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Aromatase inhibitors (AI) have become a cornerstone of adjuvant treatment for postmenopausal patients with estrogen receptor (ER)- positive early breast cancer. This chapter reviews the available evidence on endocrine effects of AI. Pharmacological activity of AI produces estradiol suppression, which represents the only known mechanism of action of such drugs, determining both side effects and antineoplastic efficacy. Overall, all third-generation AI (anastrozole, exemestane, letrozole) produce a significant suppression of estradiol levels, but there are some data suggesting that this effect might be less extensive than commonly thought and there are few comparative data to verify whether estradiol suppression varies with different AI. The most frequent side effects, related to estradiol suppression and reported in largescale clinical trials of adjuvant treatment with AI, are gynecological symptoms (less frequent and less severe than with tamoxifen, with the exception of vaginal dryness) and musculoskeletal symptoms (worse than with tamoxifen, which even has a positive effect on bone health). Disorders of lipid metabolism and cardiovascular side effects are less frequent. Among the latter, thromboembolism is less frequent with AI than with tamoxifen. There are many issues still of interest for clinical research on endocrine effects of AI. For example, it seems of utmost importance to verify whether endocrine effects might be predictive of AI efficacy and help to select the patients who can derive the greatest benefit from treatment with these drugs. [ABSTRACT FROM AUTHOR]

Purpose: The clinical and research FPG500 program (ClinicalTrials.gov identifier: NCT06020625) is currently ongoing at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS to tailor matched targeted therapies (MTTs) according to biomarkers predictive of response identified by comprehensive genome profiling (CGP)., Materials and Methods: The non-small cell lung cancer (NSCLC) cohort results from the FPG500 program are outlined. CGP was performed by TruSight Oncology 500 High Throughput (TSO500HT) assay or Oncomine Focus Assay plus Archer's FusionPlex Lung Panel according to tumor cell content and DNA/RNA quantity. Relevant issues for Molecular Tumor Board (MTB) evaluation included uncommon genomic findings, evaluation for off-label therapies, uncertain result confirmation, and variants of suspect germline origin requiring genetic counseling. Progression-free survival (PFS) and overall survival (OS) for the enrolled patients were assessed using Kaplan-Meier analysis., Results: In 2022, 283 patients with NSCLC were considered for sequencing, with 93% meeting eligibility criteria. TSO500HT sequencing was conducted in 76% of patients. Follow-up data were obtained for 187 patients, among whom 81% received treatment. Potential driver alterations were identified in 59% of patients, with 41% receiving MTT: 25% were prescribed approved MTTs, whereas 16% gained access to experimental drugs post-MTB evaluation; of note, 18% did not receive any MTT because the regimen was not yet reimbursed in our country. Median PFS and OS varied among treatment groups, with standard chemotherapy/immunotherapy at 7.7 and 10.7 months, approved tyrosine kinase inhibitors at 18.8 and 23.9 months, and MTT post-MTB discussion at 14 and 23.4 months, respectively., Conclusion: The early data of the FPG program (NSCLC cohort) support the implementation of CGP and MTB in clinical practice to grant access to patients harboring actionable molecular alterations to the most effective and individualized available treatment options, thus improving their survival outcomes.

Background: In untreated ALK-positive non-small cell lung cancer no randomized controlled trials (RCTs) are available directly comparing next-generation ALK-inhibitors. We conducted a sensitivity analysis using the likelihood of being helped or harmed (LHH)., Methods: Phase III trials comparing ALK-inhibitors to crizotinib were included. Efficacy outcomes were progression-free survival (PFS), objective response rate (ORR), PFS in patients with brain metastases and intracranial ORR. Safety outcomes were grade 3-4 adverse events (AEs), dose reductions and discontinuations., Results: Six RCTs (1524 patients) were included. Lorlatinib and brigatinib had the lowest NNT for intracranial outcomes. Alectinib demonstrated favourable LHHs for grade 3-4 AEs, dose reductions and discontinuations. Brigatinib LHHs were low for common AEs, mainly laboratory anomalies and hypertension. Ensartinib showed mainly skin toxicity. Lorlatinib LHHs were low for specific grade 3-4 AEs, mainly metabolic alterations., Conclusions: The four ALK-inhibitors exhibited favourable risk-benefit ratios. Lorlatinib showed the lowest NNT for systemic efficacy and, alongside with Brigatinib, lower NNTs for intracranial efficacy. Alectinib exhibited higher LHHs for AEs., Registration: PROSPERO registration number: CRD42023389101., Competing Interests: Declaration of competing interest L.M., G.G., E.V, G.H., J.R. and G.D. declare no conflict of interest. A.O. has declared consulting fees/advisory role for Novartis, Roche, Eli-Lilly, Amgen, Daiichi Sankyo, travel and accommodation by Daiichi Sankyo, Novartis, Roche, Pfizer. D.G. received educational courses fee from MSD and Amgen. G.T. is supported by funds of Ministero della Salute (Ricerca Corrente 2022). E.B. is currently supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under Investigator Grant (IG) No. IG20583. E.B. is supported by Institutional funds of Università Cattolica del Sacro Cuore (UCSC-project D1). E.B. is supported by funds of Ministero della Salute (Ricerca Corrente 2023). E.B. received speakers’ and travels’ fee from MSD, Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis and Roche. E.B. received institutional research grants from Astra-Zeneca, Roche., (Copyright © 2024. Published by Elsevier Ltd.)

Tumor heterogeneity refers to the diversity observed among tumor cells: both between different tumors (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). These cells can display distinct morphological and phenotypic characteristics, including variations in cellular morphology, metastatic potential and variability treatment responses among patients. Therefore, a comprehensive understanding of such heterogeneity is necessary for deciphering tumor-specific mechanisms that may be diagnostically and therapeutically valuable. Innovative and multidisciplinary approaches are needed to understand this complex feature. In this context, proteogenomics has been emerging as a significant resource for integrating omics fields such as genomics and proteomics. By combining data obtained from both Next-Generation Sequencing (NGS) technologies and mass spectrometry (MS) analyses, proteogenomics aims to provide a comprehensive view of tumor heterogeneity. This approach reveals molecular alterations and phenotypic features related to tumor subtypes, potentially identifying therapeutic biomarkers. Many achievements have been made; however, despite continuous advances in proteogenomics-based methodologies, several challenges remain: in particular the limitations in sensitivity and specificity and the lack of optimal study models. This review highlights the impact of proteogenomics on characterizing tumor phenotypes, focusing on the critical challenges and current limitations of its use in different clinical and preclinical models for tumor phenotypic characterization.

Background: Several regimens have been introduced in clinical practice in the last twenty years to treat chemotherapy-induced nausea and vomiting (CINV). However, direct comparative data remain insufficient, as many new regimes lack head-to-head comparisons. In this study, through an indirect comparison, we overcome this limit by providing the most up-to-date estimate of the efficacy and safety of all combinations used for HEC-induced nausea and vomiting., Patients and Methods: We retrieved randomized controlled trials (RCTs) published in Pubmed, Embase, and Cochrane Library until June, 30th 2022. We included phase II-III RCTs, including adults with any cancer receiving HEC, and compared different antiemetic regimes to prevent CINV. The primary outcome was the overall complete response (defined as the absence of vomiting and of the use of rescue drugs from 0 to 120 hrs since chemotherapy); secondary outcomes were acute (absence of vomiting and use of rescue medicine 0-24 hrs after chemotherapy) and delayed (24-120 hrs) response and adverse events., Results: A total of 53 RCTs enrolling 22 228 patients were included. We classified the different antiemetic regimes into 21 different groups. Overall, 3- or 4-drug regimens containing a combination of dexamethasone, 5HT3 antagonists, mirtazapine or olanzapine with or without NK antagonists, yielded the highest probability to be the most effective regimen in terms of complete response. Regimens containing a combination of dexamethasone and 5-HT3 antagonist have the lowest probability of being the most effective regimen in terms of complete, acute, and delayed response., Conclusion: In our network meta-analysis, 4-drug regimens with olanzapine displayed the highest probability of efficacy in terms of complete response. A 3-drug regimen with olanzapine represents a valid option in a limited resource context., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R. G. declared financial interests with Roche (Expert Testimony, Personal, Advisory Board for Clinician's expertise on Drug Management), Molteni (Writing Engagement, Personal, Pubblication fee for open access manuscript), Novartis (Advisory Board, Personal, Advisory Board), Angelini Pharma (Invited Speaker, Personal, Invited Speaker to national and international congress), Pfizer (Advisory Board, Personal, Advisory Board) and Takeda (Expert Testimony, Personal, Expert testimony on Drug Managemen). F. S. reported personal/consulting fees from Pfizer, Bristol Myers Squibb, MSD, Roche, Pierre Fabre Oncology, Leo Pharma, Bayer, Mylan/Viatris, Mundi Pharma, Astellas, Vifor Pharma, Amgen, Arrow, Biogaran, and Helsinn and nonfinancial support from Pierre Fabre Oncology. G. S. has served as consultant for TESARO Bio Italy S.r.l and Johnson & Johnson. He received onoraria from Clovis Oncology Italy S.r.l, and institutional research funding from MSD Italy S.r.l. G. D. has served on advisory board of Beigene and received support for travel and accomodation from Roche. The other authors declare that they have no conflict of interest.., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In hormone-receptor positive/HER2-negative metastatic breast cancer (mBC) no randomized comparisons are available between CDK4/6 inhibitors. We undertook this systematic review and meta-analysis to assess the reliability of the likelihood of being helped or harmed (LHH)., Methods: PubMed, CENTRAL, Embase and oncological meetings websites were searched to September 13th, 2022. We included phase III randomized controlled trials (RCTs) investigating palbociclib, ribociclib and abemaciclib in addition to endocrine therapy (ET) compared to placebo in hormone-receptor positive/HER2-negative advanced or mBC. Outcomes were progression-free survival (PFS), overall survival (OS), adverse events (AEs), dose reductions and discontinuations. Hazard ratios (HRs) and risk differences were computed with a random effect model to estimate the number needed to treat/harm (NNT/NNH). LHH was computed as (1/NNT)/(1/NNH). PROSPERO registration number: CRD42022362417., Findings: 2204 records were screened and seven RCTs (4415 patients) were included. A significant PFS benefit was observed in patients treated with a CDK4/6 inhibitor compared to placebo (HR 0.549; 0.508-0.594, I 2  = 0). Palbociclib, ribociclib and abemaciclib had similar NNTs (4.4, 5.0 and 4.4). Palbociclib and ribociclib showed lower LHHs for grade 3-4 neutropenia (0.33 and 0.35) and febrile neutropenia ([FN], 14.27 and 15.52), while abemaciclib the lowest LHH for any grade diarrhea (0.42). Abemaciclib had a lower LHH for grade 3-4 fatigue (9.92) and the highest LHH for all grade 3-4 AEs (0.62), while ribociclib the lowest LHH (1.75) for grade 3-4 hepatotoxicity. Palbociclib had the highest LHH for dose reductions and discontinuations (0.65 and 6.17). Considering OS, an overall benefit was observed (HR 0.788, 0.727-0.856, I 2  = 0%); ribociclib and abemaciclib had lower NNTs (9.7 and 10.0). Ribociclib showed the highest LHH for diarrhea (1.29), fatigue (7.37), dose reductions (0.28) and discontinuations (2.40), while abemaciclib the highest LHHs for neutropenia (0.40), FN (12.53) and hepatotoxicity (2.23)., Interpretation: Palbociclib and ribociclib showed lower LHHs for haematological toxicities and abemaciclib for diarrhea. Palbociclib confirmed to be a manageable drug. The LHH appears to be a reliable synthesis tool for balancing risks and benefits of experimental drugs when head-to-head comparisons are missing., Funding: None., Competing Interests: L.M., G.G., G.D. declare no conflict of interest. A.O. has declared consulting fees/advisory role for 10.13039/100004336Novartis, 10.13039/100004337Roche, Eli-Lilly, 10.13039/100002429Amgen, Daiichi Sankyo, travel and accommodation by Daiichi Sankyo, 10.13039/100004336Novartis, 10.13039/100004337Roche, 10.13039/100004319Pfizer. A.P. has declared consulting fees/advisory role for 10.13039/100002429Amgen, MSD, 10.13039/100004336Novartis, travel and accommodation by 10.13039/100004319Pfizer. D.G. received educational courses fee from MSD and 10.13039/100002429Amgen. A.F. has declared consulting fees/advisory role for Astra Zeneca, Daiichi Sankyo, 10.13039/501100003769Eisai, Eli-Lilly. Epionpharma, exact science, MSD, 10.13039/100004336Novartis, Pierre Fabre, 10.13039/100004337Roche, Seagen. G.T. is supported by funds of 10.13039/501100003196Ministero della Salute (Ricerca Corrente 2022). E.B. is currently supported by the 10.13039/501100005010Associazione Italiana per la Ricerca sul Cancro (AIRC) under Investigator Grant (IG) No. IG20583. E.B. is supported by Institutional funds of Università Cattolica del Sacro Cuore (UCSC-project D1). E.B. is supported by funds of 10.13039/501100003196Ministero della Salute (Ricerca Corrente 2022). E.B. received speakers' and travels’ fee from MSD, Astra-Zeneca, 10.13039/100004319Pfizer, Eli-Lilly, BMS, 10.13039/100004336Novartis and 10.13039/100004337Roche. E.B. received institutional research grants from Astra-Zeneca, 10.13039/100004337Roche., (© 2023 The Authors.)

Aim: AT-rich interaction domain 1A ( ARID1A ) encodes a key component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that participates in gene expression. ARID1A alterations are quite common among cancer patients, although their role remains debated. The aim of this article was to study ARID1A-mutated cancer patients., Methods: Molecular and clinical data of cancer patients evaluated at Phase 1 Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS were collected. Molecular analyses were performed using FoundationOne ® CDx (Foundation Medicine Inc., Cambridge, MA, United States). Cancer patients with at least one molecular alteration in ARID1A gene were identified as ARID1A + ., Results: Among the 270 patients undergoing molecular analysis, we found 25 (9%) with at least one pathogenic alteration in ARID1A. The vast majority of these patients were female (84%). The median age at diagnosis was 59; most of the cancers (15, 60%) were gynecological (especially endometrioid endometrial cancers and clear cell ovarian cancers), diagnosed at an early stage. Frameshift alterations in ARID1A were the most common (19/31, 61%) alterations. The median number of mutations in ARID1A + population was higher compared to ARID1A - population (6 vs . 4), as well as tumor mutational burden (TMB) [20 mutations/megabase (mut/Mb) vs. 1.26 mut/Mb]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ), phosphatase and tensin homolog ( PTEN ), catenin beta 1 ( CTNNB1 ), and lysine methyltransferase 2D ( MLL2 ) mutations were enriched in ARID1A + population. In this cohort, ARID1A did not display any relation with response to platinum chemotherapy. Cancers with double alterations in ARID1A (ARID1A 2+ ) were all gynecological cancers (83% endometrioid endometrial cancers)., Conclusions: This analysis provides clinical and molecular details about the phenotypes of ARID1A + cancers, in particular the subgroup of gynecologic cancers. The high frequency of concurrent mutations in the phosphoinositide 3-kinase (PI3K) pathway among endometrioid endometrial cancers may support the proposal of a new treatment strategy based on the combination of ataxia telangiectasia and Rad3-related (ATR) inhibitor and PIK3CA inhibitor., Competing Interests: RF, MF, PL, VA, and FPS declare that they have no conflicts of interest. GS has served on advisory boards for TESARO Bio Italy S.r.l, Johnson & Johnson, Clovis Oncology Italy S.r.l. He received support for travel or accommodation from MSD Italy S.r.l and Clovis Oncology Italy S.r.l. GD has served on advisory board of Beigene and received support for travel and accommodation from Roche., (© The Author(s) 2023.)

Hereditary and sporadic renal cell carcinomas (RCCs) are often associated with Von Hippel-Lindau (VHL)-gene inactivation. Patients with VHL disease have an increased risk of RCC, leading to bilateral nephrectomy and dialysis. In patients with advanced RCC, no standard second-lines are available after progression to immune checkpoint inhibitors (ICIs), and new agents are required to manage progression. HIFs have emerged as a promising target for metastatic RCC patients who have progressed to ICI-based combinations, as well as for those with RCC and VHL syndrome where the goal is to delay surgery and/or and preserve kidney function and avoid dialysis. This review describes the available evidence supporting the use of the small-molecule HIF-2 alpha inhibitor, belzutifan (MK-6482), as well as other new anti-HIF molecules that have demonstrated significant efficacy in VHL disease-related RCCs as well as for sporadic RCC that has progressed after the use of ICI-based combinations., (Copyright © 2022 Elsevier B.V. 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.)

Background: High grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. Tumor heterogeneity and rapid acquisition of resistance to conventional chemotherapeutic approaches strongly contribute to poor outcome of patients. The clinical landscape of HGSOC has been radically transformed since the advent of targeted therapies in the last decade. Nevertheless, the lack of predictive biomarkers informing on the differential clinical benefit in select subgroups, and allowing patient-centric approaches, currently limits the efficacy of these novel therapies. Thus, rational selection of the best possible treatment for each patient represents a clinical priority in order to improve outcome, while limiting undesirable effects., Main Body: In this review, we describe the state of the art and the unmet needs in HGSOC management, illustrate the treatment options that are available and the biomarkers that are currently employed to orient clinical decisions. We also describe the ongoing clinical trials that are testing new therapeutic approaches for HGSOC. Next, we introduce the organoid technology as a promising, expanding strategy to study cancer and to develop personalized therapeutic approaches. In particular, we discuss recent studies that have characterized the translational potential of Patient's Derived Organoids (PDOs) to inform on drug sensitivity of HGSOC patients., Conclusions: PDOs can predict the response of patients to treatments and may therefore guide therapeutic decisions. Although preliminary results appear encouraging, organoids still need to be generated and expanded efficiently to enable drug screening in a clinically meaningful time window. A new generation of clinical trials based on the organoid technology should guarantee tailored approaches to ovarian cancer management, as it is now clear that the one-size-fits-all approach cannot lead to efficient and meaningful therapeutic advancements.

Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug., Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m 2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m 2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m 2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17., Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related., Interpretation: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice., Funding: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types., Objective: To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer., Data Sources: In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials., Study Selection: Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm., Data Extraction and Synthesis: Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019., Main Outcomes and Measures: Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria., Results: In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS., Conclusions and Relevance: This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.

Purpose: Antiemetics are being used both for the treatment and prophylaxis of opioid-induced nausea and vomiting (OINV) in clinical practice, despite the lack of evidence for the prophylactic benefit. Studies among Japanese physicians demonstrated over 80% prescribe antiemetics, with neuroleptic antipsychotics as the most commonly prescribed drugs. Our objective was to elucidate the current scenario of the prophylactic use of antiemetics for OINV among Italian physicians., Methods: We conducted a web-based cross-sectional national survey. All the invited participants received an e-mail with an 11-item electronic questionnaire accessible through a direct link. Anonymity was guaranteed. According to the exploratory intent of the survey, we did not predefine any formal statistical hypothesis. Associations between variables were tested by the Pearson chi-square or the Fisher exact test., Results: From January to March 2017, 112 completed the electronic questionnaire (112/256, overall response rate, 43.7%). Nearly half of the participants were oncologists (54; 48.2%). Sixty-one (54.4%) physicians worked in palliative care units. About 45% of the interviewed prescribed prophylactic antiemetics at the beginning of opioid prescription. The most commonly chosen drugs for this purpose were prokinetics such as metoclopramide and domperidone (84%), followed by 5-HT3 antagonists (8%), neuroleptic antipsychotics (6%), and corticosteroids (2%). Ninety-one physicians (81%) declared to prescribe antiemetics at the occurrence of OINV, mainly prokinetics (N = 70; 77%)., Conclusion: Italian physicians do not commonly prescribe prophylactic antiemetics for OINV. Unlike previously reported data, dopamine antagonists resulted the most commonly prescribed drugs. Prospective clinical trials are necessary to evaluate the real efficacy of this practice.

Background: Chemotherapy-induced neutropenia (CIN) has been associated with improved prognosis in several cancer conditions. Contrasting data have been produced in ovarian cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cervical cancer cells often express Epidermal Growth Factor Receptor (EGFR). Cetuximab (CET), an anti-EGFR antibody, can be safely combined with carboplatin (C) and paclitaxel (P), a standard treatment for advanced/recurrent cervical cancer (ARCC) patients., Patients and Methods: ARCC patients, ECOG PS ≤ 1, were randomized to CP for 6 cycles with or without CET (400 mg/m 2 one week before starting CP, then 250 mg/m 2 weekly) until disease progression or unacceptable toxicity. Event-free survival (EFS) was the primary endpoint. With a 4.5 months expected median EFS and a 6.4 months predicted EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis., Results: 108 patients were assigned to CP (n = 53) or CP-CET (n = 55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. After a median follow-up of 23 months, 102 patients had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0 months (one-tail P = 0.43), median PFS was 5.2 and 7.6 months (one-tail P = 0.20) and median OS was 17.7 and 17 months (one-tail P = 0.27), with CP and CP-CET, respectively. There was no difference in the occurrence of severe adverse events, except for skin toxicity. Biomarker analysis, in a small subgroup of patients, suggests that PIK3CA mutation might be predictive of CET resistance., Conclusion: CP-CET was not more active than CP alone in unselected ARCC patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Few data are available on the outcome of surgery after a bevacizumab-containing regimen. The MITO 16A- MaNGO OV2A phase 4 trial evaluates the outcomes of first-line CPB in a clinical-practice-like setting. Here we present the results of the subgroup of patients undergoing IDS after neoadjuvant treatment or suboptimal primary surgery., Methods: 400 chemonaïve epithelial ovarian cancer patients, age≥18, ECOG PS 0-2 were eligible to receive C (AUC 5 d1, q21) plus P (175mg/m 2 d1, q21) and B (15mg/kg d1 q21) for 6cycles followed by B maintenance until cycle 22nd., Results: 79 patients (20%) underwent IDS. Overall, 74 patients received at least one administration of B before IDS. Median age was 61.2, 70% of the patients had FIGO IIIC disease. The median number of cycles before IDS was 3 both for chemotherapy and bevacizumab respectively. A residual disease ≤1cm was achieved in 64 patients (86.5%). Four percent of the patients experienced fever and 4% required blood transfusion after surgery. Surgical wound infection and/or dehiscence, pelvic abscess, intestinal sub-occlusion and fistula were experienced by one patient each., Conclusions: In the MITO16A-MaNGO OV2A phase 4 trial, combined chemotherapy and bevacizumab did not hamper IDS and the rate of perioperative complications was similar to what expected without bevacizumab. These data support the hypothesis that adding bevacizumab to first line chemotherapy for ovarian cancer might not be denied to patients for whom IDS is planned., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Treatment of locally advanced non-small cell lung cancer (NSCLC) remains a significant challenge for oncologists, despite progress made in recent years in early diagnosis and therapy. This review focuses on integrated therapeutic approaches of patients with locally advanced NSCLC, summarizing the available evidence for patients with potentially resectable disease (stage IIIA-0/3) and with unresectable disease (stage IIIA-4/IIIB) and discussing several key questions related to the use of integrated approaches in NSCLC. Based on current evidence, neoadjuvant platinum-based combination chemotherapy is a treatment option in patients with potentially resectable stage IIIA-0/3: a 2-drug combination of platinum combined with a third-generation drug seems preferable, and at least 3 cycles of chemotherapy should be administered. There are no definitive evidences of clear superiority of surgery compared to radiotherapy for patients obtaining a response with neoadjuvant treatment: however, surgery is associated with a better local control, and subgroup analyses of randomized trials suggest improved outcome in patients in whom a complete resection could be obtained with a lobectomy, avoiding the increased surgical mortality associated with pneumonectomy. Standard treatment for patients with locally advanced, unresectable NSCLC is currently represented by combination of chemotherapy and radiotherapy. Concomitant approach has been proven superior to the sequential administration, although it is associated with higher risk of toxicity. All patients should be evaluated by a multidisciplinary team, skilled in multimodality treatment and should be counselled about risks and potential benefits of the different therapeutic approaches.