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Gynaecological Oncology
Data deriving from prospective studies are limited. In a well- ‘spacing out’ regimen (with the addition of a progestin for 14 days
designed, small, prospective study, Vassilopoulou-Sellin et al.
31
every three months), it was proposed that the shorter duration of
followed 56 women treated with conjugated oestrogen alone and progestin exposure was correlated with the lower breast cancer
243 untreated women for a minimum of five years. Among the ORT recurrence risk observed in the Stockholm trial compared with the
users, 30 women took ORT for more than five years, 20 women took HABITS trial, in which a traditional HRT regimen was used.
ORT for two to five years and six women took ORT for <2 years. As far
as receptor and lymph-node status are concerned, 70% in the In last few years, after a number of promising pilot studies had been
randomised group and 66% in the non-randomised group were published,
35,36
the feasibility of using tibolone – a synthetic steroid
oestrogen-receptor positive (OR
+
), while 83% of both groups had up hormone that combines oestrogenic, progestinic and androgenic
to three lymph nodes involved. The study participants were women activities – as an effective alternative to oestrogen-based hormone
who had survived breast cancer stage I or II and had remained therapy for menopausal symptoms in breast cancer patients has
disease-free for at least two years. There was no association became a much-discussed matter.
between ORT use and time to recurrence of breast cancer whether
the analysis was performed for the randomised group only or for the Definitive safety data were expected to be provided by Livial
entire group combined (overall 3.6% of ORT users and 13.5% non- Intervention following Breast cancer: Efficacy, Recurrence And
users developed new or recurrent disease, respectively). Tolerability End-points (LIBERATE), a wide multicentre, randomised,
double-blind, placebo-controlled trial to investigate the safety and
In 2003, the steering committee of the Hormonal Replacement efficacy of tibolone in breast cancer patients suffering from
Therapy After Breast Cancer Diagnosis – Is It Safe? (HABITS) study
32
climacteric complaints, in which 3,148 breast cancer survivors with
decided to halt the trial prematurely and recommended that all vasomotor symptoms were randomised at 245 centres in 31
patients on HRT stop treatment. The HABITS trial started to recruit countries. The primary outcome variable was breast cancer
women in 1997, examining whether two-year HRT treatment for recurrence, while secondary end-points included vasomotor
menopausal symptoms was safe in women with previously treated symptoms, bone mineral density, health-related quality of life and
breast cancer (in situ up to stage II breast cancer). The choice of the overall survival. The study was carried out from July 2002 and
specific type of HRT was directed by local practice, so oestrogen– prematurely stopped in December 2007, six months before the
progestin combinations were used, except tibolone. Due to slow planned trial end: unless tibolone was significantly more effective
recruitment, in 2002 HABITS and a similar parallel trial in Stockholm than placebo in reducing hot flushes and increasing bone mineral
were joined.
33
density, preliminary data showed a trend for an increase in breast
cancer recurrence in the tibolone group (HR 1.40, 95% CI 1.14–1.70;
The joint analysis of the two studies showed that the risk of breast p=0.001) after a follow-up of 3.1 years. The highest risk of breast
cancer recurrence was significantly associated with menopausal cancer recurrence was demonstrated in women with OR
+
tumour
hormone therapy (HR 1.8, 95% CI 1.03–3.1). However, there was a status taking tibolone (data presented at the 12th World Congress on
statistically significant (p=0.02) heterogeneity between the two the Menopause, 19–23 May 2008, Madrid). According to the results
studies; in HABITS the HR was significantly increased (HR 3.3, 95% from the LIBERATE trial, tibolone remains contraindicated for breast
CI 1.5–7.4), whereas in the Stockholm trial it was 0.82 (95% CI cancer survivors.
0.35–1.9). Several factors may have caused these opposite results:
the type of HRT, fewer patients treated with tamoxifene in the Cervical Cancer
HABITS trial compared with the Stockholm study (21 and 52%, The extent to which non-viral factors influence cervical carcinogenesis
respectively) and the higher number of women with positive nodes remains unclear. The presence of oestrogen and progesterone
and OR
+
tumours in the HABITS trial (26% versus 16% in the receptors in the cervix suggests that the cervical epithelium may
Stockholm trial). respond to exogenous hormones, but an association between the use
of HRT and cervical carcinoma has not been proved.
37
An update of the results was published in 2008 by Holmberg et al.
34
including data on 442 women with a follow-up period of four years. Ploch reported a study of 120 women treated for stage I–II cervical
Thirty-nine of 221 women in the HRT arm and 17 of 221 women in cancer in which HRT showed no change either in survival or disease-
the control arm experienced a new breast cancer event (HR 2.4, free survival at five years.
38
Generally, HRT is not refused to women
95% CI 1.3–4.2). Cumulative incidence at five years was 22% in the complaining of menopausal symptoms after squamous cervical cancer.
HRT arm and 8% in the control arm. By the end of the follow-up, six
women in the HRT arm had died of breast cancer and six were alive Adenocarcinomas of the uterine cervix account for approximately
with distant metastasis. In the control arm, five women had died of 15% of all cervical carcinomas. According to some, this histotype is
breast cancer and four had metastatic breast cancer (p=0.51). dependent on oestrogen stimulation in the same way as EC. In a case-
After longer follow-up, there was a clinically and statistically control study, the group of women on HRT showed an overall RR of
significant increased risk of a new breast cancer event in survivors 2.1 (95% CI 0.95–4.6) for adenocarcinoma versus 0.85 (95% CI
who took HRT. 0.34–2.1) for squamous cell carcinoma.
39
The risk was higher in cases
of oestrogens alone: RR for adenocarcinoma 2.7 (95% CI 1.1–6.8)
Recent studies have shown that oestrogen combined with progestin versus 0.86 (95% CI 0.26–2.8) for squamous cell carcinoma. With
may carry a higher risk of the development of breast cancer combined treatment the RR for adenocarcinoma was 1.1 (95% CI
compared with ORT. A goal of the Stockholm trial was to minimise the 0.26–5.0). According to these data, oestrogen use after treatment for
use of progestinscompared with the HABITS trial. As 73% of women in adenocarcinoma of the cervix should follow the same indications as
the Stockholm trial were offered either oestradiol alone or the for endometrial adenocarcinoma.
70 EUROPEAN OBSTETRICS & GYNAECOLOGY
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