There have also been other phase 2 studies of aromatase inhibitors in ovarian cancer with lower response rates, which may be due to the very different populations treated in the various studies.11,24 Although most patients who had an objective response in these studies had ER-positive tumors, this was not a consistent finding in all studies, and the discrepancy could be due to the differences in techniques of measuring ER, size of the studies, the extent of prior treatment, and possibly also the effect of prior hormonal therapy.
It seems reasonable to speculate that the optimal time to consider hormonal treatment is earlier in the disease trajectory, such as in asymptomatic patients with CA125 progression and small-volume disease and who have hormone receptor-positive tumors. These patients do not benefit from early initiation of chemotherapy before symptomatic progression,25 and watchful waiting and inclusion in novel trials using CA125 response or change in doubling time as end point are potential treatment strategies.26 This population has not been specifically targeted in the studies to date, and most studies have included a very heterogeneous group of patients usually with advanced chemotherapy-resistant disease. However, there may also be a place for hormonal therapy in selected patients with hormone receptor-positive recurrent cancer who have more advanced disease who have had a number of lines of chemotherapy, and arguably, they represent a group of patients in whom disease control with minimal toxicity is particularly important.
There are only scattered case reports regarding hormonal therapy in women with recurrent borderline or microinvasive ovarian cancers and in women with recurrent low-grade serous cancers,9 but ER and PR overexpression is relatively common among these tumor types,2,9 and a more rigorous assessment of hormonal therapy is warranted. There remains a need to determine the role of hormonal therapy, specifically aromatase inhibitors, in ovarian cancer and specifically to identify patients more likely to respond on the basis of ER and/or PR status.
Endometrial cancer is the most prevalent gynecological cancer in the Western world. Endometrial cancers can be subdivided into type 1 (potentially hormone responsive) and type 2 (hormone independent) subtypes. Type 1 endometrial cancers are ER related and are histologically low-grade endometrioid carcinomas. Most of these tumors express either ER and/or PR receptors. These patients typically have risk factors such as obesity, diabetes, and hypertension. Even though these patients generally have a good prognosis, a small number present with metastases, and others relapse at a later time, whereas others may be unfit for surgery or radiotherapy at presentation.
A response rate of up to 70% with progestogens has been reported in women with PR-positive endometrial cancers compared with 12% in women with PR-negative tumors.5,12,27 Using more rigorous response criteria in multi-institutional studies, the objective response rates are lower and range from 15% to 20%.5 Features that predict a better response are hormone receptor expression, low-grade histology, and a long disease-free interval between initial diagnosis and recurrence.5,12,27 In 1 GOG study, the response rates to progestogens were 37% in PR-positive and 8% in PR-negative tumors, and similar differences in response were seen in grade 1 versus grade 3 tumors.5 Although progestogens have been the mainstay of hormonal treatment in women with recurrent/metastatic endometrial cancer for many years, these agents are associated with significant adverse effects, including weight gain, hypertension, fluid retention, increased blood sugar, insomnia, tremor, thrombosis, and pulmonary emboli. These can potentially worsen the quality of life and may be life threatening.5
Tamoxifen also has documented single-agent activity in 10% to 20% of women when given first line, but is much lower in the second-line setting.12 The median survival of women in the GOG studies with progestogens was about 11 months, and clearly more effective hormonal therapies are needed.5
In postmenopausal women, the principal source of ER is through conversion of androstenedione by aromatase in peripheral adipose tissue. In addition to peripheral aromatization, aromatase is elevated in endometrial cancer stroma, and locally produced ER may act in a paracrine fashion to stimulate cancer growth.10,12,18
The response rates to aromatase inhibitors in recurrent and metastatic endometrial cancer have been low (10% objective response rates), but this almost certainly reflects the population who were treated.18 In the studies that have been reported, most patients have had high-grade, hormone receptor-negative cancers, where a low likelihood of response would be expected. There is still a need to evaluate aromatase inhibitors in women with well-differentiated and/or hormone receptor-positive tumors, where the expected response to treatment is likely to be higher.
Uterine sarcomas are uncommon malignancies that include ESSs, leiomyosarcomas (LMSs), and adenosarcomas. There have been individual case reports of response to hormonal therapy in all these subtypes; however, drawing any conclusions is impossible because of the small numbers of patients.12,19,28-30 Despite the lack of prospective trials, hormone therapy has become standard of care in patients with metastatic ESS.14
A large proportion of ESS is ER positive and PR positive, and durable responses to progestogens have been reported.4,12,29 Tamoxifen is contraindicated in these patients as there have been reports of stimulation of growth due to the partial ER agonist effect of tamoxifen.31 Aminoglutethimide has been reported to be active, and 2 patients with lung metastases had complete responses for 14 and 7 years, respectively.29 Aminoglutethimide has been superseded by third-generation aromatase inhibitors such as anastrozole and letrozole. There are few reports of response to letrozole. One study reported 8 responses from 10 patients treated.14,31 Interestingly, most low-grade ESSs express aromatase. The staining pattern, however, is heterogeneous.14,28 The high percentage of aromatase positivity in low-grade ESSs may have implications in the management of these tumors. Patients with measurable disease and metastatic ESS should be considered for treatment with an aromatase inhibitor. In addition, patients who are at high risk of progression, either following resection of metastases or surgical debulking, and have small-volume, nonmeasureable disease should also be considered for treatment with an aromatase inhibitor.
Although hormonal therapy has not been widely used to treat women with uterine LMSs, a study using paraffin-embedded tissue blocks from 15 cases of uterine LMS from the Cleveland Clinic Foundation suggests that hormonal treatment may have a role.1 These tumors are usually chemoresistant, and there are few options for patients with metastatic disease, particularly after chemotherapy. The investigators performed immunohistochemical staining for ER and PR on tumor specimens. Nuclear staining was evaluated by 2 observers in a semiquantitative manner according to percentage of nuclei stained: 0 = no nuclear staining, 1+ = 1% to 25%, 2+ = 26% to 50%, 3+ = 51% to 75%, or 4+ = 76% to 100% of nuclei stained. The majority of uterine LMSs stained for ER (13/15, 87%), PR (12/15, 80%), or both ER and PR (12/15, 80%), with most cases showing 3+ or 4+ positive staining.1 These data strongly support a study of hormonal therapy in patients with ER-/PR-positive metastatic LMS who are not suitable for aggressive chemotherapy regimens or after relapse after chemotherapy.
GRANULOSA CELL TUMORS
Granulosa cell tumors account for about 2% to 5% of all ovarian cancers. They are usually confined to the ovary and tend to have a good prognosis, but they can recur and metastasize many years after diagnosis. In 1 series from the Royal Marsden, 40% of patients with stage I disease and 60% of patients with stage II tumors had a recurrence.32 They tend to be refractory to standard cytotoxic chemotherapy, leaving surgery as the mainstay of treatment. Serum inhibin levels are valuable tumor markers for the diagnosis of primary or recurrent granulosa cell tumors.33
Granulosa cell tumors are also potentially hormonally responsive, with about 30% of granulosa tumors ER positive and almost 100% PR positive. Hormonal agents such as progestogens or LHRH agonists have been used widely to treat these patients as they are often elderly and not suitable for aggressive chemotherapy.8,9,12,32,34 More recently, there have been a few case reports of durable response to aromatase inhibitors in patients with metastatic granulosa cell tumors who had received multiple prior treatments.20,34
Small clinical series and case reports have described responses to LHRH agonists or progestesterones. One series of 13 patients reported a 50% response rate to LHRH agonists, whereas in 2 separate series, a total of 4 of 5 patients were reported as having responded to a progestogen.8,9 Two recent case series have reported durable responses to aromatase inhibitor in a total of 6 patients.20 All these patients had been intolerant of chemotherapy or experienced tumor progression despite receiving chemotherapy, and 2 of patients described had also previously received leuprolide. In all cases, there was evidence of complete or partial radiological response and sustained benefit on treatment for more than 12 months. These findings need confirmation in larger trials.
Hormonal therapy is an attractive option in patients with recurrent/metastatic gynecological cancers where the objective of treatment is palliation and prolongation of survival rather than cure. Aromatase inhibitors are generally well tolerated and in contrast to chemotherapy can be administered for prolonged periods with relatively little cumulative toxicity. The degree of activity and response rates reported in previous studies have varied considerably. This variability almost certainly reflects the heterogeneous populations treated, which have included women with ER and PR receptor-negative tumors as well as those with a poor performance status where response rates are generally low. There is a clear need to investigate the role of hormonal therapies, particularly aromatase inhibitors, in selected women with potentially hormone-responsive recurrent/metastatic gynecological cancers. Prospective studies are warranted in this patient population, and future trials should focus on clinical benefit and quality of life, as well as establishing accurate response rates and identifying predictors of response. It has been very difficult to investigate the role of hormonal therapy, particularly for uncommon and rare subtypes of gynecological cancers. PARAGON (ACTRN12610000796088, CRUK/10/056) is a large prospective international study that has recently opened and will help to clarify the role of aromatase inhibitors in women with potentially hormone-responsive recurrent/metastatic gynecological tumors (Fig. 3). This study has a unique design that increases the likelihood of successfully recruiting patients. Investigators will be able to submit a single protocol and ethics application that will encompass all eligible patients with potentially hormone-responsive recurrent/metastatic gynecological cancers, which will greatly increase recruitment and give more patients with relatively rare tumors access to clinical trials.
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Keywords:Copyright © 2011 by IGCS and ESGO
Aromatase inhibitors; Gynecological neoplasms; Ovarian neoplasms; Endometrial neoplasms; Hormonal therapy