Claudia Marchetti

The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis

STUDY QUESTION Does surgical treatment of endometriomas impact on the ovarian reserve as evaluated with antral follicle count (AFC)? SUMMARY ANSWER This meta-analysis of published data shows that surgery for endometrioma does not significantly affect ovarian reserve as evaluated by AFC. WHAT IS KNOWN ALREADY Surgical excision of an ovarian endometrioma significantly affects ovarian reserve evaluated with anti-Mullerian hormone (AMH) levels. Data for other reliable markers of ovarian reserve, such as AFC, have not been pooled in meta-analyses. STUDY DESIGN, SIZE, DURATION A systematic review with electronic searches of PubMed, MEDLINE and Embase up to April 2014 was conducted to identify articles evaluating AFC before and after surgery for ovarian endometriomas, or before or after surgery for the affected versus the contralateral ovary. PARTICIPANTS/MATERIALS, SETTING, METHODS Of the 24 studies evaluated in detail, 13 were included for data extraction and meta-analysis, including a total of 597 patients. The primary outcome at pooled analysis was AFC (mean and SD) for affected ovaries before and after surgery. Secondary outcomes were AFC for the affected ovary versus the contralateral ovary before surgery, and AFC for the operated versus the contralateral ovary after surgery. The data were pooled using the RevMan software by the Cochrane Collaboration. Heterogeneity between studies was based on the results of the χ(2) and I(2) statistics. A random-effect model was used for the meta-analysis because of high heterogeneity between studies. MAIN RESULTS AND THE ROLE OF CHANCE AFC for the operated ovary did not change significantly after surgery (mean difference 0.10, 95% CI -1.45 to 1.65; P = 0.90). Lower AFC for the diseased ovary compared with the contralateral one was present before surgery, although the difference was not significant (mean difference -2.79, 95% CI -7.10 to 1.51; P = 0.20). After surgery, the operated ovary showed a significantly lower AFC compared with the contralateral ovary (mean difference -1.40, 95% CI -2.27 to -0.52; P = 0.002). LIMITATIONS, REASONS FOR CAUTION Heterogeneity among the selected studies was high; therefore, limiting the conclusions of the present systematic review. WIDER IMPLICATIONS OF THE FINDINGS Ovarian reserve evaluated with AFC is not reduced after surgical treatment of an endometrioma. A lower AFC is present for the affected ovary both before and after surgery. Recently, concerns have been raised as to the reliability of AMH as a marker of ovarian reserve. Based on the present findings, surgical treatment of an endometrioma may be considered safer for the ovarian reserve than previously thought. STUDY FUNDING/COMPETING INTERESTS No external funding was sought or obtained for this study. No conflicts of interest are declared.

Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers.

BackgroundWomen with BRCA1 and BRCA2 mutation carriers are at substantially elevated risk of developing ovarian cancer. The aim of the meta-analysis is to clarify the role of risk-reducing salpingo-oophorectomy (RRSO) to reduce ovarian cancer risk and mortality in women with BRCA 1 and BRCA 2 mutation carriers.MethodsPubmed, Medline and Scopus were searched to select English-language articles. Two investigators independently extracted characteristics and results of selected studies. Articles were included only if prospective and if absolute numbers of ovarian cancer and death events were available or derivable from the test. Pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using fixed effects model.ResultsMeta-analysis of 3 prospective studies demonstrated a significant risk reduction of ovarian cancer with RRSO in BRCA 1 and BRCA 2 mutation carriers, as well as benefit in all-causes mortality incidence.ConclusionsIt may be justified to recommend RRSO to reduce ovarian cancer risk and all-causes mortality in women with a mutation in BRCA 1 and BRCA 2.

Targeted drug delivery via folate receptors in recurrent ovarian cancer: A review

Ovarian cancer is the most common cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease; although chemotherapeutic advances have improved progression-free survival, conventional treatments offer limited results in terms of long-term responses and survival. Research has recently focused on targeted therapies, which represent a new, promising therapeutic approach, aimed to maximize tumor kill and minimize toxicity. Besides antiangiogenetic agents and poly (ADP-ribose) polymerase inhibitors, the folate, with its membrane-bound receptor, is currently one of the most investigated alternatives. In particular, folate receptor (FR) has been shown to be frequently overexpressed on the surface of almost all epithelial ovarian cancers, making this receptor an excellent tumor-associated antigen. There are two basic strategies to targeting FRs with therapeutic intent: the first is based on anti-FR antibody (ie, farletuzumab) and the second is based on folate–chemotherapy conjugates (ie, vintafolide/etarfolatide). Both strategies have been investigated in Phase III clinical trials. The aim of this review is to analyze the research regarding the activity of these promising anti-FR agents in patients affected by ovarian cancer, including anti-FR antibodies and folate–chemotherapy conjugates.

First-line treatment of advanced ovarian cancer: current research and perspectives

Epithelial ovarian cancer is the fourth biggest cause of cancer-related death in women. Over recent decades, improvements have been made in treatment outcome in terms of response rate and survival. To date, intensive surgical staging and cytoreduction, followed by primary chemotherapy with the carboplatin–paclitaxel regimen, are considered the gold standard for the management of this disease. Nevertheless, despite good initial response to systemic therapy after optimal debulking surgery, the long-term survival remains poor, with a high risk of recurrence. Furthermore, medical therapy of ovarian cancer impacts quality of life owing to the common occurrence of chemotherapy side effects, such as alopecia, neurotoxicity and fatigue. In order to improve the efficacy and reduce the toxicity of first-line chemotherapy, more than 10,000 women have been involved in worldwide randomized trials in the last 10 years. Several treatment alternatives have been investigated, such as intraperitoneal chemotherapy, alternative doublets and triplet regimens, in the effort to find an optimal first-line treatment strategy. In this review we discuss the results of these trials, the recent progresses and the most important ongoing studies, including those with emerging target and biological agents.

Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression

Surgery is the primary therapeutic strategy for most solid tumours; however, modern oncology has established that neoplasms are frequently systemic diseases. Being however a local treatment, the mechanisms through which surgery plays its systemic role remain unknown. We have investigated the influence of cytoreduction on the immune system of primary and recurrent ovarian cancer. All ovarian cancer patients show an increase in CD4+CD25+FOXP3+ circulating cells (CD4 Treg). CD4/CD8 ratio is increased in primary tumours, but not in recurrent neoplasms. Primary cytoreduction is able to increase circulating CD4 and CD8 effector cells and decrease CD4 naïve T cells. CD4+ Treg cells rapidly decreased after primary tumour debulking, while CD8+CD25+FOXP3+ (CD8 Treg) cells are not detectable in peripheral blood. Similar results on CD4 Treg were observed with chemical debulking in women subjected to neoadjuvant chemotherapy. CD4 and CD8 Treg cells are both present in neoplastic tissue. Interleukin (IL)‐10 serum levels decrease after surgery, while no changes are observed in transforming growth factor‐β1 and IL‐6 levels. Surgically induced reduction of the immunosuppressive environment results in an increased capacity of CD8+ T cells to respond to the recall antigens. None of these changes was observed in patients previously subjected to chemotherapy or affected by recurrent disease. In conclusion, we demonstrate in ovarian cancer that primary debulking is associated with a reduction of circulating Treg and an increase in CD8 T‐cell function. Debulking plays a beneficial systemic effect by reverting immunosuppression and restoring immunological fitness.

Simple extrafascial trachelectomy and pelvic bilateral lymphadenectomy in early stage cervical cancer.

OBJECTIVE To determine the feasibility and safety of simple extra-fascial trachelectomy plus pelvic lymphadenectomy in young patients affected by early stage cervical cancer. METHODS We have prospectively identified all patients with early-stage cervical cancer (stages IA2-IB1) referred to our department. Inclusion criteria were: age ≤ 38 years, strong desire to maintain fertility, FIGO stage ≤ IB1, tumor size<2 cm, no LVSI, no evidence of nodal metastasis. Surgical technique included two steps: laparoscopic pelvic lymphadenectomy and vaginal simple extrafascial trachelectomy. Patients were followed up for oncological and obstetrical outcomes. RESULTS Fourteen patients were enrolled in the study. Median age was 32 years (range 28-37); histotype was squamous in 11/14 (79%) cases and adenocarcinoma in 3/14 cases (21%); FIGO stage was IA2 in 5/14 (36%) patients, IB1 in 9/14 (64%) patients; median tumor size was 17 mm (range 14-19); median operative time was 120 min (range 95-210). No severe intraoperative complications were recorded. Postoperative complications were observed in two patients. No recurrences were detected. One patient died for other disease. Eight patients became pregnant and 3 of them had a term delivery. CONCLUSION Low risk early-cervical cancer patients could be safely treated by simple extrafascial trachelectomy in order to maintain fertility. More studies are needed to better define the role of conservative and ultraconservative surgical approaches (i.e. conization) in this setting, either for fertility purposes or to minimize surgical complications.

Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors

Ovarian cancer is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies to improve the outcomes. Advances in understanding the role of immune system in the pathogenesis of cancer have led to the rapid evolvement of immunotherapy, which might establish a sustained immune system response against recurring cancer cells. Recently, it has emerged that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called “immune checkpoints,” which turn off the immune system. Similarly, cancer cells are able to use these checkpoints to avoid immune control and rejection. Inhibition of these inhibitory pathways represents a potent strategy in the fight against cancer and is currently under investigation with encouraging results in some cancers, such as melanoma. In ovarian cancer researches are still in an early phase, but with promising results. In this review we will explore the rationale of immunotherapy in ovarian cancer with a special focus on these emerging molecules.

Olaparib, PARP1 inhibitor in ovarian cancer

Introduction: Ovarian cancer is the most important cause of gynecological cancer-related mortality. Conventional treatments for advanced or recurrent disease offer limited results in terms of long-term responses and survival. Researches have recently focused on target therapies, which represent a new, promising, therapeutic approach, able to maximizing tumor kill and minimizing toxicity. The family of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors is currently one of the most hopeful and investigated alternatives. Areas covered: Preclinical and clinical studies of Olaparib, the most investigated PARP inhibitor in ovarian cancer, are analyzed and discussed. Data were obtained by searching for all English peer-reviewed articles on Medline, on Cochrane Database and all on-going Phase I and II studies registered on National Cancer Institute Clinical Trials; also any related abstracts recently presented on Olaparib at major international congresses will be included. Expert opinion: Bad prognosis and drug resistance usually affect ovarian cancer. Recent trends toward the knowledge of molecular-specific pathways have produced new target drugs. PARP inhibition mediated by Olaparib in BRCA1 (breast cancer 1) and BRCA2 (breast cancer 2)-mutated and in sporadic ovarian cancer represents a promising field of investigation. Further studies are needed to confirm initial exciting results.

Current knowledge and open issues regarding Bevacizumab in gynaecological neoplasms

In the last fifty years the combining of different drugs has progressively improved response and survival rates in gynaecological malignancies. Results are, however, far from being satisfactory. Treatments used in cases of advanced or recurrent disease offer limited results in terms of long-term responses and the urgent need for new drugs has prompted researchers to investigate and propose new therapeutic modalities. One of the most important avenues that are being explored is represented by monoclonal antibodies (MoAb) directed against Vascular Endothelial Growth Factor (VEGF). Several antibodies against this target are now available and Bevacizumab appears to be one of the most promising agents. VEGF has been confirmed as an important therapeutic target in several clinical trials and in multiple disease settings, including gynaecological cancers, for its biological and clinical significance in tumour angiogenesis. The binding and blocking of VEGF growth factor is the basis of tumour growth inhibition, since angiogenesis is essential in the process of tumour growth and progression. Several clinical trials have utilized this agent successfully, either alone or in combination with other drugs. Despite initial concerns, adverse reactions have not been significant with side effects being more tolerable than those associated to conventional chemotherapy. Furthermore, the limited toxicity profile of this, as well as other target therapies, allows it to be combined with cytotoxic drugs without the requirement for a significant dose reduction of the latter. This review outlines the rationale for studying this anti-angiogenetic compound, summarizing the existing and emerging clinical evidence related to the use of Bevacizumab in the treatment of gynaecological malignancies, focusing on its potential benefits and adverse effects.

Hormone therapy in oophorectomized BRCA1/2 mutation carriers.

ObjectiveBRCA1/2 mutation carriers have greatly elevated lifetime risks of breast, ovarian, and fallopian tube cancers. Bilateral prophylactic salpingo-oophorectomy is recommended to prevent cancer in these women. As it is often performed before natural menopause, it may be accompanied by menopausal symptoms, impaired quality of life, and increased cardiovascular risk. MethodsIn this review, we describe the indications, timing, and implications of salpingo-oophorectomy for BRCA-positive women, with a special focus on the risks and benefits of hormone therapy (HT). Furthermore, retrospective and prospective trials of HT in BRCA mutation carriers undergoing prophylactic salpingo-oophorectomy are debated. ResultsHormonal deprivation after prophylactic salpingo-oophorectomy may negatively impact health and quality of life; most women experience menopausal symptoms shortly after surgical operation. Literature data suggest that HT generally reduces vasomotor symptoms related to surgical menopause, improving sexual functioning without affecting survival. ConclusionsDespite the limitations of retrospective and prospective observational studies, short-term HT seems to improve quality of life and does not seem to have an adverse effect on oncologic outcomes in BRCA1 and BRCA2 mutation carriers without a personal history of breast cancer. Therefore, randomized and larger trials are urgently needed.