endometrial cancer
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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 .
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