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…………….