Early Stage Endometrial Cancer: Adjuvant Treatment

Gynecologic Radiation Oncology Early Stage Endometrial Cancer: Adjuvant Treatment Fernanda Herrera M.D. Department of Radiation Oncology Centre Hospitalier Universitaire Vaudois

Outline Is there any subgroup of patients who do not need adjuvant irradiation? Is there any subgroup of patients for whom a brachytherapy treatment would be enough? Is there any subgroup of patients that will certainly need adjuvant pelvic RT +/- brachytherapy? Should we administered EBRT to those that did not received lymphadenectomy?

Endometrial Cancer Most common gynecological cancer 20 cases/100.000 Postmenopausal women Obese Comorbide: DBT, HTA, etc. TAH-BSO LND is the cornerstone of treatment. 75-80% of cases are confined to the uterus (early disease) 70% have low-intermediate risk features 30% have high risk features 15% will developed mtts disease.

Classification of Disease Categories Simple Risk Assessment Table Early Stage Stage IA (Glands inv only) Stage IB (<50% inv.) Stage IC (deeply invnow IB) G1 Low Low Interm. G2 Low Low Interm. 20-25% LRR G3 Interm. Interm. High

Classification of Disease Categories GOG 33 (Creasman W. Cancer 1987/Morrow P. G&O1991) Probability of recurrence having a single risk factor: 1/3 myometrial inf: 15% Grade 3 tumors: 16% LVSI: 26% Cervix: 16% One risk factor: recurrence frequency of 20% Two risk factors: 40%

Classification of Disease Categories: GOG 33 Intermediate risk group: At least one of these features 20-25% risk of LRR >60 year old >50% myometrial inv. G3 LVSI

Does everyone needs adjuvant post-op radiation? Indication to be consider according to: Surgical stage Myometrial invasion Grade LVSI Histology Cervix Patient decision based on informed consent of risk benefit assessment

Intermediate Risk - Early Stages 5 Randomized Studies evaluating role of RT Aalders 1980 (Obstet Gynecol 56:419, 1980) GOG 99: Keys (Gynecol Oncol, 92:744, 2004) Portec-1: Creutzberg (Lancet 355:1404, 2000) MRC ASTEC/ NCIC EN5 (The Lancet 373:137, 2009) Portec-2: (The Lancet 375:816, 2010)

Keys et al GOG 99 (G&O 2004) 1987-1995 Stage IB, IC, II (any grade) low-intermediate risk Excluded serous papillary and clear cell Groups well balanced. Analysis by ITT principle. 448 women entered TAH-BSO-LND (pelvic and PAO) + washing 31 ineligible 25 ineligible 190 pts EBRT 50.4 Gy (CO60 allowed) No Bq. 202 pts. NFT 1 endpoint: recurrence free survival

Keys et al GOG 99 392 patients in 8 years. Median follow-up 69m Low-Intermediate risk: 82.3% inner and middle third invasion Only 17.6% outer third invasion 80% G1-2 High-intermediate risk: (⅓ of the patients accrued) G3, LVSI, outer 1/3 myometrial inv. 50 year old + 2 facteurs 70 year old + 1 facteur

Keys et al GOG 99 Recurrences Decreased HR for recurrences among those in RT arm. HR= 0.42 (90% CI 0.25-0.73), P= 0.007 RT: 3% (90% CI 0.02-0.06) vs. NFT: 12% (90% CI 0.09-0.17)

GOG 99 - Low Intermediate Risk (Keys et al. GynOnc 92:744, 2004) Recurrence Overall survival 100 100 % with recurrence 80 60 40 20 Time (years) No RT RT % surviving 80 60 40 20 0 0 1 2 3 4 5 Time (years)

GOG 99 - High Intermediate Risk (Keys et al. GynOnc 92:744, 2004) Recurrence Overall survival 100 100 Pelvis RT % with recurrence 80 60 40 20 No RT Pelvic RT 0 1 2 3 4 5 Time (years) % surviving 80 60 40 20 0 0 1 2 3 4 5 Time (years)

Keys et al GOG 99: Recurrence sites TAH-BSO ONLY POST-OP RT DM Vagina 7.4% DM DM+Pelvis Pelvis Vagina 1.06% Pelvis

Keys et al GOG 99 2 death due to GI toxicity in the RT arm (p<0.001) Significant diff. (p<0.001) in hematologic, genitourinary, gastrointestinal and cutaneous toxicities for those receiving RT. 6 bowel obstructions (G3-4) in the RT arm No significant diff. in lymphaoedema.

Keys et al GOG 99: Conclusions Adjunctive RT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit this high intermediate risk definition.

Creutzberg et al: PORTEC-1 (Lancet 2000) TAH+BSO, no LND, washings recomm. Main characteristics: 715 pts randomized (10 NE) 1990-1997 Median follow-up: 73 months Groups well balanced 1 endpoints : LRR & OS. 2 endpoints: morbidity & SV after relapse 354 Sx+RT (Linac 46Gy/2Gy fx. No bq) 4 NE 339 received RT 22 mayor violations 8 minor violations 354 were followed 361 NFT 355 NFT 6 mayor violations: got RT 2 minor violations 1 lost FU 360 were followed

Creutzberg et al: PORTEC-1 (Lancet 2000) Inclusion Criteria: >60 year old: 72% Low risk included: IB G2 = 30% Intermediate risk included: IB G3=10% IC G1-2=60% IC G3 excluded! LVSI 6% Seropap. et clear cells included (10 pts) No central pathology review upfront and done in 80% of pts. at the time of pub. Deep of inv? *20% unavailable for review

Creutzberg et al: PORTEC-1 (Lancet 2000) Locoregional recurrences at 5 y. LRR: 14% NFT vs. 4 % RT (p<0.001) Most recurrences were in the vaginal vault (73%). 5 pts. had simultaneous DM (10%). 9 pts. developed DM after the LRR (18%). 79% 2-yr survival after vaginal relapse

Creutzberg et al: PORTEC-1 (Lancet 2000) Overall survival at 5y. Idem 81% vs. 85% (p=0.31) 105 patients died Dead of disease 40% Intercurrent death: 61%

Creutzberg et al: PORTEC-1 Scholten et al., IJROBP 63:834 (2005) Local Recurrences Correlated with grade G3: 18% Risk of death from EC Correlated with grade G3 (16%) Persisted at multivariate analysis and stronger than myo inv % Local recurrence-free 569 pts with path review ( RT) 20 G3 (86 pts) 15 G2 (88 pts) 10 G1 (395 pts) 5 Remember: Deeply invasive G3 not eligible!!! 0 Time in years

Creutzberg et al: PORTEC-1 Significant toxicity with EBRT Acute toxicity G3: 60% of patients (mainly GI) Late complications: 25% vs. 6% (p<0.001) G1: 68% mainly GI G3-4: 2% bowel obstruction

MRC ASTEC Radiotherapy and NCIC EN.5 Trial (Lancet 2009) Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: results of the randomised MRC ASTEC and NCIC CTG EN.5 trials ASTEC ISRCTN 16571884 EN.5 clinicaltrials.gov NCT 00002807

Trial design for ASTEC/EN.5 Surgery EN.5: July 1996-2005 ASTEC: July 1998-2005 71% ATH BSO 29% ATH BSO PLN (median #12) High intermediate risk pathology RANDOMIZED 905 cases IC, IIA any grade IA-B G3 N+ or washings + 453 cases 452 cases No EBRT External beam RT 45 Gy 2% EBRT, 52% Brachytherapy 98% EBRT 68 deaths 67 deaths Analyzed by ITT principle Median follow-up: 58 months Primary endpoint: Overall survival Secondary endpoint: DSS, LRR, toxicity

ASTEC / EN.5 TRIAL The study was not controlled for adjuvant therapies in the observational arm

ASTEC / EN.5 TRIAL Main characteristics: Groups well balanced except for : 25% HR in the obs. arm vs. 20% Rxt Local path used (pathologists from 7 countries ) Endometrioide : 83% HR: 22% and IR:76% LVSI +: 25%

ASTEC / EN.5 TRIAL No significant differences in: OS (84% in both groups) 36% of death due to other causes. 60% of death due to endometrial cancer Disease specific survival (90% NFT vs. 89% EBRT) Recurrence free survival (84.7 NFT vs. 85.3 EBRT)

ASTEC / EN.5 TRIAL Cumulative incidence of isolated vaginal or pelvic initial recurrence 5 years cumulative incidence rate of 6.1% NFT vs. 3.2% EBRT HR=0.46; 95% CI 0.24-0.89, p=0.02) Absolute diff.: 2.9% (95%CI <0.1%-5.9%)

ASTEC / EN.5 TRIAL Significant toxicity with EBRT Acute: 57% vs. 27% Late: 61% vs. 45%

ASTEC / EN.5 There is no evidence that the effect of external beam radiotherapy is different in women who have had lymphadenectomy as part of primary surgery (test for interaction for overall survival = 0.79, for disease-specific survival p=0.22)».

ASTEC / EN.5 TRIAL Conclusions: EBRT: No evidence of OS, DFS, RFS improvement in the intermediate risk group Can we generalize results for high-risk group (>50% inv., G3, LVSI+)? Suggests that brachy could be enough for LC. Also for high risk? The # of pts. who had LND was small not allowing for firm conclusions regarding the interaction between RT and LND

Incidence of Vaginal recurrences at 5 years TAH-BSO NFT (%) EBRT (%) Aalders et al 14.7 (sx+bq) 6.6 (+BQ) GOG 99 7 2 (no BQ) PORTEC-1 13.7 4.2 (no BQ) ASTEC/EN.5 6.1 (50% brachy) 3.2 (no BQ) With an estimated decrease in local relapse from 15% to 4%, 1 in 10 patients will benefit from the procedure

2002-2006 VBT (3 fx 7 Gy) vs. EBRT PORTEC-2 Nout et al Lancet 2010 Randomized, non inferiority study (non inferiority margin of 6% in vaginal recurrence) 427 patients Median follow-up: 2 years and 9 months

PORTEC-2 New classification of intermediate risk called: high intermediate risk >60 years old and IC (deeply inv.)-g1-2 or IB G3 All ages and: IIA (glandular only) G1-2-3 Only G3 with <50% myom. Inv. Att: >50% myometrial inv. and G3 or LVI+ were excluded.

PORTEC-2 No statistically significant differences: Rate of vaginal recurrences (0.9 EBRT vs. 2% VBQ) Locoregional control and overall survival Slightly but not significant increased on pelvic recurrences (3.6 vs 0.7%) 0.10 0.08 0.06 0.04 0.02 Vaginal Recurrence P = 0.74 VBT EBRT Years since randomization

PORTEC-2 / QUALITY OF LIFE JCO 2009 348 pts. (81%), Follow-up 2,7 years. RT intestinal symptoms. Diarrhea (12,9% EBRT vs. 5,6% VBT) Fecal leakeage (8,7% EBRT vs. 1,7% VBT) Sexual life: no significant difference Conclusion: VBT = better Q of L Missing data: 19% non responders in the EBRT arm Impact of late vs. Acute quality of life not assesed

Conclusions: PORTEC-2 VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. Att: High-intermediate risk for PORTEC is low risk for others

What is High Intermediate Risk? GOG High intermediate-risk G2-3 + LVSI + outer 1/3 50 YO + 2 features 70 YO + 1 feature PORTEC-2 High intermediate-risk IC, G1-2 + > 60 YO IB, G3 + >60 YO IIA + G1-2 IIA + G3 + inner 1/2 37

G3, >50% excluded Path review (357/427): Pelvic vs. VBT (PORTEC-2 Trial) G1 (48% 79%) G2 (44% 9%) 14% ineligible for trial (IBG1) Other issues: Reliability of depth estimates Incomplete F/U Underpowered Nout et al. Lancet 375:816, 2010 40 *14% unavailable for review

Other questions without answer? What is high-intermediate risk? How does LND influences the role of EBRT and QOL. Does modern radiotherapy improve side effects and increases therapeutic ratio? Role of chemotherapy in high risk and high intermediate risk? PORTEC 3: Pelvis RT vs. CRT + carbo taxol. GOG 249: Pelvis RT vs VBT + carbo taxol.

Creutzberg C. IJGC 2010

Current International Recommendations Low risk (IA, G1-2): Intermediate risk IB, G1-2 IA, G3? Observation VBT ***Take always in to account other prognostic factors like: LVI, age > 60 year old If HIGH RISK (deeply inv., G3, LVI+, papillary sereus, clear cell): PELVIS EBRT Stages according to FIGO 2009