Role of Retinoblastoma Protein Family (Rb/p105 and Rb2/p130) Expression in the Histopathological Classification of Borderline Ovarian Tumors.

Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. The identification of valuable markers for the diagnosis and classification of these tumors is in need. Among the molecular candidates, the Retinoblastoma (Rb) family members Rb/p105 and Rb2/p130 seem to play a pivotal role in ovarian cancer. In particular, Rb/p105, when in the unphosphorylated form, acts as a growth suppressor controlling cell cycle and tumor progression; whereas, the phosphorylated form activates gene transcription and cellular proliferation. While Rb/p105 is ubiquitously confined to the nuclei of cycling and quiescent cells, Rb2/p130 activity is also regulated by intracellular localization. According to this, Rb family members could represent a novel marker in diagnosis and classification risk for patients with BOT. In this study, we evaluated the expression and subcellular localization of proteins of the retinoblastoma (Rb) gene family in 65 ovarian borderline tumors. Statistically significant differences were found in nuclear and cytoplasmic expressions of Rb/p105 and Rb2/p130 according to different examined histotypes. In detail, the nuclear expression of Rb/p105 and Rb2/p130 was more frequently detected in serous (84.6%) than sero-mucinous (42.1%) and mucinous (50%) types. Conversely, the cytoplasmic expression of Rb2/p130 was not detected in serous tumors and frequently observed in mucinous subtypes (80%). Our findings suggest that Rb proteins do not play a key role in the tumor progression of serous borderline tumors since any cases showed cytoplasmic localization. By contrast, the observed higher cytoplasmic expression of Rb2/p130 in intestinal mucinous BOTs is indicative of Rb protein family involvement in the cancerogenesis pathway of mucinous ovarian tumors. Also, mucinous BOTs of intestinal-type, exhibiting low nuclear and high cytoplasmic levels of Rb2/p130 might potentially be considered a high-risk category of malignant evolution. Further studies on larger series are needed to clarify how BOTs could be stratified in different prognostic groups according to their Rb proteins immunohistochemical profile.

ToleRability of BevacizUmab in elderly Ovarian cancer patients (TURBO study): a case-control study of a real-life experience.

OBJECTIVE: Bevacizumab maintenance following platinum-based chemotherapy is an effective treatment for epithelial ovarian cancer (EOC), both in primary and recurrent disease. Our aim was to identify criteria to select elderly patients who can safely benefit from bevacizumab addition. METHODS: This is a case-control study on patients with primary or recurrent EOC who received platinum-based chemotherapy plus bevacizumab, between January 2015 and December 2016. Patient characteristics, treatment details and adverse events were reviewed and analyzed in 2 settings: younger (<65 years, group 1) and elderly (≥65 years, group 2). A binary logistic model was applied to correlate clinical variables and severe (grade ≥3) toxicity risk. RESULTS: Overall, 283 patients with EOC were included, with 72 (25.4%) older patients compared with 211 (74.6%) younger women. Bevacizumab had been administered to 234 patients (82.7%) as first-line treatment and in 49 (17.3%) with recurrent disease. At diagnosis, elderly patients presented with at least one comorbidity and were taking at least 1 medication in 84.7% and 80.6% of the cases respectively, compared with correspondingly 47.4% and 37.4% in group 1 (p<0.001). Nonetheless, the occurrence of serious (grade ≥3) adverse events did not increase among the older group. Creatinine serum levels >1.1 g/dL, estimated glomerular filtration rate (eGFR) ≤60 mL/min, ≥3 comorbidities were independently associated with a higher severe toxicity. CONCLUSIONS: Elderly patients with EOC can safely be treated with bevacizumab; factors other than age, as higher creatinine serum levels, eGFR and number of comorbidities should be considered to better estimate bevacizumab-related toxicity risk.

The MITO CERV-2 trial: A randomized phase II study of cetuximab plus carboplatin and paclitaxel, in advanced or recurrent cervical cancer.

BACKGROUND: Cervical cancer cells often express Epidermal Growth Factor Receptor (EGFR). Cetuximab (CET), an anti-EGFR antibody, can be safely combined with carboplatin (C) and paclitaxel (P), a standard treatment for advanced/recurrent cervical cancer (ARCC) patients. PATIENTS AND METHODS: ARCC patients, ECOG PS ≤ 1, were randomized to CP for 6 cycles with or without CET (400 mg/m2 one week before starting CP, then 250 mg/m2 weekly) until disease progression or unacceptable toxicity. Event-free survival (EFS) was the primary endpoint. With a 4.5 months expected median EFS and a 6.4 months predicted EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis. RESULTS: 108 patients were assigned to CP (n = 53) or CP-CET (n = 55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. After a median follow-up of 23 months, 102 patients had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0 months (one-tail P = 0.43), median PFS was 5.2 and 7.6 months (one-tail P = 0.20) and median OS was 17.7 and 17 months (one-tail P = 0.27), with CP and CP-CET, respectively. There was no difference in the occurrence of severe adverse events, except for skin toxicity. Biomarker analysis, in a small subgroup of patients, suggests that PIK3CA mutation might be predictive of CET resistance. CONCLUSION: CP-CET was not more active than CP alone in unselected ARCC patients.

Bilateral Salpingo-Oophorectomy Versus GnRH Analogue in the Adjuvant Treatment of Premenopausal Breast Cancer Patients: Cost-Effectiveness Evaluation of Breast Cancer Outcome, Ovarian Cancer Prevention and Treatment.

BACKGROUND AND OBJECTIVE: There is no available evidence to recommend gonadotropin-releasing hormone (GnRH) analogue-based ovarian suppression versus bilateral salpingo-oophorectomy (BSO) in the adjuvant treatment of early breast cancer, since the two approaches are considered equivalent in terms of oncologic outcome. The role of surgical ovarian ablation has been revitalized based on the advances of minimally invasive surgery, and a better understanding of clinical and molecular basis of hereditary breast/ovarian cancer syndromes. The aim of this study is to analyze the cost-effectiveness of laparoscopic BSO and GnRH analogue administration in patients aged 40-49 years with hormone-sensitive breast cancer. METHODS: A probabilistic decision tree model was developed to evaluate costs and outcomes of ovarian ablation through laparoscopic BSO, or ovarian suppression through monthly injections of GnRH analogue. Results were expressed as incremental costs per quality-adjusted life years (QALYs) gained. RESULTS: Laparoscopic BSO strategy was associated with a lower mean total cost per patient than GnRH treatment, and considering the difference in terms of QALYs, the incremental effectiveness did not demonstrate a notable difference between the two approaches. From the National Health Service perspective, and for a time horizon of 5 years, laparoscopic BSO was the dominant option compared to GnRH treatment; laparoscopic BSO was less expensive than GnRH, €2385 [95% confidence interval (CI) = 2044, 2753] vs €7093 (95% CI = 3409, 12,105), respectively, and more effective. CONCLUSION: Surgical ovarian ablation is more cost-effective than GnRH administration in the adjuvant treatment of hormone-sensitive breast cancer patients aged 40-49 years, and the advantage of preventing ovarian cancer through laparoscopic BSO should be considered.

Real-World Management of Trabectedin/Pegylated Liposomal Doxorubicin in Platinum-Sensitive Recurrent Ovarian Cancer Patients: A National Survey.

BACKGROUND: Trabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients. METHODS: We carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians' approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions. RESULTS: Fifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients' choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%. CONCLUSIONS: This survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs.

Neoadjuvant Chemotherapy Followed by Maintenance Therapy With or Without Bevacizumab in Unresectable High-Grade Serous Ovarian Cancer: A Case-Control Study.

OBJECTIVE: The aim of this study was to compare the toxicity, perioperative outcomes of interval debulking surgery (IDS), and duration of progression-free survival (PFS) in women with unresectable high-grade serous advanced ovarian cancer (AOC) receiving neoadjuvant chemotherapy (NACT) with or without bevacizumab. METHODS: Twenty-five patients with high-grade serous AOC treated with bevacizumab-based NACT (cases) were matched according to initial disease extension assessed by laparoscopy, and age, in a 1:2 ratio, with 50 high-grade serous AOC patients treated with standard NACT without bevacizumab (controls). RESULTS: Both groups received a median of four NACT cycles before IDS (p = 0.867), and the median time interval between NACT and IDS was 27 days in both groups (p = 0.547). Twenty-two cases (88.0 %) showed complete/partial radiologic response compared with 36 controls (72.3 %; p = 0.054). A higher percentage of cases showed complete serological response (48 vs. 35.1 %; p = 0.041). At IDS, complete cytoreduction was achieved in 20 cases (80.0 %) and 36 controls (72.3 %) [p = 0.260]. No differences were observed between groups in terms of surgical complexity score, perioperative outcomes, surgical complications, and chemotherapy-related adverse events. One death due to gastrointestinal perforation was observed among cases. Cases showed a longer median PFS compared with controls (18 months vs. 10 months; p = 0.001), and the administration of bevacizumab (hazard ratio 3.786; p = 0.001) retained a prognostic role for longer PFS at multivariate analysis. CONCLUSIONS: The incorporation of bevacizumab in NACT prolongs PFS without affecting the safety of IDS. The risk of gastrointestinal perforation should be considered prior to attempting bevacizumab-based NACT in women with diffuse bowel involvement at initial laparoscopic evaluation.

Emerging drugs for endometrial cancer.

INTRODUCTION: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings. AREAS COVERED: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials. EXPERT OPINION: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.

Exploring the scope of practice and training of obstetricians and gynaecologists in England, Italy and Belgium: a qualitative study.

INTRODUCTION: This study explores the scope of practice of Obstetrics and Gynaecology specialists in Italy, Belgium and England, in light of the growth of professional and patient mobility within the EU which has raised concerns about a lack of standardisation of medical speciality practice and training. METHODS: Semi-structured qualitative interviews were conducted with 29 obstetricians and gynaecologists from England, Belgium and Italy, exploring training and scope of practice, following a common topic guide. Interviews were recorded, transcribed and coded following a common coding framework in the language of the country concerned. Completed coding frames, written summaries and key quotes were then translated into English and were cross-analysed among the researchers to identify emerging themes and comparative findings. RESULTS: Although medical and specialty qualifications in each country are mutually recognised, there were great differences in training regimes, with different emphases on theory versus practice and recognition of different subspecialties. However all countries shared concerns about the impact of the European Working Time Directive on trainees' skills development. Reflecting differences in models of care, the scope of practice of OBGYN varied among countries, with pronounced differences between the public and private sector within countries. Technological advances and the growth of co-morbidities resulting from ageing populations have created new opportunities and greater links with other specialties. In turn new ethical concerns around abortion and fertility have also arisen, with stark cultural differences between the countries. CONCLUSION: Variations exist in the training and scope of practice of OBGYN specialists among these three countries, which could have significant implications for the expectations of patients seeking care and specialists practising in other EU countries. Changes within the specialty and advances in technology are creating new opportunities and challenges, although these may widen existing differences. Harmonisation of the training and scope of practice of OBGYN within Europe remains a distant goal. Further research on the scope of practice of medical professionals would better inform future policies on professional mobility.

Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence.

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented.

An update on the pharmacotherapy for endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the seventh most common malignancy in women. Most cases have a favorable prognosis because they present an early stage disease at diagnosis. Treatment currently comprises surgery with or without adjuvant approaches. A combination of radiation therapy, chemotherapy or hormonal therapy (HT) is usually administered. This article gives an update concerning the role of synthetic drugs in EC, reviewing the most recent data from Phase III randomized-controlled trials onwards. AREAS COVERED: Over the years, chemotherapy has become the treatment mainstay in both high-risk or locally advanced EC and in metastatic or recurrent disease. Carboplatin plus paclitaxel is currently considered the standard chemotherapy regimen with a well-tolerated toxicity profile. HT is an alternative option in women with advanced EC and important co-morbidities, and in young women with very early stage disease. EXPERT OPINION: Basic results of EC treatment during the last decade were collected. There is a need of more advances in treatment. The use of biomarkers, necessary for the success of a therapeutic strategy, and the identification of an ad-hoc population, are two important goals. In the authors' opinion, the development of comprehensive tumor bio-banks and international networks represent the right approach to foster translational studies and obtain improvement in patient outcomes.

Trabectedin as single agent in the salvage treatment of heavily treated ovarian cancer patients: a retrospective, multicenter study.

OBJECTIVE: The aim of this multicenter, retrospective study was to evaluate the efficacy and the safety of single agent Trabectedin (ET-743, Yondelis) in very heavily treated, relapsed ovarian cancer (ROC) patients. PATIENTS AND METHODS: Response to treatment was classified according to RECIST criteria. Progression-free (PFS), and overall survival (OS) were also assessed. RESULTS: 98 patients were analyzed (originally 67 platinum sensitive, and 31 platinum refractory/resistant). Median number of previous regimens was 4 (range: 1-6). In the whole population, overall response rate (ORR) was 27.5%; stable disease (SD) was observed in 33 patients (33.6%), and clinical benefit was achieved in 60 cases (61.2%). ORR was 38.6% in fully platinum sensitive population, and 26.1% in partially platinum sensitive patients. In platinum refractory/resistant disease, ORR was 12.9%. Overall, median PFS and OS were 5, and 13 months, respectively. Patients responding to Trabectedin showed a more favorable PFS (median = 9 months) than patients with SD (median = 6 months), or progression (median = 2 months). Median OS of responding patients was 18 months compared to 14 months in SD patients, and 9 months in progressing patients. Grade 3-4 neutropenia was observed in 17 (17.3%) patients. Transient and non-cumulative Grade 3-4 AST and ALT level elevation was found in 7 (7.1%), and 13 (13.3%) cases, respectively. There was 1 case of Grade 3, and 1 case of Grade 4 cardiac toxicity. CONCLUSIONS: Trabectedin, as a single agent, retains its efficacy in terms of rate of ORR and clinical benefit in heavily treated ROC patients, especially in the group of platinum sensitive disease.

Emerging drugs for ovarian cancer.

IMPORTANCE OF THE FIELD: Ovarian cancer has the highest mortality of all female reproductive tract cancers, which reflects both the absence of proven ovarian cancer screening tests and the development of drug-resistant cancer cell. Apart from varying the dosages, schedules, mode of delivery and combinations of existing drugs, efforts must continue to identify signaling pathways in tumor cells sufficiently different from normal cells that can be a target for maximizing tumor kill and minimizing toxicity. AREAS COVERED IN THIS REVIEW: Some of the most important cellular pathways are analyzed and discussed and the most interesting clinical trials, both closed and ongoing, described. WHAT THE READER WILL GAIN: The reader will gain a panoramic vision of all the most active drugs in clinical investigations in ovarian cancer. The reader will also better understand what the unresolved problems of molecular research are and how complicated the process 'from the bench to the bedside' is. TAKE HOME MESSAGE: It is only with a strong commitment, cooperation and collaboration from the international ovarian cancer community that significant improvement in patient outcomes can be attained beyond the marginal gains achieved so far.

Treatment of cervical cancer in Italy: strategies and their impact on the women.

Treatment of cervical cancer greatly varies according to the stage of the disease. Laparoscopic surgical staging is emerging as a valid approach, compared to clinical and imaging staging, to better identify the treatment plan. Minimally invasive surgery plays the greatest role in the treatment of early cervical carcinoma (ECC). Laparoscopically assisted radical vaginal hysterectomy (LARVH) is an alternative surgical strategy in this subset of patients. Interest has been increasing in using conservative fertility-sparing surgery such as laparoscopic vaginal radical trachelectomy (LVRT) or chemo-conization, options to be preferred in selected patients, with early-stage disease and asking for future fertility. Chemoradiotherapy currently represents the gold standard in the treatment of patient with locally advanced cervical cancer (LACC). In Italy, neoadjuvant chemotherapy (NACT) followed by radical surgery is today emerging as a valid alternative to the standard chemoradiation and the paclitaxel, ifosfamide and cisplatin (TIP) regimen is one of the most active neoadjuvant chemotherapeutic treatments. Moreover, the combination of different strategies to maximize local control should be considered. Among different approaches to this issue the use of a three-modality treatment, including radiotherapy, chemotherapy and surgery has been investigated. Our data on a large single-institutional series of LACC patients treated with chemoradiation followed by radical surgery confirm that this three-modality treatment can achieve overall survival (OS) and Disease Free Survival (DFS) rates at least comparable to chemoradiation alone, with an acceptable rate of complications. Tailoring of radical surgery, on the basis of intraoperative findings, such as lympho-nodes status, might play an important role in diminishing the overall rate of complications and eventually improve quality of life (QoL) of these patients. Cervical cancer generally has an aggressive impact on relatively young women and, as we experienced, the relevance of psychosocial aspects in gynaecologic oncology has become a main issue.