrioid histology suggests
endometrial origin and mucinous tumors in young patients
are most often of endocervical origin, both histologic types
can arise in either site.
 Metastatic tumors from the colon, breast, or other sites
may involve the cervix secondarily.
 Malignant mixed mullerian tumors, adenosarcomas, and
leiomyosarcomas occasionally arise in the cervix but more
often involve it secondarily.
 Primary lymphomas and melanomas of the cervix are
extremely rare.
 Preinvasive disease during routine cervical cytologic
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screening.
Early invasive disease usually detected during screening
examinations
abnormal vaginal bleeding, often following coitus or
vaginal douching.
a clear or foul-smelling vaginal discharge
Pelvic pain
Flank pain (hydronephrosis complicated by pyelonephritis)
The triad of sciatic pain, leg edema, and hydronephrosis is
almost always associated with extensive pelvic wall
involvement by tumor.
hematuria or incontinence from a vesicovaginal fistula
External compression of the rectum by a massive primary
tumor may cause constipation
Diagnosis
 an ideal target for cancer screening
 cervical cytologic examination and pelvic examination
has led to a decrease in the mortality rate
 Only nations with well-developed screening programs
have experienced substantial decreases in cervical
cancer death rates
Screening (The American Cancer Society)
 3 years after the onset of vaginal intercourse, but no later
than 21 years of age
 annually with conventional cervical cytology smears
 every 2 years using liquid-based Pap cytology
( until age 30 years)
 Starting at age 30 years, women who have had three
consecutive, technically satisfactory negative test results may
be screened every 2 to 3 years.
‫موارد قطع اسکرینینگ‬
Women age 70 years and more who have had three
consecutive
2. no abnormal test result within 10 years
3. who have had a total hysterectomy for benign
gynecologic disease.
4. Women with a history of CIN 2 or CIN 3 prior to or as
an indication for hysterectomy should be screened
until they have had three consecutive normal test
results and no abnormal test results for 10 years.
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Women with a history of cervical cancer, women
exposed in utero to diethylstilbestrol (DES), and
women who are immunocompromised should
continue regular screening as long as they are in
reasonably good health.
The rate of false-negative findings on the Pap test is
about
1. 20% to 30% in women with high-grade CIN
2. 10% to 15% in women with invasive cancer.
Dx
 Detection of high endocervical lesions may be
improved when specimens are obtained with a
cytobrush.
 Because hemorrhage, necrosis, and intense
inflammation may obscure the results, the Pap smear
is a poor way to diagnose gross lesions; these should
always be biopsied.
 the sensitivity of a screening program is usually
increased by repeated annual testing. The sensitivity of
individual tests may be improved by ensuring
adequate sampling of the squamocolumnar junction
and the endocervical canal; smears without
endocervical or metaplastic cells are inadequate, and
in such cases the test must be repeated. Because
adenocarcinoma in situ originates near or above the
transformation zone, it may be missed with
conventional cervical smears.
liquid-based Pap methods
 greater sensitivity than conventional Pap smears.
 the likelihood of drying artifact is reduced,
 cellular sampling tends to be better
 the cells are more evenly distributed on the slide.
 Greater sensitivity comes at the cost of somewhat
poorer specificity, which is balanced by the less
frequent need for repetition of the study to achieve
adequate screening.
HPV testing
 although it is not yet recommended for routine
screening, HPV testing of ASCUS smears followed by
colposcopy in patients with HPV-positive lesions
appears to provide a highly accurate and cost-effective
means of detecting HSIL in equivocal smears.
Patients with abnormal findings on cytologic
examination who do not have a gross cervical lesion
must be evaluated with colposcopy and directed
biopsies. Following application of a 3% acetic-acid
solution, the cervix is examined under 10- to 15-fold
magnification with a bright, filtered light that
enhances the acetowhitening and vascular patterns
characteristic of dysplasia or carcinoma. The skilled
colposcopist can accurately distinguish between lowand high-grade dysplasia, but microinvasive disease
cannot consistently be distinguished from
intraepithelial lesions on colposcopy.
In a patient with an atypical Pap smear finding, if no
abnormalities are found on colposcopic examination
or if the entire squamocolumnar junction cannot be
visualized, endocervical curettage should be
performed. Some authorities advocate the routine
addition of endocervical curettage to colposcopic
examination to minimize the risk of missing occult
cancer within the endocervical canal. However, it is
probably reasonable to omit this step in previously
untreated women if the entire squamocolumnar
junction is visible with a complete ring of unaltered
columnar epithelium in the lower canal
Cervical cone biopsy
is used to diagnose occult endocervical lesions and is an
essential step in the diagnosis and management of
microinvasive carcinoma of the cervix.
 Cervical cone biopsy yields an accurate diagnosis and
decreases the incidence of inappropriate therapy when
(1) the squamocolumnar junction is poorly visualized
on colposcopy and a high-grade lesion is suspected, (2)
high-grade dysplastic epithelium extends into the
endocervical canal, (3) the cytologic findings suggest
high-grade dysplasia or carcinoma in situ, (4) a
microinvasive carcinoma is found on directed biopsy,
(5) the endocervical curettage specimens show highgrade CIN, or (6) the cytologic findings are suggestive
of adenocarcinoma in situ.
Clinical Evaluation of Patients with Invasive Carcinoma
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detailed history
physical examination,
complete blood cell count and renal function and liver
function tests
chest radiography
intravenous pyelography (or computed tomography [CT])
Cystoscopy and either a proctoscopy or a barium enema
study should be done in patients with bulky tumors.
CT S or MRI
PET
CT S or MRI to evaluate regional nodes, but these studies
have suboptimal accuracy because they fail to detect small
metastases and because patients with bulky necrotic
tumors often have enlarged reactive lymph nodes that may
be free of metastasis.
PET appears to be a very sensitive noninvasive method of
evaluating the regional nodes of patients with cervical
cancer74 and a useful method for following response to
treatment,80 although its high cost has prevented
widespread routine use.
MRI can provide useful information about the distribution
and depth of invasion of tumors in the cervix but tends to
yield less accurate assessments of the parametrium.
International Federation of Gynecology and Obstetrics Staging of
Carcinoma of the Cervix (1994)
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Carcinoma in situ, intraepithelial carcinoma.
I
The carcinoma is strictly confined to the cervix (extension to the corpus
should be disregarded)
IA
microscopically
Invasion is limited to measured stromal invasion with a maximum depth of
5 mm and no wider than 7 mm. Vascular space involvement, either venous
or lymphatic, should not alter the staging).
IA1
Measured invasion of stroma no greater than 3 mm in depth and no wider
than 7 mm.
IA2
Measured invasion of stroma greater than 3 mm and no greater than 5 mm
in depth and no wider than 7 mm.
IB
Clinical lesions confined to the cervix or preclinical lesions greater than IA
IB1
Clinical lesions no greater than 4 cm in size
IB2
Clinical lesions greater than 4 cm in size
II
The carcinoma extends beyond the cervix, but has not
extended onto the pelvic wall; the carcinoma involves the
vagina, but not as far as the lower third
IIA
No obvious parametrial involvement
IIB
Obvious parametrial involvement.
III
carcinoma has extended onto the pelvic wall; on rectal
examination there is no cancer-free space between the
tumour and the pelvic wall; the tumour involves the lower
third of the vagina; all cases with a hydronephrosis or
nonfunctioning kidney should be included, unless they are
known to be due to other cause.
IIIA
No extension onto the pelvic wall, but involvement of the
lower third of the vagina
IIIB
Extension onto the pelvic wall or hydronephrosis or
nonfunctioning kidney.
IV
The carcinoma has extended beyond the true
pelvis or has clinically involved the mucosa
of the bladder or rectum
IVA
Spread of the growth to adjacent organs
IVB
Spread to distant organs.
Up todate
 TNM stage
 FIGO stage
 T1b =IB :Clinically visible lesion confined to the cervix
or microscopic lesion greater than IA2
 AJCC stage grouping
 adenocarcinoma in situ
Clinical Staging
 FIGO stage is based on careful clinical examination
and the results of specific radiologic studies and
procedures.
 The clinical stage should never be changed on the
basis of subsequent findings.
 When it is doubtful ,case should be assigned to the
earlier stage.
Clinical Staging
 According to FIGO, growth fixed to the pelvic wall by a
short and indurated, but not nodular, parametrium
should be allotted to stage IIb.
 A case should be classified as stage III only if the
parametrium is nodular to the pelvic wall or if the
growth itself extends to the pelvic wall.
FIGO rules for clinical staging,
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Palpation
Inspection
Colposcopy
endocervical curettage
hysteroscopy
cystoscopy
Proctoscopy
intravenous urography
radiographic examination of the lungs and skeleton
 Suspected bladder or rectal involvement should be
confirmed by biopsy
 Findings of bullous edema or malignant cells in
cytologic washings from the urinary bladder are not
sufficient to diagnose bladder involvement
 FIGO specifically states that findings on examinations
such as
1. lymphangiography
2. Laparoscopy
3. CT, and MRI :are of value for planning therapy but
because these are not yet generally available and the
interpretation of results is variable should not be the
basis for changing the clinical stage
 Examination under anesthesia is desirable but not
required.
 The rules and notes outlined in the FIGO staging
system are integral parts of the clinical staging system
and should be strictly observed to minimize
inconsistencies in staging between institutions.
 Although surgically treated patients are sometimes
classified according to a TNM pathologic staging
system, this practice has not been widely accepted
because it cannot be applied to patients who are
treated with primary radiotherapy.
Surgical Evaluation of Regional Spread
 transperitoneal
 extraperitoneal dissection
 laparoscopic lymph node dissection ?
 sentinel node ?
surgical staging(controversial)
 identifies patients with microscopic para-aortic or common
iliac node involvement who can benefit from extendedfield irradiation.
 debulking of large pelvic nodes before radiotherapy may
improve outcome. Because patients with radiographically
positive pelvic nodes are at greatest risk for occult
metastasis to para-aortic nodes, these patients may have
the greatest chance of benefiting from surgical staging
 Some authors have advocated pretreatment blind biopsy of
the scalene node in patients with positive para-aortic nodes
and in patients with a central recurrence who are being
considered for pelvic exenteration. The reported incidence
of supraclavicular metastasis varies widely (5% to 20% or
more) for patients with positive para-aortic lymph nodes.
Prognostic Factors
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FIGO stage
Clinical tumor diameter
presence of medial versus lateral parametrial involvement
presence of unilateral versus bilateral parametrial or pelvic wall
involvement
Lymph node metastasis
LVSI
deep stromal invasion (10 mm or more or more than 70%
invasion)
parametrial extension
inflammatory response
Uterine-body involvement ( distant metastases )
histologic features
histologic grade (adenocarcinomas)
HGB(locally advanced )
 Operative findings often do not agree with clinical
estimates of parametrial or pelvic wall involvement,
and some authors have found that the predictive
power of stage diminishes or is lost when comparisons
are corrected for differences in clinical tumor
diameter.
Other clinical and biologic features that have been
investigated for their predictive power, with variable
results, include :
 Age
 peritoneal cytology
 platelet count
 tumor vascularity
 DNA ploidy or S phase
 cyclooxygenase-2 expression
 growth factor receptors.
 HPV DNA
Treatment
 tumor size
 stage
 histologic features
 evidence of lymph node metastasis
 risk factors for complications of surgery or
radiotherapy
 patient preference.
 HSILs :loop electroexcision procedure (LEEP)
 stage IA1: conservative surgery (excisional conization or
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extrafascial hysterectomy [type I])
stage IA2 and IB1 and some small stage IIA tumors:
modified radical (type II) or radical (type III) hysterectomy
or radiotherapy
stages IB2 through IVA: radiotherapy
Selected patients with centrally recurrent disease after RT
may be treated with radical exenterative surgery
isolated pelvic recurrence after hysterectomy is treated
with irradiation.
the routine addition of concurrent cisplatin-containing
chemotherapy to radiotherapy for patients whose cancers
have a high risk of locoregional recurrence.
Preinvasive Disease (Stage 0)
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HSILs : (LEEP, LEEP conization, or excisional [cold
knife] conization with a scalpel)
LEEP Conization: suspicion of occult invasion on
cytologic or colposcopic examination
ablative therapy ( cryotherapy or CO2 laser ablation
)has declined
low-grade dysplasias are often followed without
treatment
vaginal or type I abdominal hysterectomy for other
gynecologic conditions that justify the procedure
LEEP
 a charged electrode is used to excise the entire
transformation zone and distal canal. Although
control rates are similar to those achieved with
cryotherapy or laser ablation,156 LEEP is more easily
learned, is less expensive than laser ablation, and
preserves the excised lesion and transformation zone
for histologic evaluation. However, low-grade lesions
are overtreated with this method.
LEEP conization or excisional conization
with a scalpel
 microinvasive suspected
 invasive cancer suspected
 adenocarcinoma in situ.
LEEP is an outpatient office procedure that preserves
fertility. Although recurrence rates are low (1% to 5%)
and progression to invasion rare (less than 1% in most
series), patients require careful post-LEEP
surveillance.
Microinvasive Carcinoma (Stage IA)
 stage IA1 :conization or total (type I) or vaginal
hysterectomy. pelvic lymphadenectomy is not usually
recommended.
 Patients who have FIGO stage IA1 disease without LVSI
and who wish to maintain fertility may be adequately
treated with a therapeutic cervical conization if the
margins of the cone are negative. However, patients
who have this conservative treatment must be
followed closely with periodic cytologic evaluation,
colposcopy, and endocervical curettage.
residua
 The likelihood of residual invasive disease after cone
biopsy is correlated with the status of the internal cone
margin and the results of an endocervical curettage
performed after cone biopsy.
 The authors did not find any correlation between the
depth of invasion or the number of invasive foci and
residual invasion.
 Therapeutic conization for microinvasive disease is
usually performed with a scalpel while the patient is
under general or spinal anesthesia. Because an
accurate assessment of the maximum depth of
invasion is critical, the entire specimen must be
sectioned and carefully handled to maintain its
original orientation for microscopic assessment.
 Complications occur in 2% to 12% of patients, are
related to the depth of the cone, and include
hemorrhage, sepsis, infertility, stenosis, and cervical
incompetence.The width and depth of the cone should
be tailored to produce the least amount of injury while
providing clear surgical margins.
 For (FIGO stage IA2), the risk of nodal metastases is
approximately 5%. Therefore, in such patients, a
bilateral pelvic lymphadenectomy should be
performed in conjunction with a modified radical
(type II) hysterectomy.
 Although surgical treatment is standard for in situ and
microinvasive cancer, patients with severe medical
problems or other contraindications to surgical
treatment can be successfully treated with
radiotherapy.
Stage IB and IIA Disease
 Early stage IB cervical carcinomas can be treated
effectively with combined external-beam irradiation
and brachytherapy or with radical hysterectomy and
bilateral pelvic lymphadenectomy. The goal of both
treatments is to destroy malignant cells in the cervix,
paracervical tissues, and regional lymph nodes.
Patients who are treated with radical hysterectomy
whose tumors are found to have high-risk features may
benefit from postoperative radiotherapy or
chemoradiation.
stage IB
 Overall survival rates between 80% and 90%, ) with
surgery =radiation (
 However, biases introduced by patient selection,
variations in the definition of stage IA disease, and
variable indications for postoperative radiotherapy,
concurrent chemotherapy, or adjuvant hysterectomy
confound comparisons about the efficacy of
radiotherapy versus surgery. Because young women
with small, clinically node-negative tumors tend to be
favored candidates for surgery and because tumor
diameter and nodal status are inconsistently described
in published series, it is difficult to compare the results
reported for patients treated with surgery or
radiotherapy.
 The authors reported a significantly higher rate of
complications in the patients treated with initial
surgery, and they attributed this finding to the
frequent use of combined-modality treatment in this
group
stage IB1
 Patient preference
 For patients with similar tumors, the overall rate of
major complications is similar with surgery and
radiotherapy, although urinary tract complications
tend to be more common after surgical treatment and
bowel complications are more common after
radiotherapy. Surgical treatment tends to be preferred
for young women with small tumors because it
permits preservation of ovarian function and may
cause less vaginal shortening. Radiotherapy is often
selected for older, postmenopausal women to avoid the
morbidity of a major surgical procedure.
stage IB2 (bulky)
 radical hysterectomy
 radical radiotherapy
However, patients who have tumors measuring more than 4
cm in diameter usually have deep stromal invasion and are
at high risk for lymph node involvement and parametrial
extension. Because patients with these risk factors have an
increased rate of pelvic disease recurrence, surgical
treatment is usually followed by postoperative irradiation,
which means that the patient is exposed to the risks of
both treatments. Consequently, many gynecologic and
radiation oncologists believe that patients with stage IB2
carcinomas are better treated with radical radiotherapy.
concurrent administration of
cisplatin-containing chemotherapy
 bulky stage I cancers
 lymph node metastasis
 involved surgical margins
 IB2<=
 Patients who have stage IB1 cancers without evidence
of regional involvement have excellent pelvic control
rates (about 97% at 5 years) with radiotherapy alone
and probably do not require chemotherapy when they
are treated with primary radiotherapy
Radical Hysterectomy
 The standard surgical treatment for stage IB and IIA
cervical carcinomas is radical (type III) hysterectomy
and bilateral pelvic lymphadenectomy
 Modified radical (type II) hysterectomy may be used
for selected, small (less than 2-cm diameter) stage IB
lesions. For premenopausal women (i.e., younger than
50 years), the ovaries usually are not removed. Ovarian
metastases are rare in the absence of metastases to
lymph nodes or other sites. If intraoperative findings
suggest a need for postoperative pelvic irradiation, the
ovaries may be transposed out of the pelvis.
postoperative complications






blood loss (mean, 0.8 liter)
ureterovaginal fistula (1% to 2%)
vesicovaginal fistula (less than 1%)
pulmonary embolus (1% to 2%)
small bowel obstruction (1% to 2%)
postoperative fever (25% to 50%) secondary to:
deep vein thrombosis
pulmonary infection
pelvic cellulitis
urinary tract infection
wound infection
Subacute complications
 lymphocyst formation and lower-extremity edema
Lymphocysts may obstruct a ureter, but hydronephrosis
usually improves with drainage of the lymphocyst.
The risk of complications may be increased in patients
who undergo preoperative or postoperative irradiation.
Bladder complications
1. decreased bladder sensation
2. chronic bladder hypotonia or atony (3% to 5% )
3. Bladder dysfunction
4. stress incontinence(influenced by RT)
5. bladder contraction and instability(RT post s)
 constipation and, rarely, chronic obstipation
 small bowel obstruction(RT post s)
The use of radical vaginal or abdominal trachelectomy
and laparoscopic lymphadenectomy has been
advocated in carefully selected women with small IB1
(2 cm or less) lesions who are eager to preserve fertility.
The experience thus far suggests that the local control
and survival rates with these procedures are similar to
those in women who undergo a transabdominal
radical or modified hysterectomy; however, fertility is
clearly compromised: the percentage of women able to
become pregnant and carry a baby to term is less than
half the expected rate in women without cervical
cancer; and there is a significant rate of prematurity
Radiotherapy After Radical Hysterectomy
 irradiation decreases the risk of pelvic recurrence in
patients whose tumors have high-risk features
 it has been difficult to determine the impact of
adjuvant irradiation on survival.
CHRT
 Although pelvic irradiation reduces the risk of
recurrence for patients with pelvic lymph node
metastases or parametrial involvement, the risk of
pelvic and distant recurrence remains high for these
women
 significantly improved rates of pelvic disease control
and survival for patients who received chemotherapy
Radical Radiotherapy
 excellent survival and pelvic disease control rates in
patients with stage IB cervical cancer.
 Survival rates for patients with FIGO stage IIA disease
treated with radiation alone range between 70% and
85% and are also strongly correlated with tumor size.
 for patients with bulky tumors, results may be
improved further with concurrent administration of
chemotherapy
Radical radiotherapy
 goal of radical radiotherapy =cervix, paracervical tissues,
and regional LN
 ERT+BT
 Even small tumors that involve multiple quadrants of the
cervix are usually treated with total doses of 80 to 85 Gy to
point A. The dose may be reduced by 5% to 10% for very
small superficial tumors. Although patients with small
tumors may be treated with somewhat smaller fields than
patients with more advanced locoregional disease, care
must still be taken to adequately cover the obturator,
external iliac, low common iliac, and presacral nodes.
Irradiation Followed by
Hysterectomy
 low pelvic recurrence rates after concurrent treatment
with chemotherapy and radiation, suggest that there is
little role for routine treatment with adjuvant
hysterectomy.
adjuvant hysterectomy
uterine fibroids or other anatomic variations
2. involvement of the uterine fundus
In these cases, an extrafascial (type I) hysterectomy is
usually performed, in which the uterus, cervix,
adjacent tissues, and a small cuff of the upper vagina
in a plane outside the pubocervical fascia are
removed. This procedure involves minimal
disturbance of the bladder and ureters.
1.
Chemotherapy Followed by Radical Surgery?
 A number of investigators have investigated the use of
neoadjuvant chemotherapy followed by radical
hysterectomy to treat patients with bulky stage IB or
stage II cervical carcinomas.
 Neoadjuvant chemotherapy has usually included
cisplatin and bleomycin plus one or two other drugs.
Stage IIB, III, and IVA Disease
 With appropriate chemoradiotherapy, even patients
with massive locoregional disease have a significant
chance for cure.
 The success of treatment depends on a careful balance
between external-beam radiotherapy and
brachytherapy that optimizes the dose to tumor and
normal tissues and the overall duration of treatment.
 5Ys of 65% to 75%, 35% to 50%, and 15% to 20% are
reported for patients treated with radiotherapy alone
for stage IIB, IIIB, and IV tumors
Stage IIB, III, and IVA Disease
External-beam irradiation
 An initial course of external irradiation may also
improve the efficacy of subsequent intracavitary
treatment by shrinking bulky tumor and bringing it
within the range of the high-dose portion of the
brachytherapy dose distribution. For this reason,
patients with locally advanced disease usually begin
with a course of external-beam treatment. Subsequent
brachytherapy exploits the inverse square law to
deliver a high dose to the cervix and paracervical
tissues while minimizing the dose to adjacent normal
tissues.
Stage IIB, III, and IVA Disease
 Although many clinicians delay intracavitary
treatment until pelvic irradiation has caused some
initial tumor regression, breaks between externalbeam and intracavitary therapy should be discouraged,
and every effort should be made to complete the entire
treatment in less than 7 to 8 weeks.
 several studies in patients with locally advanced
cervical cancer have suggested that longer treatment
courses are associated with decreased pelvic disease
control and survival rates.
External-Beam Radiotherapy Technique
 High-energy photons (15 to 18 MV) are usually
preferred for pelvic treatment because they spare
superficial tissues that are unlikely to be involved with
tumor. At these energies, the pelvis can be treated
either with four fields or with AP-PA alone .
 When high-energy beams are not available, four fields
are usually used because less-penetrating 4- to 6-MV
photons often deliver an unacceptably high dose to
superficial tissues when only two fields are used.
External-Beam Radiotherapy Technique
 CT simulation (iliac lymph nodes.)
 Information gained from radiologic studies such as
MRI, CT, and PET improve estimates of disease extent
and assist in localization of regional nodes and
paracervical tissues that may contain microscopic
disease.
 The caudad extent of disease (radiopaque markers )
 organ motion
 to use the simpler technique for patients with bulky
tumors.
 Tumor response should be evaluated with periodic
pelvic examinations to determine the best time to
deliver brachytherapy.
 a central block after 40Gy
central block
 it can also result in overdoses to medial structures such
as the ureters or underdosage of posterior uterosacral
disease. For these reasons, other clinicians prefer to
give an initial dose of 40 to 45 Gy to the whole pelvis,
believing that the ability to deliver a homogeneous
distribution to the entire region at risk for microscopic
disease and the additional tumor shrinkage achieved
before brachytherapy
 External-beam doses of more than 40 to 45 Gy to the
central pelvis tend to compromise the dose deliverable
to paracentral tissues and increase the risk of late
complications.96
Radiation therapy
fields for cervical
cancer
Conventional anteroposterior, AP
(A), and lateral (B) radiation
portals for cervical cancer defined
by a superior field border at the L4L5 disk space, a inferior border
extending 3 to 4 cm below the
lowest extent of disease or the
bottom of the obturator foramen,
and a lateral edge 1.5 to 2 cm lateral
to the pelvic brim.
Pelvic radiation
therapy field with
vaginal marker
Radiograph (A) and
computed
tomography (CT)
scan (B)
demonstrating a
radiopaque vaginal
marker, placed to
aid in localization of
the vagina for
treatment planning.
Parametrial boost for cervical
cancer
 Treatment fields for a parametrial
boost for a stage IIB cervical cancer.
Extended field
radiation therapy
(EFRT) for cervical or
endometrial cancer
Extended field
anteroposterior
(AP) radiation
portal covering the
para-aortic nodes.
IMRT
 In particular, there has been considerable interest in
the use of IMRT to treat the pelvis in patients with
endometrial and cervical cancer. Unlike standard twofield and four-field techniques, IMRT makes it
possible to deliver a lower daily dose to the intrapelvic
contents than to surrounding pelvic lymph nodes .
 reduced bone marrow toxicity and acute
gastrointestinal side
IMRT
 IMRT is less sparing of bowel.
 IMRT allows delivery of doses exceeding 60 Gy with
relative sparing of adjacent critical structures.
 increase error
 influence of internal organ motion and intratreatment
tumor response on the doses to tumor and critical
structures.
 There is no evidence that IMRT can safely be used as
an alternative to brachytherapy for routine treatment
of intact cervical cancer.
 IMRT cannot accurately reproduce the high-dose
gradients produced with intracavitary therapy.
 unpredictable variations mandate the use of large
treatment margins
Role of Para-Aortic Irradiation
 para-aortic node involvement :25% to 50% enjoy long-term
survival after extended-field irradiation .
 even 10% to 15% of patients with gross lymphadenopathy
appear to be curable with aggressive management.
 Survival is also strongly correlated with the bulk of central
disease.
 patients who had small primary disease that could be
controlled with radiotherapy demonstrates that extensive
regional spread can occur without distant metastases and
that patients with para-aortic node metastases can often be
cured if their primary disease can be sterilized.
 occult disease can be cured if the para-aortic nodes are
included in the radiation fields
 concurrent chemotherapy
 PET and minimally invasive surgery add to the expense
of treatment and are still infrequently performed in
patients with locally advanced cervical cancer, these
methods may provide better means of identifying
patients with regional metastases who can benefit
from extended regional irradiation
Radiation Therapy Techniques
 External irradiation is used to treat the whole pelvis
and the parametria including the common iliac and
para-aortic lymph nodes
 central disease (cervix, vagina, and medial parametria)
is primarily irradiated with intracavitary sources.
External-beam pelvic irradiation is delivered before
intracavitary insertions in patients with:
 Bulky cervical lesions or tumors beyond stage IIA to
improve the geometry of the intracavitary application;
 Exophytic, easily bleeding tumors;
 Tumors with necrosis or infection
 Parametrial involvement.
high-risk features
 parametrial involvement, deep stromal invasion, or
positive nodes, positive or close operative margins,
Volume Treated
 the primary tumor and the pelvic lymph nodes
 superior border at the L4-5 (external iliac and hypogastric




lymph node)
inferior border at the inferior edge of the ischium
This margin must be extended to the L3-4 interspace if
common iliac nodal coverage is indicated.
1.5-cm -2.5 cm margin on the pelvic rim;
Posterior extension of the cardinal ligaments in their
attachment to the pelvic side wall was consistently
posterior to the rectum and extended to the sacral hollow.
The uterosacral ligaments also extended posteriorly to the
sacrum. These anatomic landmarks must be kept in mind
in the correct design of lateral pelvic portals.
lateral field
 the anterior border of the lateral fields over the
anterior edge of the pubic symphysis
 the posterior at the S2-3 interspace
 Three-dimensional treatment planning for pelvic
irradiation of cervical carcinoma may reduce the
treated volume, but further research must be done to
determine whether the complication rate can be
decreased as well.
 For stage IB disease, : 15 by 15 cm at the surface (
 For patients with stage IIA, IIB, III, and IVA carcinoma,
(18 by 15 cm at surface) are required to cover all of the
common iliac nodes in addition to the cephalad half of
the vagina
 If there is no vaginal extension, the lower margin of
the portal is at the inferior border of the obturator
foramen.
 When there is vaginal involvement, the entire length
of this organ should be treated down to the introitus
 In patients with tumor involving the distal half of the
vagina, the portals should be modified to cover the
inguinal lymph nodes because of the increased
probability of metastases
 the posterior margin usually is designed to cover at
least 50% of the rectum in stage IB tumors, and it
should extend to the sacral hollow in patients with
more advanced tumors
Midline Shielding in Ap–PA Portals
 Depending on the institution and brachytherapy dose
administered, midline shielding with rectangular or
specially designed blocks are used for a portion of the
external beam dose delivered with the Ap–PA ports
Parametrial Boost
 When parametrial tumor persists after 50 to 60 Gy is
delivered to the parametria, an additional 10 Gy in five
or six fractions may be delivered with reduced AP-PA
portals (8 by 12 cm for unilateral and 12 by 12 cm
portals for bilateral parametrial coverage). The central
shield should be in place to protect the bladder and
rectum.
Para-Aortic Lymph Node Irradiation
 If para-aortic node metastases are present or
suspected, patients are treated with 45 to 50 Gy to the
para-aortic area plus a 5 to 10 Gy boost to enlarged
lymph nodes through reduced lateral or rotational
portals. With conventional techniques, the para-aortic
lymph nodes are irradiated either with an extended
field that includes both the para-aortic nodes and the
pelvis or through a separate portal
separate portal
 In this case, a “gap calculation( excessive dose to the small




intestines)
The upper margin = T12-L1
lower margin at L5-S1
The width of the para-aortic portals (in general, 8 to 10
cm) can be determined by CT scans, MRI,
lymphangiography, FDG-PET scans, or IV pyelography
outlining the ureters.
The spinal cord dose (T12 to L2-3) should be kept below 45
Gy by interposing a 2-cm wide 5–half-value layer (HVL)
shield on the posterior portal (usually after 40-Gy tumor
dose) or using lateral ports and the kidneys below 1,800
cGy
Beam Energies
 10 MV or higher
 They decrease the dose of radiation delivered to the
peripheral normal tissues (particularly bladder and
rectum) and provide a more homogeneous dose
distribution in the central pelvis.
 With lower-energy photons (Cobalt-60 or 4- to 6-MV
x-rays), higher maximum doses must be given, and
more complicated field arrangements should be used
to achieve the same midplane tumor dose (3 or 4field
pelvic box or rotational techniques) while minimizing
the dose to the bladder and rectum and to avoid
subcutaneous fibrosis
 a metallic prosthesis when using lateral fields or a box
pelvic irradiation technique may result in a dose
decrease of approximately 2% for 25-MV x-rays and
average increases of 2% for 10-MV x-rays and 5% for
60Co.
Hyperfractionated Radiation Therapy for Locally
Advanced Cervix Cancer
1.2 Gy to the whole pelvis twice daily at 4- to 6-hour
intervals, 5 days per weeka total pelvic dose of 57.5
Gy.A boost dose with brachytherapy
Concomitant Boost
 On Monday, Wednesday, and Friday of the last 3
weeks, an additional 1.6-Gy boost was given 6 hours
after the whole pelvis treatment (14.4 Gy) through
lateral fields encompassing the parametria and
primary tumor, for a total tumor dose of 59.4 Gy.
 A single LDR brachytherapy procedure was performed
within 1 week after the external-beam radiation
therapy to raise the point A dose to 85 to 90 Gy in 42
days. Mean total treatment time was 46 days.
Three-Dimensional or IMRT
 Bladder-filling control and accurate definition of
margins for the PTV with image-guided position
verification have been advocated to achieve a better
application of IMRT.
 patients with stage IIB or IVA cervical cancer with
medical illness or severe tumor-related anatomic
distortion that limited delivery of brachytherapy.
IMRT was used to provide a simultaneous boost dose
to the primary tumor at the time of external-beam
treatment to a larger pelvic field given in conventional
fractions. The toxicity of IMRT was acceptable, and
early tumor responses were encouraging.
IMRT
 Although not as critical in older patients, it is
important to keep in mind that while IMRT has
dosimetric advantages over conventional RT, IMRT
exposes a greater amount of normal tissues to lower
irradiation levels, which has the potential to increase
the incidence of radiation-induced second cancers .
Brachytherapy
 (137Cs) is the most popular LDR source
 (192Ir) for HDR
 Brachytherapy can be delivered with intracavitary
techniques using a variety of applicators consisting of an
intrauterine tandem and vaginal colpostats or, when
necessary, vaginal cylinders, the majority of which are
afterloading. Radiographs are always obtained using
dummy sources, and the active sources can be inserted
after the films have been reviewed and the position of the
applicators judged to be satisfactory .
 The vaginal packing is contrast material to identify it on
the radiographs.
Remote afterloader
for(HDR) brachytherapy
A remote afterloader
stores a single
(HDR) radioactive
source, typically Ir192, and through a
computer controlled
mechanism
advances it within
the catheter or
applicator that has
been placed in the
patient.
(HDR) cervix
brachytherapy
applicators
Intrauterine
tandem with (A)
vaginal ovoids,
with (B) vaginal
cylinders, or with a
(C) vaginal ring.
Cervical
interstitial
brachytherapy
Syed-type
interstitial
implant used
for cervical
brachytherapy
Brachytherapy
reference points
Tandem and
ovoid cervical
brachytherapy
illustration of
point A.
High dose rate (HDR)
cervical brachytherapy
planning
Orthogonal radiographs,
(A) and (B), depicting
placement of intrauterine
tandem and vaginal
ovoids. The images show
the instruments in place in
the uterus and vagina. In
addition, there is barium
contrast in the rectum,
contrast in the Foley
catheter balloon and
radiopaque vaginal
packing.
Vaginal cuff
brachytherapy
applicators
Vaginal ovoids
(A) and vaginal
cylinders (B) for
vaginal cuff
brachytherapy
for endometrial
cancer
 For LDR treatments, the median pelvic EBRT dose was
45 to 50 Gy and the LDR brachytherapy dose was 42
and 45 Gy for early and advanced cancers, respectively.
 For HDR treatments, the median EBRT dose was 48 to
50 Gy and the median HDR dose was 29 and 30 Gy for
early and advanced cancers, respectively.
 The median HDR dose per fraction was 6 Gy with a
median of five fractions.
 Interstitial brachytherapy was used as a component of
treatment
 computer-generated dose distributions provide the
best means of determining the doses to point A, point
B, bladder, and rectum
 In general, an intrauterine tandem with three or four
sources [15 or 20-10-10-(10) mCi mgRaEq with LDR] is
inserted in the uterus and two colpostats (2 cm in
diameter, loaded with 20 mCi mgRaEq LDR sources)
are placed in the vaginal vault and packed with
iodoform gauze to deliver 0.6 to 0.8 Gy per hour to
point A.
 miniovoids (usually loaded with 10 mCi mgRaEq LDR
sources).
 Special attention should be paid to obtain as
symmetric and homogeneous dose distribution as is
technically allowed by the geometry of the
cervix/vagina and the configuration of the tumor.
When even miniovoids cannot be inserted, it is better
to use a protruding source in the vaginal vault, which
is inserted in the afterloading tandem (usually 20 to 30
mCi mgRaEq) with an overlying plastic sleeve (3 cm in
diameter).
 With HDR intracavitary applicators the use of a rectal
retractor has been shown to substantially reduce the
rectal dose
 Interstitial implants with radium (226Ra), 137Cs needles,
or 192Ir afterloading plastic catheters to limited tumor
volumes are helpful in specific clinical situations (e.g.,
localized residual tumor, parametrial extension.
 Further, the American Endocurietherapy Society
recommended that mgh and mgRaEq be replaced by
the integrated reference air-kerma.
 As Fletcher emphasized, conditions for an adequate
intracavitary insertion include the following
The geometry of the insertion must prevent
underdosing around the cervix;
Sufficient dose must be delivered to the paracervical
areas; and
Vaginal mucosal (and, we add, bladder and rectal)
tolerance doses must be respected.
Biology of High–Dose-Rate Brachytherapy for
Cervical Carcinoma
 Late damage rises sharply as the number of HDR
fractions is decreased.
 Displacing the bladder and rectum away from the
HDR sources for the short duration of therapy may
offset the radiobiologic disadvantage of using a few
brachytherapy fractions
Clinical Experience
 There is increasing use of HDR sources in
brachytherapy of carcinoma of the cervix; basic
principles of brachytherapy are similar to those of LDR
 At Washington University, patients are treated with
HDR brachytherapy with a tandem or a vaginal
cylinder, which is placed in the patient before each
treatment with sedation and without anesthesia. An
indwelling bladder catheter is used during the
procedure, and gentle packing of the vagina with
iodoform gauze helps to maintain the applicators in
place. Their position is verified with anteroposterior
and lateral pelvic radiographs taken before the actual
HDR treatment in each application. The usual dose
per fraction prescribed at 0.5-cm depth is 3 to 6 Gy,
and three to six fractions are given once or twice
weekly
 Most HDR insertions are performed weekly and are
interdigitated by giving four fractions of EBRT per
week with one HDR treatment per week
 The number of HDR fractions used to treat cervical
cancer varies among centers from as few as two to
more than 10. The optimal time–dose–fractionation
scheme and the technique for remote-control
afterloading intracavitary brachytherapy for cervical
cancer have yet to be established through systematic
clinical trials
 n vivo bladder and rectal dosimetry is performed
during the HDR procedure
 Other centers obtain normal tissue doses from points
located on dosimetry films and dose distribution
curves
 Treatment planning for HDR brachytherapy can be
accomplished by a variety of techniques, ranging from
use of an atlas of applications and source loadings, to
planning of only the initial insertion followed by
replicating the insertion for subsequent treatments, to
customized optimization of source loading for each
HDR insertion
The optimal time–dose–
fractionation scheme for HDR
brachytherapy for cervical cancer
has yet to be established
The American Brachytherapy Society published recommendations
for HDR brachytherapy for carcinoma of the cervix
Each institution should follow a consistent treatment
policy
2. point A to at least a total LDR equivalent of 80 to 85
Gy for early stage disease and 85 to 90 Gy for
advanced-stage disease.
3. The pelvic sidewall :50 to 55 Gy for early lesions and
55 to 65 Gy for advanced ones.
4. As with LDR BT, every attempt should be made to
keep the bladder and rectal doses below 80 Gy and
75 Gy LDR-equivalent doses, respectively.
1.
5.Interstitial brachytherapy should be considered when
the tumor cannot be optimally encompassed by
intracavitary brachytherapy.
6. It was emphasized that the responsibility for the
medical decisions ultimately rests with the treating
radiation oncologist.
Doses of Radiation
 Stage IA (microinvasive) tumors are treated with
intracavitary therapy only (LDR 60 Gy in one insertion
or 75 to 80 Gy in two insertions to point A, or HDR 35
to 42 Gy in five to six insertions of 7 Gy to point A, one
or two fractions per week).
 The optimal dose for invasive carcinoma of the cervix
is delivered with a combination of EBRT whole pelvis,
intracavitary, and, at times, interstitial therapy.
 Some institutions such as ours use lower doses of
whole pelvis external irradiation (10 Gy for stage IB
and 20 Gy for stages IIA, IIB, and III) in addition to
parametrial doses to complete 50 Gy in stage IB and
IIA or 60 Gy to the involved parametrial tissues for
more advanced stages.
 At Washington University, step-wedges designed in
accordance with the isodose curves of the intracavitary
applications are used to block the midline
 We tend to reduce the total doses by 10% in women
older than 70 years.
Illustration of IMRT treatment plan to irradiate pelvic lymph nodes, while sparing
organs at risk.
Brachytherapy
 Fletcher described three conditions that should be met
for successful cervical brachytherapy:
 (1) the geometry of the radioactive sources must
prevent underdosed regions on and around the cervix
 (2) an adequate dose must be delivered to the
paracervical areas
 (3) mucosal tolerance must be respected.
 high-dose rate (HDR)
 pulsed dose-rate,
 interstitial brachytherapy
 low-dose rate (LDR)
 Brachytherapy is usually delivered using afterloading
applicators that are placed in the uterine cavity and
vagina. A number of different intracavitary systems
have been used
 The intrauterine tandem and vaginal applicators are
carefully positioned, usually with the patient under
anesthesia, to provide an optimal relationship between
the system and adjacent tumor and normal tissues.
Vaginal packing is used to hold the tandem and
colpostats in place and to maximize the distance
between the sources and the bladder and rectum.
Radiographs should be obtained at the time of
insertion to verify accurate placement, and the system
should be repositioned if positioning can be improved.
 Encapsulated radioactive sources are inserted in the
applicators after the patient has returned to her
hospital bed, reducing exposure to personnel during
applicator placement. Today, many practices are using
remote afterloading units that employ an iridium
source that is used to deliver a single dose at HDR or
multiple pulsed doses delivered at hourly or greater
intervals (pulsed dose-rate therapy)
 a single stepping source that travels through the
applicator tubes, pausing for varying times in a series
of dwell positions to deliver the desired dose to
adjacent tissues.
 The activity of sources used for HDR or pulsed doserate brachytherapy is approximately 10 Ci and 0.5 to 1
Ci, respectively.
 Because a computer controls insertion of the source,
exposure to personnel is negligible with HDR or
pulsed dose-rate methods.
Brachytherapy Dose
 Ideal placement of the uterine tandem and vaginal
ovoids produces a pear-shaped distribution, delivering
a high dose to the cervix and paracervical tissues and a
reduced dose to the rectum and bladder
 Paracentral doses are most frequently expressed at a
single point, usually designated Point A. This reference
point has been calculated in a number of different
ways.
1. The most accepted definition of Point A is a point 2
cm lateral to the cervical collar and 2 cm above the
top of the colpostats, measured at their intersection
with the tandem midpoint on the lateral radiograph
2. an alternative definition places Point A 2 cm lateral
and vertical to the external cervical os. These
definitions can produce quite different dose
estimates. Point A usually lies approximately at the
crossing of the ureter and the uterine artery, but it
bears no consistent relationship to the tumor or
target volume.
Point A uses
 It was meant to be used in the context of a detailed set
of rules governing the placement and loading of the
intracavitary system and was intended to be used
primarily as a means of reporting treatment intensity,
not as the sole parameter for treatment prescription.
Today this context is often lost.
 Whatever system of dose specification is used,
emphasis should always be placed on optimizing the
relationship between the intracavitary applicators and
the cervical tumor and other pelvic tissues. Source
strengths and positions should be carefully chosen to
provide optimal tumor coverage without exceeding
normal tissue tolerance. However, optimized source
placement can rarely correct for a poorly positioned
applicator.
Concurrent Chemoradiation
 addition of concurrent cisplatin-containing
chemotherapy to standard radiotherapy reduces the
risk of disease recurrence by as much as 50%, thereby
improving the rates of pelvic disease control and
survival
 stage IIB-IVA disease
RT , CHRT
 the Radiation Therapy Oncology Group also conducted a
trial in which radiotherapy alone (including prophylactic
para-aortic irradiation) was compared with pelvic
irradiation plus concurrent cisplatin and 5-FU
 highly significant differences were detected in the rates of
local control, distant metastasis, overall survival, and
disease-free survival favoring the treatment arm that
included chemotherapy. Although acute toxic effects of
treatment were greater with chemotherapy, the dose and
duration of radiation were similar in the two arms
 Taken together, the randomized trials provide strong
evidence that the addition of concurrent cisplatincontaining chemotherapy to pelvic radiotherapy
benefits selected patients with locally advanced
cervical cancer. However, all of the studies explicitly
excluded patients with evidence of para-aortic lymph
node metastases, poor performance status, or
impaired renal function.
radiosensitizing effects
 cisplatin
 epirubicin
 mitomycin
 5-FU
are being studied :
 Paclitaxel
 carboplatin,
 and several biologic response modifiers
Extended RT +CHT
 Extended-field irradiation (including the aortic nodes)
has proven effective in the treatment of patients with
known or suspected aortic-node metastasis but the
role of extended-field irradiation needs to be clarified
in the context of these new results. Combinations of
extended-field irradiation and chemotherapy appear
to be feasible, but their acute toxicity is considerable,
and late toxicity may be greater than with extendedfield radiotherapy alone.
Neoadjuvant Chemotherapy with Radiotherapy
 CHT
 CHT
 CHT ‫تنها‬
RT ‫بی نتیجه‬
CRT ‫تست نشده‬
OUTCOME‫ بدون تغییر‬، ‫پاسخ‬
despite the high rate of response of locally advanced
cervical cancers to neoadjuvant chemotherapy,
randomized studies have demonstrated little or no
improvement in outcome with the addition of
neoadjuvant chemotherapy to
radical radiotherapy.
chemotherapy.
Stage IVB Disease
Single-Agent Chemotherapy
2. Combination Chemotherapy
1.
Patients who present with disseminated disease are
almost always incurable. The care of these patients
must emphasize palliation of symptoms with use of
appropriate pain medications and localized
radiotherapy. Tumors may respond to chemotherapy,
but responses are usually brief.
Single-Agent Chemotherapy
 Cisplatin
 Ifosfamide
 , carboplatin,
 irinotecan
 , paclitaxel
response rates of 10% to 20%
Combination Chemotherapy
 combination chemotherapy can improve both
progression-free survival (cisplatin plus paclitaxel vs.
single-agent cisplatin, cisplatin plus topotecan vs.
single-agent cisplatin) and overall survival (cisplatin
plus topotecan) when it is administered as treatment
for recurrent or metastatic carcinoma of the cervix.
 cisplatin plus topotecan :a median overall survival of
9.4 months, compared with 6.5 months (P = .17) for
single-agent cisplatin.
Palliative Radiotherapy
 Localized radiotherapy can provide effective relief of
pain caused by metastases in bone, brain, lymph
nodes, or other sites. A rapid course of pelvic
radiotherapy can also provide excellent relief of pain
and bleeding for patients who present with incurable
disseminated disease
Special Treatment Problems
Treatment of Locally Recurrent Carcinoma of the Cervix
 Patients should be evaluated for possible recurrent
disease if a new mass develops; if, in irradiated
patients, the cervix remains bulky or nodular or
cervical cytologic findings are abnormal 3 months or
more after irradiation; or if symptoms of leg edema,
pain, or bleeding develop after initial treatment.
 The diagnosis must be confirmed with a tissue biopsy,
and the extent of disease should be evaluated with
appropriate radiographic studies, cystoscopy,
proctoscopy, and serum chemistry studies before
treatment is administered.
After Radical Surgery
 The treatment of choice for patients who have an
isolated pelvic recurrence after initial treatment with
radical hysterectomy alone is aggressive radiotherapy.
 TX isolated vaginal recurrence
Implants may need to be inserted under laparoscopic
or laparotomy guidance.
After Radical Surgery
 TX Pelvic wall recurrences are often treated with
external-beam irradiation alone, although surgery and
intraoperative therapy may contribute to local control
in selected patients. Reported survival rates usually
range between 20% and 40% for patients treated with
radical radiotherapy.2
After Definitive Irradiation
 an isolated central recurrence can be cured with
surgical treatment.
 Less extensive operations, such as radical
hysterectomy or anterior exenteration, are reserved for
selected patients with small tumors confined to the
cervix or lesions that do not encroach on the rectum,
respectively.
After Definitive Irradiation
contraindication for pelvic exenteration
involvement of the pelvic sidewall
The triad of unilateral leg edema, sciatic pain, and
ureteral obstruction almost always indicates
unresectable disease on the sidewall.
2. Although advanced age is usually considered a
1.
After Definitive Irradiation
 preparation for total pelvic exenteration
counseling of the patient and family
inspection of the abdomen
 30% of operations are aborted intraoperatively.
 Frozen section biopsies
After Definitive Irradiation
complications
 The surgical mortality rate is less than 10%, with most
postoperative complications and deaths related to
sepsis, pulmonary thromboembolism, and intestinal
complications such as small bowel obstruction and
fistula formation. The rate of gastrointestinal
complications may be reduced by using unirradiated
segments of bowel and by closing pelvic floor defects
with omentum, rectosigmoid colon, or myocutaneous
flaps. Advances in low colorectal anastomosis and
techniques for creating continent urinary reservoirs
have improved the quality of life for selected patients
quality of patients' lives after surgical
salvage
 At all points of evaluation, the patients' quality of life




was most affected by worries about the progression of
the tumor.
Ostomies
vaginal reconstruction
urostomy or colostomy.
Vaginal dryness and vaginal discharge
 The 5-year survival rates for patients who undergo
anterior or total pelvic exenteration are 33% to 60%
and 20% to 46%, respectively.
 Unresectable disease :
Several groups are
exploring the role of intraoperative irradiation in the
treatment of selected patients with recurrent disease
that involves the pelvic wall. However, most patients
who have unresectable pelvic recurrences after
radiotherapy are treated with chemotherapy alone
(previously discussed); response rates and prognosis
are generally poor.
Unresectable disease
 Intraoperative irradiation ( involves the pelvic wall)
 chemotherapy alone (previously discussed); response
rates and prognosis are generally poor.
Treatment After Simple Hysterectomy that Reveals
Unsuspected Invasive Cancer
 planned hysterectomy should be carefully screened
 invasion of less than 3 mm without LVSI usually
require no treatment after simple hysterectomy.
 more extensive disease : with postoperative
radiotherapy or, in selected cases, with radical
parametrectomy and lymphadenectomy.
 posthysterectomy treatment
(1) microinvasive cancer,
(2) tumor confined to the cervix with negative surgical
margins,
(3) positive surgical margins but no gross residual
tumor,
(4) gross residual tumor by clinical examination
documented by biopsy
(5) patients referred for treatment more than 6 months
after hysterectomy (usually for recurrent disease).
5-year survival rates of 79% and 59% for patients in
groups 2 and 3, respectively. (groups 4 and 5) was 41%
Carcinoma of the Cervical Stump
 more extensive involvement who have negative
margins are treated with 45 to 50 Gy of pelvic
radiotherapy to treat the pelvic nodes and paracolpal
tissues. Most clinicians follow this with vaginal
intracavitary therapy, delivering an additional vaginal
surface dose of 30 to 50 Gy.
ERT+BT
 positive margins : higher dose of ERTthrough reduced
fields designed to include the region at highest risk
(e.g., parametria and posterior bladder wall).
 RT+CHT should probably be considered for patients
with group 3 or 4 disease(M+)
Carcinoma of the Cervical Stump
 The natural history, staging, and workup of cervical
stump carcinomas are the same as for carcinomas of
the intact uterus
Carcinoma of the Cervical Stump
stage IA1: simple trachelectomy
2. selected patients with stage IA2 or small stage IB
tumors : radical trachelectomy and pelvic lymph
node dissection
3. most patients with irradiation alone using a
combination of ERT+ BT.
If possible, the cervix should be probed at the beginning
of treatment to determine the length of the uterine
canal. MRI may be an important aid to treatment
planning in these patients
1.
 endocervical canal is 2 cm or longer, and after ERT,
patients can be adequately treated with intracavitary
therapy. The endocervical canal is usually loaded with
20 to 30 mgRaEq of cesium, depending on the length
of the endocervical canal, and vaginal ovoids are
loaded according to their diameter and position.
Remote afterloading systems provide somewhat
greater flexibility in source loading.
 If the endocervical canal cannot accommodate any
sources, aboost dose may be delivered to the tumor
with interstitial therapy or transvaginal irradiation.
Vaginal ovoids alone rarely deliver an adequate dose to
the cervix.
 If brachytherapy is impossible, some patients can be
cured using reduced fields of external-beam
irradiation. However, brachytherapy should be used
whenever possible.
 When brachytherapy is used, most investigators have
reported survival rates similar to those for patients
with carcinomas of the intact cervix.
Carcinoma of the Cervix During Pregnancy
 0.02% to 0.9%( invasive cervical cancer during
pregnancy )
 0.5% and 5% (pregnancy in patients with invasive
cervical cancer)
Carcinoma of the Cervix During Pregnancy
 Delayed in Diagnosis
 a careful pelvic examination and Pap smear at their first
antenatal visit
 Any suspicious lesion should be biopsied
 If the Pap smear is positive for malignant cells and the
diagnosis of invasive cancer cannot be made with
colposcopy and biopsy, a diagnostic conization may be
necessary. Because conization subjects the mother and
fetus to complications, it should be performed only in the
second trimester and only in patients with inadequate
colposcopy and strong cytologic evidence of invasive
cancer. Conservative conization under colposcopic
guidance may reduce the risk.
delay definitive treatment
Carcinoma in situ or stage IA disease until the fetus
has matured
2. whose disease invades less than 3 mm and no LVSI
A vaginal hysterectomy 6 weeks after childbirth
3. Patients whose disease invades 3 to 5 mm and those
with LVSI may also be followed to term
The infant may be delivered by a cesarean section,
which is followed immediately by modified radical
hysterectomy and pelvic lymph node dissection.
1.
 Modern neonatal care affords a 75% survival rate for
infants delivered at 28 weeks of gestational age and
90% for those delivered at 32 weeks. Fetal pulmonary
maturity can be determined by amniocentesis, and
prompt treatment can be instituted when pulmonary
maturity is documented. It is probably wise to avoid
delays in therapy of more than 4 weeks whenever
possible, although this guideline is controversial.
 IB1 : classic cesarean section followed by radical
hysterectomy with pelvic lymph node dissection.
 stage II-IV , bulky stage IB : radiotherapy.
If the fetus is viable, it is delivered by classic cesarean
section and radiotherapy is begun postoperatively. If
the pregnancy is in the first trimester, external-beam
irradiation can be started with the expectation that
spontaneous abortion will occur before the delivery of
40 Gy. In the second trimester, a delay of therapy may
be entertained to improve the chances of fetal survival.
If the patient wishes to delay therapy, it is important to
ensure fetal pulmonary maturity before delivery is
undertaken.
 cervical cancer during pregnancy have slightly better
overall survival because an increased proportion have
stage I disease.
 in the postpartum period tends to be associated with a
more advanced clinical stage and a corresponding
decrease in survival
 Although studies differ in their conclusions about
whether pregnancy has an independent influence on
the prognosis of patients with cervical cancer, recent
case-matched studies have demonstrated similar
survival rates for pregnant and nonpregnant patients
Recurrence at episiotomy
 Patients who are diagnosed with invasive cervical
cancer shortly after a vaginal delivery and who had an
episiotomy appear to be at risk for recurrence at the
site of their episiotomy. At least 13 cases demonstrating
this unusual pattern of failure have been reported.