Violante Di Donato

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.

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.

Quality of Life and Sexual Function after Type c2/Type III Radical Hysterectomy for Locally Advanced Cervical Cancer: A Prospective Study

INTRODUCTION The introduction of screening programs have made cervical cancer detectable at earlier stages and in younger patients. Nevertheless, only a few studies have examined the QoL and sexual function in disease-free cervical cancer survivors. AIM The objective of this study is to evaluate the sexual function in a cervical cancer patients group treated with neoadjuvant chemotherapy (NACT) plus type C2/type III radical hysterectomy (RH). METHODS We have enrolled in the oncologic group (OG) sexually active patients affected by cervical cancer (stage IB2 to IIIB) treated with NACT followed by RH. MAIN OUTCOME MEASURES Included subjects were interviewed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CX24 Questionnaire. Two consecutive assessments were recorded: at the first evaluation postoperatively (T1) and at the 12-month follow-up visit (T2). Results were compared with a benign gynecological disease group (BG) and with a healthy control group (HG). RESULTS A total of 33 patients for OG, 37 for BG, and 35 women for HG were recruited. After surgery, sexual activity has been resumed by 76% of the OG patients and 83.7% of the BG patients (P = not significant). Cancer survivors had clinically worse problems with symptom experience, body image, and sexual/vaginal functioning than controls (P < 0.05). OG patients also reported more severe lymphedema, peripheral neuropathy, menopausal symptoms, and sexual worry. For sexual activity, the score difference between cancer survivors and women with benign gynecological disease is not statically significant. Concerning sexual enjoyment assessment, our study shows comparable results for OG and BG. CONCLUSION Nevertheless, the worsening of symptom experience, body image, and sexual/vaginal functioning, OG patients have same sexual activity and sexual enjoyment data compared with those of BG patients. Thus, NACT followed by RH could be a valid therapeutic strategy to treat and improve well-being especially in young cervical cancer patients.

Implementation of laparoscopic approach for type B radical hysterectomy: a comparison with open surgical operations.

OBJECTIVE To investigate the safety, feasibility and effectiveness of laparoscopic approach in the management patients undergoing modified radical hysterectomy for early stage cervical cancer. METHODS Consecutive data of 157 women who had class II radical hysterectomy, for stage IA2 and stage IB1 <2 cm cervical cancer, were prospectively collected. Data of patients undergoing surgery via laparoscopy (LRH) were compared with those undergoing open surgical operations (RAH). A propensity-matched comparison (1:1) was carried out to minimize as possible selection biases. Post-operative complications were graded per the Clavien-Dindo classification. Five-year survival outcomes were assessed using Kaplan-Meier model. RESULTS After the exclusion of 37 (23.5%) patients on the basis of propensity-matching, 60 patients undergoing LRH were compared with 60 patients undergoing RAH. No between-group differences in baseline, disease and pathological variables were observed (p > 0.05). Patients undergoing surgery via laparoscopy experienced longer operative time than patients undergoing RAH; while LRH correlated whit shorter length of hospitalization and lower blood loss in comparison to RAH. Intra- and post-operative complication rate was similar between groups (p = 1.00). The execution of LRH or RAH did not influence site of recurrence (p > 0.2) as well as survival outcomes, in term of 5-year disease-free (p = 0.29, log-rank test) and overall survivals (p = 0.50, log-rank test). CONCLUSION Laparoscopic approach is a safe procedure, upholds the results of RAH, reducing invasiveness of open surgical operations. Further large prospective investigations are warranted.

Neoadjuvant chemotherapy followed by radical surgery in patients affected by vaginal carcinoma.

BACKGROUND Radiotherapy represents the standard treatment for patients affected by FIGO stage II vaginal cancer. Several authors have suggested that neoadjuvant chemotherapy followed by radical surgery might be a valid treatment option in patients affected by cervical cancer. The objective of this study was to analyse the feasibility and results obtained by neoadjuvant chemotherapy followed by surgery in patients affected by invasive vaginal cancer with paravaginal tissue involvement not reaching the pelvic side wall. METHODS Eleven patients affected by FIGO stage II vaginal cancer were treated with paclitaxel 175 mg/m(2) and cisplatin 75 mg/m(2) every 21 days for three courses followed by radical surgery. RESULTS All patients were subjected to the 3 planned chemotherapy courses. Three (27%) patients achieved a complete clinical response and seven (64 %) patients achieved a partial clinical response. All patients were subjected to radical hysterectomy and vaginectomy. At a median follow up of 75 months two (18%) patients suffered a disease recurrence and one of these died of disease. CONCLUSIONS Neoadjuvant chemotherapy followed by radical surgery is a feasible therapeutic strategy with good short- and long-term results. In women affected by vaginal cancer, a larger series reporting the result of this therapeutic strategy or the results obtained by surgery alone will aid physicians to choose the best therapeutic strategy for each individual patient.

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.

continuous versus cyclic oral contraceptives after laparoscopic excision of ovarian endometriomas: a systematic review and metaanalysis

In the lack of evidence consistently supporting the use of continuous vs cyclic oral contraceptives after surgery for endometriosis, we conducted a systematic review and metaanalysis with the objective of comparing a continuous vs a cyclic oral contraceptive schedule administered after surgical excision of ovarian endometriomas. A PubMed, MedLine, and Embase search through December 2014 was conducted, with the use of a combination of key words and text words related to endometrioma, endometriosis, oral contraceptives, oral estroprogestins, laparoscopy, and surgery. Studies directly comparing a continuous vs a cyclic schedule administered after surgical treatment of endometriomas were included, with pain and endometrioma recurrence rates as the primary outcomes. Three reviewers independently assessed methodology and extracted data from selected studies. The primary outcomes were considered pain recurrence (evaluated separately for dysmenorrhea, noncyclic chronic pelvic pain, and dyspareunia) and endometrioma recurrence evaluated at ultrasonography. Dichotomous outcomes from each study were expressed as risk ratio (RR) with a 95% confidence interval (CI). Three randomized clinical trials and 1 prospective controlled cohort study were included, for a total of 557 patients with endometriosis, 343 patients of whom had ovarian endometriomas completing the assigned treatment and follow-up. Lower recurrence rates for dysmenorrhea were obtained with a continuous schedule (RR, 0.24; 95% CI, 0.06-0.91; P = .04). Nonsignificant differences were present for chronic pelvic pain and dyspareunia. A continuous oral contraceptive schedule was associated with a nonsignificant reduction of cyst recurrence rates compared with a cyclic schedule (RR, 0.54; 95% CI, 0.28-1.05; P = .07). A continuous oral contraceptive regimen, as opposed to a cyclic regimen, may be suggested after surgery for endometriomas because of lower dysmenorrhea recurrence rates. Due to the small number and small sample sizes of the included studies, further randomized clinical trials are needed to confirm the findings of the present systematic review. Also, outcomes related to patient satisfaction and quality of life should be addressed.

Secondary analyses from a randomized clinical trial: age as the key prognostic factor in endometrial carcinoma

OBJECTIVE The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. STUDY DESIGN Survival outcomes of trial patients were analyzed in relation to age (≤65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. RESULTS Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in ≤65 years and >65 years patients, respectively, P < .0001; 5-y CSS 93.8% and 83.5% in ≤65 years and >65 years patients, respectively, P = .003). Among women ≤65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients (P = .009 and P = .002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients (P = .55 and P = .58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. CONCLUSION Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis.

Neoadjuvant Chemotherapy Followed by Radical Surgery in Patients Affected by FIGO Stage IVA Cervical Cancer

BackgroundConcomitant chemoradiotherapy represents the standard treatment for patients affected by locally advanced cervical cancer. Survival rates in patients affected by FIGO stage IVA disease remain poor. Some authors have suggested that neoadjuvant chemotherapy followed by radical surgery might be a valid alternative to standard treatment. The objective of this study was to analyze the feasibility and results obtained by neoadjuvant chemotherapy in patients affected by stage IVA disease.MethodsEighteen patients affected by FIGO stage IVA cervical cancer were treated with 175 mg/m2 paclitaxel and 75 mg/m2 cisplatin every 21 days for three courses followed by radical surgery when feasible.ResultsAll patients were subjected to the three planned chemotherapy courses. Two patients achieved a complete clinical response, and 10 patients achieved a partial clinical response. Ten patients were subjected to anterior pelvic exenteration, whereas the remaining eight patients were treated with chemotherapy, radiotherapy, and concomitant chemoradiotherapy. The estimated 3-year and 5-year overall survival rates were 47.4% and 31.6%, respectively. Patients eligible for surgery benefited from significantly longer survival rates.ConclusionsNeoadjuvant chemotherapy followed by radical surgery is feasible in approximately half of patients affected by FIGO stage IVA cervical cancer. Overall survival rates appear similar to those reported with concomitant chemoradiotherapy. Patients who are amenable to radical surgery after chemotherapy may benefit from long-term survival rates.

A Small Molecule SMAC Mimic LBW242 Potentiates TRAIL- and Anticancer Drug-Mediated Cell Death of Ovarian Cancer Cells

Background Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. Principal Findings LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. Conclusion LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer.