Transcript 1499cb826a7a6ac86083fdc2bed48a8d

Endometrial and
other cancers
David W. Sturdee
Endometrial cancer
Hysterectomy specimen showing
cancer invading myometrium
following unopposed estrogen therapy for 15 years
Endometrial cancer world-wide
World age-standardized incidence and mortality rates
(selected)
North America
Western Europe
Northern Europe
Southern Europe
Eastern Europe
Australia/New Zealand
South America
Western Africa
Central America
South-Eastern Asia
Southern Africa
Eastern Africa
Eastern Asia
Middle Africa
Northern Africa
South-Central Asia
Western Africa
Incidence
Mortality
0
4
8
12
16
20
24
Rate per 100,000 females
Ferley J, et al. IARC Cancer Base No. 5, version 2.0, 2004
Endometrial histology in peri- and
postmenopausal women without symptoms
Histology
Atrophic
Proliferative
Secretory
Hyperplasia
All
Cystic
Simple
Adenomatous
Cellular atypia
Cancer
Insufficient tissue
n
%
373
133
54
46.9
16.7
6.8
41
31
9
1
4
1
195
5.2
3.9
1.1
0.1
0.5
0.1
24.5
Archer D, et al. Am J Obstet Gynecol 1991;165:317–22
Unopposed estrogen
and endometrial cancer
Year
Smith
Ziel
Mack
Antunes
Jick
Hammond
Weiderpass
1975
1975
1976
1979
1979
1979
1999
Risk ratio
4.5
5.6–7.6
8
6–15
10
3.8
6.2
Unopposed estrogen
and endometrial hyperplasia
PEPI trial
Placebo
Other studies:
OR = 5.4 (1.4–20.9)
16.0 (9.3–27.5)
62% at 36 months
2% at 36 months
for 6 months
for 36 months
Lethaby A, et al. In The Cochrane Library, Issue 4, 2004 (ISSN 1464-780X)
HRT in postmenopausal women:
endometrial hyperplasia and irregular bleeding
(Cochrane Review)
30 randomized controlled trials were suitable
for review
• Unopposed estrogen significantly increases
•
•
•
hyperplasia
Oral progestogen reduces rate of hyperplasia
Suggestion that continuous therapy over long
duration is more protective from hyperplasia
Hyperplasia is more likely when progestogen
is given every 3 months
Lethaby A, et al. In The Cochrane Library, Issue 4, 2004 (ISSN 1464-780X)
HT: the addition of progestogen
• For at least 10 days in each cycle to
•
prevent endometrial hyperplasia and
carcinoma
In sequential regimens to imitate the
ovarian cycle and to promote a
regular and predictable bleed
Complex endometrial hyperplasia
Atypical endometrial hyperplasia
Malignant potential
of endometrial hyperplasia
• Simple
• Complex
• Atypical
1–3% over 15 years
3–4% over 13 years
25% over 11 years
Norris HJ, et al. Clin Obstet Gynaecol 1986;13:725–38
Deligdisch L, Cohen CJ. Cancer 1985;56:1452–5
Endometrial cancer and duration of
sequential estrogen/progestogen HRT
Duration of HRT
Cases (%) Controls (%)
Never used HRT
387 (87.3) 685 (89.0)
Current users:
Progestogen 10–21 days per month
6–59 months
12 (3.1)
48 (6.2)
> 60 months
12 (3.1)
15 (1.9)
Odds ratio
1.0
0.7 (0.4–1.4)
2.7 (1.2–6.0)
Beresford SA, et al. Lancet 1997;349:458–61
HRT and risk of
endometrial cancer
OR (95% CI)
Duration
< 5 years
> 5 years
Per year
Sequential E + P
1.5 (1.0–2.2)
2.9 (1.8–4.6)
1.1 (1.06–1.15)
Weiderpass E, et al. J Natl Cancer Inst 1999;911:1131–7
Period-free therapy
Continuous combined therapy:
estrogen + low-dose progestogen
every day (CCEPT) or tibolone
•
•
•
•
Same benefits as sequential
No cycle
Period-free
Atrophic endometrium
PEPI study:
endometrial hyperplasia at 3 years
Histology
CEE + MPA
or MP (cyclic)
Normal
Simple
Complex
Atypical
Cancer
Total
226
9
2
1
0
238
CEE + MPA
(continuous)
119
1
0
0
0
120
CEE, conjugated equine estrogen 0.625 mg/day; MPA, medroxyprogesterone acetate 2.5 mg;
MP, micronized progesterone 200 mg; Cyclic, MPA or MP × 12 days
The Writing Group for the PEPI Trial. JAMA 1996;275:370–5
Endometrial histology during
sequential and after changing to
continuous combined therapy
(estradiol 2 mg + norethisterone acetate 1 mg daily for 9 months)
CSEPT (%)
(n = 1192)
Unassessable
Inactive/atrophic
Proliferative
Secretory
Complex hyperplasia
18.0
7.6
15.1
47.4
5.5
CCEPT (%)
(n = 823)*
37.3
30.0
2.3
26.2
0.0
* Including 42 with previous complex hyperplasia
Sturdee DW, et al. BJOG 2000;107:1392–400
HT and risk of endometrial cancer
OR (95% CI)
Duration
Sequential
E+P
< 5 years
> 5 years
Per year
1.5 (1.0–2.2)
2.9 (1.8–4.6)
1.1 (1.06–1.15)
Continuous
combined
0.8 (0.5–1.3)
0.2 (0.1–0.8)
0.86 (0.77–0.97)
Weiderpass E, et al. J Natl Cancer Inst 1999;911:1131–7
WHI study: gynecological cancers
(annualized %)
Outcome
CEE + MPA
n
8506
Duration (months) 67.8
Ovary
20 (0.04)
Endometrium
27 (0.06)
Endometrioid (%) 14 (51.9)
Cervix
8 (0.02)
Placebo
Hazard 95% CI
ratio
8102
66.8
12 (0.03) 1.58 0.77–3.24
31 (0.07) 0.81 0.48–1.36
17 (54.8)
5 (0.01) 1.44 0.47–4.42
Anderson GL, et al. JAMA 2003;290:1739–48
Progestogen in HT
•
•
•
•
Only needed to protect the endometrium
Other effects, e.g. on breast, lipids
Premenstrual syndrome-type side-effects
Logical to give direct to the endometrium
by intrauterine system
MLS 10 µg LNG/day Mirena 20 µg LNG/day
Intrauterine application of progestins
in hormone replacement therapy
• Since 1991, 16 studies of intrauterine
•
•
•
•
levonorgestrel in combination with different
types and routes of estrogen (n = 809)
Duration 6 months – 5 years
IUS + oral CEE and E2, patch, gel and implant
New 10 µg system: 3 studies for 1–2 years
All 0% hyperplasia
“Confirms endometrial safety for this application”
Riphagen FE. Climacteric 2000;3:199–21
Endometrial and breast cancer
in the Million Women Study
Standardized incidence rates/1000 women/5 years
CCEPT CSEPT Tibolone E only Never use
Breast
Endometrial
Total
30
2
32
28
3
31
19
6
25
18
5
23
13
3
16
CCEPT, combined continuous estrogen and progestogen therapy;
CSEPT, combined sequential estrogen and progestogen therapy
Million Women Study Collaborators. Lancet 2005;365:1543–51
THEBES
Tibolone Histology of the Endometrium
and Breast Endpoint Study
• Multicenter world-wide
• Tibolone 1.25 and 2.5 mg vs. CEE/MPA
•
•
•
•
0.625/2.5 mg (Prempro)
24 months
3240/3000 subjects (1:1:2 randomization)
Endometrial histology – hyperplasia and cancer
Endometrial thickness, bleeding, breast pain,
health-related quality of life
THEBES
Livial
n
Women-years
Endometrial hyperplasia
Endometrial cancer
Polyps at 1 year
Polyps at 2 years
1598
2402
0
0
33 (2.6%)
24 (2.5%)
Prempro 2.5
1626
2415
2 (0.1%)
0*
40 (3.1%)
25 (2.5%)
* 1 endometrial stromal sarcoma
Archer DF, et al. J Clin Endocrinol Metab 2007;92:911–18
Estimated cumulative additional cancers
over 10 years HT per 1000 women
Million Women Study
Breast cancer
Endometrial cancer
Unopposed
estrogen
Combined
E+P
5
10
19
0
Million Woman Study collaborators. Lancet 2003;362:419–27
Breast cancer
and hormone therapy
Million Women Study
“…little advantage to using
estrogen/progestogen in
preference to estrogen-only HRT
for women who still have a uterus”
Million Women Study collaborators. Lancet 2003;362:419–27
Is combined estrogen/progestogen
therapy worth the risk?
• Combined estrogen/progestogen therapy
•
•
•
•
•
associated with four-fold greater risk of breast
cancer than unopposed estrogen therapy
Risk of endometrial cancer from unopposed
estrogen therapy much less
After cessation of unopposed estrogen, risk of
endometrial cancer persists for many years
Other implications of unopposed estrogen
Against perceived wisdom over last 25 years
Hysterectomy rate
Raloxifene: endometrial health
• Uterine bleeding
•
•
– no difference from placebo
Endometrial thickness by transvaginal
ultrasound scan
– no difference from placebo
Endometrial biopsy
– no stimulation of atrophic endometrium
Cummings S, et al. JAMA 1999;281:2189–97
Impact of recent reports
and regulatory authorities
• Lowest dose for shortest time
• Lower dose regimens being produced
• Is there a threshold dose/circulating level
•
of estrogen at which symptoms can be
relieved and bone spared without causing
endometrial stimulation?
Is there a similar threshold for progestogen
at which the endometrium will still be
protected without affecting breast tissue?
Endometrial hyperplasia rates after
1 and 2 years of low-dose E + P
Women’s HOPE Study
Hyperplasia rate (%)
30
Year 1
25
Year 2
20
15
10
5
0.00
0
0.625 mg
0.45 mg
0.3 mg
0.00
0.00
0.00
0.00
0.00
0.625/
2.5 mg
0.45/
2.5 mg
0.45/
1.5 mg
0.3/
1.5 mg
Placebo
CEE
CEE/MPA
Women’s HOPE, Women’s Health, Osteoporosis, Progestin, Estrogen;
CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate
Pickar JH, et al. Fertil Steril 2003;80:1234–40
Unopposed ultra-low-dose
transdermal estradiol
• 417 postmenopausal women (60–80 years)
•
•
•
mean 67 ± 5 years
Randomly assigned to placebo or
transdermal 14 µg/day for 2 years
Baseline serum
E2 = 4.8 pg/ml
On treatment
E2 = 8.6 pg/ml
Johnson SR, et al. Obstet Gynecol 2005;105:779–87
Unopposed ultra-low-dose
transdermal estradiol
Endometrial effects:
• Proliferation 8.5% vs 1.1% p = 0.6
• Bleeding
12.4% vs 8.6% p = 0.3
• Atypical hyperplasia × 1
• Adenosarcoma × 1
Conclusions:
• “This therapy apparently causes little or
no endometrial stimulation”
Johnson SR, et al. Obstet Gynecol 2005;105:779–87
HT and endometrial safety
• Endometrial cancer still a risk for
•
•
•
postmenopausal women taking HT
Duration of progestogen important
Change to CCEPT for long-term
endometrial health
? Ultra-low-dose combination or
unopposed estrogen
Hormone therapy
and ovarian cancer
David W. Sturdee
Ovarian cancer: background
• Ovarian cancer is the second leading
•
•
•
cause of death from gynecologic cancers1
Ovarian cancer is usually diagnosed in its
advanced stage
An estimated one woman in 70 will
develop ovarian cancer in her lifetime, and
one in 100 will die from the disease2
Median age of diagnosis is 63 years2
1American
Cancer Society. Cancer Facts and Figures 2003.
Available at: www.cancer.org/docroot/STT/stt_0.asp.
2Schneider HPG. Maturitas 2002;43:S35–52
Centers for Disease Control
meta-analysis: ovarian cancer and HRT
European/Australian Case-Control Studies
Hospital/Clinic Controls
Booth et al, 1998
La Vecchia et al, 1982
Parazzini et al, 1994
Polchronopolou et al, 1993
Tzonou et al, 1984
Community Controls
Purdie et al, 1995
US/Canadian Case-Control Studies
Hospital/Clinic Controls
Annegers et al, 1979
Hartge et al, 1988
Hempling et al, 1997
Hildreth et al, 1981
Kaufman et al, 1989
Community Controls
Cramer et al, 1983
Lee et al, 1986
Risch, 1996
Weiss et al, 1982
0.4
0.6
1.0
1.4 1.8 2.22.6 3.0
4.0
5.0
Relative risk (95% CI)
Schneider HPG. Maturitas 2002;43:S35–S52. ©2002 Elsevier Ireland, Ltd. Used with permission
Ovarian cancer risk with HT
Nationwide case-control trial: Sweden
655 cases and 3899 controls, 1993–1995
Odds ratio compared to never users
Use
E alone
CSEPT
CCEPT
Ever
1.43
(1.02–2.0)
2.4
(1.03–4.46)
1.54
(1.15–2.05)
2.1
(NS)
1.02
(0.73–1.43)
1.8
(NS)
 10 years
Riman T, et al. J Natl Cancer Inst 2002;94:497–504
Effect of HT on ovarian cancer risk
National Cancer Institute, NIH, USA
Follow-up of 44,241 postmenopausal women, mean age
56.6 years; 329 developed ovarian cancer
Non-user
E alone,  4 years
E alone, 4–9 years
E alone, 10–19 years
E alone,  20 years
E + P,  2 years
E + P,  2 years
0.1
1
10
Relative hazard (95% CI)
Lacey JV Jr, et al. JAMA 2002;288:334–41
WHI study: gynecological cancers
(annualized %)
Outcome
CEE +
MPA
n
Duration (months)
Ovary
Endometrium
Cervix
8506
67.8
20 (0.04)
27 (0.06)
8 (0.02)
Placebo
8102
66.8
12 (0.03)
31 (0.07)
5 (0.01)
Hazard 95%
ratio
nCI
1.58 0.77–3.24
0.81 0.48–1.36
1.44 0.47–4.42
Anderson GL, et al. JAMA 2003;290:1739–48
Ovarian cancer
and hormone replacement therapy
in the Million Women Study
•
•
•
•
Current users incidence
RR = 1.20 (1.09–1.32)
Current users mortality
RR = 1.23 (1.09–1.38)
Increased with duration of use
Past users at no increased risk
One extra case of ovarian cancer
for every 2500 users
One extra death from ovarian cancer
in every 3300 users
Million Women Study collaborators. Lancet 2007;369:1703–10
Hormone therapy
and colorectal cancer
David W. Sturdee
Colorectal cancer
• Third most common cancer in US women,
•
•
•
and third most common cause of cancer
death in women
A woman’s lifetime risk of developing
colorectal cancer is 5.5%, with 91% of
cases occurring after age 50 years
Colon 72%, rectal 28%
5-year survival for women with colorectal
cancer is 63%
American Cancer Society. Cancer Facts and Figures 2005
Available at: www.cancer.org/docroot/STT/stt_0.asp
HT use and
risk of colorectal cancer
Jacobs et al, 1994*†
Newcomb and Storer, 1995*†
Folsom et al, 1995*†
Troisi et al, 1997‡
Kampman et al, 1997†
Grodstein et al, 1998†
Paganini-Hill, 1999‡
Hully et al, 2002†
Chlebowski et al, 2004†
Meta-analysis: Nanda et al, 1999*†
Meta-analysis: Grodstein et al, 1999‡§
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Relative risk (95% CI)
*Statistic refers to colon cancer risk only
†Multivariate risk analysis
‡Risk assessment adjusted for age only
§Meta-analysis includes 2 studies of colorectal cancer mortality
1.4
WHI results: effect of HT
on risk of colorectal cancer
Kaplan-Meier estimate
Cumulative hazard
for colorectal cancer
0.015
HR = 0.56
95% nCI = 0.38–0.81
95% aCI = 0.33–0.94
Placebo
0.010
0.005
E+P
0.000
0
1
2
3
4
5
6
7
Time (years)
Chlebowski RT, et al. N Engl J Med 2004;350:991–1004
Colorectal cancer:
absolute risk after 5 years of E + P
• A 50-year-old woman has approximately
•
a 0.5% chance of developing colorectal cancer
by age 60 years1
– This translates to an absolute risk of 5.0 cases
per 1000 women
WHI reported HR for colorectal cancer of 0.56
after 5 years of E + P use = 44% decrease in
risk2
– This translates to an absolute risk of 2.8 cases
per 1000 users
1Feuer
EJ, Wun LM. Available at: http://srab.cancer.gov/devcan/canques.html
2Chlebowski RT, et al. N Engl J Med 2004;350:991–1004
Mortality outcomes for colorectal
cancer patients: ever-users of HT
Calle et al, 1995
Sturgeon et al, 1995
Persson et al, 1996
Meta-analysis: Nanda et al, 1999
0.5
1.0
2.0
Relative risk (95% CI)
10
Gastric and esophageal cancers
• Unexplained male predominance
• Nested case–control study from UK GP
•
•
•
•
Research Database
313 women with gastric cancers
299 women with esophageal cancers
3191 randomly selected matched controls
1,619,563 person-years follow-up
Lindblad M, et al. Br J Cancer 2006;94:136–41
Gastric and esophageal cancers
HRT users
Gastric cancers (all)
Gastric non-cardia
Gastric cardia
Esophageal
Odds ratio
95% CI
0.48
0.34
0.68
1.17
0.29–0.79
0.14–0.78
0.23–2.01
0.41–3.32
Lindblad M, et al. Br J Cancer 2006;94:136–41
Effect of HRT
on risk of endometrial
and cancers other than breast
Conclusions:
• Estrogen alone and combined therapy
with progestogen can affect the risk of
endometrial and colorectal cancers in
postmenopausal women but the data
on ovarian and gastric cancer risks
are less certain
IMS, 2007
Acknowledgement
Some of these slides have been adapted
from those provided by the
Council on Hormone Education