Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case-control study.

OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the role of non-platinum doublet pegylated liposomal doxorubicin/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitor maintenance. METHODS: This case-control study includes patients with recurrent epithelial ovarian cancer treated between March 2016 and April 2021 who progressed under PARP inhibitor maintenance. Data of patients treated with pegylated liposomal doxorubicin/trabectedin (experimental group) were matched 1:1 with a series of patients who received platinum-based treatment (control group). The study outcomes were overall clinical benefit (including complete, partial, and stable response), progression-free survival, and overall survival. The safety of both treatments was also evaluated. RESULTS: A total of 26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) patients in the control group (p=0.38). Patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months of progression-free survival, compared with 5 months in patients treated with platinum-based treatment (p=0.62). Patients in the experimental group achieved a median overall survival of 16 months compared with 19 months in the control group (p=0.26) There was no difference concerning severe toxicities (G3-G4) between groups, except for hepatic toxicity, which was experienced in 30% of the patients receiving pegylated liposomal doxorubicin/trabectedin and none in the control group (p<0.009). CONCLUSIONS: Pegylated liposomal doxorubicin/trabectedin might be an alternative option to platinum-based treatment in patients experiencing disease progression during PARP inhibitor maintenance with an acceptable toxicity profile. This might be a therapeutic option in this setting, sparing platinum compounds for subsequent relapse.

MITO39: Efficacy and Tolerability of Pegylated Liposomal Doxorubicin (PLD)-Trabectedin in the Treatment of Relapsed Ovarian Cancer after Maintenance Therapy with PARP Inhibitors-A Multicenter Italian Trial in Ovarian Cancer Observational Case-Control Study.

OBJECTIVE: While PLD-Trabectedin is an approved treatment for relapsed platinum-sensitive ovarian cancer, its efficacy and tolerability has so far not been tested extensively in patients who progress after poly ADP-ribose polymerase inhibitor (PARPi) treatment. METHODOLOGY: This multicenter, retrospective analysis had the objective of comparing patients receiving PLD-Trabectedin after being treated with PARP-I (cases) with PARPi-naïve patients. Descriptive and survival analyses were performed for each group. RESULTS: Data from 166 patients were collected, composed of 109 cases and 57 controls. In total, 135 patients were included in our analyses, composing 46 controls and 89 cases. The median PFS was 11 months (95% IC 10-12) in the control group vs. 8 months (95% IC 6-9) in the case group (p value 0.0017). The clinical benefit rate was evaluated, with an HR for progression of 2.55 (1.28-5.06) for the case group (p value 0.008), persisting when adjusted for BRCA and line with treatment. We compared hematological toxicity, gastro-intestinal toxicity, hand-foot syndrome (HFS), fatigue, and liver toxicity, and no statistically significant disparity was noted, except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was also equally represented. CONCLUSION: The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

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.

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.

NLR and BRCA mutational status in patients with high grade serous advanced ovarian cancer.

Laboratory-markers of the systemic inflammatory-response, such as neutrophil/lymphocyte-ratio (NLR) have been studied as prognostic factors in several tumors but in OC-patients their role is still controversial and no data about the possible correlation with the BRCA-status has been ever reported. We consecutively enrolled a series of 397 newly diagnosed high-grade serous-advanced OC-patients. All patients were tested for BRCA-mutational-status and blood-parameters have been collected 48 h before staging-surgery. A significant correlation of NLR with disease distribution (p < 0.005) was found and patients with NLR < 4 underwent primary-debulking-surgery more frequently (p-value 0.001), with a lower surgical-complexity-score (p-value 0.002). Regarding survival-data, patients with NLR < 4 had a significant 7-month increase in mPFS (26 vs 19 months, p = 0.009); focusing on the BRCA-status, among both BRCA-mutated and BRCA-wild type patients, those with lower NLR had a significantly prolonged mPFS compared to patients with NLR > 4 (BRCA-mutated: 35 vs 23 months, p = 0.03; BRCA-wt: 19 vs 16 months, p = 0.05). At multivariate-analysis, independent factors of prolonged PFS were BRCA mutational status, having received complete cytoreduction and NLR < 4. Also, the strongest predictors of longer OS were BRCA-mutational status, having received complete cytoreductive surgery, NLR < 4 and age. NLR is confirmed to be a prognostic marker in OC-patients and it seems unrelated with BRCA-mutational status.

Medical treatment of patients with gynecologic cancer during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, cancer care had to be reorganized; national and international recommendations were published to manage anticancer treatments safely and to reduce the risk of SARS-CoV-2 infection for patients and health workers. OBJECTIVE: To evaluate whether the adoption of recommendations for the management of patients with gynaecologic cancer receiving treatment during the pandemic resulted in containment of infections and continuing oncologic care. METHODS: Based on the published recommendations, and according to the local Health Direction guidelines, we developed and drafted a security protocol to modify access of patients with gynaecologic cancer to the "Fondazione Policlinico Agostino Gemelli-IRCCS, Rome" between February 1 and April 30, 2020 and compared results with the corresponding 3 months of 2019. RESULTS: Between February and April 2019, we registered 3254 admissions, including 2253 patients receiving intravenous chemotherapies, 298 receiving oral therapies, and 703 having hospital visits. Between February and April 2020, we registered 3213 admissions, including 2221 patients receiving intravenous chemotherapies, 401 receiving oral therapies, and 591 having hospital visits. Oral treatments and general visits were different in the two time periods (p<0.001). Despite the elevated patient flow, only one patient (0.1%) tested positive for COVID-19 and there were no cases among healthcare staff. CONCLUSIONS: Based on the adopted security protocol we provided continuity of care for all patients and limited the spread of the COVID-19 infection.

Post-conization cervical stenosis treated with silicone catheter in microinvasive cervical cancer patient: A case report.

INTRODUCTION: Cervical stenosis can represent a hard complication to treat after conization for microinvasive cervical cancer. PRESENTATION OF CASE: A young woman with cervical stenosis post-trachelectomy for a microinvasive cervical cancer came to our Department. We introduced a silicone catheter of 18 French in cervical canal. The catheter was removed after 20 days. The procedure was resolutive. DISCUSSION: Cervical stenosis is one of the most frequent complication of conization. Among the different described techniques proposed in literature, we would here report the successful use of a silicon urethral catheter into the cervical canal. CONCLUSION: This method can be an easy and cheap procedure to take in consideration.

Rucaparib: An emerging parp inhibitor for treatment of recurrent ovarian cancer.

Recently, Poly-ADP-Ribose Polymerase (PARP) inhibitors are one of the most intensively studied group of antiblastic agents for the management of recurrent ovarian cancer. Among this family, Olaparib was the first to be approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Following that, the Food and Drug Administration (FDA) approved Olaparib monotherapy as fourth or later line of treatment in advanced ovarian cancer with deleterious germ-line BRCA1/2 mutation. On March 2017, Niraparib, was approved as maintenance treatment of patients with recurrent epithelial ovarian, who are in complete or partial response to platinum-based chemotherapy, independently of BRCA mutation. Rucaparib inhibits PARP-1, 2 and 3, PARP-4, -12, -15 and -16, as well as tankyrase 1 and 2. On December 2016, it was granted accelerated approval by the FDA, based on data from two multicenter, single arm, phase II trials that evaluated the efficacy of Rucaparib in patients with deleterious, germline and/or somatic BRCA mutation-associated, advanced OC, who have been treated with two or more lines of chemotherapy. The maximum tolerated dose reported was 600 mg twice a day administered orally. Phase III studies are currently ongoing to further validate the efficacy of Rucaparib in the treatment setting and explore its usefulness in a maintenance setting as well. The focus of our review is to report the most recent investigations and clinical progress regarding Rucaparib for treatment of recurrent ovarian cancer.

Screening program in ovarian cancer: A logical step in clinical management? A meta-analysis.

OBJECTIVE: Treatment of ovarian cancer (OC) is a challenge and its poor prognosis still remains a problem of major importance. Due to the lack of early and specific symptoms, the vast majority of women are diagnosed with an advanced stage disease. The aim of this meta-analysis is to evaluate the impact of OC screening program in asymptomatic women on clinical outcomes. METHODS AND MATERIAL: A systematic literature electronic search was conducted in Pubmed, Medline, Scopus, and ClinicalTrials.gov databases. Articles were selected with a systematic approach. Clinical trials concerning screening strategy compared with usual care in asymptomatic OC women were considered, without any restrictions on the publication date. Trials were eligible if participants were asymptomatic and postmenopausal women. Outcomes included OC diagnosis and disease specific mortality. The pooled relative risk (RR) was calculated using a fixed-effects model. RESULTS: Overall, 3 randomized controlled trials met inclusion criteria, totaling 353,590 asymptomatic women. In total 177,188 women were assigned to screening program, and 176,402 women were assigned to usual care. The risk of OC diagnosis, both overall and at an early stage, was higher in screening group (RR = 1.07, 95% CI: 0.98-1.18; and RR = 1.30, 95% CI: 1.14-1.49, respectively). The RR for disease specific mortality was 0.96 (95% CI: 0.85-1.10). CONCLUSION: Our results suggest the possible benefit of OC screening program in term of early stage diagnosis and reduced specific OC mortality. Further studies of environmental or constitutional factors may lead to the identification of patient populations that could benefit from a screening program.

Short-Infusion Trabectedin in Heavily Pretreated Ovarian Cancer Patients: A Single-Institution Experience.

OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of trabectedin given every 10 days as a single agent in recurrent ovarian cancer after 3 prior regimens. METHOD: Trabectedin 0.6 mg/m2 was administered as a 3-h infusion every 10 days on a 21-day cycle. The study population was compared to patients treated with weekly paclitaxel 80 mg/m2 intravenously on days 1, 8, 15, and 22 every 4 weeks. RESULTS: We identified 34 patients previously submitted to at least 3 lines of chemotherapy who received single-agent trabectedin between 2010 and 2015. They were matched with a historical series of 34 patients who received weekly paclitaxel. No significant differences in response rate were found. Median progression-free survival was 4 months; 5 months in the trabectedin group and 4 months in the paclitaxel group. Overall survival (OS) was 13 months for the trabectedin group and 7 months for the paclitaxel group (p = 0.015). Patients who received platinum after trabectedin had a significant OS increase compared to those who received platinum after paclitaxel (18 vs. 9 months, respectively; p = 0.009). The most frequent drug-related grade 3/4 toxicities were reversible hepatic toxicity, neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity. CONCLUSION: Single-agent trabectedin every 10 days is an active treatment with a manageable toxicity profile in heavily pretreated advanced relapsed ovarian cancer patients.

Bevacizumab in Ovarian Cancer: State of the Art and Unanswered Questions.

Ovarian cancer is a most lethal gynecologic tumor. The mainstay treatment is cytoreductive surgery followed by platinum-based chemotherapy. However, a high percentage of patients recur, thus needing multiple treatments with a frequently poor prognosis. In the last two decades, research has focused on the potential of target therapies to improve the survival of patients affected by ovarian cancer. Bevacizumab is one of the most studied target therapies, and it is approved for first- and second-line treatment of advanced epithelial ovarian, fallopian tube, and primary peritoneal tumors. Despite its widespread use with favorable results, controversy regarding patient selection and the best schedule, dosage, and timing of bevacizumab still exists. This review summarizes the state of the art on the use of bevacizumab for ovarian cancer in front-line, recurrence, and neoadjuvant settings. This study focuses on the results of pivotal trials, emerging data, ongoing research, and still unanswered questions about the most adequate dosage of bevacizumab and its potential activity after disease progression or rechallenge in previously treated patients.

Dose-Dense Neoadjuvant Chemotherapy plus Radical Surgery in Locally Advanced Cervical Cancer: A Phase II Study.

OBJECTIVE: To assess the efficacy and toxicity profile of dose-dense cisplatin-based neoadjuvant chemotherapy (NACT) followed by radical surgery in patients affected by locally advanced cervical cancer. METHODS: Patients affected by carcinoma of the uterine cervix FIGO (International Federation of Obstetrics and Gynecology) stage IB2-IIIB were enrolled into the study. The treatment schedule consisted of 5 cycles of intravenous paclitaxel 60 mg/m(2) plus cisplatin 60 mg/m(2) every 10 days; patients were then submitted to radical hysterectomy and pelvic lymphadenectomy. RESULTS: From January 2011 to March 2013, 22 patients were enrolled. Median age was 47 (26-83) years. FIGO stages included 1 IIA, 15 IIB, 1 IIIA, and 5 IIIB. Ninety-one percent of patients completed all the 5 planned cycles of NACT. Three patients experienced allergic reactions to paclitaxel. Grade 3-4 hematological toxicity was observed in 18% of cases. In 3 cases, grade 3-4 extra-hematological adverse and life-threatening events were reported (1 ototoxicity, 1 transient ischemic attack, and 1 myocardial infarction). No treatment-related death occurred. The operability rate was 86.4%. The overall response rate was 52.6%: 5 patients (26.3%) experienced clinical complete response, and 5 (26.3%) showed a clinical partial response. Stable disease was observed in 47.4% of patients, with no progressive disease recorded. Pathological response was observed in 57.9% of cases. Six out of 19 (31.6%) patients were submitted to adjuvant treatment. CONCLUSION: Dose-dense cisplatin-based NACT showed a response rate in approximately half of patients. However, in consideration of the reported extra-hematological toxicity, further studies on and new strategies with dose-dense platinum-based NACT are required to improve outcome in cervical cancer patients.

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.

Nonabsorbable suture granuloma mimicking ovarian cancer recurrence at combined positron emission tomography/computed tomography evaluation: a case report.

INTRODUCTION: This is the first case of suture granuloma mimicking isolated ovarian cancer relapse. Only six analogous cases have been previously reported in other malignancies. CASE PRESENTATION: We report the case of a 44-year-old Caucasian woman with partially platinum-sensitive ovarian cancer in which radiological features, including computed tomography and combined 18F-fluorodeoxyglucose-positron emission tomography/computed tomography, were strongly suggestive of isolated cancer relapse in her right subdiaphragmatic region. Laparoscopic examination resulted negative, but was not completely suitable due to widespread adhesive syndrome. The laparotomy for secondary cytoreductive surgery and biopsy of the suspected area showed inflammatory granuloma caused by nonabsorbable propylene suture, without evidence of neoplastic cells. Moreover, unexpected peritoneal carcinosis was found. CONCLUSIONS: This evidence suggests that clinical details about previous surgical procedures are necessary for adequate interpretation. Although much progress has been made in imaging techniques, especially in the promising field of combined 18F-fluorodeoxyglucose positron emission tomography/computed tomography, these procedures should be still thoroughly investigated in order to promptly rule out tumor recurrence and avoid unnecessary surgery.

Dualistic classification of epithelial ovarian cancer: surgical and survival outcomes in a large retrospective series.

BACKGROUND: Ovarian cancers have been recently categorized into types I and II according to a dualistic model of tumorigenesis. Data on the correlation between this classification and clinical outcome are still scarce and controversial. METHODS: A retrospective analysis of patients with ovarian cancer treated from 1998 to 2013 and operated by the same surgeon was conducted. Patients were classified into two groups: type I (125 patients), including low-grade serous, mucinous, endometrioid, and clear cell tumors; and type II (286 patients), including high-grade serous tumors, unspecified adenocarcinomas, and undifferentiated carcinomas. RESULTS: Type II patients had a significantly higher incidence of advanced disease than type I (88.4 vs. 65.6 %, P = 0.0001) and required more aggressive surgical procedures. Rates of optimal tumor debulking were almost similar between groups (92.6 vs. 91.7 %, type I vs. II, P = NS). After a median follow-up of 41 months, 207 patients (50.4 %) were alive and 204 (49.6 %) were dead; 79 type I patients (63.8 %) and 237 type II patients (82.7 %) experienced relapse (P = 0.02). Progression-free survival was significantly different between groups: 25 months for type I vs. 17 months for type II (P = 0.023). Overall survival was not significantly different between groups, with a median overall survival of 75 months for type I vs. 62 months for type II (P = 0.116). CONCLUSIONS: The dualistic histotype-based classification into types I and II of ovarian cancer does not seem to correlate with prognosis. Different molecular characteristics of type I and II tumors may have therapeutic implications and should be deeply investigated.

An unexpected complete remission of advanced intestinal-type vulvar adenocarcinoma after neoadjuvant chemotherapy: a case report and a literature review.

Vulvar cancer represents approximately 3%-5% of all gynecological malignancies. Squamous cell carcinoma is the most frequent histotype, whereas melanomas, adenocarcinomas, basal cell carcinomas, and sarcomas are much less common. Intestinal-type adenocarcinoma is a rare variant of vulvar carcinoma with only few cases found in the literature. The origin of this neoplasia is still much debated, but the most reliable hypothesis is the origin from cloacal remnants that may persist in the adult in different organs. Because of its extremely low incidence, the optimal management of this kind of vulvar cancer is still debated. We report the case of a woman affected by advanced intestinal-type vulvar adenocarcinoma, who achieved a complete clinical and pathological response after neoadjuvant chemotherapeutic treatment with platinum and paclitaxel.