Systemic Therapy for Uterine Cancer

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

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

Cancer Incidence Cancer Deaths* Women668,470 Women272,810 • 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 • 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

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 IITumor invades the cervical stroma but not the uterus Stage IIIA The tumor invades the uterine serosa or adnexa not positive washings Stage IIIBVaginal or parametrial metastases Stage IIICThe 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

Five year survival by stages • Stage I 85-90% • Stage II 80% • Stage III<25% • Stage IV <10%

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

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

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)

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

Summary for Low/Int Endometrial Cancer 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 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)

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/m2 + Cisplatin 50 mg/m2 • Q 3 weeks X 7 cycles • 25 % clear cell/serous histology

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)

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%

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

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%

Chemotherapy with AP significantly improved progression-free (when corrected for stage)and overall survival compared with WART • Nevertheless, furtheradvances 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

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

Adjuvant CAP vs Pelvic RT in IC/II G3Chemo and RT survival equivalent

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

RTOG Phase II Concurrent and Adjuvant Chemotherapy Phase II trial RTOG (46 pts): • stage I-II high risk or stage III (66%) • Concurrent: cisplatin 50 mg/m2 days 1, 28 • Adjuvant: 4x cisplatin 50 mg/m2 and paclitaxel 175 mg/m2 • 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 Greven et al, Gynecol Oncol 2006

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

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

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

TAH-BSO + peritoneal cytology +/- other biopsies No residual disease High-risk or advanced stage 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 Randomize Radiotherapy plus concurrent and adjuvant chemotherapy Concurrent: 2x cisplatin 50 mg/m2 Adjuvant: 4x carboplatin AUC 5 and paclitaxel 175 mg/ m2 @ 3 wk intervals Radiotherapy alone Pelvic RT: 27 fractions of 1.8 Gy -> 48.6 Gy Brachytherapy if cervical invasion

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)

PMH Proposed Endo Ca Policy

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

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

Study Phase N Prior hormonal therapy Treatment Overall response rate Thigpen et al 1999 3 III 299 No Oral medroxyprogesterone acetate 200mg/day versus 1g/day Low dose 25% (25CR,11PR); high dose 16% (14CR,10PR) Lentz 35 II 63 No Oral medroxyprogesterone acetate 800mg/day 24% (6CR,7PR) Thigpen et al 2001 4 II 68 No Tamoxifen 20mg bid 10% (3CR,4PR) Rose et al 36 II 23 Yes Anastrozole 1mg/day 9% (No CR, 2PR) Lhomme et al 34 II 24 Yes Sustained release LHRH agonist (Triptorelin) 8.7% (1CR, 1PR) Covens et al 1997 32 II 25 Yes GnRH agonist (Leuprolide) 0% Jeyarajah et al 1996 33 II 32 Yes GnRH agonist 28%

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

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

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.

TAP Taxol 160mg/m2 Adria 45mg/m2 Cisplatin 50mg/m2 RR 57% 12 months OS 58% Toxicity, TAP: Neutropenia Gr 4 36% Neuro grade 3 or 4 12% Neuro grade 2/3 40% Congestive Heart Failure 3 pts AP Adria 60mg/m2 Cisplatin 50mg/m2 RR vs 34% 12 months OS 50% Toxicity AP: Neutropenia Gr 4 50% Neuro grade 3 or 4 1% Congestive Heart Failure 0 pts TAP vs AP. GOG 177 Fleming et al 2004

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

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/m2 Sovak et al. ASCO 2005

Carbo/Taxol: A retrospective study

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

EGFR/HER2 inhibitors BMS 387032 Angiogenesis inhibitors GW572016 Survivin AS AEG35156 Pro-Apoptotics ZD6474 ZD2171 PTK787 TRAIL RAD001, mTOR inhibitors MG98 PXD101 SAHA

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

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

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

The mTOR Pathway

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…………….

Systemic Therapy for Uterine Cancer