Background:
Endometrial cancer (EC) is the second most common gynaecological malignancy
in the UK, 6,002 new cases reported in 2000, 1,549 deaths in 2002. The
overall 5y survival rate is 65-82%, but early diagnosis improves survival
(Stages lA and lB 5y survival is 91% compared to 50% with Stages lllA-C)
(3). Estrogen exposure increases, and progestogens reduce the risk of
EC (18). Women with germline mutations in DNA mismatch repair genes causing
hereditary non-polyposis colorectal cancer (HNPCC, “Lynch Syndrome”)(usually
MSH2, MLH1 and MSH6) have an increased likelihood of developing EC, lifetime
risk 43-71% (2% in general population), peak incidence at mean 49y (40-60y)
(55-65y in general population) (34;48;10;49;47;4), 20% diagnosed before
50y (1% in general population)(4;42). Sequential premalignant changes
from hyperplasia to complex atypical hyperplasia to endometrioid adenocarcinoma
are documented in women with HNPCC, with reduced differentiation, increased
lymphangio-invasive growth and lymphocytic tumour invasion in the cancers
(44;42). There is also an increased risk of ovarian cancer (OC), lifetime
risk 8% (population risk 1/73), with younger age at diagnosis than sporadic
cases (mean 43y vs 59y) (45). Little is known of the molecular carcinogenic
pathways in HNPCC, and whether they differ from those in sporadic EC (32;2;7;21;23;36;28).
80% of postmenopausal women with EC present with postmenopausal bleeding,
but symptoms of early EC are much less obvious premenopausally. Endometrial
assessment by transvaginal ultrasound scans (TVS) in combination with
endometrial biopsy has been shown to be effective in detecting atypical
endometrial hyperplasia and early EC in at-risk women, positive predictive
value of 92%, but less effective postmenopausally (13;27;8;38;16;50; 43;51;2;6;33;21).
Such procedures are well-tolerated in the out-patient setting, as is hysteroscopy
(22). However, evidence documenting the effectiveness of endometrial surveillance
in HNPCC is conflicting, based mostly on relatively small or heterogeneous
population studies (9; 38). The Cancer Genetics Studies Consortium advocates
surveillance for women with HNPCC by annual TVS and endometrial sampling
(46;5;39).
Severe complex atypical endometrial hyperplasia has a risk of concurrent
EC of about 25% and is usually managed with hysterectomy. Screening may
result in greater numbers of women having hysterectomies before the menopause.
Some women with HNPCC may opt for prophylactic hysterectomy (with salpingo-oophrectomy)
to reduce their risk of EC (and OC), but many do not wish to take up this
option, particularly premenopausally. There is therefore a need to consider
the possibility of prophylaxis.
Locally-released levonorgestrel (20mcg per day) by the Mirena intrauterine
system (IUS) reduces endometrial hyperplasia and atypia in women on tamoxifen
(40;12; 45), avoiding the systemic effects of progestogens, and is a potential
risk-reducing option. It causes the development of a thin inactive endometrium
with decidualisation of the stroma, atrophy of the endometrial glands
and a surface papillary pattern, reducing menstrual flow by 90% It has
been documented to reduce or reverse endometrioid endometrial cancer development
(18;15;29;41;37;12;1;14). However, there have been reports of EC developing
with a Mirena IUS in situ (19). The Mirena IUS is a widely-used and well-tolerated
contraceptive and has been granted a four year licence for protection
from endometrial hyperplasia in women using oestrogen replacement therapy
(20).
Two of our collaborators have performed pilot investigations of the acceptability
of the Mirena IUS (Leeds (5) and St. George’s (15), London) in women
with HNPCC on surveillance by TVS and endometrial biopsies. They found
a high level of acceptability of surveillance and the Mirena IUS, only
one device removed because of heavy uterine bleeding. Biopsies were obtained
successfully on all but two occasions, repeat biopsies successful in those.
In two patients it was not possible to measure endometrial thickness on
TVS. The IUS did not impede surveillance procedures. After six months’
therapy, endometrial biopsies were obtained in 8/9 patients at St George’s,
and showed pseudo-decidualisation consistent with exposure to progestogen
(30;31;51).
A large-scale trial of the prophylactic effects of the Mirena IUS in HNPCC,
with evaluation of the effectiveness of surveillance, and of the psychological
impact, is clearly timely.
Principal Research Questions
Primary question:
1) Does treatment with intrauterine progestogens reduce the incidence
of atypical endometrial hyperplasia and endometrial cancer in women with
HNPCC?
Secondary questions:
(1) What is the age-related incidence of atypical endometrial hyperplasia
and EC in women with HNPCC?
(2) What is the sensitivity and specificity of surveillance with TVS and
endometrial biopsy to detect atypical endometrial hyperplasia and carcinoma
in women with HNPCC?
(3) What is the premalignant pathway to carcinoma in women with HNPCC?
(4) Does the Mirena IUS reduce the rate of therapeutic hysterectomy for
atypical endometrial hyperplasia or cancer in women with HNPCC?
(5) Are there psychological benefits or adverse effects from the use of
the Mirena IUS?
(6) What is the satisfaction and compliance with screening?
(7) What is the extent of adverse effects of surveillance and use of the
Mirena IUS?
(8) In the longer term, we need to determine the molecular changes associated
with premalignant changes in the endometrium in women with HNPCC, and
possibly the utility of tests on cervical mucus samples to diagnose endometrial
neoplasia.
Study Group:
400 women with HNPCC aged 35-65y with an intact uterus.
Method:
Baseline gynaecological evaluation to exclude endometrial
pathology. Women with normal endometrium, or simple endometrial hyperplasia
only, will be offered entry into a randomised trial of the Mirena IUS
for 4y with surveillance, or no treatment, with surveillance, comprising
annual menstrual history, pelvic ultrasound scans and usually endometrial
biopsies by pipelle, (or hysteroscopy) to document atypical endometrial
hyperplasia and carcinoma; pathology confirmed.
Annual questionnaires addressing personal health and cancer, hormone/contraceptive
exposure, pregnancies, and satisfaction with interventions, will be administered,
and the mood profile questionnaire (POMS) will be completed at trial entry,
and at two and five years.
Design:
Interventional non-blinded randomised control trial.
Longitudinal observational study
Inclusion criteria:
Women aged 35-65y with an intact uterus who are not pregnant or actively
seeking to become so, who do not wish to have a prophylactic hysterectomy
within the next five years, and are either 1) proven to carry a pathogenic
germline mutation in a DNA mismatch repair gene causing HNPCC (usually
MSH2, MLH1, MSH6), or 2) women from a family fulfilling the Amsterdam
or the modified Amsterdam criteria for HNPCC (Three relatives with an
HNPCC-related cancer (colorectal, small bowel, ovarian, urothelial or
hepatobiliary), one the first-degree relative of the other two, two generations
affected, and one diagnosis before 50y. age) who themselves have had colorectal
cancer, a large, villous or severely dysplastic colorectal adenoma before
the age of 40y, or small bowel, hepatobiliary, or urothelial cancer.
Exclusion criteria:
Women without an intact uterus (or who are planning a prophylactic hysterectomy),
or on current therapy for cancer, or who are outside the age-range for
the study, are pregnant or trying to become pregnant.
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