Interventions for the treatment of Paget's disease of the vulva.

BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 10, 2013.Extramammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery. OBJECTIVES: To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and Embase (via Ovid) up to 8 May 2018. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and well-designed non-randomised studies that compared different interventions in women with Paget's disease of the vulva, DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, analysed no data. MAIN RESULTS: The search for the original version of the review identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease.This update between September 2013 and May 2018 identified 35 new studies. None of these met the inclusion criteria. There was only one prospective study of 5% imiquimod in recurrent Paget's disease of the vulva, which although of good quality only included eight women. AUTHORS' CONCLUSIONS: Since the last version of the review was published there are many more cases in the literature reporting a clinical response to 5% imiquimod cream. There is one prospective study of eight women treated with 5% imiquimod for recurrent Paget's disease of the vulva, and one prospective trial of 20 women was due to be reported. This increasing evidence for the safety and efficacy of 5% imiquimod will be helpful for women and clinicians alike. Ideally, a multicentre RCT of reasonable size is needed, but ongoing publications of high-quality non-randomised prospective studies will enhance the current available literature.

Hormone replacement therapy for women previously treated for endometrial cancer.

BACKGROUND: Endometrial cancer is the sixth most common cancer in women worldwide and most commonly occurs after the menopause (75%) (globocan.iarc.fr). About 319,000 new cases were diagnosed worldwide in 2012. Endometrial cancer is commonly considered as a potentially 'curable cancer,' as approximately 75% of cases are diagnosed before disease has spread outside the uterus (FIGO (International Federation of Gynecology and Obstetrics) stage I). The overall five-year survival for all stages is about 86%, and, if the cancer is confined to the uterus, the five-year survival rate may increase to 97%. The majority of women diagnosed with endometrial cancer have early-stage disease, leading to a good prognosis after hysterectomy and removal of the ovaries (oophorectomy), with or without radiotherapy. However, women may have early physiological and psychological postmenopausal changes, either pre-existing or as a result of oophorectomy, depending on age and menopausal status at the time of diagnosis. Lack of oestrogen can cause hot flushes, night sweats, genital tract atrophy and longer-term adverse effects, such as osteoporosis and cardiovascular disease. These changes may be temporarily managed by using oestrogens, in the form of hormone replacement therapy (HRT). However, there is a theoretical risk of promoting residual tumour cell growth and increasing cancer recurrence. Therefore, this is a potential survival disadvantage in a woman who has a potentially curable cancer. In premenopausal women with endometrial cancer, treatment induces early menopause and this may adversely affect overall survival. Additionally, most women with early-stage disease will be cured of their cancer, making longer-term quality of life (QoL) issues more pertinent. Following bilateral oophorectomy, premenopausal women may develop significant and debilitating menopausal symptoms, so there is a need for information about the risk and benefits of taking HRT, enabling women to make an informed decision, weighing the advantages and disadvantages of using HRT for their individual circumstances. OBJECTIVES: To assess the risks and benefits of HRT (oestrogen alone or oestrogen with progestogen) for women previously treated for endometrial cancer. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to April, week 4, 2017) and Embase (1980 to 2017, week 18). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs), in all languages, that examined the efficacy of symptom relief and the safety of using HRT in women treated for endometrial cancer, where safety in this situation was considered as not increasing the risk of recurrence of endometrial cancer above that of women not taking HRT. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 2190 unique records, evaluated the full text of seven studies and included one study with 1236 participants. This study reported tumour recurrence in 2.3% of women in the oestrogen arm versus 1.9% of women receiving placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.54 to 2.50; very low-certainty evidence). The study reported one woman in the HRT arm (0.16%) and three women in the placebo arm (0.49%) who developed breast cancer (new malignancy) during follow-up (RR 0.80, 95% CI 0.32 to 2.01; 1236 participants, 1 study; very low-certainty evidence). The study did not report on symptom relief, overall survival or progression-free survival for HRT versus placebo. However, they did report the percentage of women alive with no evidence of disease (94.3% in the HRT group and 95.6% in the placebo group) and the percentage of women alive irrespective of disease progression (95.8% in the HRT group and 96.9% in the placebo group) at the end of the 36 months' follow-up. The study did not report time to recurrence and it was underpowered due to closing early. The authors closed it as a result of the publication of the Women's Health Initiative (WHI) study, which, at that time, suggested that risks of exogenous hormone therapy outweighed benefits and had an impact on study recruitment. No assessment of efficacy was reported. AUTHORS' CONCLUSIONS: Currently, there is insufficient high-quality evidence to inform women considering HRT after treatment for endometrial cancer. The available evidence (both the single RCT and non-randomised evidence) does not suggest significant harm, if HRT is used after surgical treatment for early-stage endometrial cancer. There is no information available regarding use of HRT in higher-stage endometrial cancer (FIGO stage II and above). The use of HRT after endometrial cancer treatment should be individualised, taking account of the woman's symptoms and preferences, and the uncertainty of evidence for and against HRT use.

Interventions for the treatment of Paget's disease of the vulva.

BACKGROUND: Extra-mammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery. OBJECTIVES: To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to September 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles and contacted experts in the field. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and well-designed non-randomised studies that compared different interventions in women with Paget's disease of the vulva, DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, no data were analysed. MAIN RESULTS: The search strategy identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease. AUTHORS' CONCLUSIONS: We found no reliable evidence to inform decisions about different interventions for women with Paget's disease of the vulva. Ideally, a multicentre RCT of reasonable size is needed. In particular, evidence regarding the increasing use of imiquimod would be helpful to women and clinicians alike. Well-designed non-randomised studies, that use multivariate analysis to adjust for baseline imbalances, as well as other key methodological strengths, are also lacking.

The age of ovarian failure following premenopausal hysterectomy with ovarian conservation.

OBJECTIVE: To test the hypothesis that premenopausal hysterectomy compromises ovarian function and accelerates ovarian failure. DESIGN: Longitudinal prospective cohort study. Annual follow-up with serum follicle-stimulating hormone levels with all women being 46 years of age or less at the time of hysterectomy for benign disease. SETTING: Gloucestershire Royal Hospital, Gloucester, UK. PARTICIPANTS: Five hundred and thirty-one women recruited over a four-year period from 1994 to 1997. RESULTS: The median age of women in the study was 37 (range 22-46). Women had earlier ovarian failure after unilateral oophorectomy (hazard ratio 2.41, 95% confidence interval (CI) 1.44-4.04) and after vaginal hysterectomy (hazard ratio 2.04, 95% CI 1.33-3.14) compared with abdominal hysterectomy. The mean age of ovarian failure across all groups was 45.87 (+/-3.58), and 59 (11%) women remained in the study at the end of 10 years who had not yet entered the menopause. CONCLUSION: This is the largest number of cases collected prospectively looking at ovarian failure after hysterectomy. Earlier ovarian failure occurred in those women having unilateral oophorectomy or vaginal hysterectomy. Early ovarian failure was not confirmed across the study group with only 2% of women having confirmed ovarian failure by Kaplan-Meier estimate one year after surgery and 14% at five years.

Compliance with estrogen hormone replacement therapy after oophorectomy: a prospective study.

OBJECTIVE: To quantify compliance with using estrogen-only hormone replacement therapy (HRT) up until the time of mean age of natural menopause in women undergoing either bilateral oophorectomy or removal of one remaining ovary at the time of hysterectomy for benign disease. DESIGN: Prospective study. Annual questionnaire follow-up for ten years of women undergoing hysterectomy and bilateral oophorectomy for benign disease aged 46 or less at the time of surgery. SETTING: Gloucestershire Royal Hospital. PARTICIPANTS: Five hundred and twenty-one women recruited over a four-year period from 1994 to 1997. MAIN OUTCOME MEASURES: Compliance with HRT use, changes in HRT preparations and reasons for discontinuation. RESULTS: The median age of women at the time of hysterectomy was 42 (range 22-46) years; 4.9% (n = 24) stopped HRT within the first two years and 16.5% (n = 86) by the end of the study. The majority of women were prescribed HRT tablets (253, 48%) and the next most common being patches. In total, there were 1271 episodes of changing HRT, with the range between 0 and 18 changes per woman over the ten-year period. In all, 32% of changes were to a different route of HRT, 19% were to a different preparation of the same route, 18% were to an increased dose of the same preparation and 7% were to a decreased dose of the same preparation. CONCLUSIONS: Compliance with HRT use was high throughout the study, although responses decreased after five years. Change to HRT preparations was consistently high across all preparations. Women requiring HRT after surgical menopause need to be supported in finding the right preparation for them.