Hormonal therapies and gynaecological cancers

Best Practice & Research Clinical Obstetrics and GynaecologyVol. 22, No. 2, pp. 407–421, 2008

doi:10.1016/j.bpobgyn.2007.08.003
available online at http://www.sciencedirect.com
11

Hormonal therapies and gynaecological

cancers

Andrea Garrett* MBBS, MRANZCOG

Oncology Fellow

Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia

Michael A. Quinn MB ChB Glas, MGO Melb, MRCP, FRCOG, FRANZCOG, CGO

Director of Oncology

Melbourne University and Royal Women’s Hospital, Carlton, Victoria 3053, Australia

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

Key words: gynaecological cancer; endometrial; ovarian; hormonal treatment; progestagens;tamoxifen.

ENDOMETRIAL CANCER

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 suc-cumb to the disease. The majority of women present with Stage I disease following anepisode of abnormal bleeding, and the 5-year survival rate for this group is 75%.1

* Corresponding author. Tel.: þ61 3 8458 4444; Fax: þ61 3 8458 4878.

E-mail address: [email protected] (A. Garrett).

1521-6934/$ - see front matter Crown Copyright ª 2007 Published by Elsevier Ltd. All rights reserved.

mailto:[email protected]

http://www.sciencedirect.com

408 A. Garrett and M. A. Quinn

Women presenting with more advanced disease or recurrence have a much poorerprognosis, with a 5-year survival rate of 25%.

The strongest risk factor for endometrial cancer is a hyperoestrogenic state.2 Thisexposure to excess oestrogen can be endogenous or exogenous. Endogenous sourcesof hormones include nulliparity, late menopause, obesity, chronic anovulatory cycles,polycystic ovary syndrome, diabetes mellitus and oestrogen-secreting tumours ofthe ovary, which include the sex cord stromal tumours and epithelial tumours, partic-ularly Krukenberg, endometrioid and mucinous tumours. In obese women, the andro-gens produced by the adrenal glands, particularly androstenedione, are converted tooestrogens by aromatization in adipose tissue and muscle, thereby producing a hyper-oestrogenic state.3 Exogenous sources comprise tamoxifen use and hormone-replace-ment therapy (HRT), in particular unopposed oestrogen therapy. Unopposedoestrogen significantly increases the risk of development of endometrial cancer.4

This risk decreases to normal if progestagen therapy is added (either continuous orsequential).

There is a 1.3–2-fold increase in risk of endometrial cancer in tamoxifen users.5,6

Some studies have shown up to a 7-fold increased risk with, not unexpectedly, the du-ration of tamoxifen use being an important determinant.7 The risk is increased 2-foldafter 2 years of tamoxifen use, and up to 4-fold for use over 5 years.7 Women usingtamoxifen who develop endometrial cancer are thought to have low-grade, highly cur-able lesions.8 However, Bergman et al showed that these women often have a highergrade and stage of disease and worse survival compared with non-users.7 The inci-dence of uterine sarcomas may also be increased. Currently, routine endometrial sur-veillance in women receiving tamoxifen is not indicated due to the very poorspecificity of ultrasound, but women should be warned to report any abnormalbleeding.8

Treatment of endometrial cancer is primarily surgical. Women typically undergohysterectomy and bilateral salpingo-oophorectomy with lymph node dissection inselected high-risk cases. Risk of metastases to lymph nodes is low in tumours witha low histological grade and minimal myometrial penetration. The precise selectionof patients who require lymph node dissection is somewhat controversial9; however,parameters of large tumour size (>2 cm), >1/2 myometrial invasion and Grade 2 or 3histology are often used to justify nodal dissection. Prognosis is based primarily onstage of disease; however, other prognostic variables such as age, histological subtype,presence of lymphovasvular invasion, and oestrogen and progesterone receptor statusmay be important.10,11

PROGESTAGENS

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 endo-metrial cancer.

Progesterone acts as an anti-oestrogen by reducing oestrogen receptor contentand the ability of the endometrium to make new receptors, and by increasingoestradiol dehydrogenase.13 This causes both a suppression of endometrial glandgrowth and stromal decidualization. Once the hormone and receptor interact, the

Hormonal therapies and gynaecological cancers 409

hormone–receptor complex undergoes dimerization and binds to the hormone-responsive element within a specific DNA site.

The progesterone receptor occurs in the nucleus of the cell and appears in two forms:a high-molecular-weight form containing 933 amino acids (A); and a low-molecular-weight form containing 769 amino acids (B).12 Progestagens produce a variety of re-sponses in target tissue depending on which receptor type is expressed by the tissueand the number of progesterone receptors present.12,13 A greater response is seen ifthere is an abundance of B-type receptors.3 As in all situations where steroids areadministered, the dose and duration of exposure determine the type of response.

Side-effects include oedema, weight gain, gastrointestinal tract disturbance andthromboembolic events. Given a reported 15–25% response rate with progestagensin advanced disease12,14 and a reasonably favourable toxicity profile, oral therapy isoften attractive in an elderly and/or unwell population.2

Adjuvant setting

Progestagens have been administered following primary surgery in the hope that thiswill prevent recurrence.15 Several studies have shown that this is not the case. A Co-chrane review comprising six randomized controlled trials addressed the use of adju-vant vs no adjuvant progesterone therapy in women having a hysterectomy forendometrial cancer. A total of 4351 women were studied and progesterone was givenorally or intramuscularly for 3–5 years. There was no overall survival benefit forwomen given adjuvant progestagen therapy [odds ratio 1.05, 95% confidence intervals(CI) 0.88–1.24].1,15 Another study by the South West German Gynecologic OncologyGroup (GOG) compared progesterone [500 mg medroxyprogesterone acetate(MPA)/day], tamoxifen (20 mg/day) and observation following primary surgery. Therecurrence-free and overall survival rates were not significantly different betweenthe three groups.3 Therefore, it is currently recommended that progestagens haveno role in the adjuvant treatment of endometrial cancer.15 However, it should benoted that the majority of patients in these studies had high-risk tumours which areusually receptor negative. The survival of women with low-risk receptor-positivetumours is so good that a huge number of patients would need to be studied toascertain the potential benefit of hormones in the adjuvant setting.

Primary therapy

Endometrial cancer mainly affects postmenopausal women; however, increasing num-bers of premenopausal women, particularly in the setting of obesity, chronic anovula-tion and polycystic ovary syndrome, are being diagnosed, with 25% of cases affectingthis group.16

If fertility is required in young women with a diagnosis of endometrial cancer, pro-gestagens have been used as primary therapy. There are few studies in this area andthe majority are case reports. Nonetheless, most would only use this conservativeapproach when the tumour is well differentiated and receptor rich. A retrospectivereview by Gotlieb et al17 looked at fertility-sparing treatment of premenopausalwomen with endometrial cancer. Thirteen patients were identified as having receivedprogestin therapy. Follow-up curettage revealed that all patients responded favourably,with 77% responding within the first 3 months. Patients were followed-up for a meanperiod of 82 months, and six (46%) developed a recurrence. The recurrences


occurred at a median of 40 months. All recurrences were of well-differentiatedtumours.

Plante reported a series by Randall, where 12 out of 33 women, under 40 years ofage, diagnosed with well-differentiated carcinoma were treated with progestagens.18

Nine (75%) had complete remission of their lesion.Others have reported a 62–75% response with negative histology at subsequent cu-

rettage.12 The optimal method of delivery (oral/intramuscular/intra-uterine), dose, du-ration and type of progestin is not known, but many months of therapy, even up to1 year, may be required to see a benefit.1 Tamoxifen as an adjunct has been proposedin view of downregulation of oestrogen receptors with prolonged use and the knowl-edge that tamoxifen can increase progesterone receptors.18

The risk of disease progression during or after progestagen therapy is small, of theorder of 5%.18 However, relapse in these women can be as high as 24%, with a mediantime to recurrence of 40 months.3 These women need to be regularly followed withcurettage during their treatment and following complete remission. If a pregnancy isnot desired after completing successful primary therapy, maintenance therapy with on-going progestagens is necessary until childbearing is wanted.16

In total, 50 births have been reported following progestagen treatment of endome-trial cancer.17 These pregnancies were either conceived naturally or with assisted re-productive techniques. Assisted reproductive techniques do not appear to worsen theprognosis in women with a history of endometrial cancer, increase the chances of suc-cessful conception and decrease the interval to conception.16,18

Fertility-preserving therapy should only be offered to carefully selected patients, i.e.those with early-stage disease, Grade 1 lesions, and imaging evidence of little or nomyometrial invasion and no evidence of extra-uterine spread.12 Some purport thatpelvic lymph node metastases need to be excluded and therefore laparoscopic lympha-denectomy should be performed.19 Following completion of childbearing, it is reason-able to recommend hysterectomy to avoid the need for ongoing surveillance given thehigh incidence of recurrence.10,16,17

Given that the regression rate of endometrial cancer following the administrationof progestagen therapy is 60–70%, those who are medically unfit for surgery may alsobenefit from primary progestagen therapy.

Advanced disease and recurrence

Progestagens have been widely used in the treatment of advanced or recurrent endo-metrial cancer, either alone or in combination with other agents. The average progres-sion-free interval in this setting is 4 months, with an overall survival of 10 months.1,14

Two studies by the GOG reported response rates of the order of 15–25%.3 In one, 58women were treated with 800 mg MPA/day and in the GOG 81 study, 299 womenwere randomized to receive either 1000 mg or 200 mg MPA/day. There was noadditional benefit to doses greater than 200 mg/day, and patients receiving the lowerdose displayed a trend towards longer progression-free survival and overallsurvival.2,14

Although progestagen dose does not seem to influence response, there have beenno comparisons of lower doses which might be used in dysfunctional uterine bleedingand the higher doses traditionally used in endometrial cancer. The route of administra-tion and type of progestagen also do not seem to influence response.1 A higher re-sponse rate is seen in those with Grade 1 histology, positive progesterone receptor


status or with a long interval before relapse.10 GOG 81 showed a 37% response ratein women with progesterone-receptor-positive tumours compared with only 8% inwomen with progesterone-receptor-negative tumours.2

Effects of duration of therapy are not known, and if a response is achieved, manyadvocate that progestagen should be continued indefinitely. Progestagens have had fa-vourable short-term results but have not affected long-term results, possibly becausedown-regulation of progesterone receptors occurs with prolonged use.2

In women with advanced or recurrent endometrial cancer, radiation therapy hasbeen widely used and is reported to control pelvic disease but does not alter sur-vival.11 These women have a high risk of distant relapse, and in this group, consider-ation should be given to chemotherapeutic agents. Single-agent chemotherapy inwomen with advanced or recurrent disease may lead to symptomatic improvementin one-third of patients.1 The most effective agents are ifosfamide, cisplatin, carbopla-tin, doxorubicin and paclitaxel. Response rates are higher with combination regimens(up to 40–60%); however, median survival remains similar at 7–10 months. This sur-vival is similar to progestagens alone.

The use of progestagens in combination with chemotherapeutic agents has beenevaluated. Response rates between 19% and 80% have been reported.3 Most of thesestudies involved a small number of women, with only two studies containing more than100 patients. These studies have not shown any survival advantage, which is not sur-prising given the fact that the vast majority of recurrent tumours will be receptornegative. The addition of chemotherapy should ideally be reserved for progressionfollowing initial progesterone therapy.14

Endometrial hyperplasia

Endometrial hysperplasia is considered to be a precursor of endometrioid endometrialadenocarcinoma. Progression depends on nuclear atypia, with the risk of progressionranging from 1% to 25%.20

Endometrial hyperplasia also develops as a result of a hyperoestrogenic state, mostoften associated with unopposed HRT. The risk of hyperplasia increases with higherdoses and increased duration of unopposed oestrogen.20 This can be reduced withthe addition of progesterone therapy. A continuous combined regimen provides no in-crease in endometrial hyperplasia, whereas a sequential progesterone regimen putswomen at a mildly increased risk of hyperplasia at 12 months.

Once endometrial hyperplasia has developed, the most common method of treat-ment is with oral or intra-uterine progestagen therapy. Other treatments of hyperpla-sia include endometrial resection, gonadotrophin-releasing hormone (GnRH)analogues, aromatase inhibitors and hysterectomy. Remission rates of 60% can beachieved with oral progestagen therapy and up to 100% with intra-uterinelevonorgestrol.3

Hormone-replacement therapy

Given that endometrial cancer is an oestrogen-dependant neoplasm, it is no surprisethat unopposed oestrogen significantly increases the risk of development of endome-trial cancer4, and was responsible for the large, rapid rise in endometrial cancer inci-dence seen in the 1970s in the USA. This risk returns to normal with the addition of


progestagens. Continuous combined progesterone therapy is considered to be supe-rior to sequential progesterones.20

The use of HRT in women who have been treated for endometrial cancer hasbeen controversial, with the primary concern being the possible stimulation of re-sidual receptor-positive cancer cells.21 Early studies have shown that HRT is notcontraindicated for women diagnosed and treated for endometrial cancer. The firststudy by Creasman in 1986 followed 221 women with Stage 1 disease. Forty-sevenof these women were given oestrogen therapy, and only one (2%) experiencedrecurrent disease.4 The progression-free interval was significantly longer in the oes-trogen group. McDonnell and Twiggs reported a study by Lee et al.21 In this study,none of the 44 women given oestrogen therapy experienced a recurrence, com-pared with 8% in the group of women who were not given oestrogen. These studieswere limited by the small number of women, their non-randomized nature and thenon-uniform oestrogen dosage and route of administrationn. A case-controlledstudy found a recurrence rate of 1% in HRT users compared with 15% in non-users(P¼ 0.006).4

With publication of the Women’s Health Initiative (WHI) study in 2002 indicatingan increased risk of breast cancer with the use of combined HRT, hormone replace-ment for women with endometrial cancer has again caused concern. One pros-pective randomized study by the GOG was terminated prior to completion dueto publication of the WHI results. A preliminary report from this study showed arecurrence rate of 2.3% in the HRT group compared with 1.6% in the placebogroup.21 Interestingly, the rate of breast cancer was higher in the group takingthe placebo.

Tamoxifen

Tamoxifen is a selective oestrogen receptor modulator; it has both agonist and antag-onist activity in different tissues depending on the oestradiol concentration and recep-tor type and content.22 It binds to oestrogen receptors and produces a tissue-specificresponse.12

Paradoxically, tamoxifen has also been used to treat endometrial cancer. A re-sponse rate of 10% (90% CI 5.7–17.9%) has been seen in women with advanced orrecurrent disease.23 Duration of progression-free survival was 1.9 months (90% CI1.7–3.2 months), and median duration of overall survival was 8.8 months (90% CI7.0–10.1 months). This overall duration of survival is similar to that seen withprogestagens.

When tamoxifen binds to oestrogen receptors, the hormone–receptor complextranslocates to the nucleus and causes an increase in production of progesteronereceptors and a decrease in production of oestrogen receptors.2,23 The addition oftamoxifen to progestagen therapy prevents downregulation of progesteronereceptors.11 Fiorica (GOG 153) and Whitney (GOG 119) compared combined pro-gestagen and tamoxifen therapy.2 The regimen and progestagen agent differed; how-ever, a 27–33% response rate was seen, with progression-free survivals rangingfrom 2.7 to 3 months and overall survival up to 14 months.2,3 These figures are inexcess of progestagens alone. When grade of disease was compared, alternatingprogestagen and tamoxifen therapy showed an increased response compared withprogestagen alone (22% vs 8%). Further trials are needed to evaluate theseobservations.


Aromatase inhibitors

Oestrogen is synthesized from cholesterol, with the final step requiring the enzymearomatase to convert testosterone to oestrogen. Aromatase inhibitors block thearomatase cytochrome p450 enzyme.24 This therefore reduces oestrogen concentra-tions. Aromatase inhibitors can be non-steroidal or steroidal. Non-steroidal aroma-tase inhibitors (anastrozole, letrozole) bind reversibly to the enzyme and thereforeneed to be given continuously to exert their effect. Steroidal aromatase inhibitors(exemestane) bind irreversibly to the enzyme, and more aromatase must be createdin order for oestrogen to be synthesized. Aromatase inhibitors have their best effectin postmenopausal women because the hypothalamic-pituitary-ovarian axis is inactiveand the ovarian contribution to circulating oestrogens is low. In this population, thereis a 90% reduction in aromatization.24

Aromatase inhibitors have shown a slight advantage in overall response rate, timeto treatment failure and time to progression when compared with progestagens in thetreatment of advanced breast cancer. When compared with tamoxifen, there is a sig-nificant improvement in overall response rate (30% vs 20%) and reduced side-effects.They are associated with only a 0.2% risk of endometrial cancer.24

Few studies have been performed using aromatase inhibitors in the treatment ofendometrial cancer despite significant levels of aromatase being present in endometrialcancer.1 However, only a moderate response has been demonstrated. One study usedletrozole in women with metastatic or locally recurrent endometrial cancer and founda 9.4% response rate.11 Another study found that letrozole had a response rate of15%.25 Twenty-seven patients received letrozole 2.5 mg daily. Of those with measur-able disease, one had a complete response and two had partial responses (as definedby World Health Organization criteria).

Anastrozole was used in 23 patients with a partial response rate of 9% and a pro-gression-free interval of 1–6 months.1 Multivariate analysis was performed adjustingfor prognostic factors, but the expected response rate was still less than 15%. Thesefigures are similar to both progestagen and tamoxifen alone, and therefore aromataseinhibitors are unlikely to contribute substantially to the treatment of endometrialcancer.

Danazol

Danozol affects pituitary gonadotrophins and also binds to progesterone receptors. Invitro, it has been shown to inhibit endometrial tumour cell migration and invasive ac-tivity.2 In a study by Covens et al26, 22 patients with advanced, recurrent or persistentendometrial cancer were evaluated for response to danozol (given as 100 mg qid).None of the tumours responded and disease remained stable in only 27% of patients.Median progression-free survival was 1.9 months and median overall survival was 14.4months. Danazol therefore has a limited role in the treatment of endometrial cancer.

GnRH analogues

GnRH receptors are present in endometrial cancer tissue and have an ability to inhibitoestrogen.2 Therefore, GnRH analogues have been suggested for use in the treatmentof advanced or recurrent endometrial cancer. Three different analogues have beenstudied with conflicting results; response rates varied between 8% and 33%.


In a trial by Jeyarajah et al27, 32 patients with recurrent endometrial cancer weregiven monthly injections of the GnRH analogue leuprolide. Nine patients (28%) hadan objective response, with response noted within 2 months of treatment. Therewas no correlation with previous progestagen exposure.

In contrast, a Phase II study of leuprolide found no response to treatment.28

Twenty-five women received monthly injections and none of these women had aresponse. Eight women (32%) had stable disease for a median of 5 months.

Leuprolide has also been used as primary treatment for endometrial cancer.29 Nodisease progression was observed over a 6-year period.

An 8.7% response rate to triptorelin has been reported with only one completeresponse and one partial response.3 In this study, only one patient had a completeresponse and one patient had a partial response.

In another study, 17 women with symptomatic recurrent endometrial cancer weretreated with goserelin.30 These women had previously been treated with surgery, ra-diotherapy and progesterone therapy. Six women (35%) achieved complete or partialresponses. The authors concluded that GnRH analogues have a significant place inthe treatment of recurrent endometrial cancer, comparing favourably withprogestagens.

A GOG study assessed whether the GnRH analogue goserelin was useful in thetreatment of women with advanced or recurrent endometrial cancer where proges-tagen therapy failed.31 Response rates were low with only two complete responses(5%), three partial responses (7%) and an overall response rate of 11%. The medianprogression-free survival was 1.9 months, with a median overall survival of 7.3 months.Responses were seen in Grade 1 and Grade 2 lesions, with no response in womenwith Grade 3 lesions.

The exact mechanism of action of the GnRH analogues is unknown and it seemsunlikely that they will substantially add to the hormonal armamentarium in the man-agement of endometrial malignancies.

Receptors as predictors of response

Progesterone and oestrogen receptors are intracellular steroid receptors that specif-ically bind progesterone and oestrogen. Most endometrial cancers have been shown tobe oestrogen receptor positive.12 However, progesterone receptors occur in lowerconcentrations, with concentrations decreasing as tumour grade increases. The pres-ence of progesterone receptors is thought to be a significantly favourable prognosticfactor for endometrial cancer.32

Progesterone concentrations can be determined quantitatively by biochemicalligand binding analysis and immunoassay or by immunohistochemistry.12 Cellular local-ization of steroid receptors and assessment of staining patterns, as performed in im-munohistochemical analysis, may allow for better prediction of hormoneresponsiveness.33

Women who have receptor-positive disease can be treated with hormonal manip-ulation. The well-differentiated tumours are usually progesterone receptor positiveand these tumours are less likely to recur. Poorly-differentiated tumours are usuallyreceptor negative and therefore respond poorly to hormonal therapy, yet these aremore likely to recur. Further study is required into the potential for hormonal manip-ulation of both circulating hormones and intracellular steroid receptors to altertumour growth.12


ENDOMETRIAL STROMAL SARCOMA

Background

Uterine sarcomas account for approximately 3% of all uterine malignancies.11,34 Theyarise from mesodermal tissue. Sarcomas display a more aggressive pattern of diseasecompared with endometrial adenocarcinoma, and include carcinosarcoma, leiomyosar-coma, endometrial stromal sarcoma and adenosarcoma. Endometrial stromal sarco-mas (ESSs) are divided into low- and high-grade categories according to mitoticrate. Low-grade ESSs are considered to be more indolent tumours but recurrencerates are as high as 60%.

Standard treatment involves hysterectomy and bilateral salpingo-oophorectomy.Adjuvant radiation reduces locoregional recurrence, but overall survival benefit hasnot been shown.34

Hormonal therapy for sarcomas

ESSs are responsive to hormonal therapy largely due to their steroid receptor con-tent.10 Progestagens have been used in the treatment of recurrent ESS of low grade,with response rates of approximately 50%.34 A complete response in four of eightpatients treated with progestagens for recurrent low-grade ESS has been reported.Nearly 40% of women had stable disease.10

Two case reports have been published where GnRH analogues have been used toproduce pre-operative ESS tumour shrinkage. Mesia and Demopoulos describedshrinkage of a low-grade ESS after two monthly injections of leuprolide.35 Similarly,Scribner and Walker administered leuprolide and progestagen to control bleedingand shrink tumour mass.36 Neoadjuvant hormonal use in this setting facilitated oper-ative resection.

Aromatase inhibitors display similar antitumour activity similar to progestagens andhave a more favourable toxicity profile. However, they are not commonly used in thetreatment of sarcomas. Chemotherapy is reserved for high-grade lesions or recurrentlesions that progress on hormonal therapy.

OVARIAN CANCER

Background

Ovarian cancer affects more than 20,000 women in the USA each year. It has the high-est mortality of all gynaecological cancers37,38 due to the fact that the majority ofwomen 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 repeti-tious ovulatory activity may be a factor in the malignant transformation of the ovariansurface epithelium. It is hypothesized that mitotic activity required for repair increasesthe likelihood of genetic abnormalities that may lead to malignant transformation.38

The major risk factors for ovarian cancer are genetic or reproductive. Genetic fac-tors may result in a hereditary predisposition to ovarian cancer. Three autosomal-dominant hereditary ovarian cancer syndromes have been identified, accounting for3–5% of cases.38 Up to 10% of ovarian cancer is hereditary.39 These include hereditary


breast and ovarian cancer (Breast Cancer gene mutations, BRCA 1 and 2), hereditarysite-specific ovarian cancer and hereditary non-poyposis colorectal cancer (Lynch II)syndromes. The lifetime risk of development of ovarian cancer is 1.4% if there is nofamily history, and this increases to 5–7% with an affected first- or second-degree rel-ative. With a hereditary syndrome, the lifetime risk is as high as 40%. BRCA 1 and 2mutations are increasingly being detected in sporadic cancers.

Reproductive factors include parity and use of oral contraceptives. There is a30–60% reduction in the risk of developing ovarian cancer in women with any preg-nancy, with a further reduction with three or more pregnancies. The use of oral con-traceptives exerts a strong protective effect, with a 30–60% reduction in risk39, whichincreases with duration of use and protection continues for at least 15 years.38

There have been no overwhelming data to suggest that HRT acts as an initiating orpromoting factor in women who may experience ovarian cancer.4 A few studies haveaddressed the issue of HRT in patients with ovarian cancer, but no survival differenceshave been reported.

Primary cytoreductive surgery is the initial treatment for ovarian cancer to opti-mally debulk the tumour to a size less than 1 cm with a resultant improvement in over-all survival.39 Chemotherapy is administered for all high-grade tumours regardless ofstage and in women with tumours of Stage IC or above.40 Radiotherapy is not usedroutinely in the treatment of ovarian cancer as no studies have shown a survivaladvantage with adjuvant radiotherapy in early or advanced disease.40

Response rates of up to 70% occur with platinum-based therapy, but at least 30% ofpatients diagnosed with ovarian cancer will relapse.38 Palliation is the primary goal inthe management of recurrent disease. There is no overwhelming evidence that earlyinstitution of cytotoxic chemotherapy is beneficial in patients with rising CA125 levelsalone41, although use of biological agents in this setting is theoretically attractive.Recurrence is usually treated with repeated platinum-based chemotherapy; however,the outlook is poor in those who recur within 6 months of primary treatment asthey are considered platinum resistant. Hormonal therapy, usually tamoxifen or aro-matase inhibitors, can be considered in this situation. The hormonal agents are lesstoxic and may be better tolerated in a palliative setting.

Tamoxifen use in ovarian cancer

Ovarian cancer cells possess surface receptors for oestrogen, progesterone andandrogen.37 Tamoxifen has been associated with response rates of 15–20%.42

A GOG study of 105 women with persistent or recurrent disease following surgeryand first-line chemotherapy and subsequently treated with tamoxifen 20 mg bd foundan 18% response rate.43 Ten percent of women showed a complete response and 8%showed a partial response. Thirty-eight percent of women had disease stabilization. Ofthose with a complete response, 89% had elevated oestrogen receptors comparedwith 59% with stable or progressive disease. Re-analysis of the data shows a 13%objective response rate in women with platinum refractory disease.44 The medianresponse duration was 4.4 months.

Perez-Gracia and Carrasco conducted a review of 18 trials of advanced ovariancancer where hormonal therapy was used (tamoxifen in most cases). They found a13% overall response rate.45

A recent meta-analysis examining tamoxifen use in ovarian cancer included 14 stud-ies with an overall response rate of 9.6%. Stable disease was reported in 31.9% ofpatients.37


At a tamoxifen dose of 30–40 mg daily, response rates, survival rates and prognosticfactors have been reported.37 Four out of 65 (6%) patients had a complete or partialresponse, with 50 out of 65 (77%) women reporting stable disease. Median survivalwas 3.8 months with a 5-year survival rate of 2%. Responses were reported to occurmore often in women with endometrioid cancers, lower FIGO stage and younger ageat presentation.

Progestagens and ovarian cancer

Given that ovarian cancer cells possess hormone receptors, progestagen therapyseems a suitable option. However, they are not commonly used in the treatment ofovarian cancer. Oestrogen receptor levels are high and progesterone receptor levelsfall in malignant ovarian tumours. Women with high concentrations of progesteronereceptors may have a more favourable prognosis.46

A Phase II trial of progestagens was carried out by the GOG.47 Twenty-four pa-tients with advanced or recurrent epithelial ovarian cancer who progressed on plati-num therapy were treated with MPA 50 mg tds. One patient (4.2%) had a partialresponse and nine patients (37.5%) had stable disease.

Several studies have used megestrol acetate in the palliative treatment of advancedovarian malignancy. In a study by Wilailak et al48, seven out of 36 patients responded(19.4%). All of those who achieved a complete response had an endometrioid carci-noma of the ovary. Median survival of the whole group was 5.8 months, with 12months median survival in those who responded. Minimal toxicity was observed.

In contrast to the modest response described by Wilailak et al, in another study,megestrol acetate was found to be an ineffective therapy for patients with previouslytreated ovarian carcinoma.49 None of the 33 patients enrolled achieved a response.

A Phase II study of high-dose megestrol acetate was conducted by the EORTCGynaecological Cancer Co-operative Group.50 Seventy-two women were treatedwith 800 mg/day for 1 month followed by 400 mg/day for another month. Responserates were low, with only one patient (1%) having a partial response and nine patients(12%) remaining stable.

The Northern California Oncology Group performed a similar study with high-dose megestrol.51 All patients had advanced disease and had failed prior chemotherapytreatment. There was an overall response rate of 8%, with only one completeresponse and three partial responses.

In all studies, the response rate was modest at best. The toxicity profile was gen-erally low, with the most common side-effect being weight gain ranging from less than1 kg to 20 kg.49–51

Aromatase inhibitors and ovarian cancer

Aromatase inhibitors are rarely used in the treatment of ovarian cancer. If tamoxifenhas been used, oestrogen receptors become saturated and therefore the addition ofan aromatase inhibitor is unlikely to be beneficial.46 A study by MacLusky et al52

showed that although aromatase activity was present in endometrial and ovarianprimary tumours, little is detected in metastatic tumour deposits, thus reducing theirpotential efficacy with recurrent or advanced disease.

Both letrozole and anastrozole have been studied in relapsed ovarian cancer. In onestudy, 27 patients were given letrozole 2.5 mg/day; 21 patients had measurable disease


and six had rising CA125 only.25 One complete and two partial responses were ob-tained for an objective response rate of 15% in those women with measurable disease.

The second study, by del Carmen et al53, evaluated the efficacy of anastrozole inwomen with asymptomatic ovarian, peritoneal or fallopian tube cancer. A partial re-sponse was seen in one patient, whilst 42% had stable disease for more than 90 days.

GnRH analogues and ovarian cancer

Recent studies have shown that GnRH analogues directly inhibit proliferation of ovar-ian cancer through GnRH receptors, present in 80% of tumours.54 Therefore, the roleof GnRH agonists in recurrent ovarian cancer has been evaluated.

Various studies have shown some activity in recurrent ovarian cancer, with re-sponse rates between 9% and 12% and disease stabilization in 15–30%.54,55 Most ofthese trials involved small numbers of patients.

Triptorelin was administered to women with recurrent platinum refractory ovariancancer.54 None of the 69 women enrolled showed a response, but 11 out of 68 (16%)women had stable disease with a median duration of 6 months.

Paskeviciute et al55 assessed 32 women treated with leuprolide. The overall re-sponse rate was 9% with complete remission in one patient and a partial responsein two patients. Four patients (12%) had stable disease and 78% progressed duringtreatment. Interestingly, the patient with a complete response had a long-term pro-gression-free survival of 3 years and 5 months. Despite a modest effect in somewomen, overall efficacy of this hormonal treatment is low.

SUMMARY

A variety of gynaecological cancers respond to hormonal manipulation. The presenceof steroid receptors gives a good guide to likely response in endometrial carcinomaand stromal sarcoma, but no such correlation exists with ovarian epithelial malignan-cies. A lack of trials comparing different agents and combinations, different methodsand sequencing of delivery, and different doses has led to a restricted availability ofhormonal options in this setting. Future research should be directed at ascertainingpotential uses for hormonal agents for maintaining responses after cytotoxic-inducedreduction in tumour burden, and as adjuvant therapy after primary treatment oflow-risk, receptor-rich cancers.

Practice points

� There is no place for adjuvant progestagen treatment following primary ther-apy of endometrial cancer� Receptor-rich endometrial cancer in young women wishing to preserve their

fertility can be managed by ensuring no myometrial invasion (by magnetic res-onance imaging or ultrasound) and administering progestagens� Low-grade endometrial sarcomas are the only uterine sarcomas that respond

to hormonal manipulation� Approximately 10% of advanced epithelial ovarian cancers respond to

tamoxifen

Research agenda

� The role of maintenance tamoxifen following tumour response in ovariancarcinoma� The use of combined hormonal therapies such as progestagens and tamoxifen� The role of adjuvant progestagens in low-risk, receptor-rich endometrial

carcinoma


REFERENCES

1. Elit L & Hirte H. Current status and future innovations of hormonal agents, chemotherapy and inves-

tigational agents in endometrial cancer. Curr Opin Obstet Gynecol 2002; 14: 67–73.

*2. Ferguson G & Herzog T. Current research on the use of hormonal therapy in the treatment of

advanced or recurrent endometrial cancer. Women’s Oncol Rev 2004; 4: 175–180.

*3. Lai C & Huang H. The role of hormones for the treatment of endometrial hyperplasia and endometrial

cancer. Curr Opin Obstet Gynecol 2006; 18: 29–34.

4. Creasman WT. Hormone replacement therapy after cancers. Curr Opin Oncol 2005; 17: 493–499.

5. Neven P & Vergote I. Controversies regarding tamoxifen and uterine carcinoma. Curr Opin Obstet

Gynecol 1998; 10: 9–14.

6. Benson JR & Pitsinis V. Update on clinical role of tamoxifen. Curr Opin Obstet Gynecol 2003; 15: 13–23.

7. Bergman L, Beelen M, Gallee M et al. The Comprehensive Cancer Centres’ ALERT Group. Risk and

prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–887.

8. Barakat R. Tamoxifen and endometrial neoplasia (update on endometrial cancer). Clin Obstet Gynecol

1996; 39: 629–640.

*9. Creutzberg C, van Putten W, Koper P, et al, for the PORTEC Study Group. Surgery and postoperative

radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre rand-

omised trial. Lancet 2000; 355: 1404–1411.

*10. Hacker NF. Uterine cancer. In Berek JS & Hacker NF (eds.). Practical Gynecologic Oncology. 4th edn.

Philadelphia: Lippincott Williams & Wilkins, 2005, pp. 397–442.

11. Kieser K & Oza A. What’s new in systemic therapy for endometrial cancer. Curr Opin Oncol 2005; 17:

500–504.

12. Podczaski E & Mortel R. Hormonal treatment of endometrial cancer: past, present and future. Best Pract

Res Clin Obstet Gynaecol 2001; 15: 469–489.

13. Yu Song J & Fraser IS. Effects of progestagens on human endometrium. Obstet Gynecol Surv 1995; 50:

385–394.

14. Sabbatini PJ, Alektiar KM, Barakat RR et al. Endometrial cancer. In Barakat RR, Bevers MW &

Gershenson DM (eds.). Handbook of Gynecologic Oncology. 2nd edn. London: Martin Dunitz, 2001, pp.

265–278.

15. Martin-Hirsch PL, Jarvis G, Kitchener H et al. Progestagens for endometrial cancer. Cochrane Database

Syst Rev 1999; 4: CD001040.

16. Rackow B & Arici A. Endometrial cancer and fertility. Curr Opin Obstet Gynecol 2006; 18: 245–252.

17. Gotlieb W, Beiner M, Shalmon B et al. Outcome of fertility-sparing treatment with progestins in young

patients with endometrial cancer. Obstet Gynecol 2003; 102: 718–725.

18. Plante M. Fertility preservation in the management of gynaecologic cancers. Curr Opin Oncol 2000; 12:

497–507.

*19. Marhom E & Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv

2006; 62: 58–72.

20. Lethaby A, Suckling J, Barlow D et al. Hormone replacement therapy in postmenopausal women:

endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004; 3: CD000402.


21. McDonnell B & Twiggs L. Hormone replacement therapy in endometrial cancer survivors: new perspec-

tives after the Heart and Estrogen Progestin Replacement Study and the Women’s Health Initiative.

J Lower Genit Tract Dis 2006; 10: 92–101.

*22. Mourits MJE, Hoor KAT, van der Zee AGJ et al. The effects of tamoxifen on proliferation and steroid

receptor expression in postmenopausal endometrium. J Clin Pathol 2002; 55: 514–519.

23. Thigpen T, Brady M, Homesley H et al. Tamoxifen in the treatment of advanced or recurrent endome-

trial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2001; 19: 364–367.

24. Gould R & Garcia A. Update on aromatase inhibitors in breast cancer. Curr Opin Obstet Gynecol 2006;

18: 41–46.

25. Papadimitriou CA, Markeki S, Siapkeras J et al. Hormonal therapy with letrozole for relapsed epithelial

ovarian cnacer. Long term results of a phase II study. Oncology 2004; 66: 112–117.

26. Covens A, Brunetto VL, Markman M et al. Phase II trial of danazol in advanced, recurrent or persistent

endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2003; 89: 470–474.

*27. Jeyarajah AR, Gallagher CJ, Blake PR et al. Long-term follow up of gonadotrophin-releasing hormone

analog treatment for recurrent endometrial cancer. Gynecol Oncol 1996; 63: 47–52.

28. Covens A, Thomas G, Shaw P et al. A phase II study of leuprolide in advanced/recurrent endometrial

cancer. Gynecol Oncol 1997; 64: 126–129.

29. Noci I, Borri P, Bonfirraro G et al. Longstanding survival without cancer progression in a patient

affected by endometrial carcinoma treated primarily with leuprolide. Br J Cancer 2001; 85: 333–336.

30. Gallagher CJ, Oliver RT, Oram DH et al. A new treatment for endometrial cancer with gonadotrophin

releasing hormone analogue. Br J Obstet Gynaecol 1991; 98: 1037–1041.

31. Asbury RF, Brunetto VL, Lee RB et al. Goserelin acetate as treatment for recurrent endometrial

carcinoma: a Gynecologic Oncology Group study. Am J Clin Oncol 2002; 25: 557–560.

32. Kleine W, Maier T, Geyer H et al. Estrogen and progesterone receptors in endometrial cancer and their

prognostic relevance. Gynecol Oncol 1990; 38: 59–65.

33. Van Doorn HC, Burger CW, van der Valk P et al. Oestrogen, progesterone and androgen receptors in

ovarian neoplasia: correlation between immunohistochemical and biochemical receptor analyses. J Clin

Pathol 2000; 53: 201–205.

34. Maluf F, Aghajanian C & Spriggs D. Endometrial stromal sarcoma: etiology, prognosis and treatment.

Am J Cancer 2004; 3: 13–23.

35. Mesia AF & Demopoulos RI. Effects of leuprolide acetate on low-grade endometrial stromal sarcoma.

Am J Obstet Gynecol 2000; 182: 1140–1141.

36. Scribner DR & Walker JL. Low-grade endometrial stromal sarcoma preoperative treatment with Depo-

Lupron and Megace. Gynecol Oncol 1998; 71: 458–460.

*37. Williams C & Simera I. Tamoxifen for relapse of ovarian cancer. Cochrane Database Syst Rev 2001; 1:

CD001034.

38. Kristensen GB & Trope C. Epithelial ovarian carcinoma (seminar). Lancet 1997; 349: 113–117.

39. Bhoola S & Hoskins WJ. Diagnosis and management of epithelial ovarian cancer. Obstet Gynecol 2006;

107: 1399–1410.

40. Hensley ML, Alektiar KM, Chi DS et al. Ovarian and fallopian tube cancer. In Barakat RR, Bevers MW &

Gershenson DM (eds.). Handbook of Gyneclologic Oncology. 2nd edn. London: Martin Dunitz, 2001, pp.

243–263.

41. Cannistra S. Medical progress: cancer of the ovary. N Engl J Med 2004; 351: 2519–2529.

42. Berek JS. Epithelial ovarian cancer. In Berek JS & Hacker NF (eds.). Practical Gynecologic Oncology. 4th

edn. Philadelphia: Lippincott Williams & Wilkins, 2005, pp. 443–509.

43. Hatch KD, Beecham JB, Blessing JA et al. Responsiveness of patients with advanced ovarian carcinoma

to tamoxifen. A Gynaecologic Oncology Group study of second line therapy in 105 patients. Cancer

1991; 68: 269–271.

44. Markman M, Iseminger KA, Hatch KD et al. Tamoxifen in platinum refractory ovarian cancer: a Gyne-

cologic Oncology Group ancillary report. Gynecol Oncol 1996; 62: 4–6.

45. Perez-Gracia JL & Carrasco EM. Tamoxifen therapy for ovarian cancer in the adjuvant and advanced

settings: systematic review of the literature and implications for future research. Gynecol Oncol 2002;

84: 201–209.

*46. Rao GG & Miller DS. Homonal therapy in epithelial ovarian cancer. Expert Rev Anticancer Ther 2006; 6:

43–47.


47. Malfetano J, Beecham J, Bundy B et al. A phase II trial of medroxyprogesterone acetate in epithelial

ovarian cancers: a Gynecologic Oncology Group study. Am J Clin Oncol 1993; 16: 149–151.

48. Wilailak S, Linasmita V & Srisupundit S. Phase II study of high-dose megestrol acetate in platinum

refractory epithelial ovarian cancer. Anticancer Drugs 2001; 12: 719–724.

49. Wiernik PH, Greenwald ES, Ball H et al. High-dose megestrol acetate in the treatment of patients with

ovarian cancer who have undergone previous treatment: Eastern Co-operative Oncology Group Study

PD884. Am J Clin Oncol 1998; 21: 565–567.

50. Veenhof CH, van der Burg ME, Nooy M et al. Phase II study of high-dose megestrol acetate in patients

with advanced ovarian carcinoma. Eur J Cancer 1994; 30A: 697–698.

51. Sikic BI, Scudder SA, Ballon SC et al. High-dose megestrol acetate therapy of ovarian carcinoma: a phase

II study by the Northern California Oncology Group. Semin Oncol 1986; 13(Suppl 4): 26–32.

52. MacLusky NJ, Voit R, Lazo JS et al. Aromatase activity in human ovarian cancer. Steroids 1987; 50:

423–433.

*53. del Carmen MG, Fuller AF, Matulonis U et al. Phase II trial of anastrozole in women with asymptomatic

mullerian cancer. Gynecol Oncol 2003; 91: 596–602.

54. Duffaud F, van der Burg M, Namer M et al. D-TRP-6-LHRH (triptorelin) is not effective in ovarian

carcinoma: an EORTC Gynaecological Cancer Co-operative Group Study. AntiCancer Drugs 2001;

12: 159–162.

*55. Paskeviciute L, Roed H & Engelholm S. No rules without exception: long-term complete remission

observed in a study using LH-RH agonist in platinum refractory ovarian cancer. Gynecol Oncol 2002;

86: 297–301.

Documents

Hormonal therapies and gynaecological cancers