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Abstract: Introduction: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. Methods: Patients (n =540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I–III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. Results: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41–0.99; P =0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44–0.89; P =0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46–1.03; P =0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35–0.88; P =0.01). Conclusion: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of adjuvant chemotherapy, type of ovarian surgery, and the surgical approach on fertility in patients with stage I immature teratoma of the ovary., Methods: Clinicopathologic data were retrospectively collected and analyzed from a cohort of 47 patients with childbearing desire treated for a stage I immature teratoma of the ovary at IRCCS San Gerardo dei Tintori Hospital, Monza, Italy. Multivariate logistic regression was used to address the influence of chemotherapy and type of surgery on the outcome., Results: Among the patients included, 78.7% (37/47) were able to get pregnant, with a live birth rate of 80.9% (51/63 pregnancies). These rates were not different between adjuvant chemotherapy versus surveillance group (62.5% (5/8) and 82.0% (32/39), respectively; p=0.22) nor between the type of ovarian surgery (cystectomy vs unilateral salpingo-oophorectomy; p=0.57) and surgical approach (laparotomy or laparoscopy; p=0.18). A statistically significant difference was found for stage of disease (a decrease in pregnancy rate from 86.5% (32/37) for stage IA to 50.0% for stage IC (5/10); p=0.02), but it was not confirmed in the multivariate analysis. After relapse diagnosis and management, a total of 62.5% (5/8) of patients conceived and had at least one live birth baby., Conclusions: The fertility-sparing approach is feasible in this population, and fertility does not depend on surgical approach or post-operative treatment. However, adjuvant chemotherapy should be carefully evaluated in this setting., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The standard surgical treatment of advanced ovarian carcinoma is primary debulking surgery (PDS) aiming to complete cytoreduction. The need to achieve complete cytoreduction has shifted the surgical paradigm to more complex procedures, whose impact on morbidity is controversial. The objective of this retrospective analysis is to explore the impact of extensive PDS on morbidity and oncologic outcomes in a real-world scenario., Methods: A retrospective single-center analysis was performed on 137 patients with advanced high-grade ovarian carcinoma (HGOC) who received PDS in 2015-2020. Patients treated in 2015-2017 (Group 1) were compared to patients treated in 2018-2020 (Group 2). The two periods were chosen according to the higher complexity of surgical procedures introduced in 2018., Results: The increase in complete cytoreduction observed in Group2 (RD 0: 33 % vs 61 %, p = 0,008) was related to a higher surgical complexity (Aletti Score: 4 vs 6, p = 0,003) and did not reflect an increase in peri-operative complications (CCI: 20,9 vs 20,9, p = 0,11). After a median FUP of 44 months, PFS and OS at 24 months were 33,60 % vs 47,33 % (p = 0,288) and 72,10 % vs 80,37 % (p = 0,022) in Group 1 and 2, respectively., Conclusions: An extensive surgical effort leads to a significant increase in complete cytoreduction with acceptable morbidity. Arm-in-arm with novel maintenance therapies, it contributes to increasing the outcomes of patients with advanced HGOC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population., Methods: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m 2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184., Findings: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group)., Interpretation: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests EB, FG, ER, and SU report grants from Roche to their institution to support the conduct of the study. NC reports personal fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Pfizer, Roche, and Novocure; and grants or research support from GSK and AstraZeneca. KH reports personal fees from AstraZeneca, Chugai, Eisai, MSD/Merck, Taiho, and Takeda; and grants or research support from MSD/Merck, Chugai, Takeda, AstraZeneca, and Daiichi Sankyo. EH reports personal fees from GSK and Clovis. FM reports personal fees from Roche, Eisai, Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, MSD/Merck, GSK, Clovis, Gilead, Myriad Genetics, Seagen, and Stemline Menarini; grants or research support from Roche; and participation on data safety monitoring or advisory boards for Immutep, Amgen, and Palleos Healthcare. CM reports personal fees from Roche, Novartis, MSD/Merck, AstraZeneca, Pfizer, PharmaMar, ImmunoGen, Daiichi Sankyo, Novocure, BioNTtech, Eisai, and GSK. LF-M reports personal fees from AstraZeneca, GSK, MSD/Merck, Eisai, and Pharma&. YCL reports personal fees from AstraZeneca, and grants or research support from BeiGene. EP reports personal fees from GSK and AstraZeneca. BP reports personal fees from AstraZeneca, GSK, MSD/Merck, and Pharma&. CZ reports personal fees from Roche, Eisai, Novartis, AstraZeneca, Pfizer, QuintilesIMS, Clovis, Eli Lilly, Istituto Gentili, Daiichi Sankyo, Seagen, MSD/Merck, GSK, and Gilead; and grants or research support from Roche, Novartis, AstraZeneca, Pfizer, Eisai, Clovis, Gilead, Seagen, Eli Lilly, Daiichi Sankyo, and MSD/Merck. KT reports personal fees from AstraZeneca, Chugai Pharma, Takeda, MSD/Merck, Nippon Kayaku, Eisai, and Sanofi; and grants or research support from Chugai Pharma. AF reports personal fees from GSK, AstraZeneca, and MSD/Merck. MP reports personal fees from AstraZeneca, Eisai, GSK, and MSD/Merck. MPBG reports personal fees from AstraZeneca, GSK, MSD/Merck, PharmaMar, Clovis Oncology, Eisai, Pharma&, and Kyowa Kirin; and a leadership role for Geico. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Immature teratomas are rare malignant ovarian germ cell tumours, typically diagnosed in young women, where fertility-sparing surgery is the treatment of choice. The role of adjuvant chemotherapy in stage I disease remains controversial. We evaluated the impact of surveillance versus chemotherapy on the recurrence rate in stage I immature teratomas., Methods: We collected a single centre retrospective series of patients with stage I immature teratomas treated with fertility-sparing surgery at San Gerardo Hospital, Monza, Italy, between 1980 and 2019. Potential risk factors for recurrence were investigated by multivariate logistic regression., Results: Of the 74 patients included, 12% (9/74) received chemotherapy, while 88% (65/74) underwent surveillance. Median follow-up was 188 months. No difference in recurrence was found in stage IA/IB and IC immature teratomas [10% (6/60) vs. 28.6% (4/14) (P=0.087)], grade 1, grade 2, and grade 3 [7.1% (2/28) vs. 14.3% (4/28) vs. 22.2% (4/18) (p=0.39)], and surveillance versus chemotherapy groups [13.9% (9/65) vs. 11.1% (1/9)) (p = 1.00)]. In univariate analysis, the postoperative approach had no impact on recurrence. The 5-year disease-free survival was 87% and 90% in the surveillance and chemotherapy groups, respectively; the overall survival was 100% in both cohorts., Conclusions: Our results support the feasibility of surveillance in stage I immature teratomas. Adjuvant chemotherapy may be reserved for relapses. However, the potential benefit of chemotherapy should be discussed, especially for high-risk tumours. Prospective series are warranted to confirm our findings., What Is Already Known on This Topic: To date, no consensus has been reached regarding the role of adjuvant chemotherapy in stage I immature teratomas of the ovary. Some studies suggest that only surveillance is an acceptable choice. However, guidelines are not conclusive on this topic., What This Study Adds: No difference in terms of recurrence was observed between the surveillance and the adjuvant chemotherapy group. All patients who relapsed were successfully cured with no disease-related deaths., How This Study Might Affect Research Practice or Policy: Adjuvant chemotherapy should be appropriately discussed with patients. However, it may be reserved for relapse according to our data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Marino, Grassi, De Ponti, Negri, Testa, Giuliani, Delle Marchette, Dell’Oro, Fumagalli, Donatiello, Besana, Marchetta, Bonazzi, Lissoni, Landoni and Fruscio.)

Pharmacogenomics studies how genes influence a person's response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential - namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-induced, taxane-induced, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single-nucleotide variation (SNV, formerly SNP) profiles were examined using ML to find and prioritize those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, nonhematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNVs in predicting toxicities. Important SNVs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNVs critical for predicting toxicity were identified. For each toxicity, key SNVs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28-fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for patients with ovarian cancer, which may be useful for reducing toxicities and improving toxicity management., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Epithelial ovarian cancer (EOC), a primarily high-grade serous carcinoma (HGSOC), is one of the major causes of high death-to-incidence ratios of all gynecological cancers. Cytoreductive surgery and platinum-based chemotherapy represent the main treatments for this aggressive disease. Molecular characterization of HGSOC has revealed that up to 50% of cases have a deficiency in the homologous recombination repair (HRR) system, which makes these tumors sensitive to poly ADP-ribose inhibitors (PARP-is). However, drug resistance often occurs and overcoming it represents a big challenge. A number of strategies are under investigation, with the most promising being combinations of PARP-is with antiangiogenetic agents and immune checkpoint inhibitors. Moreover, new drugs targeting different pathways, including the ATR-CHK1-WEE1, the PI3K-AKT and the RAS/RAF/MEK, are under development both in phase I and II-III clinical trials. Nevertheless, there is still a long way to go, and the next few years promise to be exciting.

Background: Squamous cell carcinoma of the vulva is a rare malignancy that affects elderly women. About one-third of vulvar cancers are diagnosed in an advanced stage, requiring extensive surgery. Neoadjuvant chemotherapy (NACT) has been introduced to reduce local tumor burden. In this retrospective study, we analyze the efficacy and toxicity of NACT followed by radical surgery., Methods: Patients with locally advanced vulvar cancer (LAVC) treated at our institution with neoadjuvant platinum and paclitaxel-based chemotherapy ± ifosfamide followed by surgery at our institution were retrospectively identified., Results: Fourteen patients (93%) completed NACT with tolerable toxicities (G3-G4 toxicity: 30%). Thirteen patients (87%) underwent surgery. The overall clinical response rate on vulvar disease was 66% (20% complete response, 46% partial response), confirmed by histopathologic analysis, while on inguinal lymph nodes it was 69% (23% complete response, 46% partial response). At the pathologic examination, all patients had negative surgical margins. Three out of 9 patients (33%) with lesions infiltrating the urethral meatus and 4 patients out of 7 (57%) with anal involvement did not require urethral amputation or colostomy, respectively, after NACT. No severe postoperative complications were described. Overall survival at 5 years was 60%, and median overall survival was 76 months., Conclusion: NACT followed by surgery in locally advanced vulvar cancer is well tolerated and allows surgical modulation.

Background/aim: To assess response rates and survival in patients with recurrent platinum-sensitive epithelial ovarian cancer (EOC) who received PARP inhibitor (PARP-i) maintenance and who subsequently underwent salvage chemotherapy for disease progression after PARPi., Patients and Methods: This retrospective investigation analyzed 103 patients who were treated in five Italian Gynecologic centers. The PARPi used was olaparib in 46 patients, niraparib in 55, and rucaparib in 2. The interval time between the last cycle of pre- PARPi platinum-based chemotherapy and the diagnosis of progression during PARPi maintenance was defined as platinum-free interval (PFI)., Results: Of the 28 patients with PFI <6 months, 23 received chemotherapy (non-platinum single agent, 20; trabectedin + pegylated liposomal doxorubicin (PLD), 3). Forty-two of the 43 patients with PFI 6-12 months underwent chemotherapy (platinum-based chemotherapy,11; trabectedin + PLD, 10; non platinum-single agent, 21). Thirty-one of the 32 patients with PFI >12 months received chemotherapy (platinum-based chemotherapy, 23; trabectedin + PLD, 3; non platinum - single agent, 5). An objective response was found in 13.0%, 26.2% and 41.9 % of the patients with PFI <6 months, 6-12 months, and >12 months (p= 0.03), respectively, and the corresponding median survivals after PARPi were 8.9 months, 17.5 months and 24.1 months (p= 0.002), respectively., Conclusion: Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from the last platinum cycle have shown response rates ranging from 47.2% to 66%. Response rates to chemotherapy for progression after PARPi appear to be lower than those expected according to PFI., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone., Methods: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5)., Results: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm., Conclusions: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population., Clinical Trial Identification: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial., Methods: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated., Results: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61)., Conclusions: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis., Trial Registration Number: NCT01706120., Competing Interests: Competing interests: RDL reports personal fees from Astellas, outside the submitted work. FR reports grants from GSK, grants from MSD, grants from Roche, grants from Pharmamar, grants from AstraZeneca, outside the submitted work. NC reports personal fees from Roche, personal fees from Pharmamar, personal fees from AstraZeneca, personal fees from MSD/Merck, personal fees from Clovis Oncology, personal fees from Tesaro, personal fees from GSK, personal fees from Novartis, personal fees from Pfizer, personal fees from Takeda, personal fees from Biocad, personal fees from Immunogen, personal fees from Mersana, personal fees from Eisai, personal fees from Oncxerna, outside the submitted work. SF reports personal fees from Pharmastar, personal fees from GSK, personal fees from Pfizer, personal fees from Novartis, outside the submitted work. DG reports personal fees from Astellas, personal fees from Bayer, personal fees and non-financial support from BMS, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Janssen, personal fees from Merck, personal fees and non-financial support from Pfizer, grants and personal fees from Sanofi, grants from Roche, from AstraZeneca, outside the submitted work. DL reports personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Clovis, grants, personal fees and non-financial support from GSK, personal fees from Pharmamar, grants and non-financial support from Genmab, grants, personal fees and non-financial support from MSD, non-financial support from Immunogen, non-financial support from Incyte, non-financial support from Roche, from Amgen, outside the submitted work. VS reports personal fees from MSD, personal fees from GSK, personal fees from Tesaro, personal fees from AstraZeneca, personal fees from Roche, personal fees from Eisai, personal fees from Clovis, outside the submitted work. FP reports personal fees from Bayer, personal fees from Ipsen, personal fees from AstraZeneca, personal fees from Bristol Myers Squibb, personal fees from Sandoz, personal fees from Incyte, personal fees from Celgene, personal fees from Pierre Fabre, personal fees from Janssen-Cilag, outside the submitted work. SP reports grants and personal fees from AstraZeneca, grants and personal fees from MSD, grants and personal fees from Roche, personal fees from Pharmamar, personal fees from Clovis, grants and personal fees from Pfizer, outside the submitted work. MCP reports personal fees from Daichii-Sankyo, personal fees from GSK, personal fees from MSD, grants from Roche, grants and personal fees from AstraZeneca, non-financial support from Bayer, outside the submitted work. The other authors do not declare conflicts of interests., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab., Methods: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m 2 ) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints., Results: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported., Conclusions: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors., Trial Registration Number: EudraCT 2012-003043-29; NCT01706120., Competing Interests: Competing interests: Dr Daniele reports travel and accommodations from Roche, outside the submitted work. Dr Raspagliesi reports grants from Roche, grants from GSK, grants from MSD, grants from Pharmamar, outside the submitted work. Dr Colombo reports personal fees from Roche, personal fees from Pharmamar, personal fees from AstraZeneca, personal fees from MSD, personal fees from Tesaro, personal fees from GSK, personal fees from Clovis, personal fees from Amgen, personal fees from Pfizer, personal fees from Biogen, personal fees from BIOCAD, outside the submitted work. Dr De Giorgi reports personal fees from Astellas - Pharma, personal fees from Bayer, personal fees and non-financial support from Bristol Myers-Squibb, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Janssen, personal fees and non-financial support from Pfizer, grants and personal fees from Sanofi, personal fees from Novartis, personal fees from MSD, grants and non-financial support from Roche, grants from AstraZeneca, personal fees from Pharmamar, outside the submitted work. Dr Lorusso reports grants, personal fees and non-financial support from Pharmamar, grants and personal fees from MSD, grants and personal fees from Clovis, grants, personal fees and non-financial support from GSK, personal fees and non-financial support from AstraZeneca, personal fees from Merck Serono, personal fees from Amgen, non-financial support from Roche, outside the submitted work. Dr Salutari reports personal fees from MSD, personal fees from GSK, personal fees from Tesaro, personal fees from AstraZeneca, personal fees from Roche, personal fees from Eisai, personal fees from Clovis, outside the submitted work. Dr Piccirillo reports personal fees from Daichii Sankyo, personal fees from GSK, personal fees from MSD, grants from Roche, grants and personal fees from AstraZeneca, non-financial support from Bayer, outside the submitted work. Dr Perrone reports grants from Roche, during the conduct of the study; grants, personal fees and non-financial support from Bayer, personal fees from Sandoz, grants and personal fees from Incyte, personal fees from Celgene, grants and personal fees from AstraZeneca, personal fees from Pierre Fabre, personal fees from Janssen Cilag, grants from Roche, grants from Pfizer, outside the submitted work. Dr Pignata reports grants from Roche, during the conduct of the study; personal fees from AZ, personal fees from MSD, personal fees from Clovis, personal fees and non-financial support from Tesaro GSK, personal fees from Roche, outside the submitted work. The other authors do not declare conflicts of interests., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL)., Methods and Materials: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed., Results: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population., Conclusions: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) represent a heterogeneous group of tumors that cannot be histologically diagnosed as unequivocally benign or malignant. For this reason, many authors are working to obtain a better definition of diagnostic and prognostic criteria. In this work, we analyzed the genomic and epigenomic profile of uterine smooth muscle tumors (USMTs) in order to find similarities and differences between STUMPs, leiomyosarcomas (LMSs) and leiomyomas (LMs), and possibly identify prognostic factors in this group of tumors. Array-CGH data on 23 USMTs demonstrated the presence of a more similar genomic profile between STUMPs and LMSs. Some genes, such as PRKDC and PUM2 , with a potential prognostic value, were never previously associated with STUMP. The methylation data appears to be very promising, especially with regards to the divergent profile found in the sample that relapsed, characterized by an overall CGI hypomethylation. Finally, the Gene Ontology analysis highlighted some cancer genes that could play a pivotal role in the unexpected aggressive behavior that can be found in some of these tumors. These genes could prove to be prognostic markers in the future.

Background/aim: The role of neoadjuvant chemotherapy (NACT) is under investigation in locally advanced cervical cancer (LACC)., Patients and Methods: A total of 49 patients with FIGO stage IB1-IIB cervical cancer who underwent two different regimens of weekly dose-dense NACT were included. The objective was to evaluate clinical/pathological response and toxicity profile., Results: A clinical complete response and partial response were obtained in 43 patients with a clinical overall response rate of 88%. Among the 42 surgically treated patients, 7 (17%) and 35 (83%) achieved a pathological overall optimal response and a suboptimal pathological response, respectively. G3-G4 neutropenia occurred in 16% of patients, whereas no cases of G3 thrombocytopenia, G3 anemia and febrile neutropenia were observed., Conclusion: Dose-dense NACT is safe, has acceptable toxicity, and obtains good clinical response, but is less effective in terms of pathological overall optimal response rates compared to other regimens., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: advanced stage clear cell ovarian cancer (CCOC) carries a higher risk of relapse and death compared to other histological subtypes. The prognosis of early-stage CCOC is controversial., Methods: Early-stage high-grade OC patients from two Italian oncologic centers were included. Patients with early-stage CCOC were compared with those with high-grade endometrioid (HGE) and serous (HGS) OC in terms of relapse-free interval (RFI), cancer-specific survival (CSS) and post relapse cancer-specific survival (prCSS). The Cox proportional hazard model and the restricted mean survival time were used., Results: Between 1981 and 2012, 134 patients with CC, 152 with HGE and 160 with HGS were treated at two referral centers. Median follow-up was 11.5 years. Ten years RFI rates were 80.6%, 72.1%, 60.6%, and CSS rates were 84.3%, 82.6%, 81.7% respectively. Adjuvant chemotherapy significantly improved RFI (aHR 0.61, 95%CI 0.40 to 0.91, P = 0.015). In the multivariable analysis HGS histotype was associated with a shorter RFI compared to CC, (Hazard Ratio [HR]: 1.81; 95%CI: 1.12-2.93; P = 0.016), whereas CSS was not statistically different. prCSS was longer in HGS compared to CCOC (HR, 0.36; 95% CI, 0.17-0.74; P = 0.006). According to the stage, IA/IB/IC1 HGSOC had a shorter RFI (HR, 2.13; 95% CI, 1.14-3.99; P = 0.018) compared to IA/IB/IC1 CCOC, but similar CSS. For prCSS, CC compared to HGS conferred a worse prognosis regardless of the initial stage., Conclusions: Early-stage CCOC is associated with a longer RFI, similar CSS and a shorter prCSS compared to HGSOC. No prognostic differences were observed between CC and HGE OC. The relapse risk was the lowest in IA/IB/IC1 CC compared to HGS, whereas CC displayed poor sensitivity to chemotherapy after relapse., Competing Interests: Declaration of Competing Interest Dr. Colombo reports personal fees from Roche, Pharmamar, Astra Zeneca, Clovis, Tesaro, GSK, Pfizer, Amgen, Immunogen, MSD, Advaxis, Takeda, Novartis, Elipses and Biocad, outside the submitted work. The authors report no other conflicts of interest in this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Background/aim: The aim of the study was to assess the outcome of advanced ovarian cancer patients who i) underwent primary surgery followed by carboplatin/paclitaxel-based chemotherapy with or without bevacizumab, ii) were in complete response after chemotherapy, iii) and subsequently recurred., Patients and Methods: The hospital records of 138 complete responders after chemotherapy with (n=58) or without (n=80) bevacizumab were reviewed., Results: Both survival after recurrence and overall survival were related to age (≤61 vs. >61 years, p=0.002 and p=0.0001), performance status (0 vs. ≥1, p=0.002 and p=0.001), histotype (serous vs. non serous, p=0.005 and p=0.01), time to recurrence (≥12 vs. <12 months, p<0.0001 and p<0.0001) and treatment at recurrence (surgery plus chemotherapy vs. chemotherapy, p=0.01 and p=0.004), but not to first-line treatment., Conclusion: This investigation failed to detect a more aggressive behavior of recurrent ovarian cancer after bevacizumab-containing primary treatment., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated., Methods: In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6  ≥ 30% as unacceptable., Results: BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%-69%) but PFS-6 was 85% (95%CI: 62%-97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%-87%) and 16% ST-6 (95%CI 7%-30%)., Conclusions: BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity., Clinical Trial Registration: NCT01735071 (Clinicaltrials.gov).

Background: Even if borderline ovarian tumours (BOTs) in young women treated with fertility-sparing treatment (FST) have an excellent outcome, the type of surgery might affect relapse and fertility. We investigated the effect of surgical approach (open surgery vs. laparoscopy) and type of surgery (salpingo-oophorectomy [SO] vs. cystectomy [Cy]) on oncologic and fertility outcomes in patients with BOT., Patients and Methods: Patients with BOT treated at San Gerardo Hospital, Monza, with FST in 1978-2013 period were included. Cox models, stratified by decade of surgery, were used to investigate the association between time to first recurrence or conception and clinical factors., Results: Among 535 patients included, 271 underwent unilateral SO and 264 underwent Cy. Median follow-up was 13.5 years. Ten-year (10-yr) recurrence rate was 23% (95% confidence interval [CI]: 18-29%) for SO and 31% (95% CI: 24-38%) for Cy group (P = 0.10) in patients with unilateral tumour, whereas it was 62% (95% CI: 44-79%) and 72% (95% CI: 59-84%), respectively, (P = 0.35) in patients with bilateral tumour. Multivariable analysis showed no association between recurrence and surgical approach (P = 0.44), type of surgery (P = 0.06) and a negative association with advanced stage (hazard ratio [HR] = 3.18; 95% CI: 2.11-4.78; P < 0.001) and bilateral tumours (HR = 2.48; 95% CI: 1.78-3.47; P < 0.001). Among 252 patients (47.1%) with pregnancy desire, multivariable analysis showed no association between conception success and the type of surgery, surgical approach, histology and tumour laterality. Fertility after surgery was positively associated with prior pregnancy (HR = 1.68; 95% CI: 1.17-2.41; P = 0.005) and negatively associated with the number of surgical procedures (HR = 0.62; 95% CI: 0.53-0.73; P < 0.001)., Conclusions: The type of surgical procedures did not influence recurrence rate or fertility. However, additional surgical procedures decreased the fertility potential. These data can support clinicians in tailoring the best strategy for FST in young patients with BOT., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The effect of chemotherapy exposure (CE) on ovarian function in young women with ovarian neoplasms undergoing fertility-sparing treatment (FST) remains unclear. We investigated whether CE is correlated with the outcomes (1) during-treatment and (2) post-treatment amenorrhea, (3) conception rate, (4) pregnancy outcome, and (5) spontaneous menopausal age., Patients and Methods: Eligibility criteria were patients with a diagnosis of epithelial (EOC) or nonepithelial (no-EOC) invasive ovarian neoplasm, premenopausal age, undergoing FST ± CE, histopathology confirmation, and adequate follow-up. The groups' outcomes were compared by logistic and linear regression analysis., Results: A total of 548 patients diagnosed during 1980 and 2014 were included, 198 in the EOC group and 350 in the no-EOC group, and 44% received chemotherapy, with a median follow-up of 15.9 years. In no-EOC patients, CE conferred a higher risk for Outcomes 1 (adjusted OR [aOR] 27; 95% CI 12 to 61; P < .0001) and 2 (aOR 5.42; 95% CI 1 to 24; P = .0256) and was associated with a younger menopausal age (adjusted β -5.52; 95% CI -10.53 to -0.52; P = .0313). Overall, 57% of patients attempted pregnancy, with a conception rate of 89%. In EOC patients, no association between CE and a decreased fertility was demonstrated (aOR, 3.05; 95% CI 0.72 to 12.88; P = .1298)., Conclusions: CE in no-EOC was associated with an increased risk of during-treatment amenorrhea, post-treatment amenorrhea, and earlier spontaneous menopausal age; CE in EOC was not associated with any item at study. Patients undergoing FST had reassuringly high conception rates and low premature ovarian failure rates; however, in pretreatment counseling, the risks of this approach in such young population should be discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Uterine smooth muscle tumors are the most common female genital tract neoplasms. While leiomyosarcoma has been studied at length, smooth muscle tumors of uncertain malignant potential (STUMPs) still have ambiguous and unresolved issues, with a risk of relapse and evolution largely undefined. We performed an array comparative genomic hybridization analysis on a primitive STUMP and its local recurrence, histologically diagnosed as undifferentiated sarcoma. To the best of our knowledge, our report is the first genomic study on primitive STUMPs and the different relapsed tumors. The results showed few copy number alterations shared between both samples and the high heterogeneity in the STUMP was apparently lost in the sarcoma. Surprisingly the STUMP presented an amplification of the BCL2 gene, not observed in the relapsed tumor. Additionally, fluorescence in situ hybridization and immunohistochemical staining were performed to confirm BCL2 amplification and expression in these samples and in two other cases of primitive STUMPs and their corresponding relapsed tumors. The presence of BCL2 in multiple copies and expression in the two primitive STUMPs and two relapsed tumors was confirmed. The marked amplification of the BCL2 gene present in the primitive STUMP and the multiple copies also observed in other cases, suggest its potential role as a marker of STUMP malignant potential and recurrence.

Background: The credibility of sentinel lymph node (SLN) mapping is becoming increasingly more established in cervical cancer. We aimed to assess the sensitivity of SLN biopsy in terms of detection rate and bilateral mapping in women with cervical cancer by comparing technetium-99 radiocolloid (Tc-99(m)) and blue dye (BD) versus fluorescence mapping with indocyanine green (ICG)., Methods: Data of patients with cervical cancer stage 1A2 to 1B1 from 5 European institutions were retrospectively reviewed. All centers used a laparoscopic approach with the same intracervical dye injection. Detection rate and bilateral mapping of ICG were compared, respectively, with results obtained by standard Tc-99(m) with BD., Results: Overall, 76 (53 %) of 144 of women underwent preoperative SLN mapping with radiotracer and intraoperative BD, whereas 68 of (47 %) 144 patients underwent mapping using intraoperative ICG. The detection rate of SLN mapping was 96 % and 100 % for Tc-99(m) with BD and ICG, respectively. Bilateral mapping was achieved in 98.5 % for ICG and 76.3 % for Tc-99(m) with BD; this difference was statistically significant (p < 0.0001)., Conclusions: The fluorescence SLN mapping with ICG achieved a significantly higher detection rate and bilateral mapping compared to standard radiocolloid and BD technique in women with early stage cervical cancer. Nodal staging with an intracervical injection of ICG is accurate, safe, and reproducible in patients with cervical cancer. Before replacing lymphadenectomy completely, the additional value of fluorescence SLN mapping on both perioperative morbidity and survival should be explored and confirmed by ongoing controlled trials.

Objective: Evaluation of the impact of sequential chemoradiotherapy in high risk endometrial cancer (EC)., Methods: Two hundred fifty-four women with stage IB grade 3, II and III EC (2009 FIGO staging), were included in this retrospective study., Results: Stage I, II, and III was 24%, 28.7%, and 47.3%, respectively. Grade 3 tumor was 53.2% and 71.3% had deep myometrial invasion. One hundred sixty-five women (65%) underwent pelvic (+/- aortic) lymphadenectomy and 58 (22.8%) had nodal metastases. Ninety-eight women (38.6%) underwent radiotherapy, 59 (23.2%) chemotherapy, 42 (16.5%) sequential chemoradiotherapy, and 55 (21.7%) were only observed. After a median follow-up of 101 months, 78 women (30.7%) relapsed and 91 women (35.8%) died. Sequential chemoradiotherapy improved survival rates in women who did not undergo nodal evaluation (disease-free survival [DFS], p=0.040; overall survival [OS], p=0.024) or pelvic (+/- aortic) lymphadenectomy (DFS, p=0.008; OS, p=0.021). Sequential chemoradiotherapy improved both DFS (p=0.015) and OS (p=0.014) in stage III, while only a trend was found for DFS (p=0.210) and OS (p=0.102) in stage I-II EC. In the multivariate analysis, only age (≤ 65 years) and sequential chemoradiotherapy were statistically related to the prognosis., Conclusion: Sequential chemoradiotherapy improves survival rates in high risk EC compared with chemotherapy or radiotherapy alone, in particular in stage III.

Objective: Neoadjuvant chemotherapy (NACT) is a valid treatment option for women with locally advanced cervical cancer (LACC). This study aims to evaluate the impact of sociodemographic factors, clinical factors, and NACT regimens on survival endpoints. The role of pathological response to NACT as a surrogate endpoint of survival was also assessed., Materials and Methods: Retrospective analysis of consecutive sample data from women with LACC (stages Ib2-IVa) who underwent NACT followed by radical surgery was performed. Response was classified as optimal response (including complete response and optimal partial response), suboptimal partial response, stable disease, and progressive disease., Results: Four hundred forty-six women who had undergone surgery from 1992 to 2011 were analyzed. The overall optimal response was 35.4%. At a median follow-up of 12.7 years, 165 women (37.0%) experienced recurrence or died. Increase in patient age at surgery, International Federation of Gynecology and Obstetrics stage III/IV versus stage Ib2, and lymph-node positivity versus negativity seemed to impact negatively on survival, whereas neoadjuvant platinum-Taxol-containing regimens (compared with platinum-based regimens) improved survival. Response to NACT could be considered a surrogate endpoint of survival., Conclusions: Age, International Federation of Gynecology and Obstetrics stage III/IV, lymph-node involvement, and type of NACT administered have a significant impact on survival. Response to NACT is a good surrogate endpoint of survival in patients with LACC.

Objective: About 50-60% of patients with stage I-II uterine leiomyosarcoma (ULMS), primarily treated with surgery, relapse and die from progressive disease. In this retrospective study we describe the impact of adjuvant chemotherapy in this subset of patients., Methods: 140 women treated from 1976 to 2011 were included in the study. Univariate and multivariate analysis were used to test the association of clinical features and adjuvant treatments with overall survival (OS) and disease-free survival (DFS)., Results: 62 women did not receive any further treatment after hysterectomy, 14 had radiotherapy (RT), 52 chemotherapy and 12 chemo-radiotherapy. Chemotherapy based on doxorubicin and ifosfamide combination was used in 54 cases. After a median follow-up of 63months, 87 women (62%) have relapsed, and 62 (44%) have died. The vast majority of patients who relapsed had distant recurrences (72%). The 5year median DFS and OS were 43% and 64% respectively. After 5years of follow up 68.7% of women treated with chemotherapy (±RT) vs 65.6% of patients only observed were alive (p=0.521). In the univariate analysis no factors had a statistical impact on DFS, while number of mitosis (>20×10HPF), age (>60years) and adjuvant radiotherapy were found as negative prognostic factors for OS. In the multivariate analysis only mitosis and age remained significant for OS., Conclusion: Adjuvant chemotherapy was not associated with a significant survival benefit and should not be considered as standard of care for patients with stage I-II ULMS until randomized clinical studies will give further information., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objectives: To develop a logistic regression model for discrimination between benign and malignant unilocular solid cysts with papillary projections but no other solid components, and to compare its diagnostic performance with that of subjective evaluation of ultrasound findings (subjective assessment), CA  125 and the risk of malignancy index (RMI)., Methods: Among the 3511 adnexal masses in the International Ovarian Tumor Analysis (IOTA) database there were 252 (7%) unilocular solid cysts with papillary projections but no other solid components ('unilocular cysts with papillations'). All had been examined with transvaginal ultrasound using the IOTA standardized research protocol. The ultrasound examiner had also classified each mass as certainly or probably benign, unclassifiable, or certainly or probably malignant. A logistic regression model to discriminate between benignity and malignancy was developed for all unilocular cysts with papillations (175 tumors in the training set and 77 in the test set) and for unilocular cysts with papillations for which the ultrasound examiner was not certain about benignity/malignancy (113 tumors in the training set and 53 in the test set). The gold standard was the histological diagnosis of the surgically removed adnexal mass., Results: A model containing six variables was developed for all unilocular cysts with papillations. The model had an area under the receiver-operating characteristics curve (AUC) on the test set of 0.83 (95% CI, 0.74-0.93). The optimal risk cut-off, as defined on the training set (0.35), resulted in sensitivity 69% (20/29), specificity 79% (38/48), positive likelihood ratio (LR +) 3.31 and negative likelihood ratio (LR-) 0.39 on the test set. The corresponding values for subjective assessment when using the ultrasound examiner's dichotomous classification of the mass as benign or malignant were 97% (28/29), 79% (38/48), 4.63 and 0.04. A model containing four variables was developed for unilocular cysts with papillations for which the ultrasound examiner was not certain about benignity/malignancy. The model had an AUC of 0.74 (95% CI, 0.60-0.88) on the test set. The optimal risk cut-off of the model, as defined on the training set (0.30), resulted in sensitivity 57% (12/21), specificity 78% (25/32), LR + 2.61 and LR- 0.55 on the test set. The corresponding values for subjective assessment were 95% (20/21), 78% (25/32), 4.35 and 0.06. CA  125 and RMI had virtually no diagnostic ability., Conclusions: Even though logistic regression models to predict malignancy in unilocular cysts with papillations can be developed, they have at most moderate performance and are not superior to subjective assessment for discrimination between benignity and malignancy., (Copyright © 2012 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To describe clinical and ultrasound features of Brenner tumors of the ovary., Methods: In this retrospective study, the databases of the International Ovarian Tumor Analysis (IOTA) studies and one tertiary center were searched to identify patients who had undergone an ultrasound scan before surgery for an adnexal mass that proved to be a Brenner tumor. Twenty-eight patients with 29 Brenner tumors were included, most of which had been collected within the framework of the IOTA studies. An experienced ultrasound examiner reviewed available ultrasound images (available for 14 tumors), searching for a pattern specific to Brenner tumors., Results: Most patients were postmenopausal and asymptomatic. Twenty-four (83%) tumors were benign, two (7%) were borderline and three (10%) were malignant. Most benign tumors (17/24, 71%) contained solid components and manifested no or minimal blood flow on Doppler examination (19/24, 79%). Information about calcifications was available for 15 benign tumors, and in 13 (87%) calcifications were present. The five borderline and invasively malignant tumors contained solid components less often than did the benign ones (3/5, 60%) and were more richly vascularized on Doppler examination. Information about calcifications was available for four borderline or invasively malignant tumors, and in three (75%) calcifications were present., Conclusion: We failed to demonstrate ultrasound features specific to Brenner tumors. A prospective study is needed to determine if ultrasound features of calcifications can discriminate between Brenner tumors and other types of ovarian tumor., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To determine the diagnostic performance of ultrasound-based simple rules, risk of malignancy index (RMI), two logistic regression models (LR1 and LR2) and real-time subjective assessment by experienced ultrasound examiners following the exclusion of masses likely to be judged as easy and 'instant' to diagnose by an ultrasound examiner, and to develop a new strategy for the assessment of adnexal pathology based on this., Methods: 3511 patients with at least one persistent adnexal mass preoperatively underwent transvaginal ultrasonography to assess tumor morphology and vascularity. They were included in two consecutive prospective studies by the International Ovarian Tumor Analysis (IOTA) group: Phase 1 (1999-2005), development of the simple rules and logistic regression models LR1 and LR2, and Phase 2, a validation study (2005-2007)., Results: Almost half of the cases (43%) were identified as 'instant' to diagnose on the basis of descriptors applied to the database. To assess diagnostic performance in the more difficult 'non-instant' masses, we used only Phase 2 data (n = 1036). The sensitivity of LR2 was 88%, of RMI it was 41% and of subjective assessment it was 87%. The specificity of LR2 was 67%, of RMI it was 90% and of subjective assessment it was 86%. The simple rules yielded a conclusive result in almost 2/3 of the masses, where they resulted in sensitivity and specificity similar to those of real-time subjective assessment by experienced ultrasound examiners: sensitivity 89 vs 89% (P = 0.76), specificity 91 vs 91% (P = 0.65). When a three-step strategy was applied with easy 'instant' diagnoses as Step 1, simple rules where conclusive as Step 2 and subjective assessment by an experienced ultrasound examiner in the remaining masses as Step 3, we obtained a sensitivity of 92% and specificity of 92% compared with sensitivity 90% (P = 0.03) and specificity 93% (P = 0.44) when using real-time subjective assessment by experts in all tumors., Conclusion: A diagnostic strategy using simple descriptors and ultrasound rules when applied to the variables contained in the IOTA database obtains results that are at least as good as those obtained by subjective assessment of a mass by an expert., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: To estimate the ability to discriminate between benign and malignant adnexal masses of different size using: subjective assessment, two International Ovarian Tumor Analysis (IOTA) logistic regression models (LR1 and LR2), the IOTA simple rules and the risk of malignancy index (RMI)., Methods: We used a multicenter IOTA database of 2445 patients with at least one adnexal mass, i.e. the database previously used to prospectively validate the diagnostic performance of LR1 and LR2. The masses were categorized into three subgroups according to their largest diameter: small tumors (diameter < 4 cm; n = 396), medium-sized tumors (diameter, 4-9.9 cm; n = 1457) and large tumors (diameter ≥ 10 cm, n = 592). Subjective assessment, LR1 and LR2, IOTA simple rules and the RMI were applied to each of the three groups. Sensitivity, specificity, positive and negative likelihood ratio (LR+, LR-), diagnostic odds ratio (DOR) and area under the receiver-operating characteristics curve (AUC) were used to describe diagnostic performance. A moving window technique was applied to estimate the effect of tumor size as a continuous variable on the AUC. The reference standard was the histological diagnosis of the surgically removed adnexal mass., Results: The frequency of invasive malignancy was 10% in small tumors, 19% in medium-sized tumors and 40% in large tumors; 11% of the large tumors were borderline tumors vs 3% and 4%, respectively, of the small and medium-sized tumors. The type of benign histology also differed among the three subgroups. For all methods, sensitivity with regard to malignancy was lowest in small tumors (56-84% vs 67-93% in medium-sized tumors and 74-95% in large tumors) while specificity was lowest in large tumors (60-87%vs 83-95% in medium-sized tumors and 83-96% in small tumors ). The DOR and the AUC value were highest in medium-sized tumors and the AUC was largest in tumors with a largest diameter of 7-11 cm., Conclusion: Tumor size affects the performance of subjective assessment, LR1 and LR2, the IOTA simple rules and the RMI in discriminating correctly between benign and malignant adnexal masses. The likely explanation, at least in part, is the difference in histology among tumors of different size., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To determine current practice and to assess the value of routine follow-up procedures for endometrial cancer surveillance. To discuss whether such procedures are feasible and effective to identify asymptomatic recurrences and describe the pattern of relapse detected by procedures., Methods: The records of 282 consecutive women with recurrent endometrial cancer treated from 1986 to 2005 were retrospectively collected in 8 Italian institutions. Primary disease, clinical history, and recurrence features and data were analyzed., Results: Thirty-five (12.4%) of 282 patients had recurrence in vaginal vault, 51 patients (18.0%) had recurrence in central pelvis, 14 patients (4.9%) had recurrence in pelvic wall, and 39 patients (13.8%) had recurrence in lymph nodes. One-hundred twenty-eight patients (45.3%) showed a distant relapse, whereas 15 patients (5.3%) developed both distant relapse and local relapse. The site of relapse influenced survival because the patients with vaginal vault recurrences lived significantly longer than the patients with recurrences in other sites. Eighty (28.4%) of the 282 patients became symptomatic and anticipated the scheduled visit, 37 (13.1 %) of the patients reported their symptoms during the follow-up meeting, and 165 (58.5 %) of the patients were asymptomatic and the diagnostic path was introduced by a planned visit or examination. Among the asymptomatic patients, the first procedure that led to further examinations was clinical visit alone for 60 (36.4%) of 165 patients, imaging for 103 patients (62.4%), and cytologic examination for 2 patients (1.2%). Symptoms at recurrence can predict survival: patients with an asymptomatic recurrence had a median survival time from relapse of 35 months versus 13 months if they had a symptomatic repetition (P = 0.0001)., Conclusions: Follow-up after endometrial cancer treatment varies in Italy. In this retrospective study, women with asymptomatic recurrence have shown a better clinical outcome compared with those with symptomatic relapse. The optimal approach is actually unknown, and guidelines comparing follow-up protocols have not been established. Prospective cost-effectiveness studies are needed.

Purpose: To externally validate and compare the performance of previously published diagnostic models developed to predict malignancy in adnexal masses., Experimental Design: We externally validated the diagnostic performance of 11 models developed by the International Ovarian Tumor Analysis (IOTA) group and 12 other (non-IOTA) models on 997 prospectively collected patients. The non-IOTA models included the original risk of malignancy index (RMI), three modified versions of the RMI, six logistic regression models, and two artificial neural networks. The ability of the models to discriminate between benign and malignant adnexal masses was expressed as the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and likelihood ratios (LR(+), LR(-))., Results: Seven hundred and forty-two (74%) benign and 255 (26%) malignant masses were included. The IOTA models did better than the non-IOTA models (AUCs between 0.941 and 0.956 vs. 0.839 and 0.928). The difference in AUC between the best IOTA and the best non-IOTA model was 0.028 [95% confidence interval (CI), 0.011-0.044]. The AUC of the RMI was 0.911 (difference with the best IOTA model, 0.044; 95% CI, 0.024-0.064). The superior performance of the IOTA models was most pronounced in premenopausal patients but was also observed in postmenopausal patients. IOTA models were better able to detect stage I ovarian cancer., Conclusion: External validation shows that the IOTA models outperform other models, including the current reference test RMI, for discriminating between benign and malignant adnexal masses.

Background: The CA-125 tumor marker has limitations when used to distinguish between benign and malignant ovarian masses. We therefore establish likelihood curves of six subgroups of ovarian pathology based on CA-125 and menopausal status., Methods: This cross-sectional study conducted by the International Ovarian Tumor Analysis group involved 3,511 patients presenting with a persistent adnexal mass that underwent surgical intervention. CA-125 distributions for six tumor subgroups (endometriomas and abscesses, other benign tumors, borderline tumors, stage I invasive cancers, stage II-IV invasive cancers, and metastatic tumors) were estimated using kernel density estimation with stratification for menopausal status. Likelihood curves for the tumor subgroups were derived from the distributions., Results: Endometriomas and abscesses were the only benign pathologies with median CA-125 levels above 20 U/mL (43 and 45, respectively). Borderline and invasive stage I tumors had relatively low median CA-125 levels (29 and 81 U/mL, respectively). The CA-125 distributions of stage II-IV invasive cancers and benign tumors other than endometriomas or abscesses were well separated; the distributions of the other subgroups overlapped substantially. This held for premenopausal and postmenopausal patients. Likelihood curves and reference tables comprehensibly show how subgroup likelihoods change with CA-125 and menopausal status., Conclusions and Impact: Our results confirm the limited clinical value of CA-125 for preoperative discrimination between benign and malignant ovarian pathology. We have shown that CA-125 may be used in a different way. By using likelihood reference tables, we believe clinicians will be better able to interpret preoperative serum CA-125 results in patients with adnexal masses., (© 2011 AACR.)

Objective: To develop a logistic regression model that can discriminate between benign and malignant adnexal masses perceived to be difficult to classify by subjective evaluation of gray-scale and Doppler ultrasound findings (subjective assessment) and to compare its diagnostic performance with that of subjective assessment, serum CA 125 and the risk of malignancy index (RMI)., Methods: We used data from the 3511 patients with an adnexal mass included in the International Ovarian Tumor Analysis (IOTA) studies. All patients had been examined using transvaginal gray-scale and Doppler ultrasound following a standardized research protocol carried out by an experienced ultrasound examiner using a high-end ultrasound system. In addition to prospectively collecting information on > 40 clinical and ultrasound variables, the ultrasound examiner classified each mass as certainly or probably benign, unclassifiable, or certainly or probably malignant. A logistic regression model to discriminate between benignity and malignancy was developed for the unclassifiable masses (n = 244, i.e. 7% of all tumors) using a training set (160 tumors, 45 malignancies) and then tested on a test set (84 tumors, 28 malignancies). The gold standard was the histological diagnosis of the surgically removed adnexal mass. The area under the receiver-operating characteristics curve (AUC), sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were used to describe diagnostic performance and were compared between subjective assessment, CA 125, the RMI and the logistic regression model created., Results: One variable was retained in the logistic regression model: the largest diameter (in mm) of the largest solid component of the tumor (odds ratio (OR) = 1.04; 95% CI, 1.02-1.06). The model had an AUC of 0.68 (95% CI, 0.59-0.78) on the training set and an AUC of 0.65 (95% CI, 0.53-0.78) on the test set. On the test set, a cut-off of 25% probability of malignancy (corresponding to the largest diameter of the largest solid component of 23 mm) resulted in a sensitivity of 64% (18/28), a specificity of 55% (31/56), an LR+ of 1.44 and an LR- of 0.65. The corresponding values for subjective assessment were 68% (19/28), 59% (33/56), 1.65 and 0.55. On the test set of patients with available CA 125 results, the LR+ and LR- of the logistic regression model (cut-off = 25% probability of malignancy) were 1.29 and 0.73, of subjective assessment were 1.45 and 0.63, of CA 125 (cut-off = 35 U/mL) were 1.24 and 0.84 and of RMI (cut-off = 200) were 1.21 and 0.92., Conclusions: About 7% of adnexal masses that are considered appropriate for surgical removal cannot be classified as benign or malignant by experienced ultrasound examiners using subjective assessment. Logistic regression models to estimate the risk of malignancy, CA 125 measurements and the RMI are not helpful in these masses., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To identify differences in the management and outcome of patients with central nervous system metastases from epithelial ovarian cancer., Methods: The clinical and pathologic characteristics, treatment, and outcome of 23 patients with brain metastases from epithelial ovarian cancer who were treated during 1982-1994 were compared with those of 20 patients treated during 1995-2010 at the same center., Results: No differences were found in terms of primary tumor characteristics, time interval from ovarian cancer diagnosis to brain involvement diagnosis, sites of metastasis, and presence of extracranial disease. The main difference between the 2 groups was the therapeutic approach. During 1982-1994, most patients received radiotherapy only, whereas most patients during 1995-2010 underwent surgical resection followed by radiotherapy and/or chemotherapy. The duration of survival during 1982-1994 was 5 months, which was significantly shorter than the duration of survival (18 months) during 1995-2010., Conclusion: An aggressive multimodal treatment approach might prolong the survival of patients with brain involvement from ovarian cancer., (Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)