1. Systemic Therapy for Uterine Cancer Helen J. Mackay Princess Margaret Hospital, University of Toronto

2. Uterine malignancy Endometroid UPSC Clear cell Mucinous Squamous Mixed histology Carcinosarcoma (MMT) Endometrial stromal tumors Leiomyosarcoma

3. Cancer Incidence Cancer Deaths* Women 272,810 25%Lung & bronchus 15%Breast 10%Colon & rectum 6%Ovary 6%Pancreas 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Multiple myeloma 2%Brain/ONS 24% All other sites 32%Breast 12%Lung & bronchus 11%Colon & rectum 6%Uterine corpus 4%Ovary 4%Non-Hodgkin lymphoma 4%Melanoma of skin 3%Thyroid 2%Pancreas 2%Urinary bladder 20%All Other Sites Women 668,470

4. FIGO Staging 1988 to 2009 Stage IA The tumor is limited to the endometrium Stage IB The tumor invades less than one-half of the myometrial thickness Stage IC The tumor invades more than one-half of the myometrial thickness. Stage IIA Cervical extension is limited to the endocervical glands Stage IIB Tumor invades the cervical stroma Stage IIIA The tumor invades the uterine serosa or adnexa or positive washings Stage IIIB Vaginal metastases Stage IIIC The tumor has spread to lymph nodes No or less than half myometrial invasion More than half myometrial invasion Stage II Tumor invades the cervical stroma but not the uterus Stage IIIA The tumor invades the uterine serosa or adnexa not positive washings Stage IIIB Vaginal or parametrial metastases Stage IIIC The tumor has spread to lymph nodes IIIC1 Positive pelvic lymph nodes IIIC2 Positive para-aortic lymph nodes with or without pelvic nodes Stage IV Tumor invades bladder and/or bowel mucosa, and/or distant metastasis

5. Five year survival by stages Stage I85-90% Stage II80% Stage III<25% Stage IV<10%

6. Systemic therapy When and what? Adjuvant Initial therapy of Stage III disease – Randall et al. ?Papillary Serous Recurrent or Metastatic disease Endometrial cancer Hormonal Therapy Chemotherapy Novel Agents

7. Endometrial Cancer “Subtypes” Type I (80%) related to unopposed estrogen arises in hyperplastic endometrium usual local disease high survival rate e.g. endometrioid Type II (10%) not related to unopposed estrogen arises in atrophic endometrium often advanced at Dx low survival rate e.g. UPSC 50% relapses

8. Endometrial Cancer: Prognostic Factors Grade Depth of myometrial invasion Histology - serous/clear cell Capillary-lymphatic invasion Age (over 60 yrs PORTEC, over 70 GOG) Not positive peritoneal cytology (in otherwise Stage I)

9. Endometrial Cancer: Risk Stratification Low Risk IA G1/2 No LVI or age >65 Intermediate Risk IB and IC G1/2 IIA High Intermediate Risk (PORTEC) Any two of: IC or G3 Age > 65 (+/- LVI) High Risk IC G3 IIB Serous and clear cell Stage I to III

10. Summary for Low/Int Endometrial Cancer Nodal staging diagnostic not therapeutic Low-risk (IA/B, G1/2) Intermediate risk (IA/B G3, IC G1/2) High Int Risk (Age, LVI) High Risk (IC G3, IIA G3, IIB) Selective PLND (avoid if RT to be used) Watch Neg PLND - brachy or watch No PLND – ? Brachy or IMRT Neg PLND - Small field RT vs brachy No PLND - IMRT PLND not recommended Pelvic IMRT +/- brachy

11. Summary for Low/Int Endometrial Cancer Nodal staging diagnostic not therapeutic Low-risk (IA/B, G1/2) Intermediate risk (IA/B G3, IC G1/2) High Int Risk (Age, LVI) High Risk (IC G3, IIA G3, IIB) Selective PLND (avoid if RT to be used) Watch Neg PLND - brachy or watch No PLND – ? Brachy or IMRT Neg PLND - Small field RT vs brachy No PLND - IMRT PLND not recommended Pelvic IMRT +/- brachy

12. WART Vs Combo Doxo/cisplatin Chemo in Advanced Endometrial Ca: GOG Phase III Trial Stage III-IV with max residual < 2cm 198 received WART, 190 AP WART: 30 Gy/20 + pelvic boost 15 Gy AP: Doxo 60 mg/m 2 + Cisplatin 50 mg/m 2 Q 3 weeks X 7 cycles 25 % clear cell/serous histology

13. Randall et al. JCO 2005 N=396, Stage III/IV TAH, BSO surg staging (nodal sampling optional) No residual disease > 2 cm Doxorubicin 60 mg/m2/cisplatin 50 mg/m2 q 21 days x 7 + 1 cisplatin (n=194) Whole abdominal radiotherapy (n=202)

14. Randall et al. JCO 2005 Completion rate chemo 63% vs. WAI 84% Grade ¾ Heme tox 88 vs. 14% Grade ¾ neuro tox 7% vs 1% Grade ¾ cardiac 15% vs. 0%

15. Randall et al. JCO 2005 AP chemo vs Whole abdominal RT

16. Randall et al. JCO 2005 PFS at 60 months 50% vs 38% OS at 60 months 55 vs 42% 5yr PFS 42 vs 38% 5yr OS 53 vs 42%

17. Chemotherapy with AP significantly improved progression-free (when corrected for stage) and overall survival compared with WART Nevertheless, further advances in efficacy and reduction in toxicity are clearly needed AP chemo associated with increased acute toxicity Many centers are now using carboplatin and taxol (less toxic), followed by radiation targeted to sites of initial disease (e.g. pelvis, pelvis and PA) Heterogeneous group of patients

18. Adjuvant chemotherapy vs. adjuvant radiotherapy N= 345, stage Ic G3,IIa- b G3 > 50% myometrial invasion, stage III TAH, BSO surg staging + nodal sampling Cyclophosphamide 600mg/m2/ Doxorubicin 45 mg/m2/cisplatin 50 mg/m2 q 28 days x 5 (n=177) Pelvic Radiotherapy (n=168) Maggi et al BJC 2006

19. Adjuvant CAP vs Pelvic RT in IC/II G3 Chemo and RT survival equivalent

20. Maggi et al 2006 Completion rate chemo 75% vs. RT 88% 5yr survival chemo 66% (CI 59-73) vs. RT 69% (CI 61-76) 5yr PFS Chemo 63 (55-70) vs. RT 63 (55-70

21. Phase II trial RTOG (46 pts): stage I-II high risk or stage III (66%)  Concurrent: cisplatin 50 mg/m 2 days 1, 28  Adjuvant: 4x cisplatin 50 mg/m 2 and paclitaxel 175 mg/m 2 4-yr locoregional relapse 4%, distant 19% 4-yr DFS 81%, OS 85% (stage III: 77 and 72%) No recurrences in stage IC, IIA, IIB  promising data, phase III needed RTOG Phase II Concurrent and Adjuvant Chemotherapy Greven et al, Gynecol Oncol 2006

22. Uterine Papillary serous carcinoma (UPSC) Stage I-II: 35-50%, III-IV 0-15% Prognostic features stage, depth invasion, LVI Stage IA chemo, yes or no? (Kelly gynae onc 2005) Radiation? GOG 94 Others no

23. Kelly et al. n=74 Stage Ia n= 12, no residual disease Stage IA, residual disease, no chemo, 6/14 chemo, 0/7 Stage IB no chemo, 10/13 chemo, O

24. Randomized Trial of Concurrent/Adjuvant ChemoRT for High Risk and Advanced Stage Endometrial Carcinoma PORTEC 3/ NCIC EN7 Carien Creutzberg, Netherlands A Fyles/ P Bessette, NCIC Rationale High risk and advanced stage endometrial cancer: increased risk of distant relapse and endometrial carcinoma death Trials of adjuvant chemotherapy needed; chemoradiation superior efficacy in most cancer sites Phase II study with promising data on efficacy toxicity profile requires modification Quality of life analysis needed

25. TAH-BSO + peritoneal cytology +/- other biopsies No residual disease Pathology Review Stage IB grade 3 + LVSI Stage IC or IIA grade 3 Stage IIB Stage IIIA or IIIC Stage IB, IC, II or III with serous/clear cell Randomiz e Radiotherapy plus concurrent and adjuvant chemotherapy Concurrent: 2x cisplatin 50 mg/m 2 Adjuvant: 4x carboplatin AUC 5 and paclitaxel 175 mg/ m 2 @ 3 wk intervals Radiotherapy alone Pelvic RT: 27 fractions of 1.8 Gy -> 48.6 Gy Brachytherapy if cervical invasion High-risk or advanced stage

26. Algorithm for Endometrial Cancer Management Clinical Stage I Risk-based therapy: Prevent over treatment, preserve QoL Low risk: TAH-BSO alone Intermediate/High-intermediate risk: vaginal brachytherapy or observe? High-intermediate risk with LVI: small field or IMRT (EBRT if pNX) High Risk, serous/clear cell and Stage III Clinical trials (EN7/PORTEC 3)

27. PMH Proposed Endo Ca Policy

28. Hormonal or Chemotherapy Treatment intent is palliative Consider extent of disease Rate of growth Patient symptoms Performance status Implications on QL Sequential therapy Hormonal therapy followed by chemotherapy

29. Hormonal Therapy Progestogens Medroxy progesterone Acetate or Provera Tamoxifen Alternating Tamoxifen and progestogens Aromatase inhibitors

30. StudyPha se NPrior hormon al therapy TreatmentOverall response rate Thigpen et al 1999 3 III299NoOral medroxyprogesterone acetate 200mg/day versus 1g/day Low dose 25% (25CR,11PR); high dose 16% (14CR,10PR) Lentz 35II63NoOral medroxyprogesterone acetate 800mg/day 24% (6CR,7PR) Thigpen et al 2001 4 II68NoTamoxifen 20mg bid10% (3CR,4PR) Rose et al 36II23YesAnastrozole 1mg/day9% (No CR, 2PR) Lhomme et al 34II24YesSustained release LHRH agonist (Triptorelin) 8.7% (1CR, 1PR) Covens et al 1997 32 II25YesGnRH agonist (Leuprolide) 0% Jeyarajah et al 1996 33 II32YesGnRH agonist28%

31. Letrozole: NCIC IND 126 Phase II Clinical trial Letrozole 2.5mg daily 32 Eligible Patients 1 CR and 2 PRs (9.4%) 11 SD for median 6.7 months (34%) Median duration of therapy 12 weeks Response rates similar irrespective of prior hormonal therapy Ma BB et al. Int J Gynae 2004

32. Chemotherapy Active Agents Cisplatin Carboplatin Doxorubicin Cyclophosphamide Paclitaxel Liposomal Doxorubicin Active Combinations CAP CA Taxol/Carboplatin Taxol/Adria/Plat Carbo/Caelyx

33. Combination Chemotherapy Combination chemotherapy – more active than single agent therapy. Cisplatin/Doxorubicin RR 35-40% AT+GCSF vs AC RR 40%vs 43% RCT of CAP vs CA No advantage with triple chemotherapy regimen Increased toxicity CA regimen of choice.

34. Fleming et al 2004 TAP vs AP. GOG 177 TAP Taxol 160mg/m 2 Adria 45mg/m 2 Cisplatin 50mg/m 2 RR 57% 12 months OS 58% Toxicity, TAP: Neutropenia Gr 436% Neuro grade 3 or 4 12% Neuro grade 2/3 40% Congestive Heart Failure 3 pts AP Adria 60mg/m 2 Cisplatin 50mg/m 2 RR vs 34% 12 months OS 50% Toxicity AP: Neutropenia Gr 4 50% Neuro grade 3 or 4 1% Congestive Heart Failure 0 pts

35. TAP + G-CSF vs AP Survival: Recurrent Endometrial Cancer Fleming et al. J Clin Oncol 2004 HR for recurrence 0.57

36. Carbo/Taxol: A retrospective study Single institution, n=85 Stage III/IV Median age 62 (36-80) Median F/up 11.7 mo Carbo AUC 4-6, Taxol 60-175 mg/m 2 Sovak et al. ASCO 2005

37. Carbo/Taxol: A retrospective study Taxol/carbo GOG #177 AP TAP RR PFS OS Neurotoxicity (G2/3) Tx stopped due to toxicity 43% 5.3 mo 13.2mo 16% 8% 34% 57% 5.3 mo 8.3mo 12.3mo 15.3mo 5% 39% 9% 24%

38. UPSC: Chemotherapy - CARBO/TAXOL Hoskins et al., JCO, 2001 CR-3, PR-6, ST-3, PROG-3, median OS - 26 months

39. AEG35156 TRAIL GW572016 RAD001, BMS 387032 ZD6474 ZD2171 PTK787 MG98 PXD101 SAHA Survivin AS AngiogenesisinhibitorsEGFR/HER2inhibitorsmTORinhibitors Pro-Apoptotics

40. Which Targets in Gynecological Cancers?--- Endometrium Apoptosis related: XIAP BCL-2 TRAIL Survivin Receptors/signaling EGFR, HER2 etc Ras, raf, MAPK Jak/Stat Akt pTEN PI3k Other cell surface CA125 Growth Factors TGF alpha Transcription Factors Myc Cell Cycle RB P53 Cyclins and cdks p16 Invasion/metastasis MMP auer VEGF E.Eisenhauer

41. CCI-779 CCI-779 is a macrocyclic lactone Novel anti-tumor mechanism of action, resulting in inhibition of translation of key proteins regulating G1 phase of cell cycle Binds to FKBP-12 (FK506 binding protein), inhibiting the function of mTOR and key signaling pathways In in vitro and in vivo preclinical studies, CCI- 779 demonstrated anti-tumor activity against a variety of tumor types

42. The mTOR Pathway The PI3-kinase (PI3K) and mTOR pathways are two of the key growth factor-mediated signal transduction pathways that regulate cell growth Activation of PI3K results in activation of a cascade of signaling kinases including Akt The mTOR pathway is thought to be activated in parallel by a nutrient-sensing mechanism PI3K and mTOR cooperate to activate downstream targets that regulate the translation of cell cycle regulatory proteins

43. The mTOR Pathway

47. The future Adjuvant Optimal regimen? Which patients? Chemo vs radiotherapy+chemotherapy Metastatic Targeted therapy MTOR, FT I, EGFR Targeted therapy plus cytotoxic chemotherapy Trials, Trials and more Trials…………….

48. The future Adjuvant Optimal regimen? Which patients? Chemo vs radiotherapy+chemotherapy Metastatic Targeted therapy MTOR, FT I, EGFR Targeted therapy plus cytotoxic chemotherapy Trials, Trials and more Trials…………….