Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis.

STUDY QUESTION: Which factors related to patient, treatment or disease are associated with ovarian function recovery after chemotherapy in premenopausal women with breast cancer? SUMMARY ANSWER: Younger age and GnRH agonist (GnRHa) administration during chemotherapy were significantly associated with menses recovery, but this recovery was less likely in patients exposed to taxanes. WHAT IS ALREADY KNOWN: To date, published meta-analyses have only assessed GnRHa administration as a possible factor for ovarian function recovery, and their results were conflicting. Current guidelines present distinct recommendations regarding the use of GnRHa for fertility preservation (FP) in women with breast cancer. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis of published studies in the English, Portuguese, French or Spanish languages (1990-2015), ongoing trials or completed trials (1990-2015) and conference proceedings (2000-2015) were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched the MEDLINE, Embase, LILACS, Scielo, Toxline and DART databases, online trial registries and conference proceedings. Studies were eligible if they included premenopausal women with early breast cancer treated with chemotherapy, reported ovarian function recovery data and identified factor(s) associated with recovery. Two authors independently screened the studies, extracted data and assessed the risk of bias. An odds ratio (OR) was estimated from the number of recovery events. A meta-analysis was conducted using a random-effects model. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen articles were included. Five different factors were analysed: younger age and baseline levels of anti-Müllerian hormone (patient-related factors), co-administration of GnRHa, addition of taxanes to anthracycline-based chemotherapy and addition of endocrine therapy to chemotherapy (treatment-related factors). Menses recovery was the most used marker. Younger age (≤40 years) and exposure to GnRHa were positively associated with menses recovery (OR 6.07 and 2.03, respectively) but exposure to taxanes adversely affected recovery (OR 0.49). Significant heterogeneity among studies was found. LIMITATIONS, REASONS FOR CAUTION: A general limitation of the included studies is the use of menses as the main recovery marker. Regarding GnRHa, the substantial heterogeneity and conflicting results limit the interpretation of our results. Studies that use additional markers and have a longer follow-up are needed. WIDER IMPLICATIONS OF THE FINDINGS: The decision for using chemotherapy regimens with taxanes must take into account their potential adverse effects on female fertility. Considering the conflicting results regarding GnRHa agonist use, other fertility preservation strategies should also be considered. STUDY FUNDING/COMPETING INTERESTS: No external funding was received. There are no conflicts of interest to declare. PROSPERO REGISTRATION NUMBER: This review was registered at PROSPERO (CRD42015013494).

Adverse reproductive health outcomes in a cohort of young women with breast cancer exposed to systemic treatments.

BACKGROUND: Breast cancer is the most common cancer in young women. Fortunately current survival rates of BC are significant which makes future fertility very important for quality of life of BC survivors. Chemotherapy carries a significant risk of infertility in BC patients so it is important to support fertility preservation decisions in premenopausal women. Amenorrhea has long been used as a surrogate marker of infertility in cancer patients but more reliable ovarian reserve (OR) markers are available. This study aimed to prospectively measure levels of OR in a cohort of young women with breast cancer exposed to chemotherapy, to identify adverse reproductive health outcomes in this population and to assess the influence of patient and treatment-related factors in those outcomes. METHODS: This prospective observational study included premenopausal women with breast cancer aged 18-40 years at diagnosis and proposed for (neo) adjuvant chemotherapy. Patients were evaluated before, during and a minimum of 9 months after the end of chemotherapy. Reproductive health outcomes: menses, hormonal and ultrasound OR markers, recovery of ovarian function and Premature Ovarian Insufficiency (POI). RESULTS: A total of 38 patients were included (mean age 32.9 ± 3.5 years). Levels of OR significantly decreased during the study. At the last follow up, 35 patients had AMH below the expected values for age; eight presented postmenopausal FSH; ten had not recovered their ovarian function and five met the defined criteria for POI. Age and baseline AMH were positively correlated with AMH at the last follow-up. AMH levels were higher in the group of patients treated with trastuzumab and lower in those under hormonal therapy, at the last follow-up. CONCLUSIONS: Significant effects of systemic treatments on several reproductive outcomes and a strong relation of those outcomes with patient's age and baseline level of AMH were observed. Our results point to a possible lower gonadotoxicity when treatment includes targeted therapy with trastuzumab. Also, this investigation highlights the lack of reliable OR markers in women under hormonal therapy.

Antineoplastic Agents and (In)fertility: Informing Patients to Improve Decisions.

PURPOSE: Infertility is a potential adverse effect of cancer treatment, and future fertility is an important issue for cancer patients. In Portugal, the Centre for Fertility Preservation of CHUC, EPE, conducted a project to develop and disseminate oncofertility information resources. In this study, we report the results of the specific component of this program, which intended to produce information resources that promote patients' awareness of the subject and to support decisions concerning fertility preservation. METHODS: Guidance for writing health information for patients and criteria for developing decision aids were gathered. Information needs were assessed (literature review and locally applied questionnaire). Resources were pre-tested with a sample of patients and professionals. Their readability, presentation quality, and ability to support decisions were evaluated. RESULTS: General information handouts on infertility risk and decision aids about fertility preservation options were developed and positively evaluated. The resources are currently being distributed in collaboration with several national organizations. CONCLUSIONS: Through our multidisciplinary information program, reproductive-age cancer patients now have access to relevant information resources that will support timely, shared decision-making concerning fertility preservation.

Hepatic and renal toxicities of indomethacin acid, salt form and complexed forms with hydroxypropyl-ß-cyclodextrin on Wistar rats after oral administration.

Indomethacin (IM), a non-steroidal anti-inflammatory drug, has the capacity to induce hepatic and renal injuries when administrated systemically. The aim of this study is to assess the IM absorption from complexed forms when orally administered to rats, by means of a comparative evaluation of its capacity to induce hepatic and renal injury in different forms, namely IM acid, IM sodium salt or IM complexed with hydroxypropyl-ß-cyclodextrin (HP-ß-CD), using freeze- and spray-drying methods. A total of 135 Wistar rats weighing 224.4 ± 62.5 g were put into 10 groups. They were allowed free access to water but were maintained on fast for 18 h before the first administration until the end of the experiment. Water and HP-ß-CD (control groups) and IM acid form, IM trihydrated-sodium-salt and IM-HP-ß-CD spray- and freeze-dried, at normal and toxic doses (test groups), were orally administered once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and a fragment of the liver and one kidney were collected and prepared for histopathological evaluation. Lesion indexes (rated 0/4 for liver and 0/3 for kidney) were developed and the type of injury scored according to the severity of damage. A statistical analysis of the severity and incidence of lesions was carried out. Animals administered with IM complexed forms showed similar hepatic and renal lesions, both in toxic and therapeutic doses, when compared with those observed in animals administered with IM acid or salt forms. This suggests that under the present experimental conditions, IM is equally absorbed from the gastrointestinal tract, independently of the administered IM form.