1. What’s New in Endometrial Cancer Henry Kitchener April 2009

2. Background Rising rates of disease Rising rates of disease Obesity epidemic Obesity epidemic Increased use of tamoxifen Increased use of tamoxifen Need to reduce deaths in high risk disease Need to reduce deaths in high risk disease

4. Endometrial Cancer Endometrioid adenocarcinoma, FIGO histological grade 1 Clear cell carcinoma showing high grade nuclear atypia Serous carcinoma with typical fine papillary architecture Serous carcinoma showing typical pattern of myometrial lyphovascular permeation

5. Carcinoma of the corpus uteri – Staging FIGO Stages 0 Primary tumour cannot be assessed No evidence of primary tumour Carcinoma in situ (preinvasive carcinoma) I*IAIBIC Tumour confined to the corpus uteri Tumour limited to endometrium Tumour invades up to less than half of myometrium Tumour invades to more than one half of myometrium II*IIA IIB IIB Tumour invades cervix but does not extend beyond uterus Endocervical glandular involvement only Cervical stromal invasion IIIIIIAIIIBIIIC Local and/or regional spread as specified in IIA, B, C Tumour involves serosa and/or adnexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings Vaginal involvement (direct extension or metastasis) Metastasis to pelvic and/or para-aortic lymph nodes IVA Tumour invades bladder mucosa and/or bowel mucosa IVB Distant metastasis (excluding metastasis to vagina, pelvic serosa, or adnexa, including metastasis to intra-abdominal lymph nodes other than para-aortic and/or inguinal nodes) * Stage IA & IB will be consolidated into IA and Stage II will be stromal invasion only

6. Incidence of pelvic lymph node involvement as a function of tumour grade and myometrial invasion in clinical stage I endometrial cancer – results of a prospective surgicopathological study Metastasis StagingPelvic(%)Aorta(%) IA G1 (N=101) G2 (N=169) G2 (N=169) G3 (N=76) G3 (N=76) 2 (2) 13 (8) 8 (11) 0 (0) 6 (4) 5 (7) IB G1 (N=79) G2 (N=119) G2 (N=119) G3 (N=77) G3 (N=77) 3 (4) 12 (10) 20 (26) 3 (4) 8 (7) 12 (16) Creasman et al (1987) Cancer 60

7. Risk Level in Endometrial Cancer Node Rate Low risk1b/G1 <5% Intermediate Risk1b/G2 5-10% High Risk1c/G3 10-20%

8. Role of Lymphadenectomy To stage disease To stage disease – Determine prognosis – Define ongoing management To remove disease containing lymph nodes To remove disease containing lymph nodes

9. Relative Hazard Rates for Disease Specific Mortality associated with Lymph Node Resection in Endometrial Cancer Relative hazards rate (95% CI) 1-10 Lymph Nodes 11-20 Lymph nodes >20 Lymph Nodes Low Risk1.00 1.12 (0.87-1.45) 1.26 (0.98-1.63) Intermediate Risk 1.00 0.80 (0.73-0.89) 0.65 (0.58-071) Lymph Node Positive 1.00 0.77 (0.65-0.91) 0.60 (0.50-0.70) Chan et al, Cancer (2006)

10. Kaplan-Meier disease specific survival by number of lymph nodes removed in patients with nodal disease Chan et al, Cancer (2006)

11. Impact of lymph node dissection on survival in endometrial cancer Lymph Node dissection (LND) Cox Multivariate Analyses of Survival End Points Hazard Ratios (p Value) Overall Disease Specific All Other Causes Cardiac Specific Absence of LND Reference >11 LN Dissected 0.74 (0.0001)0.69 (0.0001)0.77 (0.0001)0.82 (0.006) 1-11 LN Dissected 0.89 (0.0001)0.87 (0.0051)0.91 (0.0063)0.98 (0.722) Presence of LND 0.81 (0.0001)0.78 (0.0001)0.84 (0.0001)0.90 (0.0574) (0.0574) Gaffney et (2007) Int J Gynae Oncol

12. Effectiveness of Lymphadenectomy  As a therapeutic surgical procedure  As an effective means of determining adjuvant therapy NEITHER OF THESE HAD BEEN EVALUATED IN A CLEAR CUT FASHION IN GYNAECOLOGICAL CANCER

13. ASTEC Trial Design Endometrial cancer, thought pre-operatively to be confined to the corpus RANDOMISE TAH/BSOTAH/BSO + ND High risk pathology and no macroscopic disease No external beam RT External beam RT RANDOMISE Independent of lymph node status

14. Surgery Trial Profile 1408 randomised 1408 randomised 704 No Lymphadenectomy 704 No Lymphadenectomy 33% Radiotherapy within 3 months of surgery EBRT ± Brachy 25% Brachy only 8% 704 Lymphadenectomy 33% Radiotherapy within 3 months of surgery EBRT ± Brachy 24% Brachy only 9% 97% of women recruited from the UK 704 No Lymphadenectomy

15. Nodes Harvested & Involvement TAH/BSOTAH/BSO + ND Nodes harvested: Yes No 32 (5%) 628 (95%) 611 (91%) 62 (9%) Number nodes harvested 1-4 5-9 10-14 >14 missing Median 25 4 1 2 61 134 148 239 29 13 Nodal involvement: Yes No missing 9 (28%) 23 (72%) 0 54 (9%) 556 (91%) 1

16. Overall survival by treatment arm ASTEC Writing Committee, Lancet 2009

17. Disease and Treatment Related Deaths by Treatment Arm ASTEC Writing Committee, Lancet 2009

18. Recurrence-Free Survival by Treatment Arm ASTEC Writing Committee, Lancet 2009

19. ASTEC: Overall Survival ASTEC Writing Committee, Lancet 2009

20. Overall Survival ASTEC Writing Committee, Lancet 2009

21. Italian Lymphadenectomy Trial in Endometrial Cancer Lymphadenectomy Arm Median no. of nodes 26 Aortic nodes removed in 26% Nodal metastasis 13% No Lymphadenectomy Arm Enlarged nodes removed in 56 (22%) Aortic nodes removed in 5 (2%) 16 had ≤ 5 nodes removed 12 had 6-10 nodes removed 11 had 11-19 nodes removed 8 (14%) had nodal mets Nodal metastasis 3% Panici et al, JNCI (2008)

22. Adjuvant Therapies by Treatment Arm Type of adjuvant therapyLymphadenectomy arm n=64 (%) No lymphadenectomy arm n=250 (%) Total n=514 (%) No adjuvant therapy Radiation therapy Chemotherapy Chemotherapy & Radiation therapy 182 (68.9) 44 (16.7) 23 (8.7) 15 (5.7) 162 (64.8) 63 (25.2) 14 (5.6) 11 (4.4) 344 (66.9) 107 (20.8) 37 (7.2) 26 (5.1) Panici et al, JNCI 2008

23. Disease-free survival for patients with clinical early stage endometrial cancer undergoing systematic pelvic lymphadenectomy vs those undergoing resection of bulky lymph nodes only Panici et al, JNCI 2008

24. Overall survival for patients with clinical early stage endometrial cancer undergoing systematic pelvic lymphadenectomy vs those undergoing resection of bulky nodes only Panici et al, JNCI 2008

25. ASTEC Trial Conclusions Large adequately powered trial Large adequately powered trial Pelvic lymphadenectomy does not increase survival (in the presence of adjuvant therapy) Pelvic lymphadenectomy does not increase survival (in the presence of adjuvant therapy) Trend towards poorer recurrence free survival Trend towards poorer recurrence free survival Increase risk of lymphoedema with subsequent RXT Increase risk of lymphoedema with subsequent RXT

26. Post ASTEC, whom should we stage? Women of sufficient risk to warrant surgical staging Women of sufficient risk to warrant surgical staging – In whom a node negative result would negate the need for adjuvant therapy – In whom a node positive result (pelvic or para aortic) would influence adjuvant therapy Lack of therapeutic effect on overall survival requires some demonstrable benefit to justify its use. Lack of therapeutic effect on overall survival requires some demonstrable benefit to justify its use.

27. Sentinel Node Mapping in Endometrial Cancer StudyNoTechniqueSurgery Sentinel Node Detection Rate % Negative PV Holub, 200213 Blue dye to body Laparoscopy61.5 12 Blue dye to cx/body Laparoscopy83.3 Gargiulo, 200311 I’sci + blue die Laparoscopy100 Lelievre, 200412 I’sci + blue die Laparoscopy91.6100 Barranger, 2004 17 I’sci + blue die Laparoscopy94.1100 Niikura, 200428I’sciLaparotomy82100 Total9385100

28. Adjuvant Radiotherapy for Endometrial Cancer

29. Aalders et al (1980) Obstet Gynecol 56

30. Creutzberg et al (2000) Lancet 355

33. Disease Specific Survival 5 year DSS 89% 48452 42453 EventsTotals PATIENTS at Risk No EBRT EBRT 4534323792882161448337 4524223782872181458034 No EBRT EBRT Proportion Surviving from disease 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years from randomisation 01234567 HR=1.17, 95% CI=0.77 - 1.76, p=0.47 ASTEC Writing Committee, Lancet 2009

34. Isolated Vaginal or Pelvic Initial Recurrence 3% difference in 5 year cumulative incidence rate (4% in EBRT to 7% in no EBRT) Only includes 42/123 total recurrences ASTEC Writing Committee, Lancet 2009

35. ASTEC Meta-analysis ASTEC Writing Committee, Lancet 2009

36. PORTEC II Intermediate Risk Disease (IB/G3, IC/G1,2, II occult) Brachytherapy Pelvic RT Age ≥ 60 Surgery TAH/BSO

37. CAP vs RXT Overall five-year survival was 69% and 66% respectively for adjuvant radiotherapy and chemotherapy Maggi et al (2006) BJC 95

38. CAP vs RXT Cumulative incidence of distant relapses Maggi et al (2006) BJC 95

39. CAP vs RXT Cumulative incidence of local relapses Maggi et al (2006) BJC 95

40. PORTEC III - Rationale High risk and advanced stage endometrial cancer: increased risk of distant relapse and endometrial carcinoma death High risk and advanced stage endometrial cancer: increased risk of distant relapse and endometrial carcinoma death Trials on adjuvant chemotherapy needed: chemoradiation superior efficacy in most cancer sites Trials on adjuvant chemotherapy needed: chemoradiation superior efficacy in most cancer sites Phase II study with promising data on efficacy and toxicity profile Phase II study with promising data on efficacy and toxicity profile Quality of life analysis needed Quality of life analysis needed

41. PORTEC III High Risk Disease (IB/G3, IC/G3, II occult/G3, IIIA, IIIC, serous or clear cell) Pelvic RT Concurrent CR + Chemo Surgery TAH/BSO ± Lymphadenectomy

42. Targetted Therapy in Endometrial Cancer mTOR inhibitors Antiangiogenesis EGFR inhibitors

43. Preventative Strategies Primary Primary Progestins, surgery in Lynch syndrome Progestins, surgery in Lynch syndrome Progestins, obesity avoidance Progestins, obesity avoidance Secondary Secondary Treatment of atypical hyperplasia Treatment of atypical hyperplasia Hysterectomy Hysterectomy Uterine conservation e.g. Mirena Uterine conservation e.g. Mirena

44. Preventative Strategies Genetically predisposed women Genetically predisposed women Lynch syndrome Lynch syndrome Unsuccessful POET trial Unsuccessful POET trial Grossly obese women Grossly obese women Women with atypical hyperplasia Women with atypical hyperplasia

45. The Future Role of radiotherapy becoming clearer and more restrictive Role of radiotherapy becoming clearer and more restrictive Role of chemoradiation and chemotherapy Role of chemoradiation and chemotherapy Role of biological drugs Role of biological drugs International collaboration will be key International collaboration will be key Studies of primary prevention Studies of primary prevention