Cevical cancer

CERVICAL CANCERDR /Omar Hashim

ANATOMY OF CERVIX

The cervix is the lower 1/3 of the uterus, it is the narrower part of the uterus (neck of uterus) .it is rounded and directed downward and posteriorly .

Portio is the portion of the cervix that protrudes into the vagina (about 1cm long and covered by vaginal epithelium .

EPIDEMIOLOGY AND ETIOLOGY

Ca cervix is the fifth most common cancer in the women worldwide . In USA new case 11,270 and deaths n 4,070 (in2010) .

The incidence is ↓ due to screening and human papilloma virus (HPV) vaccines in the past 4th decades .but still in some area in developing countries ca cervix is the most common cancer and leading cause of death .

Risk factors ;- early age of sexual intercourse/ high number of lifetime sexual intercourse /exposure to to sexually transmitted diseases (HPV) (AIDS)/smoking / oral contraceptive/DES exposure in utero

PATHOLOGY

80% of ca cervix is squamous cell carcinoma (SCC) usually originate at the squamocolumnar junction and progress from mild,moderate,and sever dysplasia to carcinoma insitu, to invasive carcinoma .

10%--20% of ca cervix is adenocarcinoma . Usually arise in high endocervical region and originate from endocervical gland .

While SCC have ↓ in USA the incidence of Adenocarcinoma ↑

LYMPH DRAIN & LYMPH SPREAD

*Lateral trunk ;-Upper branch → upper internal iliac LNs Middle branch→obturator LNsLowest branch→gluteal ,common iliac,

presacral LNs *posterior trunk ;-Superior rectal LNs Sup-aortic LNs (sacralpromontory) *anterior trunk ;-Distal external iliac

INVOLVEMENT OF LNS GROUP( IN%) BY STAGE

Lymph nodes group stage

1 11 111

Pelvic LNs 15% 30% 50%

Para-aortic LNs 5% 20% 30%

DIAGNOSIS

CILNICAL PRESENTATION ;-Abnormal vaginal bleeding > 80% .Vaginal discharge .Late symptoms include symptoms of

pelvic organ compression or extension e.g ;-

Sciatic pain /lower extremity edemaHydronephrosis /pelvic pain /rectal

symptoms Urinary obstruction

INVESTIGATION

investigation description

Tissue diagnosis

Pap smear –ve not excluded . biopsy by endocervical curettage

lab work CBC to assess HB & CBC and differentialCount in anticipation chemotherapySerum chemistries to assess renal function

Imaging studies CXR or chest CT /abdominoplevic CT or MRI which is better in delineation . Or PET which is higher in senitivity in staging LNs or METs

DIAGNOSIS AND PRETHERAPY EVALUATION

Ca cervix suspected

complete history and physical examination

Physical exam focus;-pelvic and

rectovaginal exam/cervical portio /tumor extension to

vagina /abd-ex /supraclavicular

LNs

Procedure ;-colposcopy

Papsmear if no bleeding

BiopsyCold knife conization

Lab ;CBC /blood chem/urinalysis

Radiology;-CXR/Ctor MRI of abd-&pelvis OR

PET

Exam under anesthesia Cystoscopy,proctoscopy

Ureteral

→radical hysterectomy vs definite radiation chemotherapy

staging FIGO

con→

STAGING

Generally staging depend on history and examination and radiologic and laboratory workup . The most common used staging system is Federation Gynecology and Obstetrics (FIGO) Is based on clinical examation . FIGO permits minimal information from plain radiograph and does not incorporate information on LNs involve-

Ment .despite not altering stage categories ,cross sectional imaging (CT/MRI/PET) and invasive surgical staging provide important additional information on the extent of loco regional nodal involvement and distant disease status

FIGO &TNM STAGING OF CA CERVIXFIGO TNM Description

- Tx 1ry Tumor not assessed

- T0 No evidence of 1ry tumor

-a Tis Carcinoma in situ

1 T1 Ca cervix confined to uterus

1A T1a Invasive carcinoma (diag-microscopy) stromal invasion depth 5.0 mm & wide 7.0mm

1B

T1b Visible lesion confined to the cervix or mic->7

11 T2 Ca cervix invades out uterus but not pelv-wal

11A

T2 a Tumor without parametrial invasion

11B

T2b Tumor with parametrial invasion

111 T3 Tumor→plevic wall /lower1/3vagina/affet kid-

111A T3a tumor →Lower 1/3 of vagina/ no plevic wall

111B T3b Tumor→plevic wall or cause hydronephrosis

1v T4 Bladder or rectal invasion

1vA T4a Invade of mucosa of bladder or rectal

FIGO TNM DESCRIPTION

1VB T4b Mets-peril-/supraclavicular LNs/lunge...

3/4 N x Reg-LNs not assess

3/4 N0 No regional LNs mets

3/4 N 1 Regional LNs mets-

3/4 Mo N o distant mets

3/4 M 1 Distant met(peri-/supraclavicularLN or mediastinal LNs

CON→

Stage111 enhancement of lift internal iliac lymph nodes

Lymph nodes enhancement in cervical cancer

PROGNOSIS

Ca cervix is curable when diagnosis early ,these lead to improve out come in countries with access heath care and cytological screening .

In more advanced disease, tumor recure 1/3 of PTs-. The outcome is improved significantly with the

Introduction of of concurrent chemotherapy in stage 1B2_ 1v A . Neuroendocrine carcinoma of the cervix has ↑mets rate ,poor prognosis and spread in pattern similar to that of small cell cancer .

Low HB associated with ↓local control and survival rates specially during RT. Hypoxia also associated with poor out come

stage Local control

Disease –free survival

treatment

1A—1B 93-95% 92% Surgery/Radiation

1 B All 94%4-5cm 90%>5cm 82%

All 81-85%4-5cm 86%>5cm 67%

Radiation therapy

11A 94– 96% 70– 85% Radiation therapy

1B-11 87% 74% Radiation/chemotherapy

111—1v 71% 40—50%

Radiation /chemotherapy

1vB -- 0% Palliative chemotherapy no Radiation

TREATMENT In stage 1A , non bulky 1B ,and early stage

11A , The 1ry treatment is surgery with hysterectomy and 1ry radiation result in similar outcome

Stage 1B1 radiation alone a choice or radical hysterectomy .

Stage ≥1B2 radiation with concurrent cisplatin based chemotherapy .

Treatment modalities ;- surgery ;- Modified radical hysterectomy ;- in which

remove done to the uterus ,cardinal ligament , partially the uterosacral ligament ,pelvic LNs .

Survival > 95% /preserving ovarian function /avoidance of radiation complication

Radical hysterectomy ;- For stage 1A2 with LVS1 IB1 , non

bulky 1B2 – 11A. In which remove done to the uterus .cardinal ligament & upper 1/3 of the vagina /pelvic LNs .

Survival 80—90% . Radiation ;- used to as definitive

treatment for stage 1—11A inside of surgery .

Definitive treatment for stage 11B– 1VA with concurrent chemotherapy .

For bulky disease >5—6cm should complete in 7weeks .stage 1B-11A .

Postoperative pelvic radiation for involved LNs +ve SM (EBRT integrated with brachytherapy ) .RT

Diagnosis of ca cervix

Clinical and radiological staging

Stage 1A– B1 Stage 1B– 11A Stage 11B– 1vA

ERBT+BT↑

risk/SM/LN/param-

↑ risk/LV/depth inve-

ERBT +BT /CH

RH/pelvicLNd

issect-±PALN sam-

RH pelv LN disse- PA samp

ERBT+BT/CH

OR or

Follow up

Post op radia-Concu-chem-

Post op- RA-

CHEMOTHERAPY

AS part of definitive treatment with concurrent with RT for locally advanced cervical cancer.

Stage 1B1 concurrent CH not validated. AdjuvantCH following concurrent RT/CH may↓ overall

recurrence rate used for palliation for local, regional or systemic disease.

We use weekly cisplatin during 5weeks with pelvicEBRT with or without CH during BT.3-weekly cisplatin/5-FU is also validated level Evidence. No benefit to cisplatin to other CH.5-FU alone is not recommended .

Tow randomized trial defined the 1)utilizing of the adjuvant radiation ,and 2)adjuvant radiation with concurrent

chemotherapy after hysterectomy

Eligibility criteriaLVS1 stromal tumor

+ve deep1/3 any size

+ve middle1/3 ≥2cm

+ ve superficial1/3 ≥5cm

-ve deepormidlle ≥ 4cm

arm 1

Pelvic RT 46GY in 23 fr . 50.4 GY in 28 fr . n= 137

arm2

Observation

N=140

In the first trial show 46% reducation in risk of recurrence favoring RT arm (p=0.0007) . Deferent in overall survival

The 2nd trial 109 evaluated addition of concurrentCH. Taking stage 1A,1B, or 11A (LN +ve /paramet-+ve /SM +ve). Pts treated with RH then randomizedTo RT alone versus RT with 4 cycles of cisplatin/5FU. Overall survival was significantly improve.Analysis show particular benefit for large tumor,Multiple LNs.HR for overall survival was 1.96 (p=0.007) favoringRT/concurrent CH. OS for 4 yrs 71% with R and81% for with RT/CH.

Clinical stage 1A,1B ,11A + any of ;-1- +ve LN S2- +ve parametria3- +ve SM

ARM1 Plevic RT 49.3GY IN 29 fr

n=116

randomization

ARM2Same RT +Cisplatin /5fu96 hours infusion Every 3weeks x4 cycles n=127

GOG protocol 109 evaluated the addition of concurrent chemotherapyIs of benefit .*HR overall survival was 1.96 (p=0.007) favoring concurrent Chemo-overall survival was 4 yrs 71% with RT .and 81% with RT+CHEMO-

Trial FIGOstage

NumberOf pts

Compari-son

Follow up

HR ↑ in survival

GOG85 11B-1VA 368 PF veru-HU

8.7 yrs 0.7 10%

RTOG9001

1B(>5cm)-1vA

388 PF veru-none

43 months

0.59 15%

GOG 120

11B-1VA11B-1VA

526 526

P /HUPFHU/HU

35 months35 month

0.61 0.58

18% 18%

GOG 123

1B(>5cm-1vA

369 P versusnone

36 months

0.54 9%

NCI/canada

1B(>5cm-1vA

253 P versusnone

64 months

0.91 3%

meta analysis

1B-1VA 3,452 cth/none

62 months

0.78 ¾%

Level evidence for the benefit from 5 randomized trial evaluating radiationWith concurrent cisplatin base cth-

RT TECHNIQUES

Definitive RT ;-The definitive RT for ca cervix require EBRT (withPelvic and parametrical and nodal boosts if approp-Riate) and BT . Treatment must be individualized

based on the patient‘s tumor extend ,normal tissue anatomy ,tumor response characteristics during

The therapyEBRT ;- the field include 1ry tumor /local extension(parametria / uterosacral ligament, vagina) drainingRegional LNs,

Simulation, target volume delineation & field arrangement ;-

3-dimensional image- guide is high recommended toImprove the delineation of target structures and Exclusion of normal tissues include bowel ,bladderAnd bone marrow . By use of intravenous contrastFor CT can differentiate regional LNs from vesselsCT can not differentiate tumor from normal tissuesIn side the uterus ,so we use the MRI which show Us the tumor extend in the uterus,parametria,

1ry tumor GTV ;-entire uterus and tumor extension to para-Metria based on imagi & implanted markers

CTV ;-additional 0.7 to 1cm margin,3-cm margin to lower extension

PTV 0.5 -1cm margin

LNs Gross involved lymph nodes

CTV;- gross involved LNs+ 1cm margin in obturator,external and common iliac LNs in 111AIn distal half vagina inginal LNs. Post surgical clips &post operative seroma add0.7-cm/1-2 cm anterior to theS1-S3

PTV ;-0.5 –cm margin

Target volume for definitive radiation therapy using Ctbased planing

The final PTV = 1ry tumor PTV +nodal PTV and because of

The viabilities in the aortic bifurcation 40% of common iliac LNs are be higher to the L4-L5 interspace ,so in these case

The upper border can shifted up word by 1-3 vertebrae .

Contouring of normal structure include the rectum (up to the recto sigmoid junction), bowel (large bowel &mesentery)

With in 5cm upper border of target, the bladder and femoral

Head .if 3D NOT available the field design should be guided

By bony landmark

field borders

AP/PA Superior; L4-L5 interspacedInferior ;- 3cm bellow the lowest tumor extend (determined byGold seed or bottom of obturator formen .Lateral ;- 2cm lateral to the pelvic brim and include any surgical clips with 1-1.5 cm margin

lateral superior;- same as AP/PA inferior ;- same as AP/PPA .Anterior ;- 1cm anterior to pubic pubic symphsis .Posterior ;- at least anterior half of the sacrum

Dose and treatment delivery ;-The EBRT prescribed dose to the range 45– 50.4 GY IN

1,8 GY.the BT boost 5.4—14.4 .The total dose will be 50 in small stage 1B.and 55 GY in

moderately involved parametrial involved. And 60 GY for

Bulky parametrial .IMRT ;- is used in the treatment of the ca cervix and

show to decrease the dose to the organ at risk (bowel,bladder

Acute gasterointestinsl toxicity and bone marrow dose

Regreesion of cervical cancer after 30 GY RT Compare lift and right