Management of advanced ovarian cancer in Spain: an expert Delphi consensus

Malaltia avançada; Consens; Càncer d'ovarisEnfermedad avanzada; Consenso; Cáncer de ovariosAdvanced disease; Consensus; Ovarian cancerBackground To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors. Methods The questionnaire was developed by the byline authors. All questions but one were answered using a 9-item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale. Results In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented. Conclusions This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO-ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues.This study was sponsored by TESARO without restriction, nowadays a GlaxoSmithkline company

SEOM clinical guideline in ovarian cancer (2020)

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice

Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO)

Objective: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. Methods: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracyclinecontaining regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Results: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5–7.3) and 18.5 months (95%CI: 11.5–25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in ≤ 2nd line (25.3 months) than in ≥ 3rd (15.1 months) and with ECOG performance status ≤ 1 at trabectedin start (19.8 months) than ECOG 2–3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radiochemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4–93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in ≥ 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). Conclusions: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile

PSA Kinetics as Prognostic Markers of Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate

Background: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially asso- ciated with overall survival (OS) in patients treated with AA. Methods: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and vari- ables related to PSA kinetics were included in univariate and multivariate analyses of OS. Results: Median OS was 16.4 months (range 12.4-20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil- lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir 140 days, the combination of PSA nadir and time to PSA nadir, and low end-of- treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. Conclusion: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies

Prognostic Role of Neutrophil, Monocyte and Platelet to Lymphocyte Ratios in Advanced Ovarian Cancer According to the Time of Debulking Surgery

Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9-95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03-5.99, p = 0.043, and HR 2.91, 95% CI: 1.11-7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC)

Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting

Simple Summary Since the irruption of PARPi in the therapeutic armamentarium for ovarian cancer, concerns regarding post-progression treatment outcomes have emerged, owing to known crossed-resistance mechanisms between PARPi and platinum. In this multicentric retrospective series of ovarian cancer patients, we evaluated chemotherapy results upon progression to maintenance with PARPi in the relapsed setting. We further selected the population of platinum-sensitive patients (according to the classical definition) retreated with platinum (n = 74). In this platinum-sensitive population, overall response rate and survival outcomes of platinum rechallenge after PARPi were similar to historical series of the prePARPi era. However, within this group, analysis according to BRCA status showed that BRCA mutant patients (n = 35) presented higher rates of progression and worse survival outcomes under subsequent platinum than BRCA wild type patients (n = 39), with statistically significant differences. This is the largest real-world data series of ovarian cancer patients treated with platinum rechallenge in the post-PARPi scenario. Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8-17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6-9.2), and median OS (mOS) of 20.6 months (95% CI 13.6-28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2-22.2] and 10.3 [IQR 7.4-14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5-8.6) versus 7.5 months (95% CI 6.5-10.1, p = 0.03), and 16.4 (95% CI 9.3-27.5) versus 24.2 months (95% CI 17.2-NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors

ICO-ICS Praxis para el tratamiento médico del cáncer epitelial de ovario

Tractament mèdic; Càncer epitelial d'ovari; CirurgiaTratamiento médico; Cáncer epitelial de ovario; CirugíaMedical treatment; Ovarian epithelial cancer; SurgeryEl càncer epitelial d'ovari (CEO) és la segona neoplàsia ginecològica més freqüent als països desenvolupats i constitueix la principal causa de mort per càncer ginecològic i la quarta causa de mort per càncer en dones a Europa i als Estats Units. Els objectius d'aquesta guia són -Desenvolupar, difondre, implementar i avaluar resultats de la ICO-ICSPraxi de CEO epitelial. -Disminuir la variabilitat terapèutica entre les pacients tractades als diversos centres d’aquesta institució. -Implementar els resultats de la terapèutica en les pacients amb CEO epitelial tractades d’acord amb les recomanacions d’aquesta guia

Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial

Background: The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo. Methods: Patients were randomized 2:1 to receive once-daily maintenance niraparib (n = 487) or placebo (n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019). Results: The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd (n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9–8.9] and 4.1 [95% CI, 2.2–5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5–8.6] and 3.5 [95% CI, 1.7–5.6] months, respectively) in the HRd and ITT populations. Conclusions: In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure. Trial registration: ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016 Plain language summary: Background: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients’ quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA. Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses: ● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life. ● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects. Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib – they are known as homologous recombination deficiency (HRd) patients. ● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo. ● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo. Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients’ quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib.publishedVersionPeer reviewe