A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.

BACKGROUND: Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant allele carriers versus wild type). METHODS: A systematic review/meta-analysis of original publications indexed in Ovid Medline, Ovid Embase, and the Cochrane CENTRAL (Wiley) library from inception to 7-Dec-2020. Eligible studies evaluated at least one pre-defined treatment outcome measures (toxicity/hospitalisations/survival/overall response/quality of life). RESULTS: Of 1090 identified publications, 17 met predefined eligibility criteria. The meta-analysis observed reduced incidence of grade 3/4 overall toxicity (Risk Ratio [RR] 0.32 [95% Cl 0.27-0.39], p < 0.00001) and grade 3/4 diarrhoea (RR 0.38 [95% Cl 0.24-0.61], p < 0.0001) among PGD versus non-PGD cohorts. Within PGD cohorts, there was no statistical differences for overall response rates (complete/partial) (RR 1.31 [95% Cl 0.93-1.85], p = 0.12). Similar results were found with stable disease (RR 1.27 [95% Cl 0.66-2.44], p = 0.47). CONCLUSION: PGD improves patient outcomes in terms of grade 3/4 toxicity, in particular overall toxicity and diarrhoea, without impacting on treatment response. REGISTRATION NUMBER: The study is registered with PROSPERO, registration number CRD42020223768.

The use of menopausal hormone therapy after cancer.

The changing landscape of gynaecological and breast cancers has involved the development of more targeted and effective therapies, and improved survival. Ultimately, these changes result in an increasing number of women surviving their cancer diagnosis, with increasing emphasis on quality-of-life issues by following treatments. Many of these women experience severe menopausal symptoms associated with cancer treatments, but the hormonal nature of many gynaecological and breast cancers complicates the effective management of these symptoms. Generally, there is a paucity of high-quality data directly examining the safety of menopausal hormone therapy (MHT) following many female cancers, and more research is needed with long term follow-up to ensure the provision of comprehensive, patient-focussed care. This article aims to synthesise and evaluate the current evidence to provide comprehensive yet accessible information to clinicians to help guide treatment decisions about the use of MHT in women, who have experienced, or are at increased risk of, both gynaecological and breast cancers. These treatment decisions should often be made in a multi-disciplinary setting which encourages shared decision-making with patients.

Menopausal hormone therapy in women with benign gynaecological conditions and cancer.

The efficacy of menopausal hormone therapy for bothersome menopausal symptoms is well established. However, there are a range of benign and malignant gynaecological conditions that pose a challenge in managing menopausal symptoms. Their hormone-dependent nature either raises concerns about symptom recurrence or malignant disease progression making decisions about menopausal hormone therapy complex for both clinicians and patients. It appears there is a small potential for symptom recurrence with menopausal hormone therapy use in menopausal women with a history of severe endometriosis. Malignant transformation of previous endometriotic lesions is likely to be rare but is not adequately understood. In this setting, combined hormone therapy is preferred, including in woman post-hysterectomy. Uterine fibroids are not a contraindication to menopausal hormone therapy use but women with large fibroids at menopause should have regular follow-up of their fibroids. Generally, menopausal hormone therapy is considered appropriate for women with cervical cancer and most ovarian cancers except for low grade serous tumours. Endometrial cancer requires an individualised discussion. The overall quality of data in this area is poor but suggests women with a low risk of recurrence may consider hormonal therapy, balancing symptom impact with prognosis.

Management of menopausal symptoms and ovarian function preservation in women with gynecological cancer.

Gynecological cancers affect a growing number of women globally, with approximately 1.3 million women diagnosed in 2018. Menopausal symptoms are a significant health concern after treatment for gynecological cancers and may result from oncologic treatments such as premenopausal bilateral oophorectomy, ovarian failure associated with chemotherapy or radiotherapy, and anti-estrogenic effects of maintenance endocrine therapy. Additionally, with the growing availability of testing for pathogenic gene variants such as BRCA1/2 and Lynch syndrome, there is an increasing number of women undergoing risk-reducing oophorectomy, which in most cases will be before age 45 years and will induce surgical menopause. Not all menopausal symptoms require treatment, but patients with cancer may experience more severe symptoms compared with women undergoing natural menopause. Moreover, there is increasing evidence of the long-term implications of early menopause, including bone loss, cognitive decline and increased cardiovascular risk. Systemic hormone therapy is well established as the most effective treatment for vasomotor symptoms and vaginal (topical) estrogen therapy is effective for genitourinary symptoms. However, the role of hormone receptors in many gynecological cancers and their treatment pose a challenge to the management of menopausal symptoms after cancer. Consequently, the use of menopausal hormone therapy in this setting can be difficult for clinicians to navigate and this article aims to provide current, comprehensive guidance for the use of menopausal hormone replacement therapy in women who have had, or are at risk of developing, gynecological cancer to assist with these treatment decisions.

Management of Early Menopause/Premature Ovarian Insufficiency in Women with or at High Risk of Breast Cancer.

The global incidence of breast cancer is increasing, as is the efficacy of treatments. Consequently, increasing survival rates reinforce the importance of survivorship issues, including posttreatment menopausal symptoms, sexual function, and mental health and well-being. Breast cancer patients can experience a range of menopausal symptoms associated with their treatment. Most commonly women may experience vasomotor symptoms, including hot flushes and night sweats. Particularly for women on maintenance tamoxifen therapy, up to 80% will experience hot flushes, with almost one-third of these women reporting severe symptoms. Breast cancer patients may also experience genitourinary symptoms of menopause, which may include vaginal dryness and irritation, dyspareunia, and dysuria. Hormonal therapy has long been established as the most effective treatment for vasomotor symptoms. However, the hormonal nature of breast malignancies renders systemic hormone therapies unsuitable for these patients, posing a unique treatment challenge, which may result in clinicians not feeling confident to manage them. Consequently, this review outlines pharmacological and nonpharmacological options for women with bothersome menopausal symptoms after breast cancer treatment and provides practical, evidence-based guidance for clinicians.

Botulinum toxin in women's health: An update.

Botulinum toxin, from the bacteria Clostridium botulinum, acts by block the pre-synaptic release of acetylcholine at the neuromuscular junction, resulting in temporary muscle paralysis. There are several clinically available formulations, the most extensively studied being of onabotulinumtoxinA. This article outlines three of the common clinical applications of onabotulinumtoxinA relevant to women's health: the management of symptoms of overactive bladder, chronic migraine and facial lines. Its safety and efficacy have been well demonstrated but very few studies have directly compared treatments. Further research is needed directly comparing therapies to help guide treatment choices and predict success.

Abnormal uterine bleeding: managing endometrial dysfunction and leiomyomas.

Abnormal uterine bleeding refers to any change in the regularity, frequency, heaviness or length of menstruation. There are several potential causes for bleeding disturbance, the two most common being primary endometrial dysfunction and fibroids. Management of abnormal uterine bleeding involves both medical and surgical options and will largely depend on a patient's fertility plans. The use of levonorgestrel-releasing intrauterine devices for heavy menstrual bleeding is increasing in Australia, and they are considered first-line medical management for women accepting of hormonal therapies. Tranexamic acid, non-steroidal anti-inflammatory drugs, the combined oral contraceptive pill and oral progestins offer alternatives. Hysterectomy offers a definitive surgical approach to abnormal uterine bleeding and is associated with high levels of patient satisfaction. Women wishing to preserve their fertility, or avoid hysterectomy, may be offered myomectomy. Submucosal fibroids should be removed via hysteroscopy in symptomatic or infertile patients. Intramural and subserosal fibroids may be removed via an open or laparoscopic approach. There are several minimally invasive options, including uterine artery embolisation, magnetic resonance-guided focused ultrasound and endometrial ablation, but patients should be aware that there is insufficient evidence to ensure fertility preservation with these procedures and further research is needed. Areas for additional research include cost-effectiveness of treatments and quality of life comparisons between management options using patient reported outcome measures to evaluate patient satisfaction.

Gynaecological care after stem cell transplant: An overview.

Haematopoietic stem cell transplants are an important treatment for haematological malignancies. With increasing efficacy of treatment, it has become important to provide comprehensive long-term follow-up by experienced specialists in a multidisciplinary setting. This article gives an overview of the gynaecological implications of haematopoietic stem cell transplants, including appropriate pre-treatment counselling, the development of menopausal symptoms, bone loss, genital graft-versus-host disease and secondary genital malignancies. The evidence surrounding the occurrence, symptoms and management of these complications is outlined based on current clinical guidelines where possible. Although high-level data regarding this specific patient population are generally lacking, observational data and data from other immunocompromised populations are discussed. This article provides a clear and clinically focused framework for care for clinicians involved in the gynaecological management of these patients and outlines areas for further research to improve patient care.

Managing menopausal symptoms after breast cancer - A multidisciplinary approach.

More than 6 million women worldwide are living with a past diagnosis of breast cancer. Most survive their illness, and management of the long-term consequences of treatment has become a priority in cancer care. Menopausal symptoms affect most breast cancer survivors and may significantly impair quality of life. We describe a multidisciplinary model to evaluate and manage these women using a patient-focused approach. The 'Multidisciplinary Menopause After Cancer Clinic' includes gynecologists, endocrinologists, GPs, a psychologist and a clinical nurse specialist. Benefits of this model include improved coordination of patient care, education, communication and evidence-based decision making.