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OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.
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Indazoles , Neoplasias Ováricas , Piperidinas , Calidad de Vida , Humanos , Femenino , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Indazoles/administración & dosificación , Indazoles/efectos adversos , Indazoles/uso terapéutico , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/psicología , Anciano , Adulto , Método Doble Ciego , Piperazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Quimioterapia de Mantención/métodos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/psicología , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. RESULTS: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. CONCLUSIONS: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.
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Neoplasias Ováricas , Femenino , Humanos , Peso Corporal , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Indazoles , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Estudios ProspectivosRESUMEN
BACKGROUND: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA-mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. METHODS: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. RESULTS: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1-6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2-11.6 months). Among 33 patients (median 5 [range, 1-9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1-3.2 months) in the Pt-R group. Grade ≥ 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. CONCLUSION: Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.
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Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , España , Neoplasias Ováricas/tratamiento farmacológico , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Antineoplásicos/uso terapéuticoRESUMEN
OBJECTIVES: Accurate assessment of disease extent is required to select the best primary treatment for advanced epithelial ovarian cancer patients. Estimation of tumour burden is challenging and it is usually performed by means of a surgical procedure. Imaging techniques and tumour markers can help to estimate tumour burden non-invasively. 2-[18F]FDG PET/CT allows the evaluation of the whole-body disease. This study aimed to correlate HE4 and CA125 serum concentrations with tumour burden evaluated by volumetric 2-[18F]FDG PET/CT parameters in advanced high-grade epithelial ovarian cancer. METHODS: We included 66 patients who underwent 2-[18F]FDG PET/CT and serum tumour markers determination before primary treatment. Volumes of interest were delimited in every pathological uptake. Whole-body metabolic tumour volume (wb_MTV) and total lesion glycolysis (wb_TLG) were calculated summing up every VOI's MTV value. SUVmax thresholds were set at 40% (MTV40 and TLG40) and 50% (MTV50 and TLG50). In addition, four VOI subgroups were defined: peritoneal carcinomatosis, retroperitoneal nodes, supradiaphragmatic nodes, and distant metastases. MTV and TLG were calculated for each group by adding up the corresponding MTV values. TLG was calculated likewise. RESULTS: wb_MTV and wb_TLG were found to be significantly correlated with serum CA125 and HE4 concentrations. The strongest correlation was observed between HE4 and wb_MTV40 (r = 0.62, p < 0.001). Pearson's correlation coefficients between peritoneal carcinomatosis MTV40 and tumour markers were 0.61 (p < 0.0001) and 0.29 (p = 0.02) for HE4 and CA125 respectively. None of these tumour markers showed a positive correlation with tumour load outside the abdominal cavity assessed by volumetric parameters. CONCLUSION: HE4 performs better than CA125 to predict metabolic tumour burden in high-grade epithelial ovarian cancer before primary treatment. 2-[18F]FDG PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution. These results support the usefulness of HE4 and PET/CT to improve the stratification of these patients in clinical practice. KEY POINTS: ⢠In patients with high-grade advanced ovarian epithelial carcinoma, both CA125 and HE4 correlate to whole-body tumour burden assessed by PET/CT before primary treatment. ⢠HE4 estimates peritoneal disease much better than CA125. ⢠PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution.
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Fluorodesoxiglucosa F18 , Neoplasias Ováricas , Biomarcadores de Tumor , Carcinoma Epitelial de Ovario/diagnóstico por imagen , Humanos , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Radiofármacos/uso terapéutico , Estudios Retrospectivos , Carga TumoralRESUMEN
Human papillomaviruses (HPVs) are the causative agents of carcinoma of the uterine cervix. A number of HPV genotypes have been associated with cervical cancer and almost all tumors associated with HPV show strong p16 expression. However, there is little information on the possible impact of the HPV genotype and p16 immunostaining on the clinicopathological features or their prognostic value in cervical carcinoma. We evaluated a series of 194 patients with HPV-positive cervical cancers treated at our institution, focusing on the clinicopathological features and the relationship of the HPV genotypes and p16 immunostaining with the prognosis. A single HPV type was identified in 149 (77%) tumors, multiple HPV infection was detected in 30 cases (15%), and undetermined HPV type/s were identified in 15 (8%) carcinomas. HPV 16 and/or 18 were detected in 156 (80%) tumors. p16 was positive in 186 (96%) carcinomas, but eight tumors (4%) were negative for p16 (seven squamous cell carcinomas, one adenocarcinoma); 5/8 caused by HPV 16 and/or 18. Patients with HPV 16 and/or 18 were younger (49 ± 15 vs. 57 ± 17 years, p < 0.01) and more frequently had nonsquamous tumors than patients with other HPV types (24% [37/156] vs. 0% [0/38]; p = 0.01). Neither the HPV type nor multiple infection showed any prognostic impact. Patients with p16-negative tumors showed a significantly worse overall survival than women with p16-positive carcinomas (45 vs. 156 months, p = 0.03), although no significant differences in disease-free survival were observed. In the multivariate analysis, negative p16 immunostaining was associated with a worse overall survival together with advanced FIGO stage and lymph node metastases. In conclusion, the HPV genotype has limited clinical utility and does not seem to have prognostic value in cervical cancer. In contrast, a negative p16 result in patients with HPV-positive tumors is a prognostic marker associated with a poor overall survival.
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Carcinoma/virología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Carcinoma/mortalidad , Supervivencia sin Enfermedad , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Infecciones por Papillomavirus/mortalidad , Pronóstico , Neoplasias del Cuello Uterino/mortalidadRESUMEN
BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
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Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Núcleo Celular/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Transporte de Proteínas/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Supervivencia Celular/efectos de los fármacos , Cetuximab/administración & dosificación , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Curcumina/farmacología , Dasatinib/farmacología , Ácidos Grasos Insaturados/farmacología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Silenciador del Gen , Células HCT116 , Células HT29 , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia Molecular Dirigida , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Oxaliplatino , Panitumumab , Compuestos de Fenilurea/farmacología , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirimidinas/farmacología , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , SorafenibRESUMEN
INTRODUCTION: Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death-1 receptor (PD-1), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported. METHODS: We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab. RESULTS: The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs. Cerebrospinal fluid examination showed albuminocytologic dissociation. MRI revealed contrast enhancement of the lumbosacral roots. Electrodiagnostic studies demonstrated widespread fibrillation potentials in all four limbs, suggesting a generalized motor polyradiculopathy. Despite pembrolizumab discontinuation and treatment with steroids and intravenous immunoglobulin, limb weakness worsened. Electrodiagnostic studies were repeated, and showed marked and diffuse axonal motor damage. Seven weeks after clinical onset the patient was treated with plasma exchanges. He showed no further deterioration. DISCUSSION: We report a severe motor polyradiculopathy associated with an anti-PD-1 agent that expands the spectrum of neuromuscular complications of this class of drugs. Muscle Nerve 56: E162-E167, 2017.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Melanoma/tratamiento farmacológico , Debilidad Muscular/inducido químicamente , Polirradiculopatía/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Humanos , Masculino , Melanoma/complicaciones , Debilidad Muscular/complicaciones , Debilidad Muscular/diagnóstico por imagen , Polirradiculopatía/complicaciones , Polirradiculopatía/diagnóstico por imagen , Neoplasias Cutáneas/complicaciones , Resultado del TratamientoRESUMEN
AIM: While both efficacy and safety of anti-PD-1 agents seem to be independent of previous treatment with anti-CTLA-4, limited data exist of efficacy and toxicity of ipilimumab after progression on anti-PD-1 therapy. This retrospective analysis describes the efficacy and safety of sequential therapy with ipilimumab in patients with metastatic melanoma who progressed on anti-PD-1 antibody. METHODS: Nine patients who progressed on anti-PD-1 therapy received four cycles of ipilimumab 3 mg/kg every 3 weeks. RESULTS: Two out of nine patients (2/9; 22.2%) showed a partial response, and seven patients (7/9; 77.8%) experienced disease progression. Median progression-free survival was 3.14 months (95% CI: 2.56-3.71), and the median overall survival since the start of anti-PD-1 therapy was 16.8 months (95% CI: 8.1-25.4). Five (5/9; 55.6%) patients experienced grade 3 immune-related adverse events. No grade 4 or 5 adverse events were reported. CONCLUSION: In this small retrospective series of cases, the efficacy of ipilimumab post-anti-PD-1 was similar to that described in the previous reports on ipilimumab.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Melanoma/patología , Terapia Molecular Dirigida , Anciano , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Progresión de la Enfermedad , Femenino , Humanos , Ipilimumab , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Retratamiento , Resultado del TratamientoRESUMEN
OBJECTIVES: To evaluate the efficacy of the O-RADS MRI criteria in the stratification of risk of malignancy of solid or sonographically indeterminate ovarian masses and assess the interobserver agreement of this classification between experienced and inexperienced radiologists. METHODS: This single-centre retrospective study included patients from 2019 to 2022 with sonographically indeterminate or solid ovarian masses who underwent MRI with a specific protocol for characterisation according to O-RADS MRI specifications. Each study was evaluated using O-RADS lexicon by two radiologists, one with 17 years of experience in gynaecological radiology and another with 4 years of experience in general radiology. Findings were classified as benign, borderline, or malignant according to histology or stability over time. Diagnostic performance and interobserver agreement were assessed. RESULTS: A total of 183 patients with US indeterminate or solid adnexal masses were included. Fifty-seven (31%) did not have ovarian masses, classified as O-RADS 1. The diagnostic performance for scores 2-5 was excellent with a sensitivity, specificity, PPV, and NPV of 97.4%, 100%, 96.2%, and 100%, respectively by the experienced radiologist and 96.1%, 92.0%, 93.9%, and 94.8% by the inexperienced radiologist. Interobserver concordance was very high (Kappa index 0.92). Almost all the misclassified cases were due to misinterpretation of the classification similar to reports in the literature. CONCLUSION: The diagnostic performance of O-RADS MRI determined by either experienced or inexperienced radiologists is excellent, facilitating decision-making with high diagnostic accuracy and high reproducibility. Knowledge of this classification and use of assessment tools could avoid frequent errors due to misinterpretation. CRITICAL RELEVANCE STATEMENT: Up to 31% of ovarian masses are considered indeterminate by transvaginal US and 32% of solid lesions considered malignant by transvaginal US are benign. The O-RADs MRI accurately classifies these masses, even when used by inexperienced radiologists, thereby avoiding incorrect surgical approaches. KEY POINTS: ⢠O-RADS MRI accurately classifies indeterminate and solid ovarian masses by ultrasound. ⢠There is excellent interobserver agreement between experienced and non-experienced radiologists. ⢠O-RADS MRI is a helpful tool to assess clinical decision-making in ovarian tumours.
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In recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.
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PURPOSE: The aim of our study was to elucidate the impact of bevacizumab added to neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment and correlate the changes with the clinical outcome of the patients. EXPERIMENTAL DESIGN: IHC and multiplex immunofluorescence for lymphoid and myeloid lineage markers were performed in matched tumor samples from 23 patients with ovarian cancer enrolled in GEICO 1205/NOVA clinical study before NACT and at the time of interval cytoreductive surgery. RESULTS: Our results showed that the addition of bevacizumab to NACT plays a role mainly on lymphoid populations at the stromal compartment, detecting a significant decrease of CD4+ T cells, an increase of CD8+ T cells, and an upregulation in effector/regulatory cell ratio (CD8+/CD4+FOXP3+). None of the changes observed were detected in the intra-epithelial site in any arm (NACT or NACT-bevacizumab). No differences were found in myeloid lineage (macrophage-like). The percentage of Treg populations and effector/regulatory cell ratio in the stroma were the only two variables significantly associated with progression-free survival (PFS). CONCLUSIONS: The addition of bevacizumab to NACT did not have an impact on PFS in the GEICO 1205 study. However, at the cellular level, changes in CD4+, CD8+ lymphocyte populations, and CD8+/CD4+FOXP3 ratio have been detected only at the stromal site. On the basis of our results, we hypothesize about the existence of mechanisms of resistance that could prevent the trafficking of T-effector cells into the epithelial component of the tumor as a potential explanation for the lack of efficacy of ICI in the first-line treatment of advanced epithelial ovarian cancer. See related commentary by Soberanis Pina and Oza, p. 12.
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Terapia Neoadyuvante , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Bevacizumab/uso terapéutico , Terapia Neoadyuvante/métodos , Microambiente Tumoral , Neoplasias Ováricas/patología , Factores de Transcripción Forkhead , Quimioterapia AdyuvanteRESUMEN
Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87-159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p < 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC.
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PURPOSE: Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS: ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI >6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1-positive populations (alpha .025 for each population). RESULTS: Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1-positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1-positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION: ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1-positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.
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Antígeno B7-H1 , Neoplasias Ováricas , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/uso terapéutico , Bevacizumab , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Platino (Metal)/uso terapéutico , Calidad de VidaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Basocelular/prevención & control , Carcinoma de Células Escamosas/prevención & control , Erupciones por Medicamentos/prevención & control , Melanoma/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Basocelular/inducido químicamente , Carcinoma de Células Escamosas/inducido químicamente , Erupciones por Medicamentos/etiología , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Indoles/administración & dosificación , Indoles/efectos adversos , Queratoacantoma/inducido químicamente , Queratoacantoma/prevención & control , Queratodermia Palmoplantar/inducido químicamente , Queratodermia Palmoplantar/prevención & control , Queratosis Actínica/inducido químicamente , Queratosis Actínica/prevención & control , Queratosis Seborreica/inducido químicamente , Queratosis Seborreica/prevención & control , Masculino , Persona de Mediana Edad , Oximas/administración & dosificación , Oximas/efectos adversos , Trastornos por Fotosensibilidad/inducido químicamente , Trastornos por Fotosensibilidad/prevención & control , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , VemurafenibRESUMEN
(1) OBJECTIVE: To assess the performance of CA125, HE4, ROMA index and CPH-I index to preoperatively identify epithelial ovarian cancer (EOC) or metastatic cancer in the ovary (MCO). (2) METHODS: single center retrospective study, including women with a diagnosis of adnexal mass. We obtained the AUC, sensitivity, specificity and predictive values were of HE4, CA125, ROMA and CPH-I for the diagnosis of EOC and MCO. Subgroup analysis for women harboring adnexal masses with inconclusive diagnosis of malignancy by ultrasound features and Stage I EOC was performed. (3) RESULTS: 1071 patients were included, 852 (79.6%) presented benign/borderline tumors and 219 (20.4%) presented EOC/MCO. AUC for HE4 was higher than for CA125 (0.91 vs. 0.87). No differences were seen between AUC of ROMA and CPH-I, but they were both higher than HE4 AUC. None of the tumor markers alone achieved a sensitivity of 90%; HE4 was highly specific (93.5%). ROMA showed a sensitivity and specificity of 91.1% and 84.6% respectively, while CPH-I showed a sensitivity of 91.1% with 79.2% specificity. For patients with inconclusive diagnosis of malignancy by ultrasound features and with Stage I EOC, ROMA showed the best diagnostic performance (4) CONCLUSIONS: ROMA and CPH-I perform better than tumor markers alone to identify patients harboring EOC or MCO. They can be helpful to assess the risk of malignancy of adnexal masses, especially in cases where ultrasonographic diagnosis is challenging (stage I EOC, inconclusive diagnosis of malignancy by ultrasound features).
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Endometrial cancer (EC) is the second most common gynecological malignancy worldwide, the first in developed countries [Sung et al. in CA Cancer J Clin 71:209-249, 2021]. Although a majority is diagnosed at an early stage with a low risk of relapse, an important proportion of patients will relapse. Better knowledge of molecular abnormalities is crucial to identify high-risk groups in early stages as well as for recurrent or metastatic disease for whom adjuvant treatment must be personalized. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of EC, and to provide evidence-based recommendations for clinical practice.
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Neoplasias Endometriales , Recurrencia Local de Neoplasia , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/terapia , Femenino , Humanos , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/terapiaRESUMEN
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.
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Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.
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Since the approval of immune checkpoint anti-programmed cell death protein 1 antibodies (pembrolizumab and nivolumab) and anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) in combination or monotherapy, significant advances have been made in the treatment of metastatic melanoma. The nonspecific immune stimulation resulting from these drugs can case a wide range of side effects in many organs including the nervous system, named immune-related adverse events. Few immune-related encephalitis associated with these antibodies have been described in the literature. It is a rare complication (<1% of the total of immune-related adverse events) but it can be fatal if not diagnosed and treated on time. We describe 3 cases of patients with melanoma, which were treated with a combination of ipilimumab-nivolumab (case 1), ipilimumab monotherapy (case 2), and nivolumab monotherapy (case 3), who developed an encephalitis which was related to immune checkpoint therapy.
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Encefalitis/diagnóstico , Encefalitis/etiología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/complicaciones , Terapia Molecular Dirigida/efectos adversos , Biomarcadores de Tumor , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Melanoma/diagnóstico , Melanoma/tratamiento farmacológico , Melanoma/etiología , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
BACKGROUND: Recent evidence indicates that some minimally invasive surgery approaches, such as laparoscopic and robotic-assisted radical hysterectomy, offer lower survival rates to patients with early-stage cervical cancer than open radical hysterectomy. We evaluated the oncological results of a different minimally invasive surgery approach, that of laparoscopically assisted radical vaginal hysterectomy (LARVH) in this setting. METHODS: From January 2001 to December 2018, patients with early-stage cervical cancer were treated by LARVH. Colpotomy and initial closure of the vagina were performed following the Schauta operation, avoiding manipulation of the tumor. Laparoscopic sentinel lymph node (SLN) biopsy was performed in all cases. Women treated between 2001 and 2011 also underwent pelvic lymphadenectomy. RESULTS: There were 115 patients included. Intraoperative complications occurred in nine patients (7.8%). After a median follow-up of 87.8 months (range 1-216), seven women (6%) presented recurrence. Four women died (mortality rate 3.4%). The 3- and 4.5-year disease-free survival rates were 96.7% and 93.5%, respectively, and the overall survival was 97.8% and 94.8%, respectively. CONCLUSION: LARVH offers excellent disease-free and overall survival in women with early-stage cervical cancer and can be considered as an adequate minimally invasive surgery alternative to open radical hysterectomy.