1. Clinical session Gynecological cancers Cervical and endometrial cancers Prof. C. Sessa IOSI - Bellinzona 10° ESO-ESMO MASTERCLASS IN CLINICAL ONCOLOGY Ermatingen, 4.4.2011

3. Endometrial cancer Pathology and biology * Include also: adenocantoma, adenosquamous, undiff., squamous, mucinous Type II (10-20%) Type I (70-80%)* 43% 85% 5 yr survival p53 mut (90%) HER2 overexpress. (45%) amplific. (70%) MSI with MMR defects (20%) PTEN deletion (80%) KRAS, β caterin mut (40%) PI3K mut (39%) Molecular alterations abdominal, lymphatic local Recurrence aggressive favourable Behaviour advanced 60% early 70% Initial stage high low Grading no yes Hormone sensitivity endometrial CIN atypical hyperplasia Precursor lesions papillary serous; clear cell endometrioid adenoca. Histotype

5. Endometrial cancer The FIGO staging is surgical and pathological Old FIGO staging New FIGO staging Pathological assessment includes: M, cervical involvement, tumor size and location, extension to fallopian tubes and ovaries, grade and hystological subpypes, lymphovascular space invasion (LVSI), nodal status 75% stage I

6. Endometrial cancer Treatment * if controindications to surgery, RT and/or VBT Surgery Palliative histerectomy IV III I Stage Maximal surgical debulking no randomized studies, prognostic not therapeutic para aortic lymphadenectomy no evidence of benefit in DFS, OS (ASTEC) pelvic lymphadenectomy Comparable DFS/OS better short term outcome with lps Laparotomy/laparoscopy TAHBSO (I,A)* Abdominal inspection/washing Comments Issue Recommended

7. MRC ASTEC study: efficacy of pelvic lymphadenectomy Lancet,2009

9. Endometrial cancer Treatment Adjuvant radiotherapy VBT is the treatment of choice for intermediate high risk patients NAT vs EBRT EBRT vs VBT NAT vs EBRT 4% vs 7% (p=o.039) 2% vs 5% Locoregional recurrence 4% vs 14% (P <0.001) 84 % vs 84% 80% vs 85% Survival 81% vs 85% ASTEC/EN5 PORTEC 2 (high risk-intermediate) PORTEC 1 (intermediate) 3% vs 7% gr 3-4 TAHBSO ± lymphadenect. I AB gr 3 IC II, serous, CC acute GI 13% vs 54% TAHBSO IB gr 3 IC gr 1-2 IIA Severe complications 3% GI at 5 yrs TAHBSO IBgr2-3 ICgr1-2

10. Endometrial cancer Treatment Adjuvant Concurrent CT-RT vs RT * risk factors: gr3, >50% M ** CT: TP, AP, TEP, TAP before or after RT ongoing EBRT plus DDP x 2 ->TP x4 vs TP x 6 III-IVA GOG 258 ongoing ongoing OFS 7% PFS 78% vs 69% GOG 249 PORTEC 3 NSGO-EORTC-9501/ EORTC5591 EBRT vs VBT TP x3 I-II high risk I-II serous, CC EBRT vs EBRT plus DDP ->TP x 4 IB-C gr3, IIA gr3, serous IB-III IIIA, IIIC EBRT (VBT) + CT ** vs EBRT ( ± VBT) I-IIIa, IIIC*

13. Endometrial cancer Treatment Advanced disease (stages III-IV) Ongoing studies for endometrioid stage III for non endometrioid stage III CT/surgery/RT CT Individualized treatment IIIA only Observation GOG 209: TAP vs TP TAP more toxic AP vs TAP CT E dipendent tumors only Hormones Ridaforolimus vs Progestins mTOR inhibitors PI3K inhibitors HER2 inhibitors in serous New agents

15. mTOR inhibitors in endometrial cancer Colombo et al.

16. mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies mTOR Inhibition Chemotherapy Radiation EGFR Inhibitors Antiestrogens Antiangiogenics

18. Conclusions Outside clinical trials Endometrial cancer Surgery lymphadenectomy in selected high risk pts (grade, M, tumor size) to define need and type of adjuvant therapy Radiotherapy EBRT: no survival benefit but less recurrence in high risk. The indication for adjuvant RT should take into account the risk of vaginal recurrence (age, grade) and the benefit shown in stage IA VBT is indicated in IC gr1-2, IB gr1-2, IIA gr1-2, IIA gr3 < 50%, IA gr3, IB gr3 Medical treatment TP almost standard regimen No indication for adjuvant CT but concurrent with EBRT Promising new molecule targeted agents