Focus on Trabectedin in Ovarian Cancer: What Do We Still Need to Know?

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

Lymph node staging in grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary: Is it worth?

OBJECTIVE: The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging. METHODS: Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1-2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses. RESULTS: 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5-52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06-0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07-0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively). CONCLUSION: Staging lymphadenectomy in grade 2 endometrioid ovarian carcinoma patients was associated with improved DFS and OS. Grade 1 and grade 2 might be considered as two different entities, which could benefit from different approach in terms of surgical staging. Prospective studies, including molecular profiles are needed to confirm the survival drivers in this rare setting.

Impact of substage and histologic type in stage I ovarian carcinoma survival: a multicenter retrospective observational study.

OBJECTIVE: This international study aimed to investigate the impact of substage, histological type and other prognostic factors on long-term survival for stage I ovarian carcinoma. METHODS: Our study was a retrospective multicenter cohort study that included patients with the International Federation of Gynecology and Obstetrics (FIGO) stage I (IA-IC3) ovarian carcinoma treated at four European referral centers in Germany and Italy. Using Kaplan-Meier survival curves we compared overall and disease-free survival between the different stage I groups. RESULTS: A total of 1115 patients were included. Of these, 48.4% (n=540) were in stage IA, 6.6% (n=73) stage IB, and 45% (n=502) stage IC, of the latter substage IC1, 54% (n=271), substage IC2, 31.5% (n=158), and substage IC3, 14.5% (n=73). Five-year overall and disease-free survival rates for the entire cohort were 94% and 86%, respectively, with no difference between stage IA and IB. However, there was a significantly better overall and disease-free survival for stage IA as compared with stage IC (p=0.007 and p<0.001, respectively). Multivariate analysis revealed incomplete/fertility-sparing staging (HR 1.95; 95% CI 1.27 to 2.99, and HR 3.54; 95% CI 1.83 to 6.86, respectively), and stage IC (HR 2.47; 95% CI 1.63 to 3.75) as independent risk factors for inferior disease-free survival, while low-grade endometrioid (HR 0.42; 95% CI 0.25 to 0.72) and low-grade mucinous (HR 0.17; 95% CI 0.06 to 0.44) histology had superior disease-free survival. Considering overall survival, stage IC (HR 2.41; 95% CI 1.45 to 4.01) and older age (HR 2.41; 95% CI 1.46 to 3.95) were independent risk factors. CONCLUSION: Although stage I ovarian carcinoma exhibited excellent outcomes, the prognosis of patients with stage IA differs significantly compared with stage IC. Sub-optimal staging as an indicator for quality of care, and tumor biology defined by histology (low-grade endometrioid/mucinous) independently impact disease-free survival.

Risk reducing surgery with peritoneal staging in BRCA1-2 mutation carriers. A prospective study.

INTRODUCTION: International guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) in BRCA1-2 mutations carriers to decrease ovarian cancer occurrence. In this prospective study, we describe the incidence of occult malignancies and the surgical outcomes in asymptomatic BRCA mutation carriers submitted to RRSO. METHODS: Data on BRCA1-2 carriers undergoing RRSO with peritoneal washing and peritoneal/omental biopsies (PeS), between January 2019 until March 2021, were prospectively collected. RESULTS: A total of 132 patients were enrolled: 74 BRCA1 and 58 BRCA2 mutation carriers. 31.1% women underwent RRSO and PeS (16.2% of BRCA1 and 50% of BRCA2 carriers), while 68.9% patients were submitted also to concomitant hysterectomy. Almost all the procedures (99.2%) were performed by minimally invasive surgery. Postoperative complications occurred in twelve patients (9.1%): 10 in the concomitant hysterectomy group and two complications in the RRSO group. At the final pathological examination, 6 (4.5%) occult carcinomas were diagnosed: 3 fallopian tube carcinomas, one ovarian carcinoma and two serous tubal intraepithelial carcinomas (STICs), with negative PeS. Median age of occult carcinomas patients at RRSO was 54 (range: 48-79) years. The mean follow up was 20 (range: 7-34) months. During the follow up, no primary peritoneal cancer has been diagnosed. CONCLUSIONS: Occult pathologic findings in RRSO occurred in 4.5% (3% invasive carcinomas, STIC 1.5%) among our patients. The routine use of peritoneal biopsies does not improve the detection of occult malignancies. Our data confirm the importance of timely performing RRSO in BRCA1-2 carriers.

A Laparoscopic Adjusted Model Able to Predict the Risk of Intraoperative Capsule Rupture in Early-stage Ovarian Cancer: Laparoscopic Ovarian Cancer Spillage Score (LOChneSS Study).

STUDY OBJECTIVE: To identify preoperative/intraoperative patient and tumor characteristics associated with an increased risk of tumor spillage during minimally invasive surgery (MIS) for early-stage ovarian cancer (OC). The secondary end point was to develop a score system able to estimate the risk of tumor rupture during MIS. DESIGN: Retrospective observational study. SETTING: Patients with International Federation of Gynecology and Obstetrics stage I OC. PATIENTS: Patients aged ≥18 years old, with International Federation of Gynecology and Obstetrics stage IA to IC1 OC of any histology. INTERVENTIONS: Preoperative and intraoperative characteristics of patients treated with MIS for early-stage OC at Policlinico Universitario Agostino Gemelli, IRCCS in Rome, Italy, from January 1, 2001, to December 31, 2017, were collected. MEASUREMENTS AND MAIN RESULTS: A total of 151 patients were included. Previous pelvic surgery was more represented in patients with nonruptured tumors (46.0% vs 63.4%; p = .042). In addition, a larger tumor diameter (p <.001), a higher body mass index (p = .032), ultrasound characteristics (p = .029), and adhesions to large bowel (14% vs 2.0%; p = .003), uterus (44% vs 6.9%; p <.001), contralateral ovary (8.0% vs 0%; p = .004), ovarian fossa (64% vs 14.9%; p <.001), and pouch of Douglas peritoneum (32% vs 4.0%; p <.001) increased rupture rate. At multivariate analysis, a larger tumor diameter (p <.001) and adhesions to ovarian fossa peritoneum (p = .007) were independently associated with intraoperative cancer spillage and included in the score calculation. A disease-free survival (DFS) difference between the rupture group and the no-rupture group was detected (5-year DFS, 74.9% vs 94.4%; p = .011), with superimposable overall survival (5-year overall survival, 91.2% vs 97.9%; p = .089). CONCLUSION: Some preoperative/intraoperative characteristics increase the risk of tumor rupture during MIS for early-stage OC. A laparoscopic predictive model of capsule disruption could be considered to intraoperatively tailor surgical approach to prevent tumor spillage and avoid affecting patient's DFS.

BRCA status and platinum sensitivity in advanced ovarian cancer according to Chemotherapy Response Score.

OBJECTIVE: To evaluate a relation between BRCA1/2 status and the Chemotherapy Response Score in patients with epithelial ovarian cancer undergoing neoadjuvant chemotherapy and interval debulking surgery. METHODS: Data were retrospectively collected on patients with unresectable disease undergoing three or four cycles of neoadjuvant chemotherapy and interval debulking surgery at the Gynecologic Oncology Unit of the Catholic University of the Sacred Heart from January 2016 to December 2020. All patients were assessed for BRCA1/2 somatic mutation at diagnosis. The omental specimens obtained at the interval surgery were evaluated according to Bohm's Chemotherapy Response Score System. RESULTS: A total of 172 patients were included in the analysis, 69 (40%) patients were BRCA1/2 mutation carriers and 103 (60%) patients were wild type. In the wild-type group (BRCAwt), 73 (70.9%) patients had a Chemotherapy Response Score of 1 or 2 and 30 (29.1%) patients had a score of 3. In the BRCA1/2 carriers group (BRCAmut), 39 (56.5%) patients had a score of 1 or 2 and 30 (43.5%) patients had a score of 3. Among the BRCAwt group, those with a Chemotherapy Response Score of 3 had a prolonged median progression-free survival (22 vs 15 months, p=0.003). Among the BRCAmut carriers group, no differences were found (30 vs 27 months, p=0.55). No difference in overall survival was observed in either the BRCAmut carriers population (p=0.23) or the BRCAwt population (60 vs 44 months, p=0.06). CONCLUSIONS: Patients with BRCA1/2mut seem to achieve a score of 1, 2 or 3 with the same frequency. In contrast, patients with BRCAwt seem to have a score of 1 or 2 more frequently than a score of 3. In patients with BRCA1/2mut, this score may not be an indicator of chemosensitivity.

Evolution of Clinical Trials in Ovarian Cancer Management over the Past 20 Years: Never Settle Down, Always Go Beyond.

PURPOSE: A practice synthesis of available evidence-based medicine data in ovarian cancer (OC), aiming to provide directions for future research. MATERIALS AND METHODS: We performed a systematic review. PubMed was searched for relevant OC trials between January 2000 and December 2019. RESULTS: Out of 865 references screened, 199 trials were found eligible for inclusion. Most trials were multicenter (83.9%). There was a trend reduction in the number of patients enrolled/per study over the years. Studies testing targeted/biological therapies dominated the second decade (60 trials in 2010-2019 versus 2 trials in 2000-2009). The proportion of trials with positive survival and clinical outcomes significantly increased from 23.8% in early 2000s to 54.1% in the last 5 years. Trials with histology/molecular biomarker criteria were more likely to meet progression-free survival endpoint than those without these selection criteria (69.2% versus 32.6%). CONCLUSION: This systematic review suggests a trend of increased positive studies, mainly linked to precision medicine.

Feasibility of tumor testing for BRCA status in high-grade serous ovarian cancer using fresh-frozen tissue based approach.

OBJECTIVE: For many years, BRCA mutational status has only been considered as a predictor of ovarian cancer susceptibility and as a prognostic factor. Nonetheless, in the era of precision medicine, it has also become a predictive biomarker of response to platinum-based-chemotherapy and, more recently, to PARP-inhibitors, also in the frontline setting. We assessed the feasibility of a fresh frozen tissue-based-BRCA-screening workflow in a tertiary referral center. METHODS: We consecutively enrolled a series of 456 newly diagnosed FIGO-Stage IIIC-IV, high grade serous-ovarian cancer patients. All patients receiving tumor-biopsy underwent tBRCA-testing. RESULTS: Clinically relevant tissue-BRCA (tBRCA) variants were observed in 145 women (31.8%), particularly we recognized 89 (61.4%) patients with BRCA1-pathogenetic variants (PVs) and 56 women (38.6%) with BRCA2-PVs. Among 292 tBRCA wild-type (wt) patients, 88 cases were germline BRCA tested (gBRCA) and 86 (97.8%) were confirmed as gBRCAwt, while 1 (1.1%) had gBRCA variant of uncertain significance and 1 had gBRCA mutation (1.1%). The concordance of tumor test versus germline BRCA test was 86.3% (209/242). Large genomic rearrangements (LGRs) were suspected in 13/292 tBRCAwt patients (4.5%) by using bioinformatic algorithm and multiplex ligation-dependent probe amplification (MLPA) was performed, with evidence of PVs in only 1 case. CONCLUSIONS: Fresh-frozen tissue-based BRCA screening workflow is feasible and reliable. It allows to enlarge the BRCA mutated population that might receive PARPi with the greatest benefit, without missing cascade testing for family members and therefore, maintaining its preventive role.

Letrozole in the management of advanced ovarian cancer: an old drug as a new targeted therapy.

At present, there is no standard of care on the use of letrozole in ovarian cancer management. We performed a systematic review of the available literature addressing this issue. Data demonstrated a role for letrozole in ovarian cancer, in both the primary and recurrent setting. Letrozole, which has a favorable toxicity profile, seems to assure a prolonged recurrence-free interval, particularly when used as maintenance treatment, in low grade serous ovarian cancer; in recurrent cases it had also led to prolonged disease control. However, the optimal setting and biologically relevant patient population needs to be defined in larger trials.

Sexual Function following Laparoscopic versus Transvaginal Closure of the Vaginal Vault after Laparoscopic Hysterectomy: Secondary Analysis of a Randomized Trial by the Italian Society of Gynecological Endoscopy Using a Validated Questionnaire.

STUDY OBJECTIVE: The effect of the different types of vaginal cuff closures on posthysterectomy sexual function has not been investigated in depth. We evaluated if there is a difference between transvaginal versus a laparoscopic closure after total laparoscopic hysterectomy (TLH) on female sexual function, using a validated questionnaire. DESIGN: Secondary analysis of a prospective randomized controlled trial. SETTING: Three academic research centers. PATIENTS: Women consenting to telephone interviews on their sexual life before and after undergoing TLH were included. INTERVENTIONS: Patients were randomly assigned to a laparoscopic or transvaginal approach for vaginal cuff closure at the end of TLH for benign indications. MEASUREMENTS AND MAIN RESULTS: A validated questionnaire (the Female Sexual Function Index [FSFI]) was used to explore sexuality before and after the operation. Of the 1408 patients enrolled in the primary study, 400 patients were asked to complete the questionnaire. Of them, 182 (41.4%) were eligible and accepted enrollment in the present analysis. No difference was found in terms of pre- and postoperative FSFI scores between groups. Patients with a low preoperative FSFI score (<26.55) had a significantly higher likelihood of having a postoperative sexual disorder (p <.001). Women who received bilateral adnexectomy before menopause and those with postoperative vaginal cuff hematoma had a significantly lower postoperative FSFI score (p = .001 and p = .04, respectively). After multivariable analysis, both variables maintained at least a tendency toward an association with a lower postoperative FSFI score (odds ratio, 2.696; 95% confidence interval, 1.010-7.194; p = 0.048 and p = 0.053; odds ratio, 13.2; 95% confidence interval, .966-180.5, respectively). CONCLUSION: Transvaginal and laparoscopic cuff closures after TLH have similar sexual postoperative outcomes. A patient with sexual problems before TLH is more likely to have a low FSFI score postoperatively. Premenopausal patients undergoing bilateral ovariectomy and those with postoperative vaginal cuff hematoma have a worse postoperative sexual life. (Clinicaltrials.gov, protocol number NCT02453165, registration date May 25, 2015.).

Ectopic pregnancy in women with recurrent miscarriage.

AIM: The aim of this study was to investigate the possible association between recurrent miscarriage (RM) and ectopic pregnancy (EP). METHODS: In this case-control retrospective study, the clinical cards of women followed as outpatients in the RM and low-risk pregnancy offices of the Obstetrics and Gynecology Unit at the Policlinico Tor Vergata University Hospital were carefully reviewed for the occurrence of EP. RESULTS: Overall, 598 women with RM and 2043 normal women without RM (controls) were included in the study. Among these women, 4974 pregnancies were analyzed, in which 2028 miscarriages occurred. The EP rate (3.51%) was significantly higher in RM than in control women (1.51%) [odds ratio = 2.31 (95% confidence interval: 2.3-2.4)]; it was particularly high in women with primary RM (5.11%). However, when EP rates were calculated not by women but by overall pregnancies, no differences could be found between RM and control women. In control women, the absence of a miscarriage in the reproductive history was associated with a lower rate of EP. CONCLUSIONS: Women with RM, particularly primary RM, are at increased risk of EP. This increased risk seems to be dependent on the high number of pregnancies occurring in women with RM rather than to specific characteristics of these women.