Endometrial Cancer

T or F ● The FIGO staging for endometrial cancer is a SURGICAL staging, and thus, preoperative imaging studies(EXCEPT chest x-rays) are NOT PART of the staging

True

● Risk factors​: for endometrial cancer

Unopposed estrogen, postmeno, nulliparity, early menarche, late menopause, obesity, tamoxifen (​7.5x​), OCP

● Architectural grading is determined by the amount of solid mass of tumor cells compared to well-defined glands ○ Grade 1 ■ ________________ ○ Grade 2 ■ ______________ ○ Grade 3 ■ _______________

is an endometrioid cancer in which <5% of the tumor growth is in solid sheets is an adenocarcinoma in which 6% to 50% of the tumor is composed of solid sheets of cells occurs when >50% of the tumor is made up of solid sheets

Pelvic RT Versus Intravaginal RT ● In the PORTEC-2 trial

○ 427 patients were randomized to ■ pelvic RT (n = 214) or intravaginal RT (n = 213). ○ Patients enrolled were those with ■ stage (FIGO 1988) IB grade 3 (IA gr 3)and >60 years old ■ IC grades 1 and 2 (IB gr 1-2) and >60 years old, and ■ IIA grades 1 and 2 of all ages but with <50% myometrial invasion (IA gr 1-2) ○ During surgery, patients underwent TAH/BSO, pelvic washing, and removal of suspicious pelvic or para-aortic lymph nodes ○ Routine lymphadenectomy was NOT performed ○ The dose of pelvic RT was 46 Gy given in 23 fractions. Intravaginal RT was delivered using a cylinder to treat the upper half of the vagina ○ The dose was prescribed to 0.5 cm from the surface of the cylinder ○ Three types of brachytherapy were used: ■ HDR to 21 Gy in three fractions ■ low dose rate to 30 Gy at 0.5 to 0.7 Gy/h, and ■ medium dose rate to 28 Gy at 1 Gy/h ○ With a median follow-up of 36 months ■ the 3-year vaginal recurrence rates were 0.9% in the intravaginal RT arm and 1.9% in the pelvic RT arm(P = .97) ■ The pelvic recurrence was SIGNIFICANTLY different; the 3-year rate was 3.5% in the intravaginal RT arm compared to 0.6% in the pelvic RT arm(P = .03) ■ The corresponding rates of isolated pelvic recurrence, however, were NOT SIGNIFICANT: 0.6% versus 1.2%, respectively (P = .54). ■ There was no significant difference in disease-free or overall survival between the two arms ■ The rate of grades 1 and 2 acute GI toxicity was 53% versus 12% in favor of intravaginal RT (P< .001) ○ This trial showed that INTRAVAGINAL RT ALONE is SUFFICIENT to control vaginal recurrence even in patients with intermediate- to high-risk features ● Nout, PORTEC-2 (Lancet 2010, PMID 20206777): PRT of 427 HIR pts s/p TAH/BSO (no PLND) w/ EBRT (46 Gy /23) versus VBT (21 Gy/3 fx HDR or 30 Gy LDR). Eligibility:Age ≥60 and IB G1-2 or IA G3; or endocervical glandular involvement grades 1-3, any age, but >1⁄2 myometrial invasion w/ G3 excluded. MFU 45 mo.QOL better in VBT (social function, diarrhea, fecal incontinence, and limit of ADLs). Central path review: Tumor G2 showed poor reproducibility and on re-review, many pts considered grade 1 (see Table 44.8). On MVA, high-risk profile and LVSI were only RFs for OS and RFS.Conclusion: No difference in VR, OS, and DFS for VBT versus EBRT. In view of QOL benefit, VBT should be treatment for HIR endometrial cancer. Late Gr 3 GI tox was 2% versus none. PORTEC-2 ​[​QoL JCO '08​, ​Nout Lancet '10​, ​Wortman BJC '18​]:​ ​TAH/LND for suspicious LNs only​→ WPRT vs VBT​. VBT noninferior to EBRT for vag recurrence for less than IBG3 or old IIA with better QoL.There are fewer acute toxic GI effects with VBT.There is around a 1 in 8 chance of "bowel bother" after WPRT [​PORTEC 2 QoL​]. See [​Creutzberg nomogram​], which demonstrates grade as a significant factor for vaginal recurrence. Consider VBT for IBG3 / II. · ● 427 pts. Age > 60y with IAG3-IBG2, any age old IIA (10%) except IBG3. Primary 6% diff in vaginal relapse (85%). o ○ 46 Gy​WPRT. VBT to the upper​ half ​of vagina. HDR 21/3 or LDR 30 to 5mm (dose equiv of 45-50Gy). o ○ No UPSC/CC subtypes in this study. Unlike PORTEC 1, but PORTEC 1 only had < 1% of these types. o ○ Like PORTEC-1, no LND, but suspicious LNs removed. ~10% LVSI (focal LVSI not allowed). o ○ Central pathology review: 30% downgraded from G2→ G1. Result = 79% w G1 disease. · ● 5y Vaginal relapse ~1.7%, 5y LRR ~2→ 5% (p=0.17), 5y pelvic relapse* 0.5→ 3.8% (NNT = 333). o ○ *When adjusted to remove G1 patients, 5y pelvic recurrence ~0.5→ 3.3% (p=0.06). o ○ Almost all pelvic recurrences after VBT were associated with widespread distant recurrence. · ● 10yVR~3%.10yPR1→6%inthecontextofDM.10yDM~9%. o ○ MVA for PR: Substantial LVSI / VBT / TP53 mutant w HR of 8.7→ 4.6→ 3.8→ 3.8. o ○ MVA for DM: Substantial LVSI / L1CAM / TP53 mutant with HR of 5.4→ 4.2→ 3.4. o ○ MVA for CSS: Substantial LVSI / L1CAM / TP53 mutant with HR of 7.2→ 5.1→ 3.3. · ● DM ~7%. 5y DM for HIR and old stage IIA 6→ 27%. · ● 5y OS ~82%. 10y OS ~68%. · ● AcuteG1-2GI54→13%but~at2y.LateG32→<1%[NS]. · ● QoL at 2y demonstrated worse social fxn, more diarrhea and fecal leakage with EBRT. Note: Difference of 5-10% is considered clinically relevant.Limitation of activities due to bowel symptoms in one of eight patients who received WPRT. o ○ After RT need to remain close to the toilet 21→ 9%. 2y 13→ 8%. ​Difference 5%. o ○ After RT limitation of daily activities due to bowel sx 22→ 6%, 2y 14→ 3%. ​Difference >10%. o ○ After RT diarrhea 31→ 9%; 2y diarrhea 13→ 6%. ​Difference >5%. o ○ After RT fecal leakage 9→ 4%, 2y 9→ 2%. ​Difference >5%. o ○ After RT rectal blood loss 2→ 1%, 2y 2→ 1%.

● The average adult uterus is about (measurements)

○ 8 cm long ○ 5 cm wide ○ 2.5 cm thick

● Other subtypes of endometrioid adenocarcinoma include the: ___________ ■ which represents <2% of all endometrial carcinomas ■ is characterized by a very well-differentiated glandular patternwith much intracellular glycogen, thus resembling early secretory endometrium ■ Although the cells have clear cytoplasm, their histologic and cytologic features are different from those of clear cell carcinoma

○ Secretory carcinoma

● GOG 99

○ There were 190 patients with stage (FIGO 1988) IB to IIB (grades 1 to 3), who all underwent TAH/BSO, pelvic washing, and pelvic/paraaortic lymph node sampling and then were randomized to ■ observation versus ■ pelvic RT to a dose of 50.4 Gy at 1.8 Gy per fraction ○ At 2 years, there was a statistically significant difference in the rates of RELAPSE in favor of the adjuvant pelvic RT arm(3% vs. 12%; P = .007) ○ The 2-year estimated incidence of isolated VAGINAL/PELVIC recurrence was 1.6% in the RT group and 7.4% in the surgery-alone group ○ There was, however, NO SIGNIFICANT DIFFERENCE in 4-year overall survival (92% RT vs. 86% with surgery alone; P = .557), but there were more complications with pelvic RT Keys, GOG-99 (Gynecol Oncol2004, PMID 14984936):PRT of 392 pts with "interme- diate-risk" endometrial cancer evaluating TAH/BSO with pelvic and para-aortic nodal sampling, cytology randomizedto no adjuvant therapy or WPRT. Eligibility: old FIGO IB-occult stage II (2009 FIGO stages IA, IB, and occult II) disease. Inclusion criteria were revised during trial to include onlyhigh-intermediate risk (HIR) subgroup(based on GOG 33): (a)age >70 yrs with one risk factor [G-L-D](grade 2 or 3, LVSI, outer one-third myome- trial invasion), (b)age >50 yrs with two risk factors, and (c)any age with three risk factors. All others were LIR.RT 50.4 Gy/28 fx. Primary endpoint was cumulative incidence of recurrence (CIR) and study not powered for OS. MFU 69 mos.59% of pts had stage IA disease and 82% of pts had Gr 1 or 2 disease. Greatest benefit in LR was in high-inter- mediate risk pts from 26% vs. 6% versus low-intermediate risk pts from 6% vs. 2%. Of three pelvic and vaginal recurrences in RT arm, two actually refused RT. RT had worse hematologic, GI, GU, and cutaneous toxicities.Conclusion:Adjuvant RT in early-stage intermediate-risk endometrial cancer decreases risk of recurrence in HIR pts.Comment: Grade 2 was grouped with grade 3 even though grade 2 tends to behave more similarly to grade 1. General themes to keep in mind: ● Only 2 RCTs looking at ± EBRT for early stage, IR: PORTEC 1 and GOG 99. ○ Each study excluded 1988 FIGO IC and G3 dz (2008 FIGO IB, G3). ○ Demonstrated 2/3 of LR occurs in vagina, prompting increased use of VBT! ○ High intermediate risk​: GOG 99 and PORTEC 1 identified age as an additional risk factor. There were 4x as many LVSI+ patients on GOG 99 (20%), therefore LVSI panned out as a risk factor. GOG 99​: ​Women < 50y need DGL to be considered HIR; 50-70 if 2 histologic RF, > 70y w one RF​. PORTEC 1​: ​Needed 2 of 3 risk factors for HIR (>60 y, deep invasion, G3)​. NCCN​: LVSI, LUSI, ≥ 60y, tumor size, cervical/glandular involvement. ○ High risk: IBG3. Best available evidence suggests EBRT + VBT for these patients. ● GOG studies typically have higher risk patients than the corresponding PORTEC study. ● GOG studies eventually worked towards the omission of radiation therapy. ● [​GOG 122​] and [GOG ​258​] included stage III patients. ● [​PORTEC-3​] included IBG3, IAG3 with LVSI, stage II-III, or any stage I-III UPSC/CC (>25%) ● [​GOG 258​] included more advanced nodal disease but comparable proportions of non-endometrioid histology. ● Bottom Line​ ​QS​: The addition of chemo to adjuvant pelvic radiation probably isn't worth the toxicity for patients < 70 years old with stage I-II disease (supported by GOG 249) and probably is worth it for patients ≥ 70y and/or stage III or serous histology (supported by GOG 258). And we'll channel every trial designer of the last decade to completely ignore PORTEC-2. Will someone please draw us a Venn diagram?

● Other subtypes of endometrioid adenocarcinoma include the: _________________ ■ which grows in a papillary fashion ■ The prognosis of this subtype is similar to that of low-grade endometrioid cancer ■ it must not be confused with serous carcinoma because of its papillary features

○ relatively common Villoglandular carcinoma

● PORTEC 1 trial

○ which randomized 715 patients after TAH and BSO to observation OR pelvic RT ○ Patients included were those with stage (FIGO 1988) ■ IB grades 2 and 3 and (2009 IA gr2-3) ■ those with IC grades 1 and 2 (2009 IB gr2-3) ○ Those with IB grade 1 (IA gr1) and those with IC grade 3 (IB gr3)were excluded because it was felt that adjuvant RT was not indicated for the former and most physicians would not omit it for the latter ○ No lymph node sampling was done, and the dose of pelvic RT was 46 Gy at 2 Gy per fraction ○ At 5 years, there was a statistically SIGNIFICANT DIFFERENCE in the rates of vaginal/pelvic recurrencein favor of adjuvant pelvic RT (14% vs. 4%; P < .001) ○ Overall survival, however, was NOT DIFFERENTbetween the two groups (81% RT vs. 85% surgery; P = .31), and ○ the complications with pelvic RT were significantly HIGHER(25% vs. 6%; P < .0001) ○ In addition, many of the patients who relapsed locally after surgery alone were successfully salvaged with subsequent definitive RT ● Scholten, PORTEC 1 (IJROBP 2005, PMID 15927414; Update CreutzbergIJROBP 2011, PMID 21640520): PRT of 714 pts w/ stage I endometrial ca evaluating TAH/BSO + cytology + pelvic RT (no IVRT or PLND). Eligibility: <1⁄2 MI and G2-3 OR >1⁄2 MI and G1-2 (stage IB/IC at time) endometrial ca. 99 pts w/ stage IC, G3 disease not randomized, but received post-op RT. RT 46 Gy/23 fx in two to four fields within 8 wks postop. MFU 97 mos. On MVA, RT and age <60 were favorable prognostic factors for LRR. Pts w/ >2 of 3 risk factors (age >60 y/o, >50% myometrial invasion, and Gr 3) had highest benefit from RT.In pts w/ isolated vaginal relapse, CR was obtained in 31/35 pts (89%), and 24 pts (77%) were still in CR after further f/u. 3-yr OS after vaginal relapse was 73%. On MVA of 15-year data (with 13.3 yr median follow-up), grade 3, age >60, and invasion were prognostic for both LRR and endometrial cancer death.Note: ~75% of LRs were in vaginal vault. On central pathology review, there was significant shift from G2 to G1. Conclusion: Post-op RT in stage IB, G1-2 or stage IA, G2-3 endometrial ca reduces LRR with no impact on OS. Post-op RT is not indicated in pts w/ stage IA, G2 disease, or for pts <60 years of age w/ stage IB, G1-2 or stage IA, G2-3 disease. OS after relapse is significantly better in pt group w/o prior RT. Treatment for vaginal relapse is effective. Pts w/ stage IB, G3 disease have high risk of early DM and endometrial ca-related death. Adjuvant WPRT should be avoided for pts at low or intermediate risk of recurrence. ->"D-G-L" + age -(DOI >4mm, grade LVSI/LUSI) as risk factors PORTEC-1 ​[​Creutzberg Lancet '00​, ​IJROBP '05​]: TAH/BSO/LND for suspicious LNs only​→ ± EBRT​. Long term G2 GI/GU 25%, so utilize EBRT only for HIR.PORTEC-2 later demonstrated VBT is acceptable for HIR, although perhaps ~3% worse pelvic relapses. ConsideradditionofEBRTtoVBTfor[​IBG3​]diseaseand/or[L​ VSI​]. Vaginal vault accounts for 75% of failures. Around 50% of deaths are not cancer related.There is around a 1/8 chance of SBO in the long term with EBRT, but this appears to be ~1% for IMRT [​MSKCC​]. See [​Creutzberg nomogram​], which demonstrates grade as a significant factor for LR. ● 714 pts. IB G2-3, IC G1-2, any histo (unlike GOG 99). UPSC or CC < 1% of pts study. Identified age as an additional risk factor​: ​> 60y, G3, new IB​. ○ RT:​46 Gy​. Sup border L5-S1. Lower border, lower WPRT dose. ○ Only sampled suspicious lymph nodes. Lower risk than GOG 99: Only 5% LVSI. ○ Central path review, 40% downgraded from G2→ G1. 134 pts would not have met criteria. ● 5y LRR 14→ 4%​, although HIR 18→ 5%. 5y vaginal relapse 10→ 2%. ○ 10y LRR 15→ 4%. 10y LRR for G1 / 2 / 3 of 7→ 11→ 18% [SS]. Grade seems to be more significant hazard. 10y LRR for old IB / IC of ~6→ 12% (p=0.07). These 10y results (including NS OS) stay the same even after excluding old IB G1 pts. 10yLRRforage<60/60-70/>70of~4→11→13%(p=0.07). Patients < 60y tend to fare best. 10y HIR LRR 23→ 5%​ for pts w ​2 of 3 HIR factors​:​ ​> 60y, G3, new IB​. 15y LRR 15.5→ 5.8%. ● 8y DM ~8%. ● OSat5/10/15yof~85→~70→~55%. ○ 10y OS ~66→ 74% (p=0.09). 10y CSM ~10%.■ 10y CSM for G1 / 2 / 3 of 5→ 12→ 31%. Grade seems to be more significant hazard. ● Long-term G2 of 4→ 26% (Mostly GI, 18% SBO), Late G3+ GI/GU 0→ 3% (all GI). ● Secondary cancers in ~12%: ~5% GIT, ~3% breast. GIT cancers well established connection with endometrial ca. ○ Majority of cancers CRC in RT group (RIR 2.72) and breast in control group (RIR 1.73, NS). ○ There appears to be no difference in SMN with the addition of RT [​Wiltlink​]. ● See [​Recurrence Outcomes​] from PORTEC-1. 75% of failures occur in vaginal vault. Vaginal recurrences and no prior RT have much better prognosis. After failures, ~80% of patients will have complete response in the long term, and are more likely to have DM after receiving RT while vaginal recurrences if on observation arm. Patients in the observation arm are more likely to have CR to salvage therapy and are more likely to receive salvage therapy. Overall, only around 4 of 10 patients with pelvic relapses were treated with curative intent. Suggestion of 50% of patients alive at 10y with vaginal relapse and no prior RT, while 3y survival after pelvic nodal relapse is less than 10%. We now have [​2019 data​] to suggest 3y OS is 50% for isolated pelvic or pAO relapse treated with SBRT. ● See [​ICG3 outcomes​] from PORTEC-1.Grade 3 is more prognostic than depth of invasion. Around 1/3 of ICG3 patients will have DM at 5 years.Risk for LVSI increases with increasing depth of invasion. LVSI is associated with increased DM, but not LRR. 1. LVSI in PORTEC 1-2 ​[​Bosse EJC '15​]:Substantial LVSI should receive WPRT. Substantial LVSI predicts pelvic relapse, DM and OS. Recall: PLND was not mandated in PORTEC 1 and 2, but suspicious LNs were sampled.One foci involving up to two vessels is focal, while multiple foci is substantial LVSI. o ● Any degree of LVSI in 13.9% (only 7% before review). Substantial LVSI 5%. o ● LVSI strongest independent predictive factor for pelvic relapse (HR 6.2), DM (HR 3.6) and OS (HR 2.0). o ● Only EBRT (HR 0.3) reduced risk of pelvic regional recurrence. o ● 5y pelvic relapse for no LVSI / focal / substantial LVSI of 1.7→ 2.5→ 15%. o ● 5y pelvic relapse for substantial LVSI receiving obs / VBT / EBRT of 31→ 27→ 4%. o ● Table 3 demonstrates focal LVSI one foci involves a median of nearly two vessels (1.8) per the three tiered approach.

The International Society of Gynecologic Pathologists standardized the subclassification of endometrial hyperplasia _____________________ ○ Any proliferation demonstrating cytologic abnormalities (in cellular or nuclear morphology) ○ has a much higher risk of progression to an invasive carcinoma ■ 8% for simple atypical hyperplasia ■ increasing to 29% for complex hyperplasia associated with atypia

● Atypical hyperplasia

True about adnexal/serosal involvement as a prognostic factor in endometrial can

● Jobsen et al. ○ reported on 46 patients with isolated adnexal involvement and 21 with isolated serosal involvement ○ There was no statistically significant difference in outcome between adnexal and serosal involvement ○ The 5-year disease-free survival was 76.4% versus 59.6% (P = ns), and the disease-specific survival (DSS) was 76.3% and 75.4%, respectively

● resembles renal carcinoma, but its origin from MULLERIAN structuresis now well established ● UNLIKE vaginal and cervical clear cell carcinoma, it is NOT RELATED to intrauterine diethylstilbestrol exposure ● The microscopic structure may vary from solid patterns to glandular differentiation (Fig. 74.3C) ● In the latter pattern, small cells resembling "hobnail" cells line spaces and glands ● These are cells that extruded their cytoplasm, leaving bare nuclei that protrude into the glandular lumens ● The rate of clear cell carcinoma is about 3.5% of endometrial carcinomas ● The prognosis of this cancer is inbetween that of endometrioid and serouscancer ● In the FIGO annual report, the 5-year survivalrate was ○ 62.5%compared to 83.2%for endometrioid carcinoma and 52.6%for serous carcinoma

-Clear Cell Carcinoma

● Mixed cell-type endometrial cancer composed of two or more pure types was observed in 4.5% of patientsin GOG 210 study ● By convention, in order to be designated as mixed, the other cell-type component has to comprise at least 10% of the tumor ● EXCEPT for mixed endometrioid and serous or clear cell carcinoma, the clinical significance of mixed cell type is questionable.

-Mixed Histology

● This designation requires >50% of the tumor cellsto be mucinous ● These cells are CEA positiveand are laden with mucin, which stains positively with mucicarmine and PAS stains ○ but is diastase resistant ● Because of the resemblance to endocervical adenocarcinoma, it is essential to exclude it by endocervical curettage ● Mucinous carcinomas are usually well differentiated ● have the same prognosis as ordinary endometrioid carcinomas.

-Mucinous Carcinoma

Observation Versus Pelvic RT: ● Three (3) randomized trials compared pelvic RT to observation in early-stage endometrial cancer: _____________

-PORTEC 1 -GOG 99 - MRC ASTEC and NCIC General themes to keep in mind: ● Only 2 RCTs looking at ± EBRT for early stage, IR: PORTEC 1 and GOG 99. ○ Each study excluded 1988 FIGO IC and G3 dz (2008 FIGO IB, G3). ○ Demonstrated 2/3 of LR occurs in vagina, prompting increased use of VBT! ○ High intermediate risk​: GOG 99 and PORTEC 1 identified age as an additional risk factor. There were 4x as many LVSI+ patients on GOG 99 (20%), therefore LVSI panned out as a risk factor. GOG 99​: ​Women < 50y need DGL to be considered HIR; 50-70 if 2 histologic RF, > 70y w one RF​. PORTEC 1​: ​Needed 2 of 3 risk factors for HIR (>60 y, deep invasion, G3)​. NCCN​: LVSI, LUSI, ≥ 60y, tumor size, cervical/glandular involvement. ○ High risk: IBG3. Best available evidence suggests EBRT + VBT for these patients. ● GOG studies typically have higher risk patients than the corresponding PORTEC study. ● GOG studies eventually worked towards the omission of radiation therapy. ● [​GOG 122​] and [GOG ​258​] included stage III patients. ● [​PORTEC-3​] included IBG3, IAG3 with LVSI, stage II-III, or any stage I-III UPSC/CC (>25%) ● [​GOG 258​] included more advanced nodal disease but comparable proportions of non-endometrioid histology. ● Bottom Line​ ​QS​: The addition of chemo to adjuvant pelvic radiation probably isn't worth the toxicity for patients < 70 years old with stage I-II disease (supported by GOG 249) and probably is worth it for patients ≥ 70y and/or stage III or serous histology (supported by GOG 258). And we'll channel every trial designer of the last decade to completely ignore PORTEC-2. Will someone please draw us a Venn diagram?

● also known as papillary serous cancers ● resemble ovary cancerin terms of histology and to some extent in terms of behavior ● The mere presence of papillary structure is not diagnostic because other histologic types may have papilla as well ● However, the presence of MARKED cellular atypia IN ADDITION TO papilladistinguishes serous carcinoma from others (Fig. 74.3B) ● Psammoma bodies are found in up to 33%of cases ● The incidence of serous endometrial cancer is about 11.4% that of endometrial carcinomas ● This is an aggressive subtype, with a high propensity for early lymphatic and intraperitoneal dissemination, often despite little myometrial penetration ● In the FIGO annual report, the 5-year survival rate was 52.6%compared to 83.2% for endometrioid carcinoma-Serous Carcinoma

-Serous Carcinoma

● The World Health Organization classification describes endometrial undifferentiated carcinomas as "malignant poorly differentiated endometrial carcinomas, lacking any evidence of differentiation" without any further characterization ● Dedifferentiated carcinomas ○ Undifferentiated carcinomas can also be associated with an endometrioid carcinoma component, and such tumors have been referred as such ○ is being recognized with increased frequency ● Some of these tumors may belong to the spectrum of gynecologic neoplasms seen in the setting of microsatellite instability and possibly Lynch syndrome

-Undifferentiated Carcinoma

○ Although HNPCC is thought of primarily in terms of risk of developing colorectal cancer, it is important to note that lifetime cumulative riskof ENDOMETRIAL cancer for women with HNPCCis ■ ______________ ■ which equals or exceeds their risk of colorectal cancer ○ There seems to be a high rate of _____________ involvement (LUSI) in patients with HNPCC-associated endometrial cancer.

40% to 60% lower uterine segment

○ The consensus statement from the Society of Radiologists in Ultrasound defines an endometrial thickness of ■ _____________ ○ If the TVU is abnormal but the biopsy is negative/nondiagnostic or the uterine cavity is inaccessible, then ■ ______________ ■ In addition, these methods are also helpful in premenopausal women, for whom the accuracy of TVU is limited because the endometrial thickness fluctuates, depending on the level of female hormones

5 mm or greater as being ABNORMAL saline infusion sonography or hysteroscopyshould be considered to help exclude intracavitary lesions, especially polyps that might contain cancer

● Foci of squamous differentiationare often found with endometrioid adenocarcinoma ○ The squamouscomponent could be BENIGN, with the designation of ________________ ○ or MALIGNANT, in which case it is called ________________

Adenoacanthoma adenosquamous carcinoma

GOG 99 HIR factors:

Age + ​D​epth, G​​rade, ​L​VSI​

● In the TCGA report on endometrial cancer, there was a correlation between prognosis and genomic group (Fig. 74.4) ● In the PORTEC trials, ○ patients with POLE mutations had _________________which could be attributed to its high mutational burden ● On the other end of the spectrum, patients with copy number high ○ had ___________ in the TCGA report ● The recognition that about 25% of grade 3 endometrioid adenocarcinoma (serous-like) do belong to the copy number high group(mainly serous) further highlight the prognostic importance of genomic classifications of endometrial cancer ● Patients with CTNNB1 (β catenin) mutations ○ do ______________

EXCELLENT prognosis, with VERY LOW risk of recurrence, the WORST prognosis significantly WORSE even in patients with early-stage endometrioid histology

SURGICAL MANAGEMENT of endometrial cancer

Ex-lap with inspection of omentum, liver, peritoneum, adnexa with peritoneal cytology and omental bx. TAH and BSO w PA-PLND (>10 nodes - at least one from each of 5 stations bilat; PA, CI, EI, II, obturator). Bisect uterus to determine the depth of invasion. "LOLGD": Lower uterine segment, Ovary/fallopes, LVSI, Grade, DOI/total length, margins, nodes. Interestingly, tumors arising in the lower uterine segment with higher incidence of Lynch syndrome. ● It consists of ○ simple hysterectomy ○ BSO ○ inspection of the pelvic and abdominal cavities ○ with biopsy of any suspicious extrauterine lesions ○ accompanied by peritoneal washings ● The FIGO staging system did not say that obtaining peritoneal washings is no longer required but only that the finding does not alter the stage ● Surgical assessment of lymph nodes ranges from ○ palpation, biopsy of suspicious nodes, to pelvic and para-aortic lymphadenectomy.

● In the TCGA report on endometrial cancer, there was a correlation between prognosis and genomic group (Fig. 74.4) ● Analysis of GOG 210 ○ showed that in endometrioid adenocarcinoma of the uterus, the presence of MMR defects was associated with _____________ ○ But interestingly, MMR defects were _____________

HIGHER rate of LVI and higher-grade cancers NOT associated with significantly worse prognosis

○ Is considered the MOST ACCURATE imaging studyto assess tumor extension in endometrial cancer, especially myometrial invasion

MRI

● Mass screening for endometrial cancerin women at average risk or increased riskdue to a history of unopposed estrogen therapy, tamoxifen therapy, late menopause, nulliparity, infertility or failure to ovulate, obesity, diabetes, or hypertension is ________ ● American Cancer Society (ACS) recommends that ○ women at average and increased risk should _________________ ○ should be strongly encouraged to immediately report these symptoms to their physician ● However, screening has been recommended by the ACS for women ○ who _______________

NOT RECOMMENDED be informed about risks and symptoms (in particular, unexpected bleeding and spotting) of endometrial cancer at the onset of menopause and carry, or are related to carriers of, the HNPCC mutation starting at a age 35 years, including annual transvaginal ultrasound and endometrial biopsy

● Before 1988, the staging system for endometrial cancer was CLINICAL ○ Stage I was tumor limited to the uterus, with ■ IA designation if the length was ≤8 cm and ■ IB if it was >8 cm ○ Stage II was for when cervix was involved ○ stage III when disease extension beyond uterus/cervix was limited to the true pelvis, and ○ stage IV when it extended beyond the true pelvis or involved bladder or rectum (IVA) or distant spread (IVB)

See comparison table in Radonc copper

○ also known as extrafascial hysterectomy ○ it consists of removal of the entire uterine corpus and cervix WITHOUT contiguous parametrial tissue ○ The pubocervical fascia is entered, and the ureters are NOT unroofed

Simple hysterectomy

True or False ● Endocervical glandular involvement NO LONGER AFFECTS staging; ○ only patients with cervical stromal invasion are considered stage II ● Having positive peritoneal cytology no longer affects staging ● Parametrial extension is now considered IIIB ● Patients with stage IIICare now subdivided into ○ IIIC1 if pelvic nodes are involved and IIIC2 if para-aortic nodes are involved

True

True or False ● For patients at low risk of having pelvic lymph node involvement, that is ○ endometrioid grade 1 or 2 with no or minimal myometrial invasion ■ neither lymphadenectomy nor pelvic RT is likely to be of significant benefit because of low rate of pelvic node involvement ● Those who are at higher risk of having lymph node involvement ○ may need to have their lymph nodes surgically assessed to ensure that they are pathologically negative or receive pelvic RT to control potential microscopic disease ● However, the two PORTEC trials, as well as the Swedish trial, showed that the risk of pelvic recurrence was only 2% to 6% even in the absence of lymphadenectomy ○ This low rate of pelvic recurrence, coupled with the lack of survival advantage to lymphadenectomy and pelvic RT, raises the question of whether either approach is needed for the majority of patients with early-stage endometrial cancer ● In the eyes of many, having LVI is almost indicative of nodal involvement ● Cohn et al. ○ correlated LVI and the risk of positive pelvic nodes in 366 surgically staged patients. ○ The rate of LVI was 25%, and the rate of positive pelvic nodes was 13% ○ Patients with LVI were significantly more likely to have nodal metastasis(35 of 92 vs. 11 of 274; P < .001) ○ However, the influence of LVI on pelvic nodal metastasis was the strongest in patients with ■ deep myometrial invasion and high grade ● Data from MSKCC on 126 patients with endometrioid FIGO (1988) stages IB to IIB and LVI ○ also showed that the mere presence of LVI SHOULD NOT BE A TRIGGER for giving pelvic RT, especially when patients had lymphadenectomy ○ Patients were divided into two groups: those from the old era, when treatment was often pelvic RT, and those from the modern era, when patients were more often treated with lymphadenectomy and intravaginal RT ○ The rate of pelvic relapse for patients with LVI was 7% in the old era compared to 3% (P = .3) in the modern era

True

True or False ● Prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) once childbearing is completed ○ have been shown to effectively reduce the risk of endometrial cancer in patients with HNPCC and should be strongly considered

True

● Regarding endogenousestrogen, in a nested case-control study of 93,676 postmenopausal women parent estrogens (estrone and estradiol) ○ were positively related to endometrial cancer risk ○ with the HIGHEST risk observed for ______________(OR 5th vs. 1st quintile = 6.19; 95% confidence interval [CI], 2.95 to 13.03, Ptrend = 0.0001) ○ The association with unconjugated estradiol was STRONGER for type Ithan type II tumors (Phet = 0.01)

UNCONJUGATED estradiol

● The use of tamoxifenin patients with breast cancer ○ has been associated with increased riskof endometrial cancer ○ The mechanism of action of tamoxifen is in competition with that of endogenous estrogen for estrogen receptors ○ In premenopausal women, tamoxifen has an antiestrogenic effect, but in POSTMENOPAUSAL women, it has a weak estrogenic effectbecause of the up-regulation of estrogen receptors ○ In a meta-analysis on adjuvant tamoxifen and endometrial cancer, for patients who were <55 years of age, there was little absolute risk compared to patients of 55 to 69 years of age, for whom the 15-year incidence was ■ 3.8% in the tamoxifen group versus ■ 1.1% in the control group (absolute increase 2.6% [standard error 0.6], 95% CI = 1.4 to 3.8), highlighting the influence of age and the length ofits use on the risk of endometrial cancer from tamoxifen use ○ Initial data seemed to indicate that the majority of endometrial cancers associated with tamoxifenuse were of _____________ ○ More recent data, however, show a change in the profile of these endometrial cancers, with a rise in the rate of serous, clear cell, carcinosarcoma, and sarcoma types

early stage with favorable features

○ For the sampling to be adequate, ________ lymphatic stations from each sideneed to be removed: ○ ***or a total of ____ nodes

five: ■ para-aortic ■ common iliac ■ internal iliac ■ external iliac, and ■ obturator 10 nodes

● Good-quality pelvic computed tomography (CT) scansobtained with oral and intravenous contrast ○ can demonstrate the extent of the endometrial tumor ○ The endometrial carcinoma is a ■ ______________ ○ CT is helpful in assessing regional and distant metastasis

hypodense massrelative to the normal myometrium and may be seen as a diffuse, circumscribed vegetative or polypoidal mass within the uterine cavity

○ the uterus is removed vaginally rather than abdominally ○ The benefit of using the laparoscope is to enable the surgeon to have a thorough intra-abdominal exploration and to perform BSO, which is difficult to accomplish with just a vaginal hysterectomy

laparoscopic vaginal hysterectomy/BSO (LAVH/BSO)

○ ● MRI: ​Tumor usually ________________. ○ ● Cervix. ________ Parametrium _________ ○ ● Uterine junctional zone: low (bright) T2 inner myometrium, if high (dark), think uterine invlmt.

low T1, high T2 (dark)​ [​1​] low T1, low (bright) T2 high T1, high (dark) T2.

Radiation Treatment Recommendations for Early-Stage Disease Based on Risk Factors: NCCN

see NCCN/radonc copper

● There are_______ randomized trialsregarding the role of adjuvant RT in EARLY-stage endometrial cancer, mainly pertaining to endometrioid histology and conducted in the "modern" era.

six (6)

● In GOG 99 trial ○ factors associated with an increased recurrence rate (25% at 5 years) were identified using proportional hazards regression modeling of historical data from GOG 33 ○ These factors were ■ (a) increasing age ■ (b) moderate to poorly differentiated tumor grade ■ (c) presence of LVI, and ■ (d) outer one-third myometrial invasion ○ From the results of that analysis, a subgroup of patients with high intermediate risk (HIR) was defined as follows: __________

■ (a) at least 70 years of age with only one of the other risk factors ■ (b) at least 50 years of age with any two of the other risk factors, or ■ (c) any age with all three of the other risk factors

● In GOG 99 trial ○ factors associated with an increased recurrence rate (25% at 5 years) were identified using proportional hazards regression modeling of historical data from GOG 33 ○ These factors were

■ (a) increasing age ■ (b) moderate to poorly differentiated tumor grade ■ (c) presence of LVI, and ■ (d) outer one-third myometrial invasion

● The GOG completed a trial ○ in which patients with clinical stage I to occult IIA uterine cancer ○ were randomly assigned to laparoscopy (n = 1,696) or open laparotomy (n = 920), including hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy ○ The main study endpoints were 6-week morbidity and mortality, hospital length of stay, conversion from laparoscopy to laparotomy, recurrence-free survival, site of recurrence, and patient-reported quality of life outcomes ○ Laparoscopy had:

■ FEWER moderate to severe postoperative adverse events than laparotomy(14% vs. 21%, respectively; P < .0001) ■ Hospitalization of >2 days was significantly lower in laparoscopythan in laparotomy patients (52% vs. 94%, respectively; P < .0001) ○ The study demonstrated that surgical treatment of endometrial cancer can be performed laparoscopically with relatively small differences in recurrence rates (estimated difference at 3 years, 1.14%) ○ These results, combined with improved quality of life and decreased complications associated with laparoscopy, are reassuring to patients and allow surgeons to reasonably suggest this method as a means to surgically treat and stage patients with presumed early-stage uterine cancers.

MRI ○ A clear junctional zone or preservation of a sharp delineation between the tumor and the myometrium implies __________________ ○ Disease characterized by disruption of the junctional zone,increased-signal-intensity tumor in the inner half of the myometriumwith preservation of the outer myometrium, or both __________________ ○ If there is extension of the high-signal-intensity tumor into the outer myometrium with preservation of a peripheral rim of normal, intact myometrium, then that is considered _________________

■ disease limited to the endometrium ■ correlates with superficial myometrial invasion ■ deep myometrial invasion (Fig. 74.2)

Cancer Genome Atlas (TCGA) have revolutionized our understanding of endometrial cancer ○ In that study, the genomic landscape of endometrioid and serous carcinoma histologies were evaluated Uterine SEROUS tumors and about 25% of HIGH-GRADE endometrioid tumors (serous-like) had

■ frequentTP53 mutations and ■ extensive copy number alterations, but ■ few deoxyribonucleic acid (DNA) methylation changes, and ■ low estrogen receptor/progesterone receptor levels

Cancer Genome Atlas (TCGA) have revolutionized our understanding of endometrial cancer ○ A subset of endometrioid tumors (about 10%) that was identified had a

■ markedly increased mutation frequency and ■ newly identified hotspot mutations in the exonuclease domain of POLE

endometrial cancer ○ If the patient is undergoing hysterectomy, routine D&C is not necessary after an office Pipelle sampling has documented malignancy ○ However, a D&C should be performed in the ff if:

■ symptoms persist ■ the office sampling is inadequate, or ■ the patient is being considered for conservative fertility-sparing approaches

Of the 905 patients (789 MRC and 116 NCIC) in the trial (Early stage endometrial cancer)

○ 453 were randomized to observation and 452 to pelvic RT ○ The two arms were balanced except for ■ more high-risk patients (113; 25%) in the observation arm than in the pelvic RT arm (89; 20%) ○ There were 137 (32%) patients in the observation arm in whom nodes were removed, and 5 (4%) had positive nodes ○ In the pelvic RT arm, 159 (38%) had nodes removed, and 6 (4%) were positive ○ In the observation arm, 228 (51%) patients received intravaginal RT, 7 (2%) received pelvic and intravaginal RT, 3 (1%) received pelvic RT, and 3 (1%) were unknown. ○ Only 212 (47%) received no form of adjuvant RT ○ Conversely, in the pelvic RT arm, 24 (5%) did not receive any adjuvant RT, 10 (2%) received intravaginal RT, and 2 (0.4%) were unknown ○ Combined intravaginal and pelvic RT was given to 232 (52%) patients, and only 184 (41%) received pelvic RT alone ○ The primary endpoint of this study was overall survival ○ With a median follow-up of 58 months ■ the 5-year overall survival was 84% in both arms (P = .77) ■ The 5-year cumulative incidence for isolated vaginal or pelvic recurrence was 6.1% in the observation group and 3.2% in the pelvic RT group ● This difference was statistically significant (P = .2) with a HR of 0.46 (95% CI = 0.24 to 0.89) ■ The rate of any acute toxicity was 27% in the observation arm compared to 57% for pelvic RT ● Similarly, late toxicity was more prevalent in the pelvic RT compared to observation (61% vs. 45%, respectively).

Observation Versus Intravaginal RT ● In a trial reported by Sorbe et al.

○ 645 patients with stage (FIGO 1988) IA to IB grades 1 and 2 (IA gr 1-2) endometrioidadenocarcinoma were randomized AFTER SURGERY to ■ observation (n = 326) or intravaginal RT (n= 319) ○ Surgery consisted of TAH/BSO (laparoscopic surgery was allowed), pelvic washing, and removal of enlarged nodes ○ The dose and type of intravaginal RT varied among the six centers participating in this trial, but 347 of 645 patients were treated with HDR to 18 Gy in six fractions ○ The proximal upper two-thirds of the vagina was treated with the dose prescribed to 0.5 cm from the surface of the cylinder ○ The rate of vaginal recurrence was ■ 3.1% in the observation arm compared to 1.2% for the intravaginal RT arm(P = .114) ○ The rate of pelvic recurrence was ■ 0.9% in the observation arm and 0.3% in the treatment arm(P = .326) ○ No significance difference was seen between the two arms in terms of overall survival ○ There was significantly more grade 1 vaginal toxicity with intravaginal RT(8.8% vs. 1.5%; P = .00004). ○ There was no significant difference in gastrointestinal (GI) or genitourinary toxicity. BT alone​: ​Use for up IB ​or G​ 3, but not both ​[​Sorbe '12].​ Sorbe ​[IJGC '09​]: ​± VBT​. Safe to omit VBT if Low Risk: IA, G1-2, endometrioid, no LVSI. ○ 645 pts. ​Low risk​: IA (old IA/IB), G1-2. Endometrioid. TAH/BSO, pelvic cytology, PLN sampling. ■ VBT3-8Gyx3-6fx. ○ Vaginal recurrences ~3.1→ 1.2% (p=0.11). ○ G1-2 toxicity 0.6→ 2.8%.

● The International Federation of Gynecology and Obstetrics (FIGO) annual report showed that the 5-year survival ratefor 8,110 patients with endometrial cancer treated between 1999 and 2001 was ______ ○ Such excellent outcome is a reflection of the fact that the majority of patients are diagnosed with early-stage disease ○ The tumor was limited to: ■ the corpus uteri in _____ of cases ■ involved the cervix in 12% ■ extended beyond the uterus, but short of distant spread in 13%

○ 80% 71%

● At MSKCC, a nomogram was developed for predicting overall survival of women with endometrial cancer (n = 1,735) after primary therapy ● Use of FIVE prognostic factors predicted OSwith high concordance probability:

○ Age ○ Grade ○ histologic type ○ number of lymph nodes removed, and ○ FIGO 1988 surgical stage

Treatment for No Myometrial Invasion, Grade 3

○ At MSKCC, these patients are offered either intravaginal RT alone or observation

● Ligaments of uterus:

○ Broad: From uterus to lateral to pelvic sidewall. ○ Round: From fundus anterolateral to internal inguinal ring. ○ Uterosacral: From lower uterus to posterior to sacrum. ○ Cardinal: From pelvic sidewall to cervix.

● Other subtypes of endometrioid adenocarcinoma include the: ____________________ ■ is a very rare subtype, characterized by the presence of ciliated cells comprising >75%of the tumor specimen ■ It is usually associated with a history of prior estrogen use ■ the prognosis is quite good, because most are well differentiated

○ Ciliated carcinoma

Early stage endometrial cancer: ● The triad of lack of overall survival advantage, increased toxicity, and high salvage rate of local recurrence for patients who are observed has led some to conclude that ALL FORMS of adjuvant RT, not simply pelvic RT, should be ABANDONED ● The morbidity of pelvic RT and the validity of omitting adjuvant RT in favor of RT for salvage policy will be discussed later in the chapter ● With regard to overall survival, it is considered the gold standard for primary endpoint in many randomized trials in oncology, but for EARLY-stage endometrial cancer, it is perhaps UNATTAINABLE with adjuvant RT for two reasons

○ First, many of the patients have other, competing causes of death such as hypertension, diabetes, and obesity ■ In the PORTEC trial, the 8-year actuarial rates of intercurrent death were 19.7% in the RT arm and 15.6% in the surgery-alone arm. ■ Endometrial cancer-related deaths in comparison were only 9.6% and 7.5%, respectively ■ Similarly, in the GOG 99 trial, approximately half of the deaths were due to causes other than endometrial cancer or treatment(surgery alone, 19 of 36; RT, 15 of 30). ■ This led the authors of GOG 99 to write, "With this number of intercurrent deaths in both arms, even if RT reduces the risk of endometrial cancer-related deaths, the size of this trial is not adequate to reliably detect an overall survival difference." That is why overall survival was not the primary endpoint in GOG99 but rather the disease-free interval, which was significantly different in favor of adjuvant pelvic RT over surgery alone ■ Therefore, it is not unreasonable to conclude that neither PORTEC nor GOG 99 was large enough to conclusively show whether adjuvant pelvic RT affected overall survival ○ The second difficult hurdle for adjuvant RT to overcome when discussing overall survival has to do with its localized nature ■ In the MRC/NCIC trial, the rate of first vaginal/pelvic recurrence was reduced from 11.4% (n = 37 of 453) in the observation arm to 2.8% (n = 13 of 452) with pelvic RT ■ Adjuvant pelvic RT, however, did not affect distant spread; the rate of first distant spread was 8.1% (n = 37 of 453) in the observation compared to 9% (n = 41 of 452) in the pelvic RT arm ■ One would expect adjuvant RT to make a difference in overall survival only when systemic therapy has an effect on the rate of distant spread. This is exactly the story learned from postoperative chest wall irradiation in breast cancer. ■ Because pelvic RT significantly improved local control, albeit with increased toxicity, why not replace it with intravaginal RT rather than advocating observation for all early-stage endometrial cancer?

The standard recommended treatment for atypical hyperplasiaof the uterus is:

○ Hysterectomy ■ if childbearing is complete and the patient has no other contraindications to surgery ○ In patients who desire future fertility or have an absolute contraindication to surgery ■ progestational therapies may be used with caution

-Simultaneous Tumors ● Occasionally identical tumor type, mainly ENDOMETRIOID histology, can be discovered in the ovary and endometrium ● Usually, the site of the LARGEST tumor is assigned the primary origin, but at times, true primary endometrial and ovarian malignancies may coexist ● More likely that there are Two concomitant primary tumors if:

○ If the endometrial tumor is <5 cm in diameter ○ well differentiated ○ with no vascular invasion ○ limited to less than the middle onethird of the myometrium, and ○ the ovarian lesions are bilateral

● The lymphatic drainage for the body of the uterus is mainly to the ____________ ● The lymphatics from the fundus accompany the ovarian artery and drain into the ________

○ Obturator ○ internal and external iliac lymph node ○ para-aortic lymph nodes

● Genomic analysis of CLEAR CELL carcinomaof the uterus demonstrated that, akin to endometrioid carcinomas, there are FOUR gnomically distinct groups:

○ POLE ○ MMR-deficient tumors ○ copy number low, and ○ copy number high

Cancer Genome Atlas (TCGA): Based on these results, ENDOMETRIAL cancers can be classified into four categories:

○ POLE ultramutated - best prognosis - PI3K, KRAS common. TP53 35%. ○ microsatellite instability hypermutated ○ copy number low, and ○ copy number high - worst prognosis(serous like); TP53 > 90%

● Optional lymphadenectomy is another approach (for endometrial cancer) ○ in which preoperative tumor grading with intraoperative assessment of depth of myometrial invasion, as well as histologic subtype, is frequently used to decide whether lymph node dissection is necessary at the time of hysterectomy

○ With such a policy, these patients will undergo lymphadenectomy: ■ with grade 3 disease or ● With regard to grade, preoperative FIGO grade 1 diagnosis correlates with final grade diagnosis in only 85% of cases of endometrial cancer ■ serous or clear cell histology and ■ those with deep myometrial invasion on frozen section ● Opponents of this selective lymphadenectomy approach point out that depth of invasion on frozen section correlated with final pathology in only 67% of cases

● MRC ASTEC trial in itself

○ consisted of two trials with separate randomizations designed to answer a surgical as well as a radiation question ○ The surgical question was discussed earlier and regarded the need for lymphadenectomy in clinical localized endometrial cancer ○ The radiation question was whether pelvic RT is needed ○ Intermediate- or high-risk early-stage patients were then randomized to ■ observation or pelvic RT ○ Intermediate risk included ■ stage (FIGO 1988) IA grade 3 ■ IB grade 3 ■ IC grades 1 and 2, and ■ IIA grades 1 and 2 ○ High risk included ■ IC grade 3 ■ IIA grade 3, and ■ IA to IIA serous and clear cell tumors ○ Patients who had positive pelvic nodes (stage IIIC) were allowed but not those with cervical stromal invasion (IIB) ○ The pelvic RT was given to a total dose of 40 to 46 Gy in 20 to 25 fractions over 4 to 5 weeks. ○ Intravaginal RT was permitted regardless of the pelvic RT randomization as long as it was the stated policy for the treating center to do so ○ The recommended dose was 4 Gy in two fractions prescribed to a depth of 0.5 cm treating the upper one-third of the vagina when using high dose rate (HDR) and 15 Gy when using low dose rate

● Within endometrioid adenocarcinoma, the subtypes are:

○ endometrioid carcinoma not otherwise specified (NOS) ■ Mostof the endometrioid adenocarcinomas are designated as such ○ endometrioid carcinoma with squamous differentiation ○ villoglandular endometrioid carcinoma ○ secretory carcinoma, and a ○ ciliated cell variant

● role of lymphadenectomy in endometrial cancer ● Italian study (Benedetti)

○ in which 514 eligible patients with preoperative FIGO stage I endometrial carcinoma ○ were randomly assigned to undergo pelvic lymphadenectomy (n = 264) VS no lymphadenectomy (n = 250) ○ The median number of lymph nodes removed was 30 in the pelvic lymphadenectomy arm ○ Both early and late postoperative complications occurred MORE FREQUENTLY in patients who had received pelvic systematic lymphadenectomy(81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm; P = .001). ○ Lymphadenectomy IMPROVED surgical staging, as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs. 3.2%; P < .001) ○ At a median follow-up of 49 months ■ the 5-year disease-free and overall survival ratesin an intention-to-treat analysis were SIMILAR between arms(81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the nolymphadenectomy arm, respectively)

● role of lymphadenectomy in endometrial cancer: (Medical Research Council [MRC]/A Study in the Treatment of Endometrial Cancer [ASTEC])

○ patients with endometrial cancer believed preoperatively to be confined to the uterine corpus were first randomized to ■ standard surgery consisting of hysterectomy/BSO, pelvic washing, and palpation of para-aortic nodes (n = 704) or ■ to lymphadenectomy (n = 704) ● In the lymphadenectomy group, patients underwent standard surgery plus systematic dissection of iliac and obturator nodes ● If the nodes could not be dissected, sampling of suspect nodes was recommended ● Whether to dissect the para-aortic nodes was left to the discretion of the surgeon ○ After a median follow-up of 37 months, 191 women (88 standard surgery group, 103 lymphadenectomy group) had died ■ with an absolute difference in 5-year overall survival of 1%(95% CI = 4 to 6) and ■ an absolute difference in 5-year recurrence-free survival of 6% ○ The conclusion from both trials was that pelvic lymphadenectomy SIGNIFICANTLY improved surgical staging, that is, it is a good prognosticator ■ but it DID NOT improve disease-free or overall survival

Pelvic RT Versus Intravaginal RT ● In the Swedish trial reported by Sorbe et al.,

○ patients with stage (FIGO 1988) I endometrioid adenocarcinoma with at least one of the risk factors ■ grade 3, ≥50% myometrial invasion, or DNA aneuploidy ○ were randomized to ■ adjuvant intravaginal RT (IVRT; n = 263) or ■ pelvic and IVRT (n = 264). ○ Lymphadenectomy was required ○ There was NO DIFFERENCE in vaginal recurrence,which was 2.7% (7 of 263) in the IVRT-alone arm compared to 1.9% (5 of 264) in the combined arm (P = .555) ○ Pelvic recurrence rate, however, was DIFFERENT: 5.3% in the IVRT arm compared to 0.4% in the pelvic plus IVRT arm (P = .0006) ○ There was NO significant difference in OS between the two arms (90% vs. 89%, respectively) ○ The toxicity was significantly higher in the combined arm compared to IVRT alone. Sorbe ​[​Sorbe IJROBP '12]​: TAH/BSO, selective LND, washings→ ​VBT ± EBRT​.Combined RT should be reserved for 2+ high risk factors (e.g. IBG3) due to cost, AE, and ~OS. Pelvic recurrence decreases over 90% with the addition of EBRT to VBT. ○ 512 IR pts: G1/2, endometrioid, stage I w 1 of: IB, G3 or DNA aneuploidy. VBT: 18/6, 17.7/3, 20/1 LDR to 5 mm. Upper 2/3 of vagina treated. EBRT: 46 Gy WPRT. ○ Overall recurrence 10→ 6%, 5y LRF 5→ 1.5%. ○ 5y OS ~90%. ○ G3 toxicity < 2% although VBT significantly more well tolerated. ■ Late G1-3 3→ 14.5%.

● According to the GOG surgical guidelines for endometrial cancer:

○ pelvic lymph nodes are to be removed from ■ the distal one-half of the common iliac artery down to the circumflex iliac vein, ○ nodal tissue is to be removed ■ anterior to the obturator nerve and surrounding the iliac arteries and vein ○ The para-aortic nodes include those ■ overlying the vena cava ■ between the vena cava and aorta, and ■ to the left of the aorta ○ The cephalad boundary of the para-aortic specimen is generally, but not limited to, ■ the inferior mesenteric artery, and ○ the distal boundary is ■ the midpoint of the common iliac artery ○ For the sampling to be adequate, five lymphatic stations from each sideneed to be removed: ■ para-aortic ■ common iliac ■ internal iliac ■ external iliac, and ■ obturator ○ ***or a total of 10 nodes

● The MOST COMMON PRESENTATION for endometrial cancer is: ● The incidence of endometrial cancer in women presenting with postmenopausal bleedingis

○ postmenopausal vaginal bleeding ○ which is reported by 80% to 90%of patients ○ only 10% to 15% ○ This incidence, however, could range from 1% up to 25%,depending on patient age and the presence of other risk factors

Treatment for Fifty Percent or Greater Myometrial Invasion and Grade 3

● AT MSKCC, patients with these are offered postoperative pelvic RT ○ deep myometrial invasion grade 3 who are HIR per GOG 99 ● If they are not HIR, which is not that common in this subset of patients, ○ they could be considered for INTRAVAGINAL RT, but only in the setting of adequate surgical lymph node assessment

True about histologic subtype as a prognostic factor in endometrial cancer:

● According to the FIGO annual report, the 5-year survival rate was ○ 83.2% for endometrioid adenocarcinoma, compared to ○ 52.6% for serous cancer and ○ 62.5% for clear cell cancer in 8,033 surgically staged patients. ● Patients with endometrioid histology have surgical stage III to IV disease only in 13.8% of patients, compared to 41.7% with serous and 33% with clear cell carcinoma, which could explain the worse outcome ● However, the influence of histology was seen even in patients with surgical stage I disease (n = 5,285), for whom 5- year survival dropped from 90% for endometrioid histology to 79.9% with serous and 85.1% with clear cell carcinoma

The International Society of Gynecologic Pathologists standardized the subclassification of endometrial hyperplasia __________________ ○ is characterized by back-to-back proliferation of glands with ■ intraluminal papillae ■ epithelial pseudostratification ■ few mitotic figures ○ If there is NO CYTOLOGIC ATYPIA, the risk of malignant degenerationis again quite low, on the order of 3%

● Complex hyperplasia

○ remains the gold standardby which the diagnosis of endometrial cancer is established ○ This is achieved via biopsy or dilation and curettage (D&C)

● Endometrial tissue sampling

_______________ is themost COMMONendometrial carcinoma ● constituting 75% to 80%of all cases (Table 74.1) ● The classic histologic appearance is that of marked glandular proliferation with back-to-back proliferation of glands and little intervening stroma(Fig. 74.3A) ● The name endometrioid is derived from resemblance to proliferative-phase endometrium ● Architectural grading is determined by the amount of solid mass of tumor cells compared to well-defined glands

● Endometrioid adenocarcinoma

True about lymphvascular invasion (LVSI) as a prognostic factor in endometrial cancer:

● In GOG 210 study ○ the rate of lymphovascular invasion (LVI) was 22.7% ○ The presence of LVI increased the rate of positive pelvic node from 4.1% to 37.5%, and para-aortic node from 2.3% to 23.8% ○ LVI is also associated with HIGHER rate of relapse in the vagina and a poorer outcomeespecially if it was substantial ○ The presence of LVI needs to be viewed in the context of other risk factors so that its mere presence does not trigger excessive therapy **○ PORTEC-1: Risk for LVSI increases with increasing depth of invasion. LVSI is associated with increased DM, but not LRR.

True about peritoneal cytology as a prognostic factor in endometrial can

● In the 2009 FIGO staging, having positive peritoneal cytology is no longer considered stage IIIA ● The reason for the change is due to lack of clear correlation between positive cytology and outcome for early-stage endometrial cancer ● However, the true prognostic significance of positive peritoneal cytology on outcome CANNOT be devoid of the influence of surgical techniques or other prognostic factors. ● There is some suggestion of a higher rate of positive cytology for patients undergoing laparoscopic hysterectomy, because of manipulation of the uterine cavity ● Histology also impacts the rate of positive cytology: ○ 7.7% for endometrioid histology compared to ○ 20.2% for nonendometrioid histologies. ● In patients with early-stage disease (low-grade endometrioid histology, minimal invasion), the influence of positive peritoneal cytology on outcome is NOT evident. ● In contrast, for patients with stage III disease, having positive cytology affects prognosis SIGNIFICANTLY and needs to be taken into account.

● However, the findings from the Cancer Genome Atlas (TCGA) have revolutionized our understanding of endometrial cancer ○ In that study, the genomic landscape of endometrioid and serous carcinoma histologies were evaluated (Fig. 74.4) ○ Most ENDOMETRIOID tumors had ■ frequent mutations in: ________________ ■ novelmutations in ________________ ■ few ____________

● PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS ● the SWI/SNF chromatin remodeling complex gene ARID5B, and copy number alterations or TP53 mutations

ROLE OF RADIATION in endometrial cancer

● Radiation therapy plays a significant role in the management of endometrial cancer ● It is often used as ○ an adjuvant treatment after surgery (which will be discussed here) or ○ as definitive treatment for patients who are medically inoperable or with local recurrence (which will be discussed later) ● In the past, most patients were treated with preoperative intracavitary brachytherapy with or without external beam radiotherapy, followed by hysterectomy ○ This approach is not without its merit, especially in patients with gross cervical involvement ● However, most patients nowadays undergo surgery first; then, depending on the prognostic features obtained from the pathology review, the need for radiotherapy is determined. ● In recent years, there has been a plethora of data from prospective, randomized trials addressing several aspects of the management of endometrial cancer. ● However, unlike in cervical cancer, for which the data from the majority of the randomized trials pointed in the same direction, that is, chemoradiation is better than radiotherapy (RT) alone, ○ the data in endometrial cancer are less conclusive ● Therefore, it is important for radiation oncologists to be familiar with the methodology of these studies so that objections to the use of any form of adjuvant RT can be addressed with facts

○ is NOT routinely performedin endometrial cancer because of low incidence of parametrial involvement ○ There is no evidence to show that the cure rates are any better with such radical operations. ○ The possible exception to this might be in patients with gross cervical involvement

● Radical hysterectomy

True about myometrial invasion as a prognostic factor in endometrial cancer:

● Regardless of grade, only 1.7% of tumors limited to the endometrium had lymph nodal involvement, as compared with 29% pelvic and 14.5% para-aortic involvement with deep penetration ● Before the 1988 FIGO staging system, the depth of invasion had been reported as none or inner, middle, or outer one-third of the myometrium ● The 1988 FIGO staging system subdivided myometrial invasion into none or inner or outer half ○ Under that staging system, for patients with <50% myometrial invasion, it seems that invasion to less than versus greater than one-third is not a significant predictor of outcome ● In the current 2009 FIGO staging system, depth of invasion in stage I is divided into two categories: ○ A (no or <50% myometrial invasion) and B (>50% invasion).

The International Society of Gynecologic Pathologists standardized the subclassification of endometrial hyperplasia ______________ ○ there is only glandular proliferation and enlargement with increased stromal cellularity ○ This rarely progresses to carcinoma (<1%)

● Simple hyperplasia

Treatment for: Less Than 50% Myometrial Invasion, Grade 3

● Some advocate OBSERVATION for patients with <50% myometrial invasion grade 3 ○ yet the 5-year vaginal recurrence rate in PORTEC-1 was ■ 14% for such patients treated with surgery alone compared to ■ none for those treated with pelvic RT ● Perhaps a better choice for those patients is: ○ intravaginal RT ● The incidence of positive pelvic lymph nodes at time of surgery in this subset of patients is ○ about 3.9% ● In the PORTEC-1 trial ○ none of the 37 patients with grade 3 disease and <50% myometrial invasion who were treated with TAH/BSO alone relapsed in the pelvis. ● At MSKCC ○ INTRAVAGINAL RT is recommended for this subset of patients irrespective of whether lymphadenectomy was performed.

True about race as a prognostic factor in endometrial cancer:

● The incidence of endometrial cancer is LOWER in African American than white women, yet the rate of high-risk features in this group is HIGHER

Epidemiology of endometrial cancer

● The incidence of endometrial cancer is higherin ○ more developedareas of the world (5.5%) ○ compared to less developed countries (4.2%), indicating a possible influence of environmental factors on the incidence of this disease ● The exact etiology of endometrial cancer remains unknown, but several risk factors have been associated with it, chiefly ○ UNOPPOSED ESTROGEN ● It is well established that endometrial cancer risk is increased among women who ○ have high circulating levels of bioavailable estrogensand ○ low levels of progesterone ■ so that the mitogenic effect of estrogens is insufficiently counterbalanced by the opposing effect of progesterone

True about age as a prognostic factor in endometrial cancer:

● The influence of older ageon worse outcomehas been well established ● The adverse impact of older age is often explained by pointing out that older patients tend to ○ present with aggressive histology and more advanced disease and are generally treated less aggressively ● What is intriguing, however, is that the strongest correlation between older age and poor outcome is seen in patients with otherwise favorable characteristics ● Furthermore, the adverse impact of advanced age on outcome persists even when elderly patients are treated as aggressively as their younger counterparts

True about pelvic/paraaortic involvement as a prognostic factor in endometrial can

● The pattern of lymphatic spread in endometrial cancer is different than that in cervical cancer ○ In endometrial cancer ■ a simultaneous spread to both pelvic and para-aortic nodes could occur ○ whereas in cervical cancer ■ the spread to paraaortic nodes is almost always secondary to pelvic lymph node involvement ● Overall, about 12.6% of patients with stage I and occult stage II endometrial cancer have pelvic nodal involvement ● This increases to ○ 27.7%, with deep myometrial invasion ○ 41%, with adnexal involvement ○ 45.7% with extrauterine spread, respectively ● Lymph node involvement is a major predictor of outcome; ○ the 5- year disease-free survival rates drop to 65% to 70% in patients with pelvic lymph node involvement as their only risk factor

True about lower uterine segment involvement (LUSI) as a prognostic factor in endometrial can

● The presence of LUSI is associated with WORSE OUTCOME ● In a study of 481 surgically staged endometrioid endometrial cancers (FIGO stage I to II), ○ LUSI was present in 223 cases (46.4%) ○ was associated with both ■ decreased disease-free survival(P = .02) and ■ overall survival(P = .01) in univariate analysis ● There seems to be a high rate of LUSI in patients with HNPCC-ASSOCIATED endometrial cancer

Surgical Assessment of Lymph Nodes in endometrial cancer:

● The question of which patients need ROUTINE surgical lymph nodal staging and, if so, to what extent is a matter of great debate ● The uncertainty about lymphadenectomy relates to whether the benefit from it is prognostic rather than therapeutic. ● Those who advocate FOR NO LYMPHADENECTOMY and LIMIT nodal assessment to inspection and removal of any enlarged/suspicious pelvic or paraaortic nodes ○ cite the lack of documented survival advantages to lymphadenectomy ● Furthermore, patients who have adverse pathologic features that increase the risk of microscopic lymph node metastasis are generally offered adjuvant pelvic radiation. ● Advocates for FULL-pelvic and para-aortic lymph node sampling on the other end of the spectrum reason that ○ surgical staging is the most accurate method to assess the extent of disease and that the sensitivity and specificity of palpation of lymph nodes are only 72% and 81%, respectively ● Lymphadenectomy in endometrial cancer includes removal of the fat pads surrounding the major vessels in the abdomen and pelvis without skeletonizing them

Treatment for: Fifty Percent or Greater Myometrial Invasion, Grades 1 and 2

● The risk of vaginal recurrence with surgery alone in this group of patients is NOT minimal ● In the PORTEC-1 trial ● The data from the PORTEC-2 trial and the Swedish trialin which patients with ≥50% myometrial invasion grade 1 or 2 were included indicate that ○ the OMISSION of pelvic RT increased the risk of pelvic recurrence ● In PORTEC-2 trial ○ the 3-year (pelvic recurrence) ratewas ■ 3.5% in the intravaginal RT arm compared to ■ 0.6% in the pelvic RT arm (P = .03) ● In the Swedish trial ○ the pelvic recurrence rate was ■ 5.3% in the IVRT armcompared to ■ 0.4% in the pelvic plus intravaginal RT arm(P = .0006) ● At MSKCC ○ most of these patients undergo SLN mapping ○ and if the nodes are pathologically negative, ■ they undergo intravaginal RT alone

Treatment for No Myometrial Invasion, Grades 1 and 2

● The risk of vaginal recurrenceis almost negligible ● Straughn et al. ○ reported no vaginal recurrence in 103 such patients treated with surgery alone. ○ Pelvic lymph nodal positivity was ≤3% ○ The 5-year progression-free survival (PFS) rate in this group was on the order of 95% to 98% ● It is unlikely that postoperative pelvic or intravaginal RT would add anything to the final outcome, and therefore,radiation is NOT ROUTINELY recommendedto this group of patients

Treatment for Less than 50% Myometrial Invasion, Grades 1 and 2

● This group of patients constitutes the MOST COMMON stage subgroup of all endometrial cancers ● In a randomized trial reported by Sorbe et al. ○ the vaginal recurrence rate was 3.1% for those in the observation arm compared to 1.2% for those in the intravaginal RT arm (P = .114) ○ Recall: included Stage (FIGO 1988) IA to IB grades 1 and 2 endometrioid adenocarcinoma (IA gr1-2) ○ The trial was designed to detect a difference of 1% versus 5% in the vaginal recurrence rate in the two groups ○ The data were not reported separately based on whether myometrial invasion was present or not, making it difficult to determine the true impact of intravaginal RT on the rate of vaginal recurrence in patients with myometrial invasion ● Data from MSKCC on 233 patients with <50% myometrial invasion (IA)grade 1 or 2 ○ showed a vaginal recurrence rate of only 1% using intravaginal RT alone. ● In addition, Sorbe et al. ○ reported on 110 patients with IB grade 1 or 2 who were part of a prospective, randomized trial evaluating two different intravaginal RT doses; ■ the rate of vaginal recurrence was 0.9% ○ The risk of pelvic recurrence was only 1.8%, even though lymphadenectomy was not required ○ This low rate of pelvic recurrence is similar to those reported by Straughn et al. of 0.3% (1 of 296) and by Horowitz et al. of 0% (0 of 62) in the setting of lymphadenectomy ● This indicates that pelvic RT is of limited use, and therefore, it seems reasonable to suggest that either is a reasonable option for patients with grade 1 or 2 and <50% myometrial invasion: ○ observation or intravaginal RT ● However, when deciding on whether adjuvant RT is needed, it is important to address two issues. ● First, OLDER patients tend to have HIGHER rates of relapse ● In the study by Straughn et al. ○ 8 of the 10 vaginal/pelvic recurrences were in patients ≥60 years old ● In the randomized trial by Sorbe et al. comparing adjuvant intravaginal RT to observation, ○ patients with vaginal recurrences were significantly (P = .018) older (mean age, 68.6 years) than patients without vaginal recurrences (mean, 62.6 years) ● Second, patients with LVI have a **higher chance of vaginal recurrence, as demonstrated by ● Mariani et al ○ who reported on 508 patients with endometrial cancer limited to the corpus treated with surgery alone ○ The presence of LVI significantly increased the vaginal relapse rate from 3% to 7%(P = .02) ○ The rate of vaginal relapse would have been even higher if patients without myometrial invasion (152 of 508) had been excluded because LVI is exceedingly rare in patients without myometrial invasion ● At MSKCC, patients who are these are recommended to have intravaginal RT: ○ ≥60 years old or have LVI

○ is the most prevalent and time-tested form of simple hysterectomyin endometrial cancer ○ It is an abdominal approach, usually via a vertical midline incisionthat allows thorough exploration of intra-abdominal and pelvic cavities ○ The main drawback of TAH/BSO is that it is a laparotomy-based approach, in a group of patients with pre-existing comorbidities such as obesity, hypertension, and diabetes ○ Therefore, it is not surprising that minimally invasive surgery, whether laparoscopically or robotically, has gained a great deal of acceptance in the surgical management of endometrial cancer

● Total abdominal hysterectomy/BSO (TAH/BSO)

Role of RT in Stages I and II endometrial cancer

● Treatment options for patients with early-stage endometrial cancer after hysterectomy include ○ observation ○ intravaginal RT, or ○ pelvic RT ● At MSKCC, intravaginal RT is the preferred approach for most patients because it provides the best therapeutic ratio ● As the discussion will demonstrate, observation may have the best morbidity profile, but it does not provide the best therapeutic ratio because of the increased risk of local recurrence. ● Pelvic RT, on the other hand, although very effective in reducing recurrence, has a higher morbidity profile than intravaginal RT ● The results of prospective, randomized trials will be discussed first, and then, treatment recommendations based on risk factors will follow

True about grade as a prognostic factor in endometrial cancer:

● Tumor grade is ONE OF THE MOST SENSITIVE indicatorsof prognosis ● Grade directly affects the depth of myometrial penetration and the frequency of lymph node involvement ● The rate of positive pelvic and para-aortic node based on depth of invasion and histology is shown in Table 74.4 ● In the FIGO annual report ○ grade 3 was an independent predictor of poor survival on multivariate analysis within each stage—stages I (HR, 2.45), II (HR, 2.14), III (HR, 2.44), and IV (HR, 2.55) ● The recognition that about 25% of grade 3 endometrioid histology has copy number high mutations, that is, serous-like, further highlight the impact of genomic stratification on prognosis

what endom cancer type? ○ there is strong correlation with PRIOR ESTROGEN stimulation ○ The cancers in this category are often INDOLENT in nature, with minimal myometrial invasion and low-grade histology ○ They affect premenopausal and perimenopausal women ○ PI3 K/PTEN/AKT pathway ■ The most frequently altered molecular pathway is dysregulated by oncogenic mutations, PTEN loss of function, and/or overexpression of upstream tyrosine kinase growth factor receptors, leading to uncontrolled cell proliferation and survival

● Type I endometrial cancer ○ Type I​ (70-85%) is endometrioid, estrogen-dependent. Often low grade, slow growing. ~1⁄3 MSI. ■ K-Ras, MLH1 methyl, PTEN. ■ Types​: Papillary Villoglandular Squamous Adenosquamous (High grade) Adenoacanthoma (benign appearing squamous component

what endom cancer type? ○ often affects postmenopausal women with NO PRIOR HISTORY of estrogen stimulation. ○ The histology of the tumors is often HIGH GRADE, such as SEROUS or CLEAR CELL cancers ○ with DEEP INVASION, and ○ at a MORE ADVANCED STAGE at the time of presentation ○ tumor suppressors p53 ■ the main pathway alterations

● Type II endometrial cancer Type II​(20%) UPSC/CC/MMMT 2/2 mucosal atrophy, typically UPSC or CC, high grade, aggressive. · TP53, ERBB2 (HER2). · Responsible for 1⁄2 of EC deaths. · Subdiaphragmatic/abdominal failure is the most common failure site for UPSC, like ovarian. · Types​: o Serous o Clear Cell o Carcinosarcoma (aka MMMT): ​Increased LR/DM. Mets are usually epithelial components.

● This type of cancer is extremely RARE, and the diagnosis has to be made after the exclusion of cervical origin ● The 5-year survival rate based on the FOGO report is 68.9% overall, but the prognosis is POOR for patients with extrauterine disease or distant spread

-Squamous Carcinoma

Pelvic RT Versus Intravaginal RT ● GOG 249

1. GOG 249​[​ASTRO '17​, ​Randall JCO '19​]: ​TAH/BSO/PLND​ (90%)​→​ ​WPRT alone vs. VBT→ carboP x3​.WPRT is acceptable with less pelvic failure and six times less acute toxicity than VBT with chemotherapy. Late toxicity is similar. BottomLineQ​S​:Perhaps most surprising, among the pelvic radiation alone arm, IMRT techniques resulted in numerically higher rates of acute toxicity than with the Joe Blow 4-field box approach. Turns out, when it comes to HIR endometrial cancer, a puff to the cuff isn't up to snuff...and the 4-field box still rocks. Critique: 3c of chemo didn't affect DM, but traditionally 6c given especially for HR histology. Allowed 12w for the start of RT, historically 8w as LR known to increase if 9w delay.The addition of adjuvant chemo to adjuvant pelvic radiation probably isn't worth the toxicity for patients < 70 years old with stage I-II disease (supported by ​PORTEC-3​). o ● 601 pts. HIR stage I (74%), stage II or I-II UPSC (15%) / CC (5%). 90% PLND. MFU 4.5y.HIR per GOG 99: Women < 50y need DGL to be considered HIR; 50-70 if 2 histologic RF, > 70y with one RF. § ○ WPRT: 45-50.4/25-28. § ○ BT boost encouraged for stage II or UPSC/CC in WPRT arm (35% of WPRT arm rec'd VBT). § ○ BT + chemo: 3-5 HDR or 2 LDR to ​3-5 cm​ Rx→ carboplatin AUC 6​ ​/ paclitaxel ​175​ mg/m2 q3w x3c. o ● 5y Pelvic/pAO failure 4→ 9%​, largely driven by pelvic failure 2→ 7% . o ● 3y ~OS 91→ 88% and 3y RFS ~83%. § ○ Comorbidity correlates to OS. o ● 5y OS ~86%. 5y RFS ~76%. DM ~18%. o ● Acute G3+ toxicity 11→ 64%; Equivalent late G3+ ~12.5%. § ○ Early G3+ with 3D / IMRT of 10→ 14%. o ● QoL [​ASCO '18]​: Fatigue and neurotoxicity significantly worse in VBT/chemo arm, WPRT more GI sx. *In order to affect DM, at least 6c is recommended. Toxicity is much worse when adding adjuvant chemo to VBT. Around 1 in 8 patients have long term "Bowel bother" after WPRT alone.

● Inherited genetic predisposition, especially in the setting of hereditary nonpolyposis colorectal cancer (HNPCC) ○ probably accounts for _____ of all endometrial cancer cases ○ Mutations in one of the four mismatch repair (MMR) genes ■ ___________________ ■ have been identified in patients with Lynch syndrome

<5% hMLH1, hMSH2, hMSH6, or hPMS2

PORTEC 1​: ​Needed 2 of 3 risk factors for HIR:

>60 y, deep invasion, G3)

● The somatic copy number alterations (SCNAs) analysis showed that ○ most endometrioid tumors have __________, whereas most serous and serous-like tumors (endometrioid) exhibit ______________

FEW SCNAs EXTENSIVE SCNAs