Hormonal therapies and gynaecological cancers

doi:10.1016/j.bpobgyn.2007.08.003

Best Practice & Research Clinical Obstetrics & Gynaecology

Volume 22, Issue 2, April 2008, Pages 407-421

https://doi.org/10.1016/j.bpobgyn.2007.08.003 Get rights and content

Hormonal therapy has an established place in the management of women with gynaecological malignancies, including first-line therapy for recurrent receptor-positive endometrial cancer and low-grade stromal sarcoma. There is no place for adjuvant hormonal treatment of these cancers after primary surgery. Primary treatment with either oral or intra-uterine progestagens to preserve fertility in younger women with endometrial carcinoma is effective in about 70% of cases. Response rates to tamoxifen in advanced/recurrent ovarian cancers approximates 10%. To the authors' knowledge, no studies that reasonably compare different progestagens, different routes of therapy, different doses and different hormonal preparations have been published.

Section snippets

Background

Endometrial cancer is the most common gynaecological cancer in the Western world, affecting more than 40,000 American women per year, of whom nearly 7000 will succumb to the disease. The majority of women present with Stage I disease following an episode of abnormal bleeding, and the 5-year survival rate for this group is 75%.¹ Women presenting with more advanced disease or recurrence have a much poorer prognosis, with a 5-year survival rate of 25%.

The strongest risk factor for endometrial

Role of progestagens

Progestagens were shown to have an anti-oestrogenic effect on the endometrium¹¹ and to produce marked changes in the glands and stroma as early as the 1950s¹², which led to the concept that progestagens may be useful in the treatment of endometrial cancer.

Progesterone acts as an anti-oestrogen by reducing oestrogen receptor content and the ability of the endometrium to make new receptors, and by increasing oestradiol dehydrogenase.¹³ This causes both a suppression of endometrial gland growth

Background

Uterine sarcomas account for approximately 3% of all uterine malignancies.11, 34 They arise from mesodermal tissue. Sarcomas display a more aggressive pattern of disease compared with endometrial adenocarcinoma, and include carcinosarcoma, leiomyosarcoma, endometrial stromal sarcoma and adenosarcoma. Endometrial stromal sarcomas (ESSs) are divided into low- and high-grade categories according to mitotic rate. Low-grade ESSs are considered to be more indolent tumours but recurrence rates are as

Background

Ovarian cancer affects more than 20,000 women in the USA each year. It has the highest mortality of all gynaecological cancers*37, 38 due to the fact that the majority of women present with advanced disease. Overall survival is of the order of 37–44%³⁹, with 5-year survival rates of 80% for Stage I disease and 10–15% for Stage IV disease.³⁸

The exact mechanism of development of ovarian cancer is uncertain, but repetitious ovulatory activity may be a factor in the malignant transformation of the

Summary

A variety of gynaecological cancers respond to hormonal manipulation. The presence of steroid receptors gives a good guide to likely response in endometrial carcinoma and stromal sarcoma, but no such correlation exists with ovarian epithelial malignancies. A lack of trials comparing different agents and combinations, different methods and sequencing of delivery, and different doses has led to a restricted availability of hormonal options in this setting. Future research should be directed at

References (55)

L. Elit et al.
Current status and future innovations of hormonal agents, chemotherapy and investigational agents in endometrial cancer
Curr Opin Obstet Gynecol
(2002)
G. Ferguson et al.
Current research on the use of hormonal therapy in the treatment of advanced or recurrent endometrial cancer
Women's Oncol Rev
(2004)
C. Lai et al.
The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer
Curr Opin Obstet Gynecol
(2006)
W.T. Creasman
Hormone replacement therapy after cancers
Curr Opin Oncol
(2005)
P. Neven et al.
Controversies regarding tamoxifen and uterine carcinoma
Curr Opin Obstet Gynecol
(1998)
J.R. Benson et al.
Update on clinical role of tamoxifen
Curr Opin Obstet Gynecol
(2003)
L. Bergman et al.
The Comprehensive Cancer Centres' ALERT Group. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer
Lancet
(2000)
R. Barakat
Tamoxifen and endometrial neoplasia (update on endometrial cancer)
Clin Obstet Gynecol
(1996)
C. Creutzberg et al.
Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial
Lancet
(2000)
N.F. Hacker
Uterine cancer

K. Kieser et al.

What's new in systemic therapy for endometrial cancer

Curr Opin Oncol

(2005)

E. Podczaski et al.

Hormonal treatment of endometrial cancer: past, present and future

Best Pract Res Clin Obstet Gynaecol

(2001)

J. Yu Song et al.

Effects of progestagens on human endometrium

Obstet Gynecol Surv

(1995)

P.J. Sabbatini et al.

Endometrial cancer

P.L. Martin-Hirsch et al.

Progestagens for endometrial cancer

Cochrane Database Syst Rev

(1999)

B. Rackow et al.

Endometrial cancer and fertility

Curr Opin Obstet Gynecol

(2006)

W. Gotlieb et al.

Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer

Obstet Gynecol

(2003)

M. Plante

Fertility preservation in the management of gynaecologic cancers

Curr Opin Oncol

(2000)

E. Marhom et al.

Fertility preservation options for women with malignancies

Obstet Gynecol Surv

(2006)

A. Lethaby et al.

Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding

Cochrane Database Syst Rev

(2004)

B. McDonnell et al.

Hormone replacement therapy in endometrial cancer survivors: new perspectives after the Heart and Estrogen Progestin Replacement Study and the Women's Health Initiative

J Lower Genit Tract Dis

(2006)

M.J.E. Mourits et al.

The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium

J Clin Pathol

(2002)

T. Thigpen et al.

Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study

J Clin Oncol

(2001)

R. Gould et al.

Update on aromatase inhibitors in breast cancer

Curr Opin Obstet Gynecol

(2006)

C.A. Papadimitriou et al.

Hormonal therapy with letrozole for relapsed epithelial ovarian cnacer. Long term results of a phase II study

Oncology

(2004)

A. Covens et al.

Phase II trial of danazol in advanced, recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study

Gynecol Oncol

(2003)

A.R. Jeyarajah et al.

Long-term follow up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer

Gynecol Oncol

(1996)

Cited by (43)

Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial – ANZGOG 0903
2019, Gynecologic Oncology
Citation Excerpt :
There is evidence that hormonal therapy can be associated with clinical benefit in patients with recurrent/metastatic EC and is widely used to treat a subset of patients. Most work to date has focussed on the role of progestogens and historically response rates of up to 70% were reported in women with PR-positive endometrial cancers compared with 12% in women with PR-negative tumours [2–4]. However, using more rigorous response criteria in clinical trials and institutional studies, the objective response rates are lower and range from 15% to 35% [2,5].
The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer.
Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity.
Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34–55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3–15%). The median PFS was 3.2 months (95% CI: 2.8–5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0–13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003).
Although the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.
Uterine sarcoma in Tunisia: Retrospective study about 14 cases
2014, Gynecologie Obstetrique et Fertilite
Rapporter les aspects épidémiologiques, anatomo-cliniques, pronostiques et thérapeutiques des sarcomes utérins (SU) à partir d’une série rétrospective de 14 cas tunisiens.
Notre étude rétrospective a porté sur 14 cas de SU, colligés de 1995 à 2008 dans le service de cancérologie-radiothérapie du CHU Farhat Hached de Sousse. Nous avons analysé les données épidémiologiques, anatomo-cliniques et les résultats thérapeutiques. Le bilan initial avait comporté : anamnèse, examen clinique, données de l’imagerie (radiographie du thorax, échographie abdominopelvienne dans 10 cas et TDM abdominopelvienne dans 7 cas), classification FIGO modifié. Ces patients ont eu un traitement par hystérectomie, radio- et ou chimiothérapie.
Les 14 patientes avaient un âge moyen de 48,5 ans (15 à 78 ans) et n’avaient pas d’antécédent pathologique particulier, notamment irradiation antérieure ou exposition médicamenteuse dans l’enfance. Il s’agissait de leiomyosarcomes (LMS) dans 3 cas, tumeur mûllérienne mixte (TMM) dans 7 cas (50 %) et d’un sarcome du stroma endométrial (SSE) dans 4 cas. Le diagnostic a été posé en postopératoire dans 6 cas et en préopératoire sur biopsie de curetage biopsique dans 8 cas. Les SU étaient classés stade I dans 8 cas, II dans 3 cas et III dans 3 cas. L’hystérectomie a été associée à une annexectomie dans 12 cas et à un curage iliaque bilatéral dans un cas. Huit de nos patientes ont eu en adjuvant une radiothérapie pelvienne et 3 une chimiothérapie. Avec un recul moyen de 54 mois, nous avons observé 4 rechutes locales, des métastases pulmonaires dans un cas et une carcinose péritonéale dans un autre cas. Sept patientes sont vivantes en rémission, 5 sont décédées de progression tumorale et 2 sont perdues de vue.
Les SU restent des tumeurs rares, tardivement diagnostiquées et de mauvais pronostic. Un traitement adjuvant par radio et/ou chimiothérapie doit être discuté pour les formes à haut risque et localement avancées.
To report epidemiologic, anatomoclinical treatment and results about a Tunisian retrospective serie of 14 patients with uterine sarcoma (US).
A retrospective study of 14 cases of uterine sarcoma treated in the Radiotherapy Unit of Farhat Hached Hospital of Sousse between 1995 and 2008. Epidemiologic and anatomoclinical features were assessed. A complete work-up including abdominal ultrasonography and abdominopelvic CT scan were perfomed in 7 and 10 cases, respectively.
The median age was 48.5 years (15 to 78) without previous medical history of irradiation or prolonged drug exposition. There were 3 cases of leimyosarcoma, 7 cases of mixed Mullerian tumor and 4 cases of endometrial stromal sarcoma. The diagnosis was made postoperatively in 6 patients and after curettage in 8 cases. According to the classification of the International Federation of Gynecology and Obstetrics (FIGO), 8 patients were in FIGO stage I, 3 in stage II and 3 in stage III. Hysterectomy was associated with annexectomy in 12 cases. Bilateral pelvic lymphadenectomy was performed in one patient. Eight of our 14 patients underwent postoperative pelvic radiotherapy, associated with adjuvant chemotherapy in 3 cases. The evolution was marked by the occurrence of local recurrence in 4 patients who did not have adjuvant therapy with lung metastases in one case and peritoneal carcinomatosis in another case. With a medium follow-up from 54 months, 7 patients are free from disease, 5 died of their disease (after a mean of 24 months) and 2 patients were lost to follow-up.
Uterine sarcomas are rare tumors with poor prognosis. Adjuvant therapy (radiotherapy and/or chemotherapy should be discussed due to the high risk of recurrence or metastases.
Hormone therapy in ovarian granulosa cell tumors: A systematic review
2014, Gynecologic Oncology
This systematic review assessed the effectiveness of hormone therapy (HT) in patients with a granulosa cell tumor (GCT) of the ovary.
Medline (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), prospective trial registers and PubMed (as supplied by publisher-subset) were searched up to January 13, 2014. No restrictions were applied. Two reviewers independently screened studies for eligibility and extracted data using a standardized, piloted extraction form. Studies evaluating the response to hormone therapy in patients with a GCT were included. The primary outcome was the objective response rate (ORR) to hormone therapy.
In total, nineteen studies including 31 patients were eligible. Pooled ORR to hormone therapy was 71.0% (95% Confidence Interval 52–85). In 25.8% a complete response and in 45.2% a partial response was described. Four patients had stable disease. In five patients disease was progressive. Various hormone treatments showed different results, for instance aromatase inhibitors (AI) demonstrated response in nine out of nine therapies (100%) and tamoxifen in none out of three (0%). Median progression free survival (PFS) after the start of hormone therapy was 18 months (range 0–60).
Despite the limited available data, hormone therapy appears to be a good treatment alternative for patients with advanced-stage or recurrent GCT. However, study quality is poor and prospective studies are needed to confirm clinical benefit of hormone therapy in GCTs.
Quantification of ER/PR expression in ovarian low-grade serous carcinoma
2013, Gynecologic Oncology
Citation Excerpt :
LGSC show a higher prevalence of ER and PR expression compared to HGSC (58% vs 27% for ER, and 43% versus 17% for PR) [8]. The responsiveness of advanced stage ovarian carcinoma to hormonal therapy is modest [9]. However, these results are derived from studies of the most predominant ovarian carcinoma type, HGSC, and are therefore do not address the minority types [10].
Case reports suggest that hormonal therapy may be a useful treatment option for low-grade serous carcinomas (LGSC) but the clinical value remains uncertain. We hypothesized that LGSCs show a constitutive high hormone receptor expression and that type diagnosis may be sufficient to initiate hormonal therapy.
We assessed ER and PR expression on 27 LGSC, 69 high-grade serous carcinomas (HGSC), 36 serous borderline tumors (SBOT), and five normal fallopian tubes using three different platforms/antibodies on tissue microarrays. Staining from the Leica Bond Max and DAKO PharmDx platforms was evaluated using the Allred score. Quantitative fluorescence immunohistochemistry was performed using the HistoRx AQUAnalysis platform. A second cohort of 12 LGSC and 183 HGSC was assessed using the HistoRx AQUAnalysis platform. Welch ANOVA or Fisher's Exact Test was used to compare differences in the histological types for each platform. Nonparametric bivariate density plots were used to graphically demonstrate the relationship between ER and PR for the various histological types.
LGSC have higher ER and PR expression compared to HGSC but significantly less than FT and SBOT. Nonparametric bivariate density revealed two populations of LGSC: one fifth of LGSC are ER high/PR high expressers similar to SBOT but the majority show low ER/PR expression more like HGSC.
Quantitative assessment of ER/PR expression using the HistoRx AQUAnalysis platform may be useful as a predictive diagnostic for hormonal therapy in LGSC, assuming that only the fraction of double high expressers benefit from hormonal treatment.
Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: A meta-analysis and systematic review of the literature
2012, Gynecologic Oncology
Citation Excerpt :
Invasive EC can already be found in approximately 30% of patients initially diagnosed with CAH [17]. The current standard treatment for CAH and endometrial cancer is hysterectomy and bilateral salpingo-oophorectomy [18–21] with or without surgical staging [22]. Whilst radical surgery offers good 5-year survival prospects of 75–90% [20], it also eliminates prospects of further fertility.
To investigate the efficacy of progestin treatment to achieve pathological complete response (pCR) in patients with complex atypical endometrial hyperplasia (CAH) or early endometrial adenocarcinoma (EC).
A systematic search identified 3245 potentially relevant citations. Studies containing less than ten eligible CAH or EC patients in either oral or intrauterine treatment arm were excluded. Only information from patients receiving six or more months of treatment and not receiving other treatments was included. Weighted proportions of patients achieving pCR were calculated using R software.
Twelve studies met the selection criteria. Eleven studies reported treatment of patients with oral (219 patients, 117 with CAH, 102 with grade 1 Stage I EC) and one reported treatment of patients with intrauterine progestin (11 patients with grade 1 Stage IEC). Overall, 74% (95% confidence interval [CI] 65–81%) of patients with CAH and 72% (95% CI 62–80%) of patients with grade 1 Stage I EC achieved a pCR to oral progestin. Disease progression whilst on oral treatment was reported for 6/219 (2.7%), and relapse after initial complete response for 32/159 (20.1%) patients. The weighted mean pCR rate of patients with grade 1 Stage I EC treated with intrauterine progestin from one prospective pilot study and an unpublished retrospective case series from the Queensland Centre of Gynaecologic Oncology (QCGC) was 68% (95% CI 45–86%).
There is a lack of high quality evidence for the efficacy of progestin in CAH or EC. The available evidence however suggests that treatment with oral or intrauterine progestin is similarly effective. The risk of progression during treatment is small but longer follow-up is required. Evidence from prospective controlled clinical trials is warranted to establish how the efficacy of progestin for the treatment of CAH and EC can be improved further.
Effective Luteinizing Hormone Drug Delivery by Nanocarriers in Hormonal Cancer Treatment
2023, Hormone Related Cancer Mechanistic and Nanomedicines: Challenges and Prospects

View all citing articles on Scopus

View full text

11Hormonal therapies and gynaecological cancers

Section snippets

Background

Role of progestagens

Background

Background

Summary

Current status and future innovations of hormonal agents, chemotherapy and investigational agents in endometrial cancer

Curr Opin Obstet Gynecol

Current research on the use of hormonal therapy in the treatment of advanced or recurrent endometrial cancer

Women's Oncol Rev

The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer

Curr Opin Obstet Gynecol

Hormone replacement therapy after cancers

Curr Opin Oncol

Controversies regarding tamoxifen and uterine carcinoma

Curr Opin Obstet Gynecol

Update on clinical role of tamoxifen

Curr Opin Obstet Gynecol

The Comprehensive Cancer Centres' ALERT Group. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

Lancet

Tamoxifen and endometrial neoplasia (update on endometrial cancer)

Clin Obstet Gynecol

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial

Lancet

Uterine cancer

What's new in systemic therapy for endometrial cancer

Curr Opin Oncol

Hormonal treatment of endometrial cancer: past, present and future

Best Pract Res Clin Obstet Gynaecol

Effects of progestagens on human endometrium

Obstet Gynecol Surv

Endometrial cancer

Progestagens for endometrial cancer

Cochrane Database Syst Rev

Endometrial cancer and fertility

Curr Opin Obstet Gynecol

Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer

Obstet Gynecol

Fertility preservation in the management of gynaecologic cancers

Curr Opin Oncol

Fertility preservation options for women with malignancies

Obstet Gynecol Surv

Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding

Cochrane Database Syst Rev

Hormone replacement therapy in endometrial cancer survivors: new perspectives after the Heart and Estrogen Progestin Replacement Study and the Women's Health Initiative

J Lower Genit Tract Dis

The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium

J Clin Pathol

Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study

J Clin Oncol

Update on aromatase inhibitors in breast cancer

Curr Opin Obstet Gynecol

Hormonal therapy with letrozole for relapsed epithelial ovarian cnacer. Long term results of a phase II study

Oncology

Phase II trial of danazol in advanced, recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study

Gynecol Oncol

Long-term follow up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer

Gynecol Oncol

11
Hormonal therapies and gynaecological cancers