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PRAGATHEESWARI

The document discusses the anatomy and histology of the endometrium, the lining of the uterus. It then covers endometrial cancer, including risk factors, common presentations, workup involving endometrial biopsy and imaging, and staging. Treatment is discussed for each stage, with surgery being primary treatment and adjuvant therapy depending on grade, myometrial invasion, and other pathological factors. Sentinel lymph node biopsy and recent advances are also mentioned.

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ENDOMETRIUm PRAGATHEESWARI G K
SYNOPSIS • Anatomy • Endometrial ca introduction • C/F , workup • Staging • Treatment - stage wise • Evidence for each treatment • Other Histology • Recent Advance 31.07.2022 2 PRAGATHEESWARI, MMC.
UTERUS • Uterus is the female reproductive child bearing organ located in the true pelvis between the bladder and rectum • Size:8 cm*5cm*2.5cm (adults) 31.07.2022 3 PRAGATHEESWARI, MMC.
• Uterus is divided into three parts • Fundus-part above the opening of fallopian tube • Body –line of division from cervix corresponds to internal os • Cervix-supravaginal and vaginal portion • Uterus-hollow muscular organ composed of 3 layers • Inner –endometrium[tunica mucosa] • Middle-myometrium[tunica muscularis] • Outer –perimetium[tunica serosa] 31.07.2022 4 PRAGATHEESWARI, MMC.
What is Endometrium?? • Eytmology Endo : “inner” from latin Metra: “uterus” from Greek From Maetra Means Mother • Uterus is an hollow muscular organ located in true pelvis between the bladder and rectum • Uterus is divided into fundus, body(corpus) and cervix enclosing uterine cavity • This uterine cavity is lined by Endometrium whereas the wall of the composed of myometrium (smooth muscle fibers 5
Is Endometrium just a Lining of uterine cavity? • NO! • It prevents adhesions between opposed walls of myometrium • Therefore maintains the patency of Uterine cavity Endometrial Paradox which is that the endometrium is the lining of uterine cavity but without endometrium there would be no uterine cavity 6
Changes in Endometrium during menstrual cycle Both Functional layer of endometrium and stroma are responsive to hormonal influence ➢Estrogen:- proliferative stage(follicular phase) ➢Progestron:- seceretory stage(luteal phase) 7
LYMPHATIC DRAINAGE • Body of the uterus:- drains to obturator and internal and external iliac noses • Fundus of the uterus:- para aorta as the lymphatics accompany ovarian arteries 8
ENDOMETRIAL CARCINOMA • Global:- 15th most common carcinoma worldwide and ranks sixth among cancers affecting women • India:- 0.88 million cancer cases with an incidence rate of 105.5 per 100,000 in women.The incidence of endometrial cancer cases are very low in India ➢ Highest being observed in Bangalore and Delhi 9
10
WORKUP • History & Physical Examination • CBC,RFT, LFT • Endometrial tissue sampling – Biopsy or D&C • ER/PR ,Her2neu is recommended for stage III,IV and recurrent /metastastic settings • Imaging - USG abdomen and pelvis - CT/MRI Abdomen - PET CT (not mandatory) - Chest CT/ Xray 31.07.2022 11 PRAGATHEESWARI, MMC.
Major Clinical presentation • 80 to 90% present with postmenopausal vaginal bleeding Thumb rule:- postmenopausal bleeding is assumed to be endometrial cancer until proven otherwise (eventhough the incidence of endometrial cancer presenting with postmenopausal bleeding is around 10% to 15%) 12
Presentations in early stages • 5% to 10%:- Abnormal vaginal discharge • 5%:- Asymptomatic Asymptomatic patients are suspected to have endometrial cancer in settings of ➢Abnormal pap smear in routine screening ➢Thickened endometrium in routine transvaginal ultrasound 13
Presentation in advanced stages ❖Urinary or rectal bleeding ❖Constipation ❖Lower limb lymphedema ❖Abdominal distention due to ascities ❖Pain ❖Referred pain to hypogastrium/both iliac fossa called simpson’s pain ➢ Non severe and tends to occur at the same time each day, lasting for 1-2 hours 14
Physical Examination • General examination • Systemic examination • Abdominal Examination • Bimanual per vaginal examination – confirm uterine size, adnexal mass, involvement of cervix, vagina • Digital rectal examination- Rectal mucosa, sphcinter tone, rectovaginal fistula, parametrium involvement 31.07.2022 15 PRAGATHEESWARI, MMC.
Diagnostic work up Endometrial sampling- Gold Standard Endometrial sampline achieved by two methods ✓ Biopsy ✓ Dilation and curettage 16
Endometrial Biopsy • Easily performed in the office with pipelle or similar device- It is the preferred approach. • Sensitivity :- postmenopausal status- 99.6% pre-menopausal status- 91% • BUT Specificity:- both pre and postmenopausal women – more than 98% 17
Then where is D&C used? • Routine D&C Recommended in patients who are considered for conservative fertility sparing approaches • If office sampling is inadequate • If symptoms persists 18
Can every patient with postmenopausal bleeding undergo sampling?? 19
• Only 10 to 15% patients with postmenopausal bleeding have endometrial cancer • Therefore it is unclear how feasible it is to perform endometrial sampling on every patient • Solution:- Transvaginal ultrasound may be considered as useful tool in assessing pt’s vaginal bleeding to select patients for sampling 20
Transvaginal Ultrasound • Normal endometrium • Thin • Homogenously hyperechoic • Thick • Heterogenous Abnormal endometrium 21
Endometrial Thickness(Premenopausal) PHASE THICKNESS Menstruation 2-4 mm Early proliferative phase 5-7 mm Late proliferative Up to 11mm Secretory phase 7-16 mm 31.07.2022 22 PRAGATHEESWARI, MMC.
Postmenopausal Endometrial thickness Vaginal bleeding (not on tamoxifen) • Upper limit of normal < 5mm • Risk of carcinoma is 7% if endometrium is >5mm No H/o Vaginal bleeding • Normal Cut off value </= 8 mm, upto 11mm • Risk of carcinoma is 7% if endometrium is >11mm • If on Tamoxifen normal < 5mm 31.07.2022 23 PRAGATHEESWARI, MMC.
CT SCAN • CT scan – lesion seen as hypodense mass, diffuse, circumscribed vegetative or polypoidal mass • Helpful in assessing regional node and distant mets • Loss of periureteral fat – indicates Parametrium involved 31.07.2022 24 PRAGATHEESWARI, MMC.
MRI • Most accurate imaging study to assess tumor extension in endometrial cancer, especially myometrial invasion • Clear junctional zone or preservation of sharp delineation between tumor and myometrium – Disease limited to endometrium • Extension of high signal intensity into outer myometrium with peripheral rim of normal intact myometrium – Deep myometrial invasion • MRI helpful in delineate tumor extension into cervix • Nodal mets- sensitivity is 43.5%,specificity 95.9% 31.07.2022 25 PRAGATHEESWARI, MMC.
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PET SCAN • Little benefit in assessing extension of tumor • Nodal mets sensitivity is 72% specificity is 94% • Main advantage – accuracy in detection of distant mets • Disadvantage: inability to detect mets in node < 5mm 31.07.2022 27 PRAGATHEESWARI, MMC.
CA 125 • Cancer Antigen 125 • Elevated CA 125 is seen in 25-48% of endometrial cancer • Monitoring response to treatment ( declining CA125 in response to treatment) • Normal range – 0 to 35 units/ml • Range >35 – indicates possibility of cancer • Hsieh et al – found that preoperative level >35 U/ml correlated significantly with regional lymphnode mets ,suggested such levels could be indication of full pelvic and para-aortic lymphadenectomy at time of surgical staging in absence of metastatic disease 31.07.2022 28 PRAGATHEESWARI, MMC.
Update on CA 125 • Askin et al:- • High levels of CA 125 significantly correlated with Advanced stage and lymph node metastasis • Cut off determined by this study is 20U/ml With 75% and 69.5% sensitivity and specificity But has 80.6% PPV and 84.9% NPV 29
31.07.2022 30 PRAGATHEESWARI, MMC.
Treatment • Primary treatment is Surgery • Staging laparotomy- TAH+BSO+ Pelvic node assessment with/without para aortic node dissection, peritoneal wash • why BSA ? - synchronous ovarian ca in 5% • if age >50 years it increase upto 10% • Along with visual inspection of peritoneal, diaphragmatic , serosal surface – suspicious lesion biopsy should be done, and omental biopsy • Omental biopsy- commonly done for serous, clear cell, carcinosarcoma histologies 31.07.2022 31 PRAGATHEESWARI, MMC.
SURGERY • TAH+BSO : Laparotomy based approach , simple hysterectomy is done • LAPAROSCOPIC VAGINAL HYSTERECTOMY: Minimally invasive surgery, gained importance recently • ROBOTIC HYSTERECTOMY : Alternative minimally invasive surgery in endometrial cancers • RADICAL HYSTERECTOMY : Not routinely performed due to low incidence of parametrial involvement • DEBULKING SURGERY /CYTOREDUCTION : For recurrent and advanced diseases 31.07.2022 32 PRAGATHEESWARI, MMC.
Adequate Sampling (perez) • Five lymphatic station to be removed from each side – Common iliac, internal iliac , external iliac, obturator node and para aortic node (or) • Total of 10 nodes to be removed 31.07.2022 33 PRAGATHEESWARI, MMC.
Sentinel Lymph Node Biopsy 1. The radiolabeled colloid most commonly injected into the cervix is technetium- TC99m 2. colored dyes are available in a variety of forms (Isosulfan Blue 1%, Methylene Blue 1%, and Patent Blue 2.5% sodium). 3. Indocyanine green (ICG) recently emerged as a useful imaging dye that requires a near-infrared camera for localization, provides a very high SLN detection rate, and is commonly used. 31.07.2022 34 PRAGATHEESWARI, MMC.
31.07.2022 35 PRAGATHEESWARI, MMC.
31.07.2022 36 PRAGATHEESWARI, MMC.
PATHOLOGY ASSESSMENT • Uterus – Hysterectomy type Tumor site, size Histology type Histology grade Myometrial invasion Cervical stromal invasion LVSI • Other organ involvement- fallopian tube, ovaries, vagina, parametrium, omentum • Peritoneal /ascitic fluid cytology • Lymph node resected • Isolated tumor cell in node , NO(i+), should not upstage patient but should considered in discussion of adjuvant therapy • ER/Her2 neu Testing 31.07.2022 37 PRAGATHEESWARI, MMC.
HPE (important factors) • Histology • Grade(1,2,3) • LVSI • Depth of invasion(myometrium) 31.07.2022 38 PRAGATHEESWARI, MMC.
31.07.2022 39 PRAGATHEESWARI, MMC.
Adjuvant Treatment STAGE I A • GRADE 1,2 •no myometrial invasion - observation • < 50% myometrial invasion , age >60yrs, LVI+ - IVRT •GRADE 3 •no invasion - age <60 yrs no LVSI - Observe • age >60 yrs and LVI PLUS - IVRT •< 50 % invasion - ADJ RT PORTEC 1 31.07.2022 40 PRAGATHEESWARI, MMC.
• STAGE I B • GRADE 1 & 2 - ADJ RT (PORTEC 1) 31.07.2022 41 PRAGATHEESWARI, MMC.
PORTEC 1 • AIM OF STUDY: To determine impact of pelvic irradiation on outcome in patients with early stage endometrial cancer • Surgical procedure : TAH + BSO Without any lymphadenectomy • Randomized to: NO Adj Therapy(NAT) versus Pelvic EBRT (46gy) 31.07.2022 42 PRAGATHEESWARI, MMC.
PELVIC RT NO PELVIC RT 5YR VAGINAL RECURRENCE/ PELVIC RECURRENCE <4% 14% 5YR OVER ALL SURVIVAL 81% 85% RESULT: (PORTEC1) • OVERALL SURVIVAL SIMILAR • VAGINAL/PELVIS RECURRENCE REDUCED AFTER PELVIC RT • PELVIC RT COMPLICATION ARE SIGNIFICANTLY HIGH 31.07.2022 43 PRAGATHEESWARI, MMC.
• WHY NOT IVRT ALONE vs EBRT? • PORTEC 2 • SWEDISH TRAIL • ASTEC/NCIC 31.07.2022 44 PRAGATHEESWARI, MMC.
PELVIC RT Vs VAGINAL BRACHY PORTEC 2 • Population : stage IA >/= 60yrs stage IA grade 3 stage1B grade1,2 of all ages Surgery, TAH+BSO Without lymphadenectomy • Randomized to EBRT(46gy) Vs IVRT(21gy/3#) 31.07.2022 45 PRAGATHEESWARI, MMC.
RESULT(PORTEC-2) • Vaginal recurrence : 1.9% vs 0.9% (IVRT) • Pelvic recurrence : 0.6% vs 3.5%(IVRT) • Portec 2 shows excellent and equivalent vaginal and pelvic control with both arms • No significant difference in over all survival between 2arms(90%) • This trial shows that intra vaginal Rt alone suficient to control vagina recurrence with early stage endometrial carcinoma(uterine confined) with high risk features 31.07.2022 46 PRAGATHEESWARI, MMC.
• PORTEC trial exclude STAGE IB grade 3 • Because , in higher grade we have to give • Omiting pelvic RT in the setting of no lypmhadenectomy is not advisable 31.07.2022 47 PRAGATHEESWARI, MMC.
CONCLUSION • IVRT is very effective in ensuring local control ,keeping to a minimum the risk of vaginal recurrence • IVRT achieves excellent vaginal control and rates of locoregional recurrence • Overall survival is similar to both arm • Quality of life and gastrointestinal toxic effects aRre significantly better with VBT • IVRT is better option in adjuvant treatment of early endometrial ca 31.07.2022 48 PRAGATHEESWARI, MMC.
• STAGE I - endocervical mucosal invasion • incidence 2.3% • policy IVRT • as per PORTEC 2 31.07.2022 49 PRAGATHEESWARI, MMC.
GOG 99 • Patient population: stage 1 & 2 • Excluded - no myometrial invasion • Surgery: TAH+BSO+ Nodal sampling , pelvic washing • Randomized to observe versus pelvic RT Investigators used Risk factors historical data from GOG 33 31.07.2022 50 PRAGATHEESWARI, MMC.
RESULT(GOG 99) • IRRADIATED PATIENTS had superior pelvic control • RT Pts had non significant improved overall survival PELVIC RT NO PELVIC RT LOCAL RECURRENCE 3% 12% OVERALL SURVIVAL 92% 86% 31.07.2022 51 PRAGATHEESWARI, MMC.
Here greater benefit from pelvic RT was observed in HIGH INTERMEDIATE RISK FACTORS (devita) 1. Advancing age 2. Deep myometrial invasion (outer 1/3) 3. Grade 2 &3 4. LVSI + 31.07.2022 52 PRAGATHEESWARI, MMC.
31.07.2022 53 PRAGATHEESWARI, MMC.
STAGE 2 • Cervical mucosa >50 % invasion • Grade3 • Cervical mucosa < 50 % invasion • grade 1 &2 • adequate LN sampling • <50 % myometrial invasion 31.07.2022 54 PRAGATHEESWARI, MMC.
REPORT FROM MSKCC centre EARLY STAGE - > 50 % myometrial invasion, grade 3 --- pelvic RT is must even if lymphnode sample is negative 31.07.2022 55 PRAGATHEESWARI, MMC.
CHEMOTHERAPY
GOG 249 • 609 patients , with stage 1&2 HIR • stage 1&2 , clear cell , serous HPE • randomised to • Pelvic RT 45 Gy vs IVRT 3 cy carbo + Pacli • 3yr RFS is same • os is 91 % vs 88% • pelvic recurrence 6 % vs 25 • and chemo arm experienced greater toxicity • further reports are awaited, • so IT IS CAT 2B as of now 31.07.2022 57 PRAGATHEESWARI, MMC.
Stage III & IV • Treatment (stage III & IVA ) – EBRT + Chemotherapy +/- Vaginal brachy • Combination therapy is preferred for stage III • Stage IV B - chemo +/- EBRT +/- Vaginal brachy 31.07.2022 58 PRAGATHEESWARI, MMC.
RT vs CHEMO ADJ RT vs CHEMO RT CHEMO vs CHEMO RT 31.07.2022 59 PRAGATHEESWARI, MMC.
CHEMO Vs PELVIC RT GOG 122 (Stage 3 and 4) • Assessed optimal adjuvant wholepelvic RT Versus chemotherapy (7 cycle of doxorubicin 60mg/m2) and cisplatin 50mg/m2 with additional cycle of cisplatin • Chemotherapy improved PFS (50%vs 38%) and OS compared with RT(60% vs 43%) • RT as single modality is inferior in stage 3 and 4 31.07.2022 60 PRAGATHEESWARI, MMC.
GOG 122 RECURRENCE RT(EBRT) CHEMO PELVIC 13% 18% EXTRA PELVIC 38% 30% Most recurrence are systemic , not locoregional Chemo is better in controlling systemic recurrence in advanced stage, but only after adjusting staging imbalance 31.07.2022 61 PRAGATHEESWARI, MMC.
CHEMO vs CHEMO RT GOG 258 • Compared Chemo Vs Chemo RT in Stage 3 and 4 and • serous ,clear cell histology (stage I and 2) • Arm 1- CCRT (Cisplatin 50mg/m2 day1 and 29, pelvic EBRT 45gy +/- brachy) f/b carbo& paclitaxel 4 cycle • Arm 2– CT (Carboplatin AUC 6 + paclitaxel 175mg/m2 every 21days 6 cycle) ⮚ Vaginal recurrence -2%(CCRT) vs 7%(CT) ⮚ Pelvic recurrence 11%(CCRT) vs 20%(CT) • ChemoRT is better in vaginal and pelvic recurrence control than chemo alone 31.07.2022 62 PRAGATHEESWARI, MMC.
PELVIC RT VS CHEMO RT PORTEC 3 • High risk stage II/III Endometrial cancer • After surgery randomized to • Pelvic RT(48.6gy) alone Vs Chemo RT (48.6Gy + 2cycle cisplatin ) f/b Adjuvant chemo (4cycle carboplatin+ paclitaxel) • Primary endpoint: Benefit of chemoRT over and above adjuvant RT alone by 7% Increase in FFS 5% Increase in overall survival • FFS 75%(CCRT) vs 68%, OS 81%(CCRT) vs 76% 31.07.2022 63 PRAGATHEESWARI, MMC.
• PORTEC 3 – Subset analysis(2019) shows For stage III carcinoma Significant improvement at 5 years  FFS By 10%  OS By 12%  Serous Histology  Significant improvement at 5 years  FFS By 12%  OS By 18% 31.07.2022 64 PRAGATHEESWARI, MMC.
Conventional RT • Position - Prone to displace the small intestines from the radiation field., or supine with full bladder • Target volume - pelvic lymph nodes, including obturator, external, internal, and lower common iliac groups and the proximal two- thirds of the vagina. The presacral nodes are not included unless patients have gross cervical involvement. • Energy : High-energy linear accelerators (15 MV). 31.07.2022 65 PRAGATHEESWARI, MMC.
Conventional RT • Technique : Four-field pelvic-box technique • Borders : AP/PA FIELDS • superior border - L5-S1 • Inferior border - bottom of the obturator foramina/ ischial tuberosity • Lateral border - 2 cm lateral to inlet of the true bony pelvis/ femoral pulse. • LATERAL FIELDS • Anterior border - front of the pubis symphysis • Posterior border - S2-S3. • Superior and Inferior borders are the same for the AP/PA fields 31.07.2022 66 PRAGATHEESWARI, MMC.
31.07.2022 67 PRAGATHEESWARI, MMC.
• Dose : 50.4 Gy / 1.8 Gy/#- pelvic radiation is used alone • 45 Gy/1.8 Gy/# - when combined with intravaginal RT. • When para-aortic nodes are involved, extended field RT is used. • CT simulation is crucial for accurate delineation of the kidneys, small bowel, and liver in addition to nodal target. • Lower border - same as in pelvic radiation • Upper border - T12-L1 interspace. • Lateral Border - Tip of Transverse process of vertebra • Dose is 45.0 Gy at 1.8 Gy or 1.5 Gy if patients develop GI toxicity. 31.07.2022 68 PRAGATHEESWARI, MMC.
EXTENDED FIELD RT • For pts with positive para aortic nodes. • It should include the pelvic nodes,pericaval,interaortocav al and the para aortic nodes. • Preferred approach is four field box technique, in order to lower the dose to small bowels. • Field borders: • UB-T12 /L1 interspace. • LB -L5/S1 interspace. • IMRT is the preferred choice to reduce the toxicity. 69
Brachytherapy • Is used to deliver 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 may be delivered as 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 in 3# when Combined with EBRT 31.07.2022 70 PRAGATHEESWARI, MMC.
• OUTPATIENT BASIS- WITHOUT ANAESTHESIA • 4-6 WKS AFTER SURGERY • USUALLY THREE FRACTIONS OF 7 GY TO A TOTAL OF 21 GY IN 1TO 2 WEEKS APART • DOSE IS PRESCRIBED TO 0.5 CM DEPTH FROM MUCOSAL SURFACE • USING A 3 CM DIAMETER CYLINDER- 4 TO 7 CM LENGTH 31.07.2022 71 PRAGATHEESWARI, MMC.
CHEMOTHERAPY Role of Chemotherapy • Absolute in stage III& IV (cat 1) • serous, clear cell – any stage • Uterine carcinosarcoma • Consider in stage IB (grade3) , stage II - adding chemo to adjuvant RT provide added therapeutic benefit – decrease in distant metastases – However NCCN consider adding chemo as CAT 2B recommendation because OS advantage has not been shown (GOG 249 results awaited) 31.07.2022 72 PRAGATHEESWARI, MMC.
CHEMOTHERAPY ⮚ Preferred regimen : Carboplatin & paclitaxel(cat 1) GOG 184 • Assessed combination chemotherapy 3drug (cisplatin+doxorubicin+paclitaxel) + Pelvic RT Vs 2drug (cisplatin+doxorubicin) + Pelvic RT in stage III & IVA • Result indicate that 3 drug regimen shows no survival advantage, • 3 drug resulted in greater toxicity (hematologic toxicity,sensory neuropathy,myalgia) 31.07.2022 73 PRAGATHEESWARI, MMC.
KEY NOTE 775 • phase 3 RCT, • population - advanced endometrial ca , previously treated with platinum based chemotherapy • started - june , 2018 • primary completion - oct, 2020 31.07.2022 74 PRAGATHEESWARI, MMC.
• Lenavtinib 20mg OD + Pembrolizumab 200mg IV on day 1 - Q21 days Vs • Doxorubicin 60 mg/m2 + Paclitaxel 80 mg/m2 Q21 days 31.07.2022 75 PRAGATHEESWARI, MMC.
• END POINTS • PFS - 6.6 vs 3.8 months • OS - 17.4 vs 12 months • Noe for refractory , residual disease it is recommended as • CAT 1 by NCCN. - we are yet to see the 5year survival rate 31.07.2022 76 PRAGATHEESWARI, MMC.
31.07.2022 77 PRAGATHEESWARI, MMC.
FERTILITY SPARING MANAGEMENT • CRITERIA (all must be met) ✔ Well differentiated endometrioid adenocarcinoma ✔ Disease limited to endometrium on MRI(preferred)/USG ✔ Absence of suspicious mets or metastatic disease on imaging ✔ No contraindication to medical therapy or pregnancy ✔ Patient should undergo counselling that fertility sparing option is NOT Standard of care for treatment of endometrial ca 31.07.2022 78 PRAGATHEESWARI, MMC.
• If Endometrial ca present at 6-12 month TAH/BSO With staging • Complete response at 6 months • Encourage conception (with continued surveillance / endometrial sampling every 6month, • consider maintenance progestin, if patient not trying to conceive Treatment for fertility sparing Continous progrestin based therapy ✔Megestrol ✔Medroxyprogestrone ✔Levonorgestrel IUD ✔Weight management/life style modification Endometrial evaluation every 3-6month (D&C or endometrial biopsy) 31.07.2022 79 PRAGATHEESWARI, MMC.
RECURRENCE • LOCO REGIONAL • ISOLATED METS • DISSEMINATED METS 31.07.2022 80 PRAGATHEESWARI, MMC.
NO prior RT EBRT+/- BRACHY+/- CHEMO Prior RT (EBRT) Surgical resection + chemo +/- palliative EBRT 0r Brachy +/-chemo Prior RT(BRACHY) Disease confined to vagina or paravaginal tissue ⮚ Surgical resection F/B EBRT +/- brachy , chemo Prior RT(BRACHY) NODAL METS ⮚ Surgical resection of vaginal recurrence F/B pelvic or para aortic node EBRT +/- Chemo ISOLATED METS EBRT (or) consider Resection Disseminated Mets Systemic therapy +/- palliative RT 31.07.2022 81 PRAGATHEESWARI, MMC.
OTHER HISTOLOGY • Serous ca • Clear cell ca • Undifferentiated / Dedifferentiated ca • Carcinosarcoma 31.07.2022 82 PRAGATHEESWARI, MMC.
Primary treatment: Suitable for surgery 🡪 TAH+BSO+ Pelvic node assessment with/without para aortic node dissection, peritoneal wash , omental biopsy Not suitable for surgery 🡪 EBRT+ Brachytherapy +/- chemo 31.07.2022 83 PRAGATHEESWARI, MMC.
Adjuvant Treatment • Stage I A Vaginal brachy + chemotherapy • Stage I B,II,III,IV EBRT+ brachy + chemotherapy 31.07.2022 84 PRAGATHEESWARI, MMC.
LOW GRADE ESS (Endometrial Stromal Sarcoma) ⮚Surgery: (Total hysterectomy + BSO) ✔Adjuvant Treatment • Stage I: observe • Stage II,III,IVA - antiestrogen hormone therapy ( ER/PR receptor positive), +/-EBRT(cat2b) • Stage IVB - anti estrogen hormone therapy( ER/PR positive +/- Palliatuve RT) 31.07.2022 85 PRAGATHEESWARI, MMC.
High grade ESS,UUS,uLMS (leiomyosarcoma) ⮚Surgery: (Total hysterectomy + BSO) ✔Adjuvant Treatment ⮚Stage I: observe ⮚Stage II,III,IVA : Systemic therapy and or EBRT ⮚Stage IVB : Systemic therapy +/- palliative RT 31.07.2022 86 PRAGATHEESWARI, MMC.
RECENT ADVANCE
MOLECULAR TYPES OF ENDOMETRIAL CA • POLE(ultramutated) • MSI (hypermutated) • COPY NUMBER LOW • COPY NUMBER HIGH 31.07.2022 88 PRAGATHEESWARI, MMC.
31.07.2022 89 PRAGATHEESWARI, MMC.
POLE (polymerase epsilon) MSI COPY NUMBER LOW COPY NUMBER HIGH COPY NUMBER ABBERATION LOW LOW LOW HIGH (P53 MUTATION) MSI METHYLATION MIXED MSI HIGH MSI STABLE MSI STABLE HISTOLOGY TYPE ENDOMETRIOID ENDOMETRIOID ENDOMETRIOID SEROUS, ENDO,MIXED TUMOUR GRADE MIXED (GRADE 1-3) MIXED (GRADE 1-3) MIXED (GRADE 1-3) GRADE 3 PROGRESSION FREE SURVIVAL GOOD INTERMEDIATE INTERMEDIATE POOR 31.07.2022 90 PRAGATHEESWARI, MMC.
PORTEC 4a(On going Trial) • PORTEC 4a is first randomised trial to introduce molecular factors in the adjuvant treatment of endometrial cancer • Here randomization between • standard(regular) Vs individualized treatment based on molecular risk profile • Population : stage Ia and grade 3 stage Ib grade 1&2 with age > 60 and 0r LVSI stage Ib ,grade 3 without LVSI stage II ( grade 1) 31.07.2022 91 PRAGATHEESWARI, MMC.
31.07.2022 92 PRAGATHEESWARI, MMC.
• Primary objective : To compare vaginal recurrence • Secondary objective : PFS and OS Portec 4a will provide information whether vaginal brachy can be safely omitted in patient with favorable molecular integrated risk profile Whether intensification is needed in adjuvant treatment of unfavorable risk profile. 31.07.2022 93 PRAGATHEESWARI, MMC.
REFERENCE • B D CHAURASIA Anatomy • MUDALIAR MENON Obs &Gyn • DEVITA’ oncology • Perez oncology • NCCN guidelines • PUBMED 31.07.2022 94 PRAGATHEESWARI, MMC.
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ca endometrium.pptx

  • 2. SYNOPSIS • Anatomy • Endometrial ca introduction • C/F , workup • Staging • Treatment - stage wise • Evidence for each treatment • Other Histology • Recent Advance 31.07.2022 2 PRAGATHEESWARI, MMC.
  • 3. UTERUS • Uterus is the female reproductive child bearing organ located in the true pelvis between the bladder and rectum • Size:8 cm*5cm*2.5cm (adults) 31.07.2022 3 PRAGATHEESWARI, MMC.
  • 4. • Uterus is divided into three parts • Fundus-part above the opening of fallopian tube • Body –line of division from cervix corresponds to internal os • Cervix-supravaginal and vaginal portion • Uterus-hollow muscular organ composed of 3 layers • Inner –endometrium[tunica mucosa] • Middle-myometrium[tunica muscularis] • Outer –perimetium[tunica serosa] 31.07.2022 4 PRAGATHEESWARI, MMC.
  • 5. What is Endometrium?? • Eytmology Endo : “inner” from latin Metra: “uterus” from Greek From Maetra Means Mother • Uterus is an hollow muscular organ located in true pelvis between the bladder and rectum • Uterus is divided into fundus, body(corpus) and cervix enclosing uterine cavity • This uterine cavity is lined by Endometrium whereas the wall of the composed of myometrium (smooth muscle fibers 5
  • 6. Is Endometrium just a Lining of uterine cavity? • NO! • It prevents adhesions between opposed walls of myometrium • Therefore maintains the patency of Uterine cavity Endometrial Paradox which is that the endometrium is the lining of uterine cavity but without endometrium there would be no uterine cavity 6
  • 7. Changes in Endometrium during menstrual cycle Both Functional layer of endometrium and stroma are responsive to hormonal influence ➢Estrogen:- proliferative stage(follicular phase) ➢Progestron:- seceretory stage(luteal phase) 7
  • 8. LYMPHATIC DRAINAGE • Body of the uterus:- drains to obturator and internal and external iliac noses • Fundus of the uterus:- para aorta as the lymphatics accompany ovarian arteries 8
  • 9. ENDOMETRIAL CARCINOMA • Global:- 15th most common carcinoma worldwide and ranks sixth among cancers affecting women • India:- 0.88 million cancer cases with an incidence rate of 105.5 per 100,000 in women.The incidence of endometrial cancer cases are very low in India ➢ Highest being observed in Bangalore and Delhi 9
  • 10. 10
  • 11. WORKUP • History & Physical Examination • CBC,RFT, LFT • Endometrial tissue sampling – Biopsy or D&C • ER/PR ,Her2neu is recommended for stage III,IV and recurrent /metastastic settings • Imaging - USG abdomen and pelvis - CT/MRI Abdomen - PET CT (not mandatory) - Chest CT/ Xray 31.07.2022 11 PRAGATHEESWARI, MMC.
  • 12. Major Clinical presentation • 80 to 90% present with postmenopausal vaginal bleeding Thumb rule:- postmenopausal bleeding is assumed to be endometrial cancer until proven otherwise (eventhough the incidence of endometrial cancer presenting with postmenopausal bleeding is around 10% to 15%) 12
  • 13. Presentations in early stages • 5% to 10%:- Abnormal vaginal discharge • 5%:- Asymptomatic Asymptomatic patients are suspected to have endometrial cancer in settings of ➢Abnormal pap smear in routine screening ➢Thickened endometrium in routine transvaginal ultrasound 13
  • 14. Presentation in advanced stages ❖Urinary or rectal bleeding ❖Constipation ❖Lower limb lymphedema ❖Abdominal distention due to ascities ❖Pain ❖Referred pain to hypogastrium/both iliac fossa called simpson’s pain ➢ Non severe and tends to occur at the same time each day, lasting for 1-2 hours 14
  • 15. Physical Examination • General examination • Systemic examination • Abdominal Examination • Bimanual per vaginal examination – confirm uterine size, adnexal mass, involvement of cervix, vagina • Digital rectal examination- Rectal mucosa, sphcinter tone, rectovaginal fistula, parametrium involvement 31.07.2022 15 PRAGATHEESWARI, MMC.
  • 16. Diagnostic work up Endometrial sampling- Gold Standard Endometrial sampline achieved by two methods ✓ Biopsy ✓ Dilation and curettage 16
  • 17. Endometrial Biopsy • Easily performed in the office with pipelle or similar device- It is the preferred approach. • Sensitivity :- postmenopausal status- 99.6% pre-menopausal status- 91% • BUT Specificity:- both pre and postmenopausal women – more than 98% 17
  • 18. Then where is D&C used? • Routine D&C Recommended in patients who are considered for conservative fertility sparing approaches • If office sampling is inadequate • If symptoms persists 18
  • 19. Can every patient with postmenopausal bleeding undergo sampling?? 19
  • 20. • Only 10 to 15% patients with postmenopausal bleeding have endometrial cancer • Therefore it is unclear how feasible it is to perform endometrial sampling on every patient • Solution:- Transvaginal ultrasound may be considered as useful tool in assessing pt’s vaginal bleeding to select patients for sampling 20
  • 21. Transvaginal Ultrasound • Normal endometrium • Thin • Homogenously hyperechoic • Thick • Heterogenous Abnormal endometrium 21
  • 22. Endometrial Thickness(Premenopausal) PHASE THICKNESS Menstruation 2-4 mm Early proliferative phase 5-7 mm Late proliferative Up to 11mm Secretory phase 7-16 mm 31.07.2022 22 PRAGATHEESWARI, MMC.
  • 23. Postmenopausal Endometrial thickness Vaginal bleeding (not on tamoxifen) • Upper limit of normal < 5mm • Risk of carcinoma is 7% if endometrium is >5mm No H/o Vaginal bleeding • Normal Cut off value </= 8 mm, upto 11mm • Risk of carcinoma is 7% if endometrium is >11mm • If on Tamoxifen normal < 5mm 31.07.2022 23 PRAGATHEESWARI, MMC.
  • 24. CT SCAN • CT scan – lesion seen as hypodense mass, diffuse, circumscribed vegetative or polypoidal mass • Helpful in assessing regional node and distant mets • Loss of periureteral fat – indicates Parametrium involved 31.07.2022 24 PRAGATHEESWARI, MMC.
  • 25. MRI • Most accurate imaging study to assess tumor extension in endometrial cancer, especially myometrial invasion • Clear junctional zone or preservation of sharp delineation between tumor and myometrium – Disease limited to endometrium • Extension of high signal intensity into outer myometrium with peripheral rim of normal intact myometrium – Deep myometrial invasion • MRI helpful in delineate tumor extension into cervix • Nodal mets- sensitivity is 43.5%,specificity 95.9% 31.07.2022 25 PRAGATHEESWARI, MMC.
  • 26. 26
  • 27. PET SCAN • Little benefit in assessing extension of tumor • Nodal mets sensitivity is 72% specificity is 94% • Main advantage – accuracy in detection of distant mets • Disadvantage: inability to detect mets in node < 5mm 31.07.2022 27 PRAGATHEESWARI, MMC.
  • 28. CA 125 • Cancer Antigen 125 • Elevated CA 125 is seen in 25-48% of endometrial cancer • Monitoring response to treatment ( declining CA125 in response to treatment) • Normal range – 0 to 35 units/ml • Range >35 – indicates possibility of cancer • Hsieh et al – found that preoperative level >35 U/ml correlated significantly with regional lymphnode mets ,suggested such levels could be indication of full pelvic and para-aortic lymphadenectomy at time of surgical staging in absence of metastatic disease 31.07.2022 28 PRAGATHEESWARI, MMC.
  • 29. Update on CA 125 • Askin et al:- • High levels of CA 125 significantly correlated with Advanced stage and lymph node metastasis • Cut off determined by this study is 20U/ml With 75% and 69.5% sensitivity and specificity But has 80.6% PPV and 84.9% NPV 29
  • 31. Treatment • Primary treatment is Surgery • Staging laparotomy- TAH+BSO+ Pelvic node assessment with/without para aortic node dissection, peritoneal wash • why BSA ? - synchronous ovarian ca in 5% • if age >50 years it increase upto 10% • Along with visual inspection of peritoneal, diaphragmatic , serosal surface – suspicious lesion biopsy should be done, and omental biopsy • Omental biopsy- commonly done for serous, clear cell, carcinosarcoma histologies 31.07.2022 31 PRAGATHEESWARI, MMC.
  • 32. SURGERY • TAH+BSO : Laparotomy based approach , simple hysterectomy is done • LAPAROSCOPIC VAGINAL HYSTERECTOMY: Minimally invasive surgery, gained importance recently • ROBOTIC HYSTERECTOMY : Alternative minimally invasive surgery in endometrial cancers • RADICAL HYSTERECTOMY : Not routinely performed due to low incidence of parametrial involvement • DEBULKING SURGERY /CYTOREDUCTION : For recurrent and advanced diseases 31.07.2022 32 PRAGATHEESWARI, MMC.
  • 33. Adequate Sampling (perez) • Five lymphatic station to be removed from each side – Common iliac, internal iliac , external iliac, obturator node and para aortic node (or) • Total of 10 nodes to be removed 31.07.2022 33 PRAGATHEESWARI, MMC.
  • 34. Sentinel Lymph Node Biopsy 1. The radiolabeled colloid most commonly injected into the cervix is technetium- TC99m 2. colored dyes are available in a variety of forms (Isosulfan Blue 1%, Methylene Blue 1%, and Patent Blue 2.5% sodium). 3. Indocyanine green (ICG) recently emerged as a useful imaging dye that requires a near-infrared camera for localization, provides a very high SLN detection rate, and is commonly used. 31.07.2022 34 PRAGATHEESWARI, MMC.
  • 37. PATHOLOGY ASSESSMENT • Uterus – Hysterectomy type Tumor site, size Histology type Histology grade Myometrial invasion Cervical stromal invasion LVSI • Other organ involvement- fallopian tube, ovaries, vagina, parametrium, omentum • Peritoneal /ascitic fluid cytology • Lymph node resected • Isolated tumor cell in node , NO(i+), should not upstage patient but should considered in discussion of adjuvant therapy • ER/Her2 neu Testing 31.07.2022 37 PRAGATHEESWARI, MMC.
  • 38. HPE (important factors) • Histology • Grade(1,2,3) • LVSI • Depth of invasion(myometrium) 31.07.2022 38 PRAGATHEESWARI, MMC.
  • 40. Adjuvant Treatment STAGE I A • GRADE 1,2 •no myometrial invasion - observation • < 50% myometrial invasion , age >60yrs, LVI+ - IVRT •GRADE 3 •no invasion - age <60 yrs no LVSI - Observe • age >60 yrs and LVI PLUS - IVRT •< 50 % invasion - ADJ RT PORTEC 1 31.07.2022 40 PRAGATHEESWARI, MMC.
  • 41. • STAGE I B • GRADE 1 & 2 - ADJ RT (PORTEC 1) 31.07.2022 41 PRAGATHEESWARI, MMC.
  • 42. PORTEC 1 • AIM OF STUDY: To determine impact of pelvic irradiation on outcome in patients with early stage endometrial cancer • Surgical procedure : TAH + BSO Without any lymphadenectomy • Randomized to: NO Adj Therapy(NAT) versus Pelvic EBRT (46gy) 31.07.2022 42 PRAGATHEESWARI, MMC.
  • 43. PELVIC RT NO PELVIC RT 5YR VAGINAL RECURRENCE/ PELVIC RECURRENCE <4% 14% 5YR OVER ALL SURVIVAL 81% 85% RESULT: (PORTEC1) • OVERALL SURVIVAL SIMILAR • VAGINAL/PELVIS RECURRENCE REDUCED AFTER PELVIC RT • PELVIC RT COMPLICATION ARE SIGNIFICANTLY HIGH 31.07.2022 43 PRAGATHEESWARI, MMC.
  • 44. • WHY NOT IVRT ALONE vs EBRT? • PORTEC 2 • SWEDISH TRAIL • ASTEC/NCIC 31.07.2022 44 PRAGATHEESWARI, MMC.
  • 45. PELVIC RT Vs VAGINAL BRACHY PORTEC 2 • Population : stage IA >/= 60yrs stage IA grade 3 stage1B grade1,2 of all ages Surgery, TAH+BSO Without lymphadenectomy • Randomized to EBRT(46gy) Vs IVRT(21gy/3#) 31.07.2022 45 PRAGATHEESWARI, MMC.
  • 46. RESULT(PORTEC-2) • Vaginal recurrence : 1.9% vs 0.9% (IVRT) • Pelvic recurrence : 0.6% vs 3.5%(IVRT) • Portec 2 shows excellent and equivalent vaginal and pelvic control with both arms • No significant difference in over all survival between 2arms(90%) • This trial shows that intra vaginal Rt alone suficient to control vagina recurrence with early stage endometrial carcinoma(uterine confined) with high risk features 31.07.2022 46 PRAGATHEESWARI, MMC.
  • 47. • PORTEC trial exclude STAGE IB grade 3 • Because , in higher grade we have to give • Omiting pelvic RT in the setting of no lypmhadenectomy is not advisable 31.07.2022 47 PRAGATHEESWARI, MMC.
  • 48. CONCLUSION • IVRT is very effective in ensuring local control ,keeping to a minimum the risk of vaginal recurrence • IVRT achieves excellent vaginal control and rates of locoregional recurrence • Overall survival is similar to both arm • Quality of life and gastrointestinal toxic effects aRre significantly better with VBT • IVRT is better option in adjuvant treatment of early endometrial ca 31.07.2022 48 PRAGATHEESWARI, MMC.
  • 49. • STAGE I - endocervical mucosal invasion • incidence 2.3% • policy IVRT • as per PORTEC 2 31.07.2022 49 PRAGATHEESWARI, MMC.
  • 50. GOG 99 • Patient population: stage 1 & 2 • Excluded - no myometrial invasion • Surgery: TAH+BSO+ Nodal sampling , pelvic washing • Randomized to observe versus pelvic RT Investigators used Risk factors historical data from GOG 33 31.07.2022 50 PRAGATHEESWARI, MMC.
  • 51. RESULT(GOG 99) • IRRADIATED PATIENTS had superior pelvic control • RT Pts had non significant improved overall survival PELVIC RT NO PELVIC RT LOCAL RECURRENCE 3% 12% OVERALL SURVIVAL 92% 86% 31.07.2022 51 PRAGATHEESWARI, MMC.
  • 52. Here greater benefit from pelvic RT was observed in HIGH INTERMEDIATE RISK FACTORS (devita) 1. Advancing age 2. Deep myometrial invasion (outer 1/3) 3. Grade 2 &3 4. LVSI + 31.07.2022 52 PRAGATHEESWARI, MMC.
  • 54. STAGE 2 • Cervical mucosa >50 % invasion • Grade3 • Cervical mucosa < 50 % invasion • grade 1 &2 • adequate LN sampling • <50 % myometrial invasion 31.07.2022 54 PRAGATHEESWARI, MMC.
  • 55. REPORT FROM MSKCC centre EARLY STAGE - > 50 % myometrial invasion, grade 3 --- pelvic RT is must even if lymphnode sample is negative 31.07.2022 55 PRAGATHEESWARI, MMC.
  • 57. GOG 249 • 609 patients , with stage 1&2 HIR • stage 1&2 , clear cell , serous HPE • randomised to • Pelvic RT 45 Gy vs IVRT 3 cy carbo + Pacli • 3yr RFS is same • os is 91 % vs 88% • pelvic recurrence 6 % vs 25 • and chemo arm experienced greater toxicity • further reports are awaited, • so IT IS CAT 2B as of now 31.07.2022 57 PRAGATHEESWARI, MMC.
  • 58. Stage III & IV • Treatment (stage III & IVA ) – EBRT + Chemotherapy +/- Vaginal brachy • Combination therapy is preferred for stage III • Stage IV B - chemo +/- EBRT +/- Vaginal brachy 31.07.2022 58 PRAGATHEESWARI, MMC.
  • 59. RT vs CHEMO ADJ RT vs CHEMO RT CHEMO vs CHEMO RT 31.07.2022 59 PRAGATHEESWARI, MMC.
  • 60. CHEMO Vs PELVIC RT GOG 122 (Stage 3 and 4) • Assessed optimal adjuvant wholepelvic RT Versus chemotherapy (7 cycle of doxorubicin 60mg/m2) and cisplatin 50mg/m2 with additional cycle of cisplatin • Chemotherapy improved PFS (50%vs 38%) and OS compared with RT(60% vs 43%) • RT as single modality is inferior in stage 3 and 4 31.07.2022 60 PRAGATHEESWARI, MMC.
  • 61. GOG 122 RECURRENCE RT(EBRT) CHEMO PELVIC 13% 18% EXTRA PELVIC 38% 30% Most recurrence are systemic , not locoregional Chemo is better in controlling systemic recurrence in advanced stage, but only after adjusting staging imbalance 31.07.2022 61 PRAGATHEESWARI, MMC.
  • 62. CHEMO vs CHEMO RT GOG 258 • Compared Chemo Vs Chemo RT in Stage 3 and 4 and • serous ,clear cell histology (stage I and 2) • Arm 1- CCRT (Cisplatin 50mg/m2 day1 and 29, pelvic EBRT 45gy +/- brachy) f/b carbo& paclitaxel 4 cycle • Arm 2– CT (Carboplatin AUC 6 + paclitaxel 175mg/m2 every 21days 6 cycle) ⮚ Vaginal recurrence -2%(CCRT) vs 7%(CT) ⮚ Pelvic recurrence 11%(CCRT) vs 20%(CT) • ChemoRT is better in vaginal and pelvic recurrence control than chemo alone 31.07.2022 62 PRAGATHEESWARI, MMC.
  • 63. PELVIC RT VS CHEMO RT PORTEC 3 • High risk stage II/III Endometrial cancer • After surgery randomized to • Pelvic RT(48.6gy) alone Vs Chemo RT (48.6Gy + 2cycle cisplatin ) f/b Adjuvant chemo (4cycle carboplatin+ paclitaxel) • Primary endpoint: Benefit of chemoRT over and above adjuvant RT alone by 7% Increase in FFS 5% Increase in overall survival • FFS 75%(CCRT) vs 68%, OS 81%(CCRT) vs 76% 31.07.2022 63 PRAGATHEESWARI, MMC.
  • 64. • PORTEC 3 – Subset analysis(2019) shows For stage III carcinoma Significant improvement at 5 years  FFS By 10%  OS By 12%  Serous Histology  Significant improvement at 5 years  FFS By 12%  OS By 18% 31.07.2022 64 PRAGATHEESWARI, MMC.
  • 65. Conventional RT • Position - Prone to displace the small intestines from the radiation field., or supine with full bladder • Target volume - pelvic lymph nodes, including obturator, external, internal, and lower common iliac groups and the proximal two- thirds of the vagina. The presacral nodes are not included unless patients have gross cervical involvement. • Energy : High-energy linear accelerators (15 MV). 31.07.2022 65 PRAGATHEESWARI, MMC.
  • 66. Conventional RT • Technique : Four-field pelvic-box technique • Borders : AP/PA FIELDS • superior border - L5-S1 • Inferior border - bottom of the obturator foramina/ ischial tuberosity • Lateral border - 2 cm lateral to inlet of the true bony pelvis/ femoral pulse. • LATERAL FIELDS • Anterior border - front of the pubis symphysis • Posterior border - S2-S3. • Superior and Inferior borders are the same for the AP/PA fields 31.07.2022 66 PRAGATHEESWARI, MMC.
  • 68. • Dose : 50.4 Gy / 1.8 Gy/#- pelvic radiation is used alone • 45 Gy/1.8 Gy/# - when combined with intravaginal RT. • When para-aortic nodes are involved, extended field RT is used. • CT simulation is crucial for accurate delineation of the kidneys, small bowel, and liver in addition to nodal target. • Lower border - same as in pelvic radiation • Upper border - T12-L1 interspace. • Lateral Border - Tip of Transverse process of vertebra • Dose is 45.0 Gy at 1.8 Gy or 1.5 Gy if patients develop GI toxicity. 31.07.2022 68 PRAGATHEESWARI, MMC.
  • 69. EXTENDED FIELD RT • For pts with positive para aortic nodes. • It should include the pelvic nodes,pericaval,interaortocav al and the para aortic nodes. • Preferred approach is four field box technique, in order to lower the dose to small bowels. • Field borders: • UB-T12 /L1 interspace. • LB -L5/S1 interspace. • IMRT is the preferred choice to reduce the toxicity. 69
  • 70. Brachytherapy • Is used to deliver 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 may be delivered as 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 in 3# when Combined with EBRT 31.07.2022 70 PRAGATHEESWARI, MMC.
  • 71. • OUTPATIENT BASIS- WITHOUT ANAESTHESIA • 4-6 WKS AFTER SURGERY • USUALLY THREE FRACTIONS OF 7 GY TO A TOTAL OF 21 GY IN 1TO 2 WEEKS APART • DOSE IS PRESCRIBED TO 0.5 CM DEPTH FROM MUCOSAL SURFACE • USING A 3 CM DIAMETER CYLINDER- 4 TO 7 CM LENGTH 31.07.2022 71 PRAGATHEESWARI, MMC.
  • 72. CHEMOTHERAPY Role of Chemotherapy • Absolute in stage III& IV (cat 1) • serous, clear cell – any stage • Uterine carcinosarcoma • Consider in stage IB (grade3) , stage II - adding chemo to adjuvant RT provide added therapeutic benefit – decrease in distant metastases – However NCCN consider adding chemo as CAT 2B recommendation because OS advantage has not been shown (GOG 249 results awaited) 31.07.2022 72 PRAGATHEESWARI, MMC.
  • 73. CHEMOTHERAPY ⮚ Preferred regimen : Carboplatin & paclitaxel(cat 1) GOG 184 • Assessed combination chemotherapy 3drug (cisplatin+doxorubicin+paclitaxel) + Pelvic RT Vs 2drug (cisplatin+doxorubicin) + Pelvic RT in stage III & IVA • Result indicate that 3 drug regimen shows no survival advantage, • 3 drug resulted in greater toxicity (hematologic toxicity,sensory neuropathy,myalgia) 31.07.2022 73 PRAGATHEESWARI, MMC.
  • 74. KEY NOTE 775 • phase 3 RCT, • population - advanced endometrial ca , previously treated with platinum based chemotherapy • started - june , 2018 • primary completion - oct, 2020 31.07.2022 74 PRAGATHEESWARI, MMC.
  • 75. • Lenavtinib 20mg OD + Pembrolizumab 200mg IV on day 1 - Q21 days Vs • Doxorubicin 60 mg/m2 + Paclitaxel 80 mg/m2 Q21 days 31.07.2022 75 PRAGATHEESWARI, MMC.
  • 76. • END POINTS • PFS - 6.6 vs 3.8 months • OS - 17.4 vs 12 months • Noe for refractory , residual disease it is recommended as • CAT 1 by NCCN. - we are yet to see the 5year survival rate 31.07.2022 76 PRAGATHEESWARI, MMC.
  • 78. FERTILITY SPARING MANAGEMENT • CRITERIA (all must be met) ✔ Well differentiated endometrioid adenocarcinoma ✔ Disease limited to endometrium on MRI(preferred)/USG ✔ Absence of suspicious mets or metastatic disease on imaging ✔ No contraindication to medical therapy or pregnancy ✔ Patient should undergo counselling that fertility sparing option is NOT Standard of care for treatment of endometrial ca 31.07.2022 78 PRAGATHEESWARI, MMC.
  • 79. • If Endometrial ca present at 6-12 month TAH/BSO With staging • Complete response at 6 months • Encourage conception (with continued surveillance / endometrial sampling every 6month, • consider maintenance progestin, if patient not trying to conceive Treatment for fertility sparing Continous progrestin based therapy ✔Megestrol ✔Medroxyprogestrone ✔Levonorgestrel IUD ✔Weight management/life style modification Endometrial evaluation every 3-6month (D&C or endometrial biopsy) 31.07.2022 79 PRAGATHEESWARI, MMC.
  • 80. RECURRENCE • LOCO REGIONAL • ISOLATED METS • DISSEMINATED METS 31.07.2022 80 PRAGATHEESWARI, MMC.
  • 81. NO prior RT EBRT+/- BRACHY+/- CHEMO Prior RT (EBRT) Surgical resection + chemo +/- palliative EBRT 0r Brachy +/-chemo Prior RT(BRACHY) Disease confined to vagina or paravaginal tissue ⮚ Surgical resection F/B EBRT +/- brachy , chemo Prior RT(BRACHY) NODAL METS ⮚ Surgical resection of vaginal recurrence F/B pelvic or para aortic node EBRT +/- Chemo ISOLATED METS EBRT (or) consider Resection Disseminated Mets Systemic therapy +/- palliative RT 31.07.2022 81 PRAGATHEESWARI, MMC.
  • 82. OTHER HISTOLOGY • Serous ca • Clear cell ca • Undifferentiated / Dedifferentiated ca • Carcinosarcoma 31.07.2022 82 PRAGATHEESWARI, MMC.
  • 83. Primary treatment: Suitable for surgery 🡪 TAH+BSO+ Pelvic node assessment with/without para aortic node dissection, peritoneal wash , omental biopsy Not suitable for surgery 🡪 EBRT+ Brachytherapy +/- chemo 31.07.2022 83 PRAGATHEESWARI, MMC.
  • 84. Adjuvant Treatment • Stage I A Vaginal brachy + chemotherapy • Stage I B,II,III,IV EBRT+ brachy + chemotherapy 31.07.2022 84 PRAGATHEESWARI, MMC.
  • 85. LOW GRADE ESS (Endometrial Stromal Sarcoma) ⮚Surgery: (Total hysterectomy + BSO) ✔Adjuvant Treatment • Stage I: observe • Stage II,III,IVA - antiestrogen hormone therapy ( ER/PR receptor positive), +/-EBRT(cat2b) • Stage IVB - anti estrogen hormone therapy( ER/PR positive +/- Palliatuve RT) 31.07.2022 85 PRAGATHEESWARI, MMC.
  • 86. High grade ESS,UUS,uLMS (leiomyosarcoma) ⮚Surgery: (Total hysterectomy + BSO) ✔Adjuvant Treatment ⮚Stage I: observe ⮚Stage II,III,IVA : Systemic therapy and or EBRT ⮚Stage IVB : Systemic therapy +/- palliative RT 31.07.2022 86 PRAGATHEESWARI, MMC.
  • 88. MOLECULAR TYPES OF ENDOMETRIAL CA • POLE(ultramutated) • MSI (hypermutated) • COPY NUMBER LOW • COPY NUMBER HIGH 31.07.2022 88 PRAGATHEESWARI, MMC.
  • 90. POLE (polymerase epsilon) MSI COPY NUMBER LOW COPY NUMBER HIGH COPY NUMBER ABBERATION LOW LOW LOW HIGH (P53 MUTATION) MSI METHYLATION MIXED MSI HIGH MSI STABLE MSI STABLE HISTOLOGY TYPE ENDOMETRIOID ENDOMETRIOID ENDOMETRIOID SEROUS, ENDO,MIXED TUMOUR GRADE MIXED (GRADE 1-3) MIXED (GRADE 1-3) MIXED (GRADE 1-3) GRADE 3 PROGRESSION FREE SURVIVAL GOOD INTERMEDIATE INTERMEDIATE POOR 31.07.2022 90 PRAGATHEESWARI, MMC.
  • 91. PORTEC 4a(On going Trial) • PORTEC 4a is first randomised trial to introduce molecular factors in the adjuvant treatment of endometrial cancer • Here randomization between • standard(regular) Vs individualized treatment based on molecular risk profile • Population : stage Ia and grade 3 stage Ib grade 1&2 with age > 60 and 0r LVSI stage Ib ,grade 3 without LVSI stage II ( grade 1) 31.07.2022 91 PRAGATHEESWARI, MMC.
  • 93. • Primary objective : To compare vaginal recurrence • Secondary objective : PFS and OS Portec 4a will provide information whether vaginal brachy can be safely omitted in patient with favorable molecular integrated risk profile Whether intensification is needed in adjuvant treatment of unfavorable risk profile. 31.07.2022 93 PRAGATHEESWARI, MMC.
  • 94. REFERENCE • B D CHAURASIA Anatomy • MUDALIAR MENON Obs &Gyn • DEVITA’ oncology • Perez oncology • NCCN guidelines • PUBMED 31.07.2022 94 PRAGATHEESWARI, MMC.