DR/OMAR HASHIM ENDOMETRIAL CANCER

ANATOMY OF THE UTERUS

The uterus is a hollow, pear shaped organ with thick musc-ular wall (L 8cm,W 5cm ) in young nulliparous adult. Is

Divide into the fundus,body,and cervix. The fundus is thePart lies above the entrance of the uterine tubes. The bodyIs the part lies below the entrance of the uterine tube isNarrowing inferiorly to open in the cervix by the internal os.Related interiorly to the uterovesical pouch and superiorSurface of the bladder. Posteriorly to the rectoutrine pouchLaterally to the broad ligament and uterine artery and Vein.

The uterus is covered with peritoneum until the internalOs. The uterus is lining by the mucous membrane.Lymph drainage;-From the funds go to the para-oartic nodes at the L1.Lymph from the the body and cervix d go to the internalAnd external iliac nodes

EPIDEMIOLOGY AND ETIOLOGY

New case in USA in 2010 is 42.160. it is the 4th most .Common cancer in women and ranks 8th among

causeOf cancer death . It is the most common gynecologicMalignancy .Risk factors ;- 1) age ;-postmenopausal (55--85yrs) Incidence rate higher than 95 per100,000 in age 65-

80Yrs 2)endogenous estrogen exposure ;-early

menarche/nulliparity/infertility/late menopause/estrogen producing tumor .

3) exogenous estrogen;-hermonal replacement Therapy tamoxifen

4) past medical history;- hypertension diabetes mellitus

5) family history ;-less than 1% of endometrial ca- is due to familial factors .

6) Genetic factors ;- mutations in the MLH1 or MSH2

Gene cause of defect in HNPCC (lynch syndrome11) have 20% risk to developing endometrial cancer before 50 and 60% risk after the age 60 yrs

PATHOLOGY ;-

The majority of edometrial cancer is adenocarcinomas which include serous/mucinous/clear cell/mixed cell. The epithelial non adenocarcianom include ;-squamous cell carcinoma /transitional cell carcinoma

Small cell carcinoma /un differentiated carcinoma .

The mesenchymal originated tumor of the uterus include

;- --smooth muscle tumor;- -leiomyoma -leiomyosarcoma

Of un certain malignant potential.Stromal tumor ;- sarcoma

/nodule/undifferentiated sarcoma

.

- - Miscellaneous mesenchymal tumor ;-- -mixed stromal and smooth muscle tumor- --edenomatoid tumor –perivascular epith-- Mixed epith-& mesenchymal ;- -adenofibrom-- Adenomyoma -adenosarcoma –

carcinofibroma- carcinosarcoma

DIAGNOSIS

Clinical presentation;- vaginal bleeding in unexpectedPostmenopausal lady (menorrhagia/metrorrhagia ).Profuse watery discharge is another presentation .Attention should be paid to the duration and severity ofThe symptoms. Screening for risk factors include,Obesity,hypertension,diabetic,history of estrogen use,History of endometrial atypical hyperplasia. History ofBreast cancer and treatment with tamoxifen,

Examination ;-Examination should be performed with attention to theThe abdomen,plevic (examination of the cervix and vagina).Palpation of the lymph nodes in the inguinal and supra-Clavicle regions . Then examining for metastsis disease(palpation of the bone to the pain/kidney/nerologicalsign ).Lab test;- CBC /blood chemistry/RFT/LFT/alkaline phos-Phatase.Imaging include;- transvaginal US /abd-pelvic CT to assessExtra-uterine disease

Endometrial cancer suspected

Complete history and physical exam

Endometrial biopsy

Trans-vaginal /US

observeDilatation and

curettage hysteroscopy

Pre-operative assessment

NON diagnosis

±

Diagnosis of endometrial cancer

STAGING

Endometrial cancer staging is depend on the pathologic criteria the recent change in the Federation of Gynecology and Obstetrics(FIGO)

And American Joint Committee on Cancer(JOCC)

were made to include coincide with prognosis

FIGO2008

TNM

staging

2009

group T N

M Description

1A T1a 0 0 Limited to endometrial or invades >1/2 of myometrium

1B T1b 0 0 Invades ½ or more of the myometrium

11 T2 0 0 Invades cervical stromal tissue but not beyond uterus

111A

T3a 0 0 Involve serosa and /or adnexa

111B

T3b Vaginal involvement or parametrial involvement

111C1

T1-3 1 0 Metastasis to pelvic LNs

111C2

T1-3 2 0 metastasis to para aortic LNs

1VA T4 any 0 Invade bladder mucosa or bowel mucosa

1VB any any 0 Distant metastasis

Extent of disease at diagnosis

5-yrs survival rate

Localized 96%

Regional 68%

Distant 24%

All stage 83%

Survival rate at 5yreas,based on stage classification

PROGNOSIS

Prognosis factors ;-survival strongly depend on the stage at diagnosis other factors include ;-

1) Advanced age associated with higher chance of recurrence

2) Higher grade;- associated with higher chance of recurrence .

3) Aggressive histology as clear cell adenocarcinoma,

Un differentiated papillary serous carcinoma are Associated with worse prognosis 4) depth of myometrial invasion 5)lymph vascular space invasion

TREATMENT

The stander treatment is total extrafascial hysterectomy with

bilateral salpingo-oophorectomy,peritoneal cytology and

pelvic / Para-aortic lymph nodes dissection traditionally done through vertical midline incision laparoscopic tech-

Has recently been used . Depending on the pathologicalData .high risk patients (↑rate of local recurrence)

adjuvant radiation therapy will recommended to these patients .

Systemic therapy is used inlocoregional advanced/Recurrence or metastatic disease

Treatment of early stage endometrial cancer;-1ry treatment is surgical resection, then

pathologic specimen is examined for risk factor to determined a patient risk of loco regional recurrence according to

Which determine adjuvant therapy

Total extrafascial hysterectomy +bilateral salpigo-

oopharectomy

Intermediate risk High -riskLow risk

observation

Vaginal brachy-

Therapy or EBRT± VB

EBRT + vaginal

brachytherapy

Algorithm for treatment of early stage edometrial cancer

as seen in the previous algorithm there is mixed recom-

Mendation to treatment options for intermediate riskGroup of patients these is due to patients and diseaseRelated factors GOG identifies these high –

intermediateSubgroup in which the adjuvant therapy is of benefitRisk factors ;- 1) grade 2/3 histology 2) lymphvascular invasion 3) outer 1/3 myometrial

Age <50 yrs need 3risk factors

Age 50—70 yrs need 2 risk factors

Age > 70 yrs need only one risk factors

FIGO stage

Grade

1 11 111

1A observation Observation or VB

VB or EBRT with orWithout VB

1B VB or EBRT with or Without VB

VB or EBRT with orWithout VB

EBRT with VB

11 EBRT with VB EBRT with VB EBRT with VB

Treatment of early stage endometrial cancer

VB;-vaginal brachytherapy EBRT ;-external beam radiation therapy

Locoregionally advanced endometrial cancer;-These patients usually treated by surgery

followed by Adjuvant radiation. Para-aortic irradiation

incase wherePelvic or para aortic LNs +ve.vaginal

brachytherapy isOften is added due to ↑ risk of vaginal cuff

recurrence.

Chemotherapy and hormonal therapy ;- for stage 111,1vAfter surgery the tumor mass should be examined toER,PR level (benefit of hormonal treatment).Hormonal therapy :- response occur in 20-40% of patientsDuration 1yr (improve out come) .the most frequently usedDrugs:- 1) medroxyprogesterone (Depo-Provera). 2)megestrol acetate. 3) tamoxifen.Chemotherapy :- regime containing platinum and doxorubicin used (response up to 40%,↑survival,PFS asCompared to WAI*) (GOG122).The EORTC study to the stage1-111 (high risk) reported improved 5 yrs PFS of 80% with adjuvantCH-RT over 75% to the RT alone

Trial

GOG122

DescriptionNumber of patients =388 stage 111– 1v endometrial ca-After TAH/BSO surgical staging and <2cm residual tumorRandomized to whole abdominal irradiation (WAI)Versus doxorubicin- cisplatin(AP) chemotherapyWAI =30 GY in 20 fr AP/PA +boost to pelvic/Para aortic LNs to 15 GY in 8 fr .PA every 3 week for 8 cycles .5 yrs PFS→ 38% for WAI versus 50% for AP .5yrs OS was 42% for WAI versus 52% for AP .Recurrence after WAI was 54% versus 50% afterAP .AP had more grade 3-4 hematological and gastroin-Testinal toxicity *chemotherapy improve PFS and OS as comparedTo WAI for stage 111&1v patients after surgicalresection

Adjuvant external radiation therapy ;- four randomized trials that evaluated adjuvant EBRT versus observation in the early Stage endometrial cancer (after surgery).these is local control benefit but does notTranslate in to survival benefitstudy year No of

number

eligibility

Treatment LN

VB

Randomized to EBRT

Vaginal/pelvicrecurrence

OS

Nor-wegian

1980

540 1B-1Cb NO yes 40 GYObservation-

27

87 NS90 NS

PORTEC

2000

715 1B-G2-31CG1-2

NO NO 46 GYobservation

414

81 NS85 NS

GOG-99

2004

392 1B-1COccult 11

yes NO 50.4GYobservation

312

92 NS86 NS

MRC ASREC&NCICCTG EN

2009

906 1A-1B,G3Serous papillary

30% 52%

40-46 GYobsession

3 6

85 NS 85 NS

Medically inoperable:- EBRT to the pelvis (include LNs)And other involved area (45-50 GY ) followed by intra-Cavitary BT (6GY X 3HDR) for early stage but inoperableFor medical reason (survival rates of 80% -85% at 5 yrs).In definitive RT to the uterus we need to the intra-uterineSources and upper vaginal sources.Unrespectable disease:- treated with EBRT and BT as aboveIn medical inoperable disease .Recurrence:- if no prior RT→EBRT and BT boost→60-70 GY. BT can be used in selected previously irradiatedPts.CTH can be conceder in metastasis and recurrence diseaseSpecially if not previously received

treatment of less common histological types:-1)papillary/serous/clear cell:- conceder CTH or RT to theStage 1B,1C,11, and debulked stage 111,1v . Cth± RT.While stage 1A treated by surgery.CTH include carboplatin/paclitaxel/platinum.carcinosarsarcima:- surgery –then op-RT for (sarcoma/Leimyosarcoma,and carcinosarcoma) to improve localRecurrence LC . Consider CTH for high grade undifferentiated sarcoma and leiomyosarcoma.GOG150→comparing RT(WAI) with CTH (cisplatin-Ifosphamide)→ CTH delay the recurrence more thanRT. These is more anemia/neuropathy in CTH.

RADIATION THERAPY TECHNIQUES

Simulation and field arrangement;-CT should performed (2.50-5mm) from the top of

the L4 to The lesser trochanters of the femurs. Aides used

during theSimulation include Foley catheter, intravaginal

marker or intr-avenous contrast .organ at risk include ;-

OAR dose limitation

Bladder V80 <15% / V75<25% /V70,V65 <50%

Rectum V50<50% / V60<35% /V65<25 , V70<20% ,V75<15%

Small intestine

TD5/5; 45 GY ,V45<10% /// 150ml <40 GY

Femoral head Max <40 GY

Field border used in the( EBRT) treatment of the of endo-

Metrial cancer . fields borders

Ap/PA superior op of L5 inferior ;-bottom of the obdurate foramina lateral ;-2 cm lateral to bony margin of the pelvic inlet

lateral superior and inferior as in AP/PA fields . anterior ;-in front of the pubic symphysisPosterior ;-S2-S3

3- Dimensional conformal Radiation Therapy and Intensity

-modulated Radiation therapy and target delineation ;-the benefit of these techniques in sparing of the normal Tissues .Target volume ;- GTV;- entire uterus (inoperable cases) . CTV ;- vaginal cuff,obturator lymph nodes and external/Internal/common iliac lymph nodes .PTV ;- CTV +0,5-1.0 cm .Organ at risk should be contoured are bladder/small

intestine/rectum/femoral head

Brachytherapy ;- Is used to delivery of high dose to the vagina while

minimizing the dose to the organ at risk . The vaginal Cylinder is the most common applicator used . The

radiation is delivered into ;- 1) low-dose-rate (LDR) . 2)high dose rate(HDR) .The LDR to the surface is 50-60 GY over 60-70 hrs

when Used alone . The dose is reduced to25-30 GY when Combined with EBRT .

HDR dose as prescribed by the American Brachytherapy

SocietySuggested dose of HDR alone for adjuvant

endometrial ca Number of HDR fractions

HDR dose/fraction (GY)

Dose- specific point

3 7.0 0.5-cm depth

4 5.5 0.5-cm depth

5 4.7 0.5-cm depth

3 10.5 vaginal surface

4 8.8 vaginal surface

5 7.5 vaginal surface

Suggested dose of HDR when used with45 GY EBRT for

Adjuvant endometrial cancer ;- Number of HDR fractions

HDR Dose /fraction Dose-specific-point

2 5.5 0.5 cm depth

3 4.0 0,5cm depth

2 8.0 vaginal surface

3 6.0 vaginal surface

Radiotherapy- induced side effects:-Pelvic radiation lead to clinically significant side effectSpecially when combined with other modalities ofTreatment as:- 1) RT + surgery→ lower limb lymphedema 2) RT + CTH→ hematological and gastrointestinal toxici-Ties.Long term side effect include:- 1)Urinary and rectal inflammation and fistula after months or years. 2) narrowing or scarring of the vagina 3)Pain or bleeding during with bowel movement.

Follow up ;-Follow up schedule and examination ;-

schedule frequency

first follow up 4-6 weeks after radiation therapy

years 0--2 every 3—4 months

years 3--5 every 6 months

years 5+ annually

Examination ;-

History and examination complete history and physical exam-ination

laboratory tests vaginal cuff cytology

imaging studies chest x ray (if clinically indicated)CT of the abdomen and pelvic if clinically indicated .