Abstract
Background:
The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Pre-clinical studies and small case series have suggested direct anti-tumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach.
Objective:
To describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors.
Study Design:
This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy.
Results:
Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of two (IQR, 1–3) systemic therapy regimens prior to their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common prior to first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (IQR, 4.8–16.5 months). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only one patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% CI, 54–82%). Median progression-free survival was not statistically different compared to that which followed chemotherapy (10.3 months [95% CI, 8.0–16.0 months] vs. 8.0 months [95% CI, 5.0–15.3 months], p=0.3).
Conclusion:
In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond.
Keywords: Antineoplastic Agents, Hormonal; Cohort Studies; Granulosa Cell Tumor; Hormone Receptor Agonists; Leuprolide Acetate; Ovarian Neoplasms; Receptors; LHRH
Condensation:
In the largest cohort studied to date, leuprolide acetate resulted in a 6-month clinical benefit rate of 66% in patients with recurrent granulosa cell tumors.
Introduction
Comprising less than 5% of all ovarian cancers,1 adult granulosa cell tumors (aGCTs) present unique clinical challenges. While aGCT is typically diagnosed at an early stage, approximately 25% of tumors recur, often years later.2 Patients with relapsed aGCTs have a long-term survival rate of only 66%.3 Standard treatment includes cytoreductive surgery for both primary and relapsed tumors as well as adjuvant platinum-based chemotherapy.4,5 The optimal treatment of recurrent or progressive aGCTs remains unknown.
Hormonal therapy has been proposed as an attractive treatment option for aGCTs, given their propensity to express sex steroid hormones and their receptors.6 A systematic review by van Meurs et al.7 concluded that hormonal therapy produced good responses (pooled overall response rate, 71.0%) in 31 patients across 19 studies of GCTs treated with aromatase inhibitors (AIs), progestins, selective estrogen receptor modulators (SERMs), or gonadotropin-releasing hormone (GnRH) agonists or antagonists. Furthermore, hormonal therapies often have favorable side effect profiles and convenient dosing schedules.
In laboratory studies, treatment of cultured granulosa cells with GnRH or a GnRH agonist has been shown to inhibit proliferative activity8 and increase apoptosis.9,10 Similar pro-apoptotic effects were seen in the granulosa cells of hypophysectomized rats given a GnRH agonist.11 Several case reports and small series of patients with GCTs have demonstrated clinical responses to treatment with GnRH agonists such as leuprolide acetate (LA).12–17 Despite physiologic rationale and anecdotal success, empiric evidence supporting the use of GnRH agonists in aGCT remains limited. Larger studies are thus needed to guide clinical management of relapsed aGCTs.
The objective of the present study was to describe patterns of use and clinical outcomes of LA-based treatment in a cohort of patients with recurrent GCTs treated at a large cancer center and affiliated county hospital.
Materials and Methods
This retrospective cohort study included patients enrolled in an institutional review board (IRB)-approved Rare Gynecologic Malignancy Registry who had histologically confirmed aGCTs or GCTs not otherwise specified (NOS). The LA cohort comprised patients who received LA as anti-cancer treatment in the recurrent setting and had sufficient clinical data available. Patients who received LA for another indication (i.e., ovarian suppression) or had inadequate clinical data (missing information about indication or duration of LA therapy) were excluded. A comparator group was then identified as patients who received systemic cytotoxic chemotherapy in the recurrent setting, had sufficient clinical data available, and were not included in the LA cohort. The aforementioned Rare Gynecologic Malignancy Registry includes patients treated at the University of Texas MD Anderson Cancer Center, a large referral center, and Lyndon B. Johnson Hospital, an affiliated county hospital. Data are stored on the secure Research Electronic Data Capture (REDCap) platform.18,19 The data collection cutoff date for this study was February 2023.
Data extracted from the REDCap database consisted of demographic information, details of therapy course(s), details of any prior treatment modalities, and key dates (e.g., disease progression, last contact, death). LA indication was defined as follows: maintenance if LA was initiated after a different chemotherapy or radiation therapy regimen in the absence of a new recurrence or progression, adjuvant if LA was initiated after tumor reductive surgery in the absence of a new recurrence or progression and not meeting criteria for maintenance indication, and treatment if LA was initiated in the setting of a recurrence or progression and not meeting criteria for maintenance or adjuvant indications.
The duration of LA therapy was calculated from the date of the first LA administration to the date of the most recent LA administration plus the dosing interval (i.e., the date the next dose would have been due). For patients with unknown dose schedules, a dosing interval of 30 days was imputed. The 6-month clinical benefit rate (CBR) was defined as the percentage of patients without a documented recurrence or progression within 6 months after starting therapy. Progression-free survival (PFS) was calculated from the date of the first administration of the specified treatment to the date of the next documented recurrence or progression or the date of death. PFS was censored at the date of the last office visit with a gynecologic oncologist if neither progression nor death had occurred by the time of data collection.
Data were summarized using percentages and descriptive statistics. Patients in the LA cohort’s first LA-containing regimens for treatment of recurrence or progression were compared to patients in the chemotherapy cohort’s first chemotherapy regimens for treatment of recurrence or progression. Demographic and clinical characteristics were compared between these groups with t-tests, Chi-square tests, and Fisher’s exact tests as appropriate using GraphPad Prism (version 9.0.0). Median and 6-month PFS were calculated in R (version 4.2.1)20 using the survival package (version 3.4.0).21,22 Kaplan-Meier plots of PFS were generated and compared between groups with the log-rank test in R (version 4.2.1) with the survival (version 3.4.0) and survminer packages (version 0.4.9).23 Because the sample size was limited by the number of patients meeting inclusion criteria, an a priori power analysis was not performed. IRB approval was obtained for both the data registry itself (PA17–0586) and this retrospective analysis (2020–1156). All patients provided written informed consent for inclusion in the registry or were granted a waiver of informed consent if they had not been seen at our institution within three years or were deceased.
Results
Sixty-two patients with recurrent GCTs treated with LA were identified and included in the LA cohort (Figure 1). Their median age at diagnosis was 45 years (interquartile range [IQR], 37–55 years). Most patients had a diagnosis of aGCT (89% [55/62]), whereas five patients (8%) had mixed histology of aGCT plus another sex cord-stromal histology and two patients (3%) had GCT NOS. For patients with mixed histology of the primary tumor, pathology results from recurrent tumor specimens were reviewed and confirmed that all cases did include recurrent granulosa cell tumor, though in one instance the histology was juvenile GCT (without an adult GCT component noted). The majority of the patients (63% [39/62]) had stage I disease at diagnosis. Baseline demographic and clinical characteristics of the LA cohort are summarized in Table 1.
Figure 1.
Flow diagram of patient selection. Abbreviations: NOS, not otherwise specified; LA, leuprolide acetate.
Table 1.
Baseline patient characteristics of the leuprolide acetate cohort.
| Characteristic | N | % |
|---|---|---|
| Age at diagnosis (years)* | 45 (37–55) | |
| Stage at diagnosis† | ||
| I | 39 | 63% |
| II | 6 | 10% |
| III | 6 | 10% |
| IV | 0 | 0% |
| Unknown | 11 | 18% |
| Frontline treatment | ||
| Surgery | 62 | 100% |
| Chemotherapy | 15 | 24% |
| Radiation therapy | 2 | 3% |
| Hormonal therapy | 4 | 6% |
| Histology | ||
| Adult granulosa cell tumor | 55 | 89% |
| Granulosa cell tumor NOS | 2 | 3% |
| Mixed‡ | 5 | 8% |
| Race§ | ||
| Asian | 3 | 5% |
| Black | 13 | 21% |
| White | 40 | 65% |
| Other | 5 | 8% |
| Unknown | 1 | 2% |
Median (interquartile range)
According to the International Federation of Gynecology and Obstetrics (FIGO) staging system at the time of diagnosis
Sertoli-Leydig cell tumor (n=1), sex cord stromal tumor NOS (n=2), or juvenile granulosa cell tumor (n=2) in addition to adult granulosa cell tumor
Patient-reported
Abbreviations: NOS, not otherwise specified
Patients in the LA cohort had a median of two (IQR, 1–4) recurrence or progression events and two (IQR, 1–3) systemic treatment regimens prior to their first treatment with LA (Table 2). All patients had undergone at least one prior cytoreductive surgery, with a median of two (IQR, 2–3) prior operations. Twelve patients (19%) had previously received radiation therapy. Fifty-three patients (85%) had been previously treated with cytotoxic chemotherapy, with the majority (81% [50/62]) having received a platinum-containing regimen, most commonly in the form of a platinum-taxane doublet (61% [38/62]); bleomycin, etoposide, and cisplatin (BEP; 21% [13/62]); or etoposide and cisplatin (EP; 6% [4/62]). Ten patients (16%) had received prior targeted therapy regimens, all of which included bevacizumab. Approximately half of the patients in this cohort (48% [30/62]) had been treated with a different hormonal agent prior to their first treatment with LA, most commonly an AI (44% [27/62]) or SERM (18% [11/62]).
Table 2.
Treatment regimens prior to leuprolide acetate-based therapy.
| Treatments prior to leuprolide acetate | N | % |
|---|---|---|
| No. of prior recurrence or progression events† | 2 (1–4) | |
| No. of prior pharmaceutical regimens† | 2 (1–3) | |
| No. of prior tumor reductive surgeries† | 2 (2–3) | |
| Prior treatment modalities | ||
| Surgery | 62 | 100% |
| Radiation therapy | 12 | 19% |
| Chemotherapy | 53 | 85% |
| Platinum + taxane | 38 | 61% |
| BEP | 13 | 21% |
| EP | 4 | 6% |
| Other combination | 9 | 15% |
| Single-agent taxane | 6 | 10% |
| Other single agent | 13 | 21% |
| Targeted Therapy | 10 | 16% |
| Bevacizumab | 10 | 16% |
| Chk1/2 inhibitor | 1 | 2% |
| Multi-kinase inhibitor | 1 | 2% |
| PIK3/mTOR inhibitor | 1 | 2% |
| Immunotherapy | 1 | 2% |
| WT1 vaccination | 1 | 2% |
| Hormonal Therapy | 30 | 48% |
| Aromatase inhibitor | 27 | 44% |
| Progesterone | 4 | 6% |
| SERM | 11 | 18% |
Note: For patient treated with leuprolide on more than one occasion (n=13), agents prior to their first exposure to leuprolide are included in this table
Median (interquartile range)
Abbreviations: BEP, bleomycin + etoposide + cisplatin; EP, etoposide + cisplatin; Chk1/2, checkpoint kinases 1 and 2; PIK3, phosphoinositide 3-kinases; mTOR, mammalian target of rapamycin; WT1, Wilms tumor protein 1; SERM, selective estrogen receptor modulator
Thirteen patients received LA in more than one separate treatment course, leading to a total of 78 LA-containing treatment courses, which are summarized in Table 3. Of these, 57 (73%) were for treatment of a recurrence or progression, 11 (14%) were for maintenance following another treatment modality (median [range], 49 [1–146] days after preceding treatment), and 10 (13%) were adjuvant to recurrent tumor reductive surgery (median [range], 23 [12–130] days after surgery). Dose schedules were heterogeneous, consisting of 7.5 mg monthly (28% [22/78]), 22.5 mg every 3 months (23% [18/78]), 3.75 mg monthly (15% [12/78]), 11.25 mg every 3 months (13% [10/78]), 3.75 mg every 3 months (3% [2/78]), and 30 mg every 4 months (1% [1/78]). LA dose was unknown in 13 regimens (17%). In all cases, LA was in the depot formulation and administered intramuscularly. Nearly half of the courses were single-agent LA (49% [38/78]). Combination regimens most often included an AI (23% [18/78]); other combination regimens employed SERMs (10% [8/78]), cytotoxic chemotherapy (8% [6/78]), and bevacizumab (6% [5/78]), among others.
Table 3.
Leuprolide acetate-containing therapy courses.
| Characteristic | N | % |
|---|---|---|
| Indication | ||
| Adjuvant | 10 | 13% |
| Maintenance | 11 | 14% |
| Treatment | 57 | 73% |
| Duration (months)* | 9.6 (4.8–16.5) | |
| Initial dose | ||
| 3.75 mg monthly | 12 | 15% |
| 7.5 mg monthly | 22 | 28% |
| 3.75 mg every 3 months | 2 | 3% |
| 11.25 mg every 3 months | 10 | 13% |
| 22.5 mg every 3 months | 18 | 23% |
| 30 mg every 4 months | 1 | 1% |
| Unknown | 13 | 17% |
| Concurrent treatments | ||
| None (single-agent leuprolide acetate) | 38 | 49% |
| Aromatase inhibitor | 18 | 23% |
| Bevacizumab | 5 | 6% |
| Chemotherapy† | 6 | 8% |
| Glutaminase inhibitor | 1 | 1% |
| Progesterone | 1 | 1% |
| Radiation therapy | 3 | 4% |
| SERM | 8 | 10% |
| Reason for discontinuation | ||
| Adverse events from therapy | 1 | 1% |
| Completed planned treatment | 2 | 3% |
| Deceased | 1 | 1% |
| Lack of insurance or financial aid | 1 | 1% |
| Per physician’s advice | 2 | 3% |
| Progressed disease | 60 | 77% |
| Unknown | 3 | 4% |
| Treatment ongoing | 8 | 10% |
Median (interquartile range)
Regimens included carboplatin + paclitaxel (n=2), carboplatin + etoposide (n=1), doxorubicin (n=1), etoposide + ifosfamide (n=1), and topotecan (n=1)
Abbreviations: SERM, selective estrogen receptor modulator
Regarding the 10 adjuvant regimens, all preceding surgeries were secondary, tertiary, or higher order cytoreductive surgeries performed via an open approach (nine laparotomies and one thoracotomy). The procedures performed are detailed in Table 4. Six of the cytoreductive surgeries were complete or optimal (residual tumor <1 cm; 60% [6/10]), with the others being suboptimal (residual tumor ≥1 cm; 10% [1/10]) or unknown (30% [3/10]). Most adjuvant courses were single-agent LA (70% [7/10]), with the rest consisting of LA combined with an AI (30% [3/10]).
Table 4.
Adjuvant leuprolide acetate courses.
| Characteristic | N | % |
|---|---|---|
| Surgical Approach | ||
| Laparotomy | 9 | 90% |
| Thoracotomy | 1 | 10% |
| Procedures Performed | ||
| Bowel resection | 3 | 30% |
| Colostomy takedown | 1 | 10% |
| Enterotomy repair | 1 | 10% |
| Hepatic resection | 1 | 10% |
| Hernia repair | 1 | 10% |
| Lymph node resection | 3 | 30% |
| Lysis of adhesions | 7 | 70% |
| Omentectomy | 1 | 10% |
| Peritoneal resection/stripping | 2 | 20% |
| Splenectomy | 1 | 10% |
| Tumor resection | 10 | 100% |
| Cytoreduction Status | ||
| Complete | 5 | 50% |
| Optimal | 1 | 10% |
| Suboptimal | 1 | 10% |
| Unknown | 3 | 30% |
| Concurrent treatment | ||
| None (single-agent leuprolide acetate) | 7 | 70% |
| Aromatase inhibitor | 3 | 30% |
| Carboplatin + paclitaxel | 1 | 10% |
The median duration of LA administration was 9.6 months (IQR, 4.8–16.5 months). Disease progression was the most common cause of discontinuation (77% [60/78]). Only one patient discontinued LA because of adverse events (hot flashes). Eight LA-containing courses (10%) were ongoing at the time of data collection.
In comparison, 40 patients with recurrent GCTs treated with systemic chemotherapy were identified and included in the chemotherapy cohort (Figure 1). Key demographic and clinical characteristics are compared between the first-time treatment-indication LA and chemotherapy cohorts in Table 5. Notably, patients in the chemotherapy cohort exhibited a trend toward fewer prior recurrence or progression events (median [IQR], 1 (0.75–3) vs. 2 (1–4), p=0.2) and fewer prior lines of systemic treatment (median [IQR], 1 (1–3) vs. 2 (1–3), p=0.2), though this did not reach statistical significance. Chemotherapy agents most represented were platinum-taxane doublets (50% [20/40]) and single-agent taxanes (25% [10/40]; Table 6). Eight patients (20%) received concurrent bevacizumab. As in the LA cohort, progressive disease was the most common cause of discontinuation (58% [23/40]). Four patients (10%) discontinued chemotherapy due to adverse events.
Table 5.
Comparison of select demographic and clinical factors between the chemotherapy cohort and first-time treatment-indication leuprolide acetate cohort.
| Chemotherapy cohort (N=40) | LA cohort (N=46) | ||||
|---|---|---|---|---|---|
| Characteristic | N | % | N | % | p-value |
| Age at time of recurrence* | 59.5 (45.75–63) | 58 (50–66.75) | 0.6 | ||
| Stage at diagnosis† | 0.5 | ||||
| I | 17 | 43% | 31 | 67% | |
| II-III | 6 | 15% | 7 | 15% | |
| Unknown | 17 | 43% | 8 | 17% | |
| Histology | 0.5 | ||||
| Adult GTC or GCT NOS | 35 | 88% | 42 | 91% | |
| Mixed | 5 | 13% | 4 | 9% | |
| Race‡ | 0.4 | ||||
| Asian | 0 | 0% | 2 | 4% | |
| Black | 7 | 18% | 10 | 22% | |
| White | 31 | 78% | 30 | 65% | |
| Other | 0 | 0% | 4 | 9% | |
| Unknown | 2 | 5% | 0 | 0% | |
| No. of prior recurrence or progression events* | 1 (0.75–3) | 2 (1–4) | 0.2 | ||
| No. of prior pharmaceutical regimens* | 1 (1–3) | 2 (1–3) | 0.2 | ||
| No. of prior tumor reductive surgeries* | 3 (2–4) | 3 (2–3.75) | 0.4 | ||
Note: Statistical tests were performed after excluding the “Unknown” category where applicable.
Median (interquartile range)
According to the International Federation of Gynecology and Obstetrics (FIGO) staging system at the time of diagnosis
Patient-reported
Abbreviations: LA, leuprolide acetate; GCT, granulosa cell tumor; NOS, not otherwise specified
Table 6.
Treatment regimens in chemotherapy cohort.
| Characteristic | N | % |
|---|---|---|
| Chemotherapy regimens | ||
| Platinum + taxane | 20 | 50% |
| BEP | 2 | 5% |
| Other combination | 2 | 5% |
| Single-agent platinum | 2 | 5% |
| Single-agent taxane | 10 | 25% |
| Single-agent doxorubicin | 3 | 8% |
| Other single agent | 1 | 3% |
| No. of cycles* | 5.5 (3–7.5) | |
| Concurrent treatment | ||
| None (cytotoxic chemotherapy only) | 29 | 73% |
| Bevacizumab | 8 | 20% |
| AI | 2 | 5% |
| SERM | 1 | 3% |
| Leuprolide acetate | 1 | 3% |
| Temsirolimus | 1 | 3% |
| Reason for discontinuation | ||
| Adverse events from therapy | 4 | 10% |
| Completed planned treatment | 9 | 23% |
| Per patient’s choice | 1 | 3% |
| Per physician’s advice | 1 | 3% |
| Progressed disease | 23 | 58% |
| Other | 2 | 5% |
Median (interquartile range)
Abbreviations: BEP, bleomycin + etoposide + cisplatin; AI, aromatase inhibitor; SERM, selective estrogen receptor modulator
No statistically significant difference in PFS was found between first-time LA use and first-time chemotherapy use for treatment of recurrent GCT (median [95% confidence interval (CI)], 10.3 months [8.0–16.0 months] vs. 8.0 months [5.0–15.3 months], p=0.3; Figure 3). The 6-month CBR of first-time use of LA for treatment indication was 66% (95% CI, 54–82%), which was again similar to the 6-month CBR of the chemotherapy group (59% [95% CI, 45–77%]). LA utilization and outcomes in this setting are summarized in Figure 2.
Figure 3.
Progression-free survival following first leuprolide acetate-containing therapy for treatment indication (black) and chemotherapy (pink) for recurrent granulosa cell tumor. Abbreviations: LA, leuprolide acetate.
Figure 2.
Visual summary of first leuprolide acetate-containing therapy courses for treatment indication.
In the maintenance setting, first-time LA use resulted in a 6-month CBR of 86% (95% CI, 63–100%) and median PFS of 14.8 months (95% CI, 7.98 months-not reached [NR]). For first-time adjuvant therapy, 6-month CBR was 100% (95% CI, 0–100%) and median PFS was 12.8 months (95% CI, 8.48 months-NR). Of note, the sample size for these settings was small (n=7 and n=9, respectively).
Comment
Principal Findings:
In this large cohort of patients with recurrent GCTs, the 6-month CBR for first use of LA in treatment of gross disease was 66% and the median PFS was 10.3 months. Progression-free survival outcomes were no different than chemotherapy in a comparable setting. Adverse events leading to discontinuation of LA therapy were rare.
Results in the Context of What is Known:
GnRH agonists classically suppress the hypothalamic-pituitary-gonadal axis; however, as most patients with recurrent GCTs have undergone bilateral oophorectomy, this is likely not the dominant anti-tumor mechanism. RNA sequencing24 and immunohistochemistry25 have shown that GnRH and GnRH receptors are expressed directly by granulosa cells. Binding by GnRH results in aggregation and internalization of its receptor.26 This observation, as well as the correlation between GnRH and GnRH receptor expression in human granulosa cells, suggests meaningful autocrine activity.24 Preclinical studies have shown anti-proliferative and pro-apoptotic effects of GnRH agonists on granulosa cells.8–10 Moreover, depletion of GnRH receptors by small interfering RNA knockdown abrogated the apoptotic effects of GnRH agonists, confirming the role of ligand–receptor binding on granulosa cells.27 Together, the results of these studies provide consistent evidence of direct anti-neoplastic activity of GnRH agonists in granulosa cells. Case studies and series have demonstrated efficacy of LA-containing treatment regimens in patients with GCT, including examples of prolonged response17 and success where more conventional therapies have failed.13 Our study affirms the safety and efficacy of LA for treatment of recurrent GCT in the largest cohort to date.
Clinical Implications:
In light of the finding that LA therapy has comparable outcomes to traditional chemotherapy, LA should be considered by clinicians caring for women with relapsed aGCTs. The 66% 6-month clinical benefit rate is similar to the disease control rate achieved with cytotoxic chemotherapy in our own comparator group (59%) as well as a previously published systematic review (60%).28 In our cohort as in others,16 significant toxicity was rare. Further research is needed to determine the optimal dose and frequency of LA administration for recurrent aGCT. Future research may also identify biomarkers, such as hormone or receptor expression in the tumor tissue, to predict responsiveness of aGCTs to LA treatment.
Research Implications:
Ultimately, these results warrant further investigation of LA for treatment of recurrent aGCTs in a prospective clinical trial. In the interim, when time and/or collaboration allows for studying larger patient populations, future cohort studies should focus on identifying patient, disease, or regimen characteristics associated with efficacy (or lack thereof) of LA-based therapy.
Strengths and Limitations:
This study fills a significant gap in knowledge regarding the outcomes of LA in treating recurrent aGCT. The major strength of this study is the sample size, which is large relative to prior studies of this treatment. The limitations are those inherent to observational studies including the possibility of selection bias and incomplete or inaccurate medical records. As reported, the patients in the chemotherapy cohort trended toward fewer recurrence or progression events and systemic treatment regimens prior to the index recurrence event compared to the LA cohort. This trend would tend to favor better outcomes in the chemotherapy group, as PFS typically decreases with each subsequent relapse.29 Finally, the LA courses were not standardized and thus this study includes a wide array of dosing schedules and combination regimens.
Conclusions:
In this first large cohort study of LA use in patients with recurrent GCTs, we found a clinically meaningful 6-month clinical benefit rate and only one discontinuation due to side effects. Despite a trend towards use later in the disease course, LA was not statistically different from traditional chemotherapy with respect to PFS. These results support the use of LA as a safe and effective treatment of relapsed aGCT in the second line and beyond.
AJOG at a Glance:
A. Why was this study conducted?
Mechanistic rationale and small case series support the use of the gonadotropin-releasing hormone agonist leuprolide acetate for the treatment of recurrent granulosa cell tumors; however, larger studies are needed to guide the clinical management of relapsed adult granulosa cell tumors.
B. What are the key findings?
In patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% and the median progression-free survival duration was 10.3 months, which was not significantly different compared to chemotherapy outcomes in the same setting. Serious adverse events were rare.
C. What does this study add to what is already known?
This study affirms the use of leuprolide acetate as a safe and effective treatment option for relapsed adult granulosa cell tumors in the second line and beyond.
Acknowledgements:
We thank Don Norwood, Scientific Editor, Research Medical Library, The University of Texas MD Anderson Cancer Center, for editing the manuscript.
Source of Funding:
This research was supported in part by Cancer Prevention & Research Institute of Texas grants RR2000045 (Dr. Hillman) and RP170593 (Dr. Handley), the NIH/NCI under award number P30CA016672, NIH T32 training grant CA101642 (Dr. Glassman), the Jennifer “Jenny” Song Fund for Granulosa Cell Tumor Research, The University of Texas MD Anderson Cancer Center Ovarian Cancer SPORE (NIH grant CA217685), the American Cancer Society (Dr. Sood), the Ovarian Cancer Research Alliance (Dr. Sood), and the Frank McGraw Memorial Chair in Cancer Research (Dr. Sood). Funding sources were not involved in designing the study; collection, analysis, or interpretation of data; writing the report; or the decision to submit the article for publication.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflicts of Interest: Dr. Sood is a consultant for Merck & Co., Inc., GSK, Kiyatec, and Onxeo and a shareholder in BioPath. All other authors report no conflict of interest.
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