Download Endometrial Cancer - Medical Oncology at University of Toronto

Systemic Therapy for Uterine
Cancer
Helen J. Mackay
Princess Margaret Hospital,
University of Toronto
Uterine malignancy
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Endometroid
UPSC
Clear cell
Mucinous
Squamous
Mixed histology
Carcinosarcoma (MMT)
Endometrial stromal tumors
Leiomyosarcoma
Cancer Incidence Cancer Deaths*
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32% Breast
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12% Lung & bronchus
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11% Colon & rectum
6% Uterine corpus
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Women
668,470
4% Ovary
4% Non-Hodgkin
lymphoma
Women
272,810
25%
Lung & bronchus
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15% Breast
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10% Colon & rectum
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6% Ovary
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6% Pancreas
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4% Leukemia
3% Non-Hodgkin
lymphoma
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4%
Melanoma
of skin
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3%
Thyroid
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3% Uterine corpus
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2%
Pancreas
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2% Multiple myeloma
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2%
Urinary bladder
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2% Brain/ONS
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20% All Other Sites
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24%
All other sites
FIGO Staging 1988 to 2009
Stage IA
The
is limited
to the endometrium
No ortumor
less than
half myometrial
invasion
Stage IB
More
than half
myometrial
The tumor
invades
less invasion
than one-half of the
myometrial thickness
Tumor invades the cervical stroma
The
tumor
invades more than one-half of the
but not
the uterus
myometrial thickness.
The tumor invades the uterine serosa or adnexa
Cervical
extension
not positive
washings is limited to the endocervical
glands
Vaginal or parametrial metastases
Tumor invades the cervical stroma
The tumor has spread to lymph
nodes
The tumor invades the uterine serosa or adnexa
Stage II
Stage IC
Stage IIIA
Stage IIA
Stage
Stage
Stage
Stage
IIIB
IIB
IIIC
IIIA
or
positive
washings
IIIC1
Positive pelvic
lymph nodes
Stage IIIB
IIIC2 Positive para-aortic lymph nodes
Vaginal
metastases
with or without
pelvic nodes
Stage
Stage IIIC
IV
The
tumor
hasbladder
spread
to lymph
Tumor
invades
and/or
bowel nodes
mucosa, and/or
distant metastasis
Five year survival by stages
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Stage I
Stage II
Stage III
85-90%
80%
<25%
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Stage IV
<10%
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Systemic therapy
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When and what?
Adjuvant
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Initial therapy of Stage III disease – Randall et al.
?Papillary Serous
Recurrent or Metastatic disease
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Endometrial cancer
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Hormonal Therapy
Chemotherapy
Novel Agents
Endometrial Cancer
“Subtypes”
Type I (80%)
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related to
unopposed estrogen
arises in hyperplastic
endometrium
usual local disease
high survival rate
e.g. endometrioid
Type II (10%)
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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
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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
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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
Summary for Low/Int Endometrial
Cancer
Nodal staging diagnostic not
therapeutic
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Low-risk (IA/B, G1/2)
Intermediate risk
(IA/B G3, IC G1/2)
High Int Risk
(Age, LVI)
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
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High Risk
(IC G3, IIA G3, IIB)
Pelvic IMRT +/- brachy
WART Vs Combo Doxo/cisplatin Chemo
in Advanced Endometrial Ca: GOG Phase
III Trial
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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
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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
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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
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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
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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 G3
Chemo 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
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Concurrent and Adjuvant
Chemotherapy
Phase II trial RTOG (46 pts):
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stage I-II high risk or stage III (66%)
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Concurrent: cisplatin 50 mg/m2 days 1, 28
Adjuvant: 4x cisplatin 50 mg/m2 and paclitaxel 175
mg/m2
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4-yr locoregional relapse 4%, distant 19%
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4-yr DFS 81%, OS 85% (stage III: 77 and 72%)
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No recurrences in stage IC, IIA, IIB
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promising data, phase III needed
Greven et al, Gynecol Oncol 2006
Uterine Papillary serous
carcinoma (UPSC)
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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
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Stage Ia n= 12, no residual disease
Stage IA, residual disease,
no chemo, 6/14
chemo
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, 0/7
Stage IB
no chemo, 10/13
chemo
,O
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
Pathology
Review
High-risk or
advanced stage
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/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
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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
Risk Group
(Path Review)
Low Risk
IA/B G1/2
Low
Intermediate
Risk IB G3
IC G1/2
Age <65
High
Intermediate
Risk IB G3
IC G1/2 Age
>65
High Risk
IC G3 IIB
Node staging
(chemo)
LVI
Grade 1
Grade 2
No
Watch
Watch
No
Yes
Watch
Watch
Watch
Watch or
Vag brachy
No
Yes
Watch
Watch or
brachy
Watch
Vag brachy
or watch
No
Serous/clear
cell
Node positive
Yes or No
Pelvic small
Pelvic small
field EBRT
field EBRT
or brachy
or brachy
Whole Pelvis Whole Pelvis
IMRT
IMRT
Whole Pelvis IMRT
Chemo
Yes
Grade 3
Vag brachy
Vag brachy
or Pelvic
small field
RT
Vag brachy
Whole Pelvis
IMRT
Pelvic small
field EBRT
Whole Pelvis
IMRT
Hormonal or Chemotherapy
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Treatment intent is palliative
Consider
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extent of disease
Rate of growth
Patient symptoms
Performance status
Implications on QL
Sequential therapy
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Hormonal therapy followed by chemotherapy
Hormonal Therapy
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Progestogens
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Medroxy progesterone Acetate or Provera
Tamoxifen
Alternating Tamoxifen and
progestogens
Aromatase inhibitors
Study
Pha
se
N
Thigpen et al
1999 3
III
299
Prior
hormon
al
therapy
No
Treatment
Overall
response
rate
Oral
medroxyprogesterone
acetate 200mg/day
versus 1g/day
Low dose
25%
(25CR,11PR);
high dose 16%
(14CR,10PR)
24%
(6CR,7PR)
Lentz 35
II
63
No
Oral
medroxyprogesterone
acetate 800mg/day
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
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Phase II Clinical trial
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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
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Active Agents
Cisplatin
Carboplatin
Doxorubicin
Cyclophosphamide
Paclitaxel
Liposomal
Doxorubicin
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Active
Combinations
CAP
CA
Taxol/Carboplatin
Taxol/Adria/Plat
Carbo/Caelyx
Combination Chemotherapy
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Combination chemotherapy – more active
than single agent therapy.
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Cisplatin/Doxorubicin RR 35-40%
AT+GCSF vs AC RR 40%vs 43%
RCT of CAP vs CA
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No advantage with triple chemotherapy regimen
Increased toxicity
CA regimen of choice.
TAP vs AP. GOG 177
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TAP
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Taxol 160mg/m2
Adria 45mg/m2
Cisplatin 50mg/m2
RR 57%
12 months OS 58%
Toxicity, TAP:
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AP
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Toxicity AP:
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Neutropenia Gr 4 36%
Neuro grade 3 or 4
12%
Neuro grade 2/3 40%
Congestive Heart Failure
3 pts
Adria 60mg/m2
Cisplatin 50mg/m2
RR vs 34%
12 months OS 50%
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Fleming et al 2004
Neutropenia Gr 4
50%
Neuro grade 3 or 4 1%
Congestive Heart Failure
0 pts
TAP + G-CSF vs AP
Survival: Recurrent
Endometrial Cancer
HR for recurrence 0.57
Fleming et al. J Clin Oncol 2004
Carbo/Taxol: A retrospective
study
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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
Carbo/Taxol: A retrospective
study
Taxol/carbo
RR
PFS
OS
Neurotoxicity
(G2/3)
Tx stopped due to
toxicity
43%
5.3 mo
13.2mo
GOG #177
AP
34%
5.3 mo
12.3mo
TAP
57%
8.3mo
15.3mo
16%
5%
39%
8%
9%
24%
UPSC: Chemotherapy Hoskins et al.,
CARBO/TAXOL
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
Angiogenesis
inhibitors
EGFR/HER2
inhibitors
BMS 387032
GW572016
Pro-Apoptotics
Survivin AS
AEG35156
ZD6474
ZD2171
PTK787
TRAIL
mTOR
inhibitors
RAD001,
MG98
PXD101
SAHA
Which Targets in Gynecological
Cancers?--- Endometrium
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Apoptosis related:
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Receptors/signaling
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XIAP
BCL-2
TRAIL
Survivin
EGFR, HER2 etc
Ras, raf, MAPK
Jak/Stat
Akt
pTEN
PI3k
Other cell surface
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CA125
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Growth Factors
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Transcription Factors
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Myc
Cell Cycle
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TGF alpha
RB
P53
Cyclins and cdks
p16
Invasion/metastasis
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MMP
auer
VEGF
E.Eisenhauer
CCI-779
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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, CCI779 demonstrated anti-tumor activity against
a variety of tumor types
The mTOR Pathway
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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
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Optimal regimen?
Which patients?
Chemo vs radiotherapy+chemotherapy
Metastatic
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Targeted therapy MTOR, FT I, EGFR
Targeted therapy plus cytotoxic chemotherapy
Trials, Trials and more Trials…………….
The future
Adjuvant
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Optimal regimen?
Which patients?
Chemo vs radiotherapy+chemotherapy
Metastatic
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Targeted therapy MTOR, FT I, EGFR
Targeted therapy plus cytotoxic chemotherapy
Trials, Trials and more Trials…………….