UvA-DARE (Digital Academic Repository) Improving treatment strategies in ovarian cancer: Towards individualized patient care van Meurs, H.S. Publication date 2015 Document Version Final published version Link to publication Citation for published version (APA): van Meurs, H. S. (2015). Improving treatment strategies in ovarian cancer: Towards individualized patient care. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:28 Sep 2021 Chapter 5 Hormone therapy in ovarian granulosa cell tumors: A systematic review H.S. van Meurs L.R.C.W. van Lonkhuijzen J. Limpens J. van der Velden M.R. Buist Gynecologic Oncology. 2014 Jul; 134(1):196-205 76 Chapter 5 ABSTRACT Objective This systematic review assessed the effectiveness of hormone therapy (HT) in patients with a granulosa cell tumor (GCT) of the ovary. Methods 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. Results 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). Conclusions 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. Systematic review of hormone therapy in GCT 77 INTRODUCTION An ovarian granulosa cell tumor (GCT) is a rare gynecological malignancy with an incidence of 0.61 cases per 100,000 women per year.1 The standard treatment for early stage disease is surgical excision of the tumor and due to the presence of endometrial abnormalities a total abdominal hysterectomy and bilateral salpingo-oophorectomy is often performed. Most patients present with stage I disease, with an excellent short term prognosis. However in the long term the disease often recurs which results in a 20-year survival rate of 67%.2 For advanced stage GCTs and recurrent tumors, viable treatment options are limited and the optimal treatment has not been established. If the tumor is not resectable, platinum-based chemotherapy is generally used, but with conflicting results.3 Furthermore, radiotherapy treatment has been proposed by some, but the results are controversial and not widely accepted. Several previous studies have reported responses while others have found no clear value to its use.4-7 To improve disease-free intervals and survival, and also quality of life, alternative treatment strategies are needed. 5 As GCTs generally express steroid hormone receptors, hormone treatment has been suggested as a potential treatment option, with promising results.8-12 In contrast to chemotherapy and radiotherapy, hormone therapy is generally well tolerated and can be administered for longer time periods without serious side effects.13 This systematic review aims to identify and evaluate all cases of hormonal treatments of patients with an ovarian GCT, in order to assess and quantify the evidence for or against the beneficial effects of hormonal GCT treatment. We also examined possible differences in effect between hormonal treatments. To our knowledge, this is the first systematic review on this topic. 78 Chapter 5 PATIENTS AND METHODS Search strategy This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.14 An expert librarian (JL) searched the following databases from inception till January 13, 2014: MEDLINE (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), complemented with a search of PubMed to find recent studies not yet available in OVID MEDLINE. The exhaustive search strategy consisted of Subject Headings (MeSH, SH) and words in title and abstract for GCT and different kinds of hormonal therapy. No language restrictions or methodological filters were used. The search included an iterative process to refine the search strategy through adding search terms as new relevant citations were identified and reference checking of relevant trials or systematic reviews. The bibliographic records retrieved were imported and deduplicated using Reference Manager® software (version 12.0). The full electronic search strategy for MEDLINE is provided in the supplementary data (see Appendix A). The searches for the other databases are provided by the authors upon request. Study selection All studies describing the effect of hormone therapy in individual patients with measurable GCT, gynandroblastoma and granulosa theca cell tumors were eligible. The design or number of reported patients was no exclusion criteria, because of the scarcity of data available from large, prospective, randomized trials on this rare tumor. Narrative reviews were excluded. If hormone therapy was administered as adjuvant treatment only, the study was excluded. Two reviewers (HM and LL) independently assessed all titles and abstracts of identified citations for eligibility. Reference lists of included papers and relevant systematic reviews were scanned to identify additional studies. Duplicate publications were excluded. Eligibility criteria were also independently applied by the same reviewers to the full text of each study that was potentially eligible. Disagreements were resolved by consensus at each stage. Data extraction A standardized, pilot-tested data extraction form was used. Data on authors, journal, publication year, study design, number of included patients, number of total hormone therapies, initial presentation of disease, initial treatment of disease, stage, age at diagnosis, dose, type and moment of administration of hormone therapy, duration of and maximum response to hormone treatment, progression free survival (PFS), overall survival (OS), follow-up time and hormone receptor status were recorded. Systematic review of hormone therapy in GCT 79 Statistical analysis The primary outcome for this review was the objective response rate (ORR) to hormone therapy in patients with a GCT. Secondary outcomes were PFS, OS and the ORR to specific hormone therapies. Complete response was defined as either the disappearance of all clinical or radiological evidence of tumor, normalization of tumor marker inhibin or when complete response was described in the study. To describe tumor response we applied Response Evaluation Criteria in Solid Tumors (RECIST) if possible based on the tumor measurements supplied by authors.15 If these were not available we used the definitions as used by authors. As such a partial response was defined as a decrease of 30% or more in the sum of the longest diameter of target lesions or when partial response was described in the study. Progressive disease was defined as a 20% or greater increase in the sum of the longest diameter of target lesions or a description of progressive disease in the study. Stable disease was defined as disease not meeting any of the above mentioned criteria, meaning progressive disease of less than 20% or response of less than 30% in the sum of the longest diameter of target lesions or a description of stable disease in the study. For the patient analysis, the unit of all calculations is the patient, which means that if a 5 patient received more than one hormone therapy, these were not considered separately. The hormone therapy with the maximum response was used for analysis. For the hormone therapy analysis, the unit of calculations is all the evaluated hormone therapies and each hormone therapy is considered separately. We calculated the proportion of responders to describe the ORR defined as the proportion of patients whose best overall response to hormone therapy was either complete response or partial response. Because of the indolent nature of GCTs clinical benefit rate was not used and therefore