Systemic Therapy for Uterine Cancer

Helen J. MackayPrincess 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* 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% Melanomaof skin

3% Thyroid

2% Pancreas

2% Urinary bladder

20% All Other Sites

Women668,470

FIGO Staging 1988 to 2009Stage 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 stromabut not the uterus

Stage IIIA The tumor invades the uterine serosa or adnexanot positive washings

Stage IIIB Vaginal or parametrial metastases

Stage IIIC The tumor has spread to lymph nodes

IIIC1 Positive pelvic lymph nodesIIIC2 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

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)

WatchNeg PLND - brachy or watchNo PLND – ? Brachy or IMRT

Neg PLND - Small field RT vs brachy

No PLND - IMRT

PLND not recommended

Pelvic IMRT +/- brachy

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)

WatchNeg PLND - brachy or watchNo PLND – ? Brachy or IMRT

Neg PLND - Small field RT vs brachy

No PLND - IMRT

PLND not recommended

Pelvic IMRT +/- brachy

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, 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

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 PFSChemo 63 (55-70) vs. RT 63 (55-70

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

RTOG Phase II Concurrent and Adjuvant Chemotherapy

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, 10/13chemo , O

Randomized Trial of Concurrent/Adjuvant ChemoRT for

High Risk and Advanced Stage Endometrial Carcinoma

PORTEC 3/ NCIC EN7Carien 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 biopsiesTAH-BSO + peritoneal cytology +/- other biopsiesNo residual diseaseNo residual disease

Pathology Review

Stage IB grade 3 + LVSIStage 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 chemotherapyConcurrent: 2x cisplatin 50 mg/m2

Adjuvant: 4x carboplatin AUC 5 and paclitaxel 175 mg/ m2 @ 3 wk intervals

Radiotherapy alonePelvic RT: 27 fractions of 1.8 Gy -> 48.6 GyBrachytherapy if cervical invasion

High-risk or advanced stage

Algorithm for Endometrial Cancer Management

Clinical Stage IClinical 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 hormon

al therapy

Treatment Overall responserate

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

Chemotherapy Active Agents Cisplatin Carboplatin Doxorubicin Cyclophosphamide Paclitaxel Liposomal

Doxorubicin

Active Combinations

CAP CA Taxol/Carboplatin Taxol/Adria/Plat Carbo/Caelyx

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.

Fleming et al 2004

TAP vs AP. GOG 177 TAP

Taxol 160mg/m2

Adria 45mg/m2

Cisplatin 50mg/m2

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/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 + G-CSF vs AP

Survival: Recurrent Survival: Recurrent Endometrial CancerEndometrial Cancer

Fleming et al. J Clin Oncol 2004Fleming et al. J Clin Oncol 2004

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

Taxol/carboGOG #177

AP TAP

RRPFSOS

Neurotoxicity (G2/3)Tx stopped due to toxicity

43%5.3 mo13.2mo

16%

8%

34% 57%5.3 mo 8.3mo

12.3mo 15.3mo

5% 39%

9% 24%

UPSC: Chemotherapy -CARBO/TAXOL Hoskins et al.,

JCO, 2001

Hoskins et al., JCO, 2001

Primary Advanced

Recurrent

Non-UPSC 78% (n=21)

56% (n=18)

UPSC 60% (n=20)

50% (n=4)

CR-3, PR-6, ST-3, PROG-3, median OS - 26 months

CR-3, PR-6, ST-3, PROG-3, median OS - 26 months

AEG35156

TRAIL

GW572016

RAD001,

BMS 387032

ZD6474ZD2171PTK787

MG98PXD101SAHA

Survivin AS

Angiogenesis Angiogenesis inhibitorsinhibitors

EGFR/HER2EGFR/HER2inhibitorsinhibitors

mTOR mTOR inhibitorsinhibitors

Pro-ApoptoticsPro-Apoptotics

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-779CCI-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 PathwayThe 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 PathwayThe 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…………….

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…………….