Claudia Marchetti

Real-life observational study on niraparib in older patients with primary tubo-ovarian cancer: a focus on safety and efficacy

Abstract Background Niraparib is approved for maintenance treatment of tubo-ovarian cancer patients, but data on older patients are limited. This retrospective study evaluated its safety and efficacy in primary advanced tubo-ovarian cancer, focusing on patients ≥ 75 years. Methods Women aged ≥ 50 years diagnosed with primary high-grade serous tubo-ovarian cancer, treated with niraparib between 2019–2023, were enrolled. Patients were stratified into three groups: A (50–64 years), B (65–74 years), and C (≥ 75 years). The primary outcome was progression-free survival. The secondary outcomes were toxicity and dose reduction. Results 127 patients were identified: 62 (48.8%) group A, 26 (20.5%) group B, and 39 (30.7%) group C. Baseline characteristics were comparable across groups, excluding a higher proportion of interval cytoreductive surgeries ( p  = 0.001), residual tumor ( p  = 0.01) and Eastern Cooperative Oncology Group (ECOG) > 1 ( p  = 0.01) in group C. Most patients started niraparib at 200 mg/day with dose reductions primarily occurred within fourth cycle. Dose reductions were observed in 77.4%, 69.2% and 56.4% of patients in groups A, B, and C, respectively ( p  = 0.08). In patients ≥ 75 years, 26 (66.7%) discontinued treatment due to disease progression (48.7%) or toxicity (17.9%). There were no significant differences in common or grade ≥ 3 adverse events between groups. Progression-free survival was 12 months (95%CI: 2.0–25.0) for group A, 29 months (95%CI: 11.0–52.0) for group B, and 16 months (95%CI: 1.0–31.0) for group C ( p  = 0.78). Conclusions Our findings suggest that niraparib is safe and well-tolerated in aged ≥ 75 years. Concerns about toxicity should not preclude the enrollment of elderly patients in treatment regiments.

Comprehensive genomic profiling and clinico-pathologic characterization of primary ovarian leiomyosarcoma

Primary ovarian leiomyosarcomas are exceptionally rare, accounting for less than 0.1% of ovarian malignancies. Their treatment strategies remain poorly defined, and data on comprehensive genomic profiling are lacking. This study aims to characterize the pathological features and genomic landscape of primary ovarian leiomyosarcoma, highlighting similarities with uterine leiomyosarcomas based on available literature. We retrospectively analyzed 7 histologically confirmed cases of primary ovarian leiomyosarcoma diagnosed between 2013 and 2023 at a tertiary referral center. Clinical data, histopathological findings, and immunohistochemical profiles were reviewed. Genomic profiling was performed using the TruSight Oncology 500 assay, targeting 523 cancer-related genes. Only oncogenic or likely oncogenic alterations (Tier classification system I-II) were considered. All patients had International Federation of Gynecology and Obstetrics stage IA disease and underwent radical surgery. Two patients experienced pelvic recurrence; both showed increased Ki-67 and complete loss of estrogen and progesterone receptors in the relapsed tumors. Histologically, tumors exhibited spindle or epithelioid morphology with variable atypia and mitotic indices. Genomic profiling revealed a high prevalence of TP53 (71%) and PTEN (57%) alterations. Additional copy number alterations were identified in homologous recombination repair genes (BRCA2, CHEK1/2, and ATM), fibroblast growth factor (FGF) family members (FGF7/9/14), and platelet-derived growth factor receptor beta. Tumor mutational burden was low to medium in all cases, and microsatellite status was stable. Primary ovarian leiomyosarcomas exhibit a complex genomic landscape marked by genomic instability, sharing key alterations with uterine leiomyosarcomas. TP53 and PTEN mutations may play a central role in their pathogenesis. This first genomic profiling analysis of ovarian leiomyosarcomas provides a basis for further research and potential targeted therapeutic approaches in this rare malignancy.

Failure of early interval debulking surgery after standard neoadjuvant chemotherapy: May bevacizumab add something? A large retrospective study

Data are limited on the use of bevacizumab in neoadjuvant setting for High-Grade Serous ovarian Cancer (HGSC) patients. This study explores the effect of adding bevacizumab to standard neoadjuvant chemotherapy (NACT) following the failure of early Interval Debulking Surgery (eIDS). This monocentric study retrospectively enrolled FIGO stage IIIC-IV HGSC patients (2017-2021), persisting unresectable after three NACT cycles. Eligible patients had an ECOG performance status ≤2, were aged 40-75 years, and had no contraindications to bevacizumab administration. Patients were stratified whether they added bevacizumab from cycles 4 to 6 (CPB group) or not (CP group). The primary endpoint was the cytoreduction rate after six cycles (delayed IDS, dIDS). Overall, 58(23 %) patients received neoadjuvant bevacizumab(CPB), and 190 (77 %) did not (CP). Delayed IDS was performed in 117(47.6 %) patients (CPB:31-53.4 %; CP:86-45.8 %; p = 0.38), with complete gross resection rates of 83.9 % and 88.5 %, respectively (p = 0.72). Severe postoperative complications were comparable (CP: 8 %, CPB: 9.7 %, p = 0.069). Median overall survival (OS) for dIDS patients showed no significant difference (CPB: not reached, CP:38 months, p = 0.55), nor did progression-free survival (PFS; CPB:14 months, CP:12 months, p = 0.830). Conversely, among 130(52 %) patients persisting unresectable, bevacizumab significantly improved OS in the CPB group (not reached vs.18 months, p = 0.015), although PFS remained similar (CPB: 6 months, CP: 7 months, p = 0.741). While adding bevacizumab to NACT does not seem to increase the dIDS rate, it significantly extends OS in unresectable patients. Its use may be a valuable option in selected cases after eIDS' failure.

Efficacy of Neoadjuvant Chemotherapy as pre-habilitation program in advanced epithelial ovarian cancer

Approximately 70 % of ovarian cancer patients present at diagnosis with advanced disease(AOC) and impaired clinical conditions, making them not ideal surgical candidates. We aimed to investigate whether neoadjuvant chemotherapy(NACT) can modify pre-operative characteristics of patients at high risk(HR) of perioperative complications, as defined in the Mayo Clinic Algorithm. We also compared their morbidity and survival outcomes with comparable HR women undergoing primary surgery (PCS). We retrospectively collected FIGO stage III and greater AOC patients undergoing either NACT-interval cytoreductive surgery(HR-NACT) or PCS from 01/2013 to 12/2022. HR features included: Albumin  1, stage IV disease, or complex surgery likely (more than hysterectomy, salpingo-oophorectomy and omentectomy). 400 patients were included. Among them, 298 met the criteria for the HR-NACT group; 203(68.1 %) underwent ICS after 3-4 cycles whislt 95(31.9 %) completed 6 NACT cycles. We reported an improvement in clinical variables in women undergoing 3-4 cycles of NACT: raise of ECOG = 0 rate(53.3 % vs 81.8 %; p < 0.001) and median albumin serum levels(3.0 g/dl vs 4.0 g/dl; p < 0.001). We identified 102 comparable HR-PCS patients. No difference in intraoperative complications was detected, while a difference was found in severe post-operative complications, favoring patients treated with both 3-4(5.4 % vs 18.6 % p = 0.0003) and 6 NACT cycles(7.8 % vs 18.6 %, p = 0.053). No difference in both DFS and OS was reported. We offer a rationale to combine non interventional pre-habilitation procedure with short term chemotherapy cycles, aiming to improve pre-operative conditions of selected HR patients.

New windows of surgical opportunity for gynecological cancers in the era of targeted therapies

Precision medicine through molecular profiling has taken a prominent role in the treatment of solid tumors and it is widely expected that this will continue to expand. With respect to gynecological cancers, a major change has particularly been observed in the treatment landscape of epithelial ovarian, endometrial, and cervical cancers. Regarding the former, maintenance therapy with either poly(ADP-ribose) polymerase inhibitors (PARPi) and/or bevacizumab has become an indispensable treatment option following the traditional combination of cytoreductive surgery and platinum-based chemotherapy. Considering endometrial cancer, the molecular classification system has now been incorporated into virtually every guideline available and molecular-directed treatment strategies are currently being researched, presumably leading to a further transformation of its treatment paradigm. After all, treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor has already been shown to significantly improve disease outcomes in these patients, especially in those with mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) disease. Similarly, in recurrent/metastatic cervical cancer patients, these agents elicited improved survival rates when being added to platinum-based chemotherapy with or without bevacizumab. Interestingly, implications of these targeted therapies for surgical management have been touched on to a minor extent, but are at least as intriguing. This review therefore aims to address the wide-ranging opportunities the molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and recurrent setting.

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

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. Data on BRCA1-2 carriers undergoing RRSO with peritoneal washing and peritoneal/omental biopsies (PeS), between January 2019 until March 2021, were prospectively collected. 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. 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.

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients

Despite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction. Patients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups. Of 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1-3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction. Niraparib dose reduction occurs in almost half of patients within cycles 1-3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

Low-grade versus high-grade serous ovarian cancer: comparison of surgical outcomes after secondary cytoreductive surgery

Retrospective series have shown secondary cytoreductive surgery improves oncological outcomes in recurrent low-grade serous ovarian cancer. We aim to compare surgical procedures and complications between patients with low-grade and high-grade recurrent serous ovarian cancer. This retrospective single-institution study includes patients with recurrent low-grade and high-grade serous ovarian cancer undergoing surgery between January 2012 to December 2021. Patients were propensity matched 1:3 for residual tumor at first surgery, presence of ascites and performance status. Complexity of surgery and postoperative complications were analyzed. A total of 116 patients undergoing secondary cytoreductive surgery were included with 29 patients (25%) having low-grade ovarian cancer. The median age of the patients was 54 years (range: 19-85) and 57 years (range: 29-78) in low-grade and high-grade ovarian cancer, respectively (p=0.13). Stages III/IV at diagnosis were more frequent in patients with high-grade ovarian cancers (p<0.001). Peritoneal involvement was higher in low-grade compared with high-grade ovarian cancer as shown by the higher rate of diaphragmatic (41.4% vs 21.8%, p=0.05), abdominal wall (41.4% vs 18.4%, p=0.02) and pelvic (51.7% vs 21.8%, p=0.01) peritonectomy. Multiple bowel resections were higher in low-grade ovarian cancer (24.1% vs 8.0%, p=0.04), while high-grade ovarian cancer had a higher rate of nodal recurrences (73.2%% vs 37.9%, p=0.03). Overall, surgical complexity was higher in low-grade ovarian cancer (58.6% vs 36.8%; p=0.05), with higher median estimated blood loss (400 vs 200 mL; p=0.01) compared with high-grade. Complete cytoreduction was achieved in 26 patients (89.7%) with low-grade and 84 (96.6%) with high-grade (p=0.16) ovarian cancer, with no significant differences in postoperative complications. Secondary cytoreductive surgery in low-grade serous ovarian cancer patients was associated with higher complexity, multiple bowel resections, and higher median estimated blood loss than in high-grade serous ovarian cancer. The comparable rate of postoperative complications suggests that secondary cytoreductive surgery in this group of patients is feasible in expert centers.

Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

To evaluate disease characteristics and survival according to This is a monocentric retrospective cohort of patients with ovarian cancer and brain metastases treated between 2000 and 2021. Data were collected by a retrospective review of medical records and analyzed according to: (1) Eighty-five patients with ovarian cancer and brain metastasis and known

Medicolegal and insurance issues regarding BRCA1 and BRCA2 gene tests in high income countries

Hereditary breast and ovarian cancer syndrome is an autosomal dominant cancer susceptibility syndrome mainly due to variants in

PARP inhibitors in epithelial ovarian cancer: what are their potential implications for surgical management?

Quality of life in patients with advanced ovarian cancer after primary debulking surgery versus neoadjuvant chemotherapy: Results from the randomised SCORPION trial (NCT01461850)

AbstractObjectiveTo investigate the effect of treatment with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), versus primary debulking surgery (PDS), on quality of life (QoL) in patients with advanced epithelial ovarian cancer (EOC).DesignRandomised trial conducted in a single institution.SettingDivision of Gynaecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.SamplePatients with stage‐IIIC/IV EOC and high tumour load.MethodsPatients were randomised (1:1) to undergo either PDS (PDS group) or NACT followed by IDS (NACT/IDS group).Main outcome measuresQuality‐of‐life (QoL) data, assessed using the European Organization for Research and Treatment of Cancer core QoL questionnaire (QLQ‐C30) and ovarian cancer module (OV28); co‐primary outcomes were the QLQ‐C30 global health score at 12 months (cross‐sectional analysis) and the difference in mean QLQ‐C30 global health score over time between treatment groups (longitudinal analysis).ResultsFrom October 2011 to May 2016, 171 patients were enrolled (PDS = 84; NACT/IDS = 87). We observed no clinical or statistically significant difference between treatment groups in any of the QoL functioning scales at 12 months, including QLQ‐C30 global health score (NACT/IDS group vs PDS group, mean difference 4.7, 95% CI −4.99 to 14.4, p = 0.340). Over time, we found lower global health scores for those undergoing PDS than for those receiving NACT (difference in mean score 6.27, 95% CI 0.440–12.11, p = 0.035), albeit this was not clinically relevant.ConclusionsWe found no difference in global QoL related to treatment approach at 12 months, even though patients in the NACT/IDS group reported better global health scores across the 12‐month period compared with the PDS group; these findings further confirm that NACT/IDS might be a feasible option for patients unsuitable for PDS.

Cytoreductive surgery for advanced epithelial ovarian cancer in the poly(ADP-ribose) polymerase inhibitors era—Is it time for a new paradigm shift? A systematic review and meta-analysis

In patients with newly diagnosed advanced high-grade serous and endometrioid epithelial ovarian cancer (EOC) first-line maintenance therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) tremendously improved progression-free survival (PFS). Yet, data on the effect of PARPi in proportion to postoperative residual disease status were lacking. A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items of Systematic reviews and Meta-Analysis (PRISMA) guidelines. We searched Medline/Pubmed, Embase and Cochrane databases as well as meeting abstracts until 18th March 2023. Hazard ratios (HRs) alongside their 95% confidence intervals (CIs) for PFS were extracted from the studies. A subgroup analysis was conducted to examine the effect of PARPi according to postoperative residual disease. A total of six phase III randomised controlled trials were included and comprised SOLO 1, PAOLA 1, PRIMA, PRIME, ATHENA-MONO and VELIA. Patients who received PARPi following complete gross resection showed greatest PFS benefit. Compared with placebo, maintenance with PARPi significantly improved PFS in patients with macroscopic residual disease (pooled HR 0.55; 95% CI 0.44-0.68). This magnitude was comparable to that found in patients with complete gross resection (pooled HR 0.53; 95% CI 0.41-0.67). Patients with macroscopic residual disease benefit from PARPi at the same extent as cases with complete gross resection. However, patients with complete gross resection who were treated with PARPi show the most favourable PFS rates. Hence, the pursuit of achieving complete cytoreduction remains valid in the PARPi era.

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

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. 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 (1.1 g/dL, estimated glomerular filtration rate (eGFR) ≤60 mL/min, ≥3 comorbidities were independently associated with a higher severe toxicity. 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.

Chemotherapy resistance in epithelial ovarian cancer: Mechanisms and emerging treatments

Ovarian cancer (OC) remains a fatal malignancy because most patients experience recurrent disease, which is resistant to chemotherapy. The outcomes for patients with platinum-resistant OC are poor, response rates to further chemotherapy are low and median survival is lower than 12 months. The complexity of platinum-resistant OC, which comprises a heterogeneous spectrum of diseases, is indeed far from being completely understood. Therefore, comprehending tumors' biological behaviour to identify reliable biomarkers, which may predict responses to therapies, is a demanding challenge to improve OC management. In the age of precision medicine, efforts to overcome platinum resistance in OC represent a dynamic and vast field in which innovative drugs and clinical trials rapidly develop. This review will present the exceptional biochemical environment implicated in OC and highlights mechanisms of chemoresistance. Furthermore, innovative molecules and new therapeutic opportunities are presented, along with currently available therapies and ongoing clinical trials.

Rucaparib Maintenance in Upfront Ovarian Cancer: The Long-Lasting Challenge of Predicting Response to Poly (ADP-ribose) Polymerase Inhibitors

Survival and toxicity in neoadjuvant chemotherapy plus surgery versus definitive chemoradiotherapy for cervical cancer: A systematic review and meta-analysis

Neoadjuvant chemotherapy followed by surgery (NACT + S) has been compared with definitive chemoradiothherapy (CRT) in randomized clinical trials (RCTs) in stage IB2, IIA and IIB cervical cancer (1994 Figo stage). Our aim was to evaluate efficacy and toxicity of NACT + S and CRT and identify differences in clinical outcomes and severe toxicity frequency. The PRISMA statement was applied. Random-effects models were used. Two RCTs representing 1259 patients were identified. NACT + S was not associated with significant OS improvement compared with CRT, with HR of 1.08 (95% CI = 0.86-1.36; p = 0.51). The HR of relapse was 1.32 (95%CI = 1.07-1.62) in favor of CRT. Severe acute toxicity was lower in CRT group. This meta-analysis showed similar OS rates between treatment and CRT superiority over NACT + S in terms of DFS and severe acute toxicity. Impact on long term toxicity and quality of life remain to be proven.

PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer has raised increasing concerns about PARPi-related myeloid neoplasms (PrMN). Therapy-related neoplasms, including myelodysplastic syndromes and acute myeloid leukemia, account for 10%-20% of cases. Expanding PARPi indications, longer survival, and aging populations may contribute to rising PrMN incidence. Randomized clinical trials and real-world analyses show a significant risk increase, but data on individual PARPi, treatment lines, and prior therapies are limited. We evaluated PrMN incidence across 17 Italian centers using a 71-item survey distributed to MITO (Multicenter Italian Trials on Ovarian cancer) and MaNGO (Mario Negri Gynecologic Oncology) centers, focusing on patients treated with PARPi outside clinical trials. Of 2320 patients (1254 BRCA-mutated), 56 (2.55%) developed MN: 35 myelodysplastic syndromes and 21 acute myeloid leukemia (2 patients had both, counted once). Among them, 31 had BRCA mutations (2.5%). Incidence by drug was: olaparib 2.5%, niraparib 2%, and rucaparib 3.4%. An unclear correlation emerged between treatment duration and PrMN risk, with a median onset of 18.9 months. Risk increased with additional therapy lines: 0.52% (first), 4.2% (second), 1.8% (third), 10.8% (fourth), and 12.2% (>fourth lines). Among PrMN cases, 4 achieved remission, 4 had partial responses, 8 progressed, and 37 died. While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.