Carcinoma of the Cervix - PowerPoint Presentation

Slide1

Carcinoma of the CervixSlide2

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.Slide3

کاهش مرگ در اثر کانسر سرویکس

routine

screening programs, including pelvic examinations and cervical

cytologic

evaluation

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.Slide4

International incidencescultural

attitudes

screening programs

liberal

attitudes toward sexual behaviorSlide5

اتیولوژی

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.Slide6

prophylactic HPV vaccinea 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).Slide7

علل عدم کاهش انسیدانس ادنوکارسینوما سرویکس

an increase in recognition of cases with glandular elements as adenocarcinomas

cytologic screening methods may be less effective in detecting adenocarcinomas at a preinvasive stageSlide8

ارتباط نقص ایمنی و کنسر سرویکس

T

he

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.Slide9

(

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

.

Slide10

HIV-positiveOverlapping 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.Slide11

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).Slide12

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. Slide13

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 HPV-associated 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.Slide14

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

Slide15

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. Slide16

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. Slide17

pattern of metastasCervical cancer usually follows a relatively orderly pattern of metastatic progression, initially to primary-echelon 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 boneSlide18

PathologySlide19

Cervical Intraepithelial Neoplasia

cervical

cytologic

findings

(important

characteristics

):

cellular immaturity

cellular disorganization

nuclear

abnormalities

increased

mitotic activity. Slide20

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.Slide21

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 Slide22

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)Slide23

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.Slide24

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%.Slide25

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 uncertainSlide26

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 StatesSlide27

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.Slide28

Microinvasive adenocarcinomameasuring 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.Slide29

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

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 Slide30

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.

Slide31

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 typesSlide32

Anaplastic Small Cell/Neuroendocrine Carcinoma

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

metastasesSlide33

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.Slide34

Clinical Manifestations

Preinvasive disease during routine cervical cytologic 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 constipationSlide35

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 ratesSlide36

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. Slide37

موارد قطع اسکرینینگ

Women age 70 years and more who have had three consecutive

no abnormal test result within 10 years

who have had a total hysterectomy for benign gynecologic disease.

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. Slide38

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.Slide39

The rate of false-negative findings on the Pap test is about

20% to 30% in women with high-grade CIN

10% to 15% in women with invasive cancer.

Slide40

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.Slide41

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. Slide42

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. Slide43

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.Slide44

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 low- and high-grade dysplasia, but microinvasive disease cannot consistently be distinguished from intraepithelial lesions on colposcopy.Slide45

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 canalSlide46

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. Slide47

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 high-grade CIN, or (6) the cytologic findings are suggestive of adenocarcinoma in situ.Slide48

Clinical Evaluation of Patients with Invasive Carcinoma

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

Slide49

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 cancer

74

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.Slide50

International Federation of Gynecology and Obstetrics Staging of Carcinoma of the Cervix (1994)

0

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 sizeSlide51

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.Slide52

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.Slide53

Up todateTNM stage

FIGO stage

T1b =IB :Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2

AJCC stage grouping

adenocarcinoma in situSlide54

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. Slide55

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.Slide56

FIGO rules for clinical staging,

Palpation

Inspection

Colposcopy

endocervical curettage

hysteroscopy

cystoscopy

Proctoscopy

intravenous urography

radiographic examination of the lungs and skeleton

.Slide57

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 involvementSlide58

FIGO specifically states that findings on examinations such as

lymphangiography

Laparoscopy

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. Slide59

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.Slide60

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.Slide61

Surgical Evaluation of Regional Spread

transperitoneal

extraperitoneal dissection

laparoscopic lymph node dissection ?

sentinel node ?Slide62

surgical staging(controversial)

identifies patients with microscopic para-aortic or common iliac node involvement

who can benefit from extended-field 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.Slide63

Prognostic Factors

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 )Slide64

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.Slide65

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 DNASlide66

Treatment

tumor size

stage

histologic features

evidence of lymph node metastasis

risk factors for complications of surgery or radiotherapy

patient preference. Slide67

Treatment

HSILs :loop electroexcision procedure (LEEP)

stage IA1: conservative surgery (excisional conization or 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.Slide68

Preinvasive Disease (Stage 0)

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 CO

2

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 procedureSlide69

LEEPa 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.

Slide70

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.Slide71

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.Slide72

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.Slide73

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.Slide74

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. Slide75

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.Slide76

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.Slide77

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 groupSlide78

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.Slide79

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.Slide80

concurrent administration of cisplatin-containing chemotherapy

bulky stage I cancers

lymph node metastasis

involved surgical margins

IB2<=Slide81

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 radiotherapySlide82

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.Slide83

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 infectionSlide84

Subacute complicationslymphocyst 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.Slide85

Bladder complications

decreased bladder sensation

chronic bladder hypotonia or atony (3% to 5% )

Bladder dysfunction

stress incontinence(influenced by RT)

bladder contraction and instability(RT post s)

constipation and, rarely, chronic obstipation

small bowel obstruction(RT post s)Slide86

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 prematuritySlide87

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.Slide88

CHRTAlthough 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 chemotherapySlide89

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 chemotherapySlide90

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

. Slide91

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. Slide92

adjuvant hysterectomy

uterine fibroids or other anatomic variations

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. Slide93

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. Slide94

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 tumorsSlide95

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.Slide96

Stage IIB, III, and IVA Disease

Although many clinicians delay intracavitary treatment until pelvic irradiation has caused some initial tumor regression,

breaks between external-beam 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.Slide97

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.Slide98

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

.Slide99

Tumor response should be evaluated with periodic pelvic examinations to determine the best time to deliver brachytherapy.

a central block after 40GySlide100

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 brachytherapySlide101

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.

96Slide102

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 L4-L5 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. Slide103

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. Slide104

Parametrial boost for cervical cancer

Treatment fields for a parametrial boost for a stage IIB cervical cancer.Slide105

Extended field radiation therapy (EFRT) for cervical or endometrial cancer

Extended field anteroposterior (AP) radiation portal covering the para-aortic nodes. Slide106

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 two-field 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 Slide107

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.Slide108

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 marginsSlide109

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.Slide110

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 irradiationSlide111

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. Slide112

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.Slide113

high-risk featuresparametrial involvement, deep stromal invasion, or positive nodes, positive or close operative margins, Slide114

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.Slide115

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.Slide116

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 introitusSlide117

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 tumorsSlide118

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 Slide119

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.Slide120

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 portalSlide121

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 cGySlide122

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 fibrosisSlide123

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

60

Co.Slide124

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 Slide125

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. Slide126

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.Slide127

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

.Slide128

Brachytherapy

(

137

Cs) is the most popular LDR source

(

192

Ir) 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.Slide129

Remote afterloader for(HDR) brachytherapy

A remote afterloader stores a single (HDR) radioactive source, typically Ir-192, and through a computer controlled mechanism advances it within the catheter or applicator that has been placed in the patient.Slide130

(HDR) cervix brachytherapy applicators

Intrauterine tandem with (A) vaginal ovoids, with (B) vaginal cylinders, or with a (C) vaginal ring.Slide131

Cervical interstitial brachytherapy

Syed-type interstitial implant used for cervical brachytherapySlide132

Brachytherapy reference points

Tandem and ovoid cervical brachytherapy illustration of point A. Slide133

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. Slide134

Vaginal cuff brachytherapy applicators

Vaginal ovoids (A) and vaginal cylinders (B) for vaginal cuff brachytherapy for endometrial cancerSlide135

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 treatmentSlide136

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.Slide137

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).Slide138

With

HDR

intracavitary applicators the use of a

rectal retractor

has been shown to substantially reduce the rectal dose

Interstitial implants with radium (

226

Ra),

137

Cs needles, or

192

Ir afterloading plastic catheters to limited tumor volumes are helpful in specific clinical situations (e.g., localized residual tumor, parametrial extension. Slide139

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.Slide140

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 Slide141

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 Slide142

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 weeklySlide143

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 trialsSlide144

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 curvesSlide145

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 Slide146

The optimal time–dose–fractionation scheme for HDR brachytherapy for cervical cancer has yet to be establishedSlide147

The American Brachytherapy Society published recommendations for HDR brachytherapy for carcinoma of the cervix

Each institution should follow

a consistent treatment policy

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.

The pelvic sidewall :50 to 55 Gy for early lesions and 55 to 65 Gy for advanced ones.

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. Slide148

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.Slide149

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. Slide150

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 Slide151

We tend to reduce the total doses by 10% in women older than 70 years.Slide152

Illustration of IMRT treatment plan to irradiate pelvic lymph nodes, while sparing organs at risk.Slide153

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.Slide154

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 usedSlide155

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.Slide156

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)Slide157

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 dose-rate 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. Slide158

Brachytherapy DoseIdeal 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 Slide159

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.

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

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. Slide160

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.Slide161

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.Slide162

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 Slide163

RT , CHRTthe 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 armsSlide164

Taken together, the randomized trials provide strong evidence that the addition of concurrent cisplatin-containing 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

.

Slide165

radiosensitizing effects

cisplatin

epirubicin

mitomycin

5-FU

are being studied :

Paclitaxel

carboplatin,

and several biologic response modifiersSlide166

Extended RT +CHTExtended-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 extended-field radiotherapy alone.Slide167

Neoadjuvant Chemotherapy with Radiotherapy

CHT RT

بی نتیجه

CHT

CRT

تست نشده

CHT

تنها

OUTCOME

پاسخ ، بدون تغییر

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. Slide168

chemotherapy.Stage IVB Disease

Single-Agent Chemotherapy

Combination Chemotherapy

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.Slide169

Cisplatin

Ifosfamide

, carboplatin,

irinotecan

, paclitaxel response rates of 10% to 20%

Single-Agent ChemotherapySlide170

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.

Slide171

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 diseaseSlide172

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.Slide173

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.

T

X

isolated

vaginal recurrence

Implants

may need to be inserted under laparoscopic or laparotomy guidance

.Slide174

After Radical SurgeryTX 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.

2Slide175

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.Slide176

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.

Although advanced age is usually considered

aSlide177

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

biopsiesSlide178

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 patientsSlide179

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 dischargeSlide180

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.Slide181

Unresectable diseaseIntraoperative

irradiation

(

involves the

pelvic

wall)

chemotherapy

alone (previously discussed); response rates and prognosis are generally poor.Slide182

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.Slide183

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%Slide184

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+)Slide185

Carcinoma of the Cervical Stump

The natural history, staging, and workup of cervical stump carcinomas are the same as for carcinomas of the intact uterusSlide186

Carcinoma of the Cervical Stump

stage IA1: simple trachelectomy

selected patients with stage IA2 or small stage IB tumors : radical trachelectomy and pelvic lymph node dissection

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 patientsSlide187

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,

a

boost

dose

may be delivered to the tumor with interstitial therapy or transvaginal irradiation. Vaginal ovoids alone rarely deliver an adequate dose to the cervix. Slide188

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.Slide189

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)Slide190

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.Slide191

delay definitive treatment

Carcinoma

in situ or stage IA disease until the fetus has matured

whose disease invades less than 3 mm and no LVSI

A

vaginal hysterectomy

6 weeks after childbirth

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.Slide192

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. Slide193

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.Slide194

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 patientsSlide195

Recurrence at episiotomyPatients 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.