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Platinum is the backbone of systemic treatment in ovarian cancer and development of platinum resistance is associated with poor survival. Here, we perform a comprehensive review of the literature regarding resistance mechanisms and advances in therapy for platinum resistant ovarian cancer, with a focus on high-grade serous carcinoma. Platinum resistance can be intrinsic or acquired. Resistance mechanisms are complex and diverse. Intracellular mechanisms include restoration of homologous recombination repair, reduced intracellular accumulation of platinum, blocked cellular replication and inhibition of apoptosis. These act in concert with immunosuppressive, angiogenic and stromal changes in the tumour microenvironment to drive treatment resistance. Current molecular stratification lacks prognostic and predictive validity, limited in part by the extreme genomic complexity of high-grade serous ovarian cancer. Clinical trials represent an important option for patients as standard of care treatment options have limited efficacy. The most promising trials appear to focus on rational combinations of chemotherapy, immunotherapy, anti-angiogenics, PARP inhibitors, targeted therapy and/or antibody-drug conjugates. Resistance mechanisms are multifactorial with capacity to evolve over time, making clinical detection challenging. It is increasingly apparent that clinical trials must incorporate correlative studies to elucidate predictive biomarkers. They must also adopt endpoints that can appropriately measure benefit for palliative treatments. Future research must aim to deepen our understanding of the biology of this disease, and deliver meaningful benefit in terms of improved quality of life and overall survival for women with platinum resistant ovarian cancer.
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Antineoplásicos/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Resistencia a Antineoplásicos/fisiología , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Compuestos de PlatinoRESUMEN
BACKGROUND: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. PRIMARY OBJECTIVES: To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. STUDY HYPOTHESIS: We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective. TRIAL DESIGN: Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy. PRIMARY ENDPOINTS: Emotional wellbeing at 12 months. SAMPLE SIZE: 150 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: July 2023. Results expected in 2025, 24 months after the last participant is enrolled. TRIAL REGISTRATION: ACTRN12620000332921.
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Neoplasias Ováricas , Telemedicina , Carcinoma Epitelial de Ovario , Femenino , Estudios de Seguimiento , Humanos , Rol de la Enfermera , Neoplasias Ováricas/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Estudios ProspectivosRESUMEN
BACKGROUND: Despite the growing integration of mandatory biopsies for correlative endpoints within oncology clinical trials, there are sparse data on patient-reported outcomes, perceptions, and preferences. OBJECTIVE: This study aimed to prospectively assess the impact of research biopsies on the quality of life in patients with gynecologic cancer, evaluate patient-reported outcomes, and determine factors associated with patients' willingness to undergo sequential biopsies. STUDY DESIGN: We conducted a prospective study in patients with gynecologic malignancies undergoing research biopsies between 2015 and 2019 at Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02334761). Here, we report the results of the paper-based surveys performed before and 1 week after biopsy. Although the questionnaires each assessed the impact of anxiety using a modified version of the Hospital Anxiety and Depression Scale, the postbiopsy questionnaire specifically assessed the likelihood of future biopsies, postbiopsy symptoms, complications, and perceptions. RESULTS: A total of 129 patients were enrolled, of which 91 (70.5%) completed at least 1 questionnaire. These patients had either ovarian (89%; 81 of 91) or endometrial cancer (11%; 10 of 91). Of all biopsies taken, 75% were from the abdomen or pelvis (67 of 89). There was 1 clinician-reported complication, a perihepatic hematoma (1%). Pain during the biopsy and physical discomfort were experienced by 60.3% (41 of 68) and 61.8% (42 of 68), respectively. Embarrassment and loss of dignity were experienced by 13.2% (9 of 68) and 11.8% (8 of 68), respectively. Although the mean Hospital Anxiety and Depression Scale score was in the normal range before and after biopsy, there was a significant decline in the total score after the biopsy (prebiopsy, 5.3 [standard deviation, 4.7] vs postbiopsy, 3.7 [standard deviation, 4.5]; P=.005); 84% of subjects (58 of 69) stated that they would definitely or likely consent to another biopsy. There was no impact on patients' willingness for future biopsies based on Eastern Cooperative Oncology Group status, biopsy site, age, number of cores, and pain during the biopsy; however, subjects who reported feeling physically uncomfortable (odds ratio, 0.14; P=.005), embarrassed (odds ratio, 0.03; P=.004) or experienced loss of dignity (odds ratio, 0.05; P=.01) during the biopsy and those who experienced flu-like symptoms (odds ratio, 0.2; P=.018) or felt feverish (odds ratio, 0.2; P=.035) 1 week after biopsy, were less likely to undergo a sequential biopsy. Similarly, those with higher Hospital Anxiety and Depression Scale scores before biopsy (odds ratio, 0.83; P=.008) and after biopsy (odds ratio, 0.8; P=.003) were less likely to consent for another biopsy. CONCLUSION: Research biopsies were generally well accepted. Most patients (83%) were willing to undergo serial biopsies if necessary. Addressing the potentially modifiable psychosocial aspects of the procedure may improve the experience with research biopsies for patients with gynecologic cancers.
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Neoplasias de los Genitales Femeninos/patología , Prioridad del Paciente , Medición de Resultados Informados por el Paciente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Ensayos Clínicos como Asunto , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: With the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need. PRIMARY OBJECTIVE: The primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive relapsed ovarian cancer. STUDY HYPOTHESIS: This study will test the hypothesis that ceralasertib + olaparib, or olaparib monotherapy, is tolerable, and effective at prolonging progression-free survival compared with placebo. TRIAL DESIGN: This is a phase II, multicenter study where patients will be randomized in a 1:1:1 ratio to receive either (Arm 1) ceralasertib + olaparib, (Arm 2) olaparib monotherapy, or (Arm 3) placebo. The olaparib and placebo arms will be double-blinded, whereas the ceralasertib + olaparib arm will be open label. Patients will be stratified according to BRCA status, and response to platinum-based chemotherapy. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients will have histologically diagnosed high-grade epithelial ovarian cancer, with platinum-sensitive relapse on, or after, completion of at least 6 months of any prior PARP inhibitor maintenance therapy (a minimum of 12 months is required if the patient received PARP inhibitor maintenance following first-line chemotherapy). If the prior PARP inhibitor used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Disease relapse in the second-line or third-line setting is allowed. Patients who have received secondary debulking surgery are potentially eligible if they meet all other inclusion criteria. PRIMARY ENDPOINTS: The primary endpoint is progression-free survival determined by blinded independent central review according to RECIST 1.1, with sensitivity analysis of progression-free survival using investigator assessments according to RECIST 1.1. SAMPLE SIZE: 192 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: December 2022. TRIAL REGISTRATION: NCT04239014.
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Carcinoma Epitelial de Ovario/tratamiento farmacológico , Indoles/administración & dosificación , Morfolinas/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Ensayos Clínicos Fase II como Asunto , Método Doble Ciego , Femenino , Humanos , Quimioterapia de Mantención/métodos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
AIM: This study sought to identify clinical, demographic and service-related factors associated with psychological distress amongst outpatient chemotherapy patients. BACKGROUND: Distress in cancer patients leads to increased risk of psychological comorbidity, contributing to sub-optimal treatment adherence and potentially leading to poorer health outcomes. Screening and recognition of distress and risk factors is an important aspect of holistic care within a multidisciplinary team environment. METHODS: Data were obtained via survey and chart review of ambulatory chemotherapy patients at three public tertiary referral hospitals in Perth, Western Australia. The DASS-21 was used to screen for psychological distress. Regression analyses were used to assess the relationship between distress and a range of cancer, socioeconomic and treatment factors. RESULTS: Patients with a Karnofsky Performance Score≤80 (OR 3.8, 95% CI [1.7, 78.7]) and average waiting time (between oncology outpatient appointment and commencement of chemotherapy infusion) >60min (OR 2.4, 95% CI [1.04, 5.5]) were at increased risk of moderate-severe distress. Patients with a household income between $AU 50-75,000 p.a. had a lower risk of distress compared to <$25,000 p.a. (OR 0.05, 95% CI [0.01, 0.52]). On sub-scale analysis, depression and anxiety contributed more to overall distress than the stress subscales. CONCLUSIONS: Performance status, waiting times and household income were key predictors of distress. Findings could assist clinicians to identify higher-risk population subsets that could benefit from targeted screening and additional psychological and social work support. Findings could also assist administrators to consider the contribution of modifiable factors such as waiting times to patient distress.
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Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Ansiedad/psicología , Trastorno Depresivo/psicología , Neoplasias/tratamiento farmacológico , Pacientes Ambulatorios/psicología , Estrés Psicológico/psicología , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/inducido químicamente , Trastorno Depresivo/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estrés Psicológico/inducido químicamente , Encuestas y Cuestionarios , Centros de Atención Terciaria , Australia OccidentalRESUMEN
Objective: Poly-ADP ribose polymerase inhibitors (PARPi) have expanded the management armamentarium against high grade serous tubo-ovarian cancer (HGSOC) in patients with germline and somatic BRCA pathogenic variants (PVs). Germline testing has been available in Western Australia (WA) since July 2015, whilst somatic BRCA testing was previously only available through interstate laboratories. We hypothesized that due to complexity of referral, testing rates for somatic BRCA would be low. We aimed to demonstrate that improving education and information systems would improve testing rates in our service. Methods: Retrospective data were collected for all patients with HGSOC reviewed between June - November 2021. BRCA testing for this period was discussed at multi-disciplinary tumor board. Patients eligible to commence PARPi that had not received somatic testing were referred. Changes were implemented to patient outcome reports, the results application was adjusted to flag clinicians, departmental guidelines were developed, and teaching sessions conducted. Testing rates from March - August 2022 were compared. Results: From June - November 2021, 98% of patients had germline BRCA testing performed. PVs in BRCA1/2 were detected in 18% of patients. Of those without germline PVs, further somatic BRCA testing was referred in 42% of patients. One somatic PV was detected. From March - August 2022, 99% of patients had germline BRCA testing and 17% had PVs detected. Further somatic BRCA testing was referred in 72% of patients. No somatic PVs were detected. Conclusion: Testing rates for germline BRCA variants in patients with HGSOC in WA are high. Focused education and information systems improved somatic BRCA testing rates.
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AIM/BACKGROUND: The FACT COST is a patient-rated measure of financial toxicity, developed and validated in a North American population. We aimed to confirm the validity and reliability of the FACT COST in Australian cancer patients, because the Australian healthcare funding structure is different to that in North America. METHODS: A single center, cross-sectional study design investigated financial toxicity in oncology outpatients. Eligible adults had current malignancy, with or without active cancer treatment. The primary endpoint was the degree of financial toxicity experienced via the COST questionnaire; secondary endpoints included health-related quality of life (Functional Assessment of Cancer Therapy-General), anxiety, and depression (Hospital Anxiety and Depression Scale). Clinical and demographic data were recorded. Statistical analysis determined the internal consistency, test-retest reliability and validity of COST, and correlations between COST score and secondary endpoints. RESULTS: A total of 257 patients participated (79% response rate). Fifty-three percent were female; median age 63 years (range 19-88). COST scores were skewed toward less financial toxicity, median 26 (SD 10.3, range 1-43), lower scores indicating higher toxicity. High internal consistency (Cronbach's α = 0.884), test-retest reliability (ICC = 0.801), and convergent validity were demonstrated. Financial toxicity was greatest in younger participants, those with more inpatient admissions, those with a change in employment status following diagnosis, and those in the lowest income quintile. Financial toxicity was associated with worse health-related quality of life, and greater depression and anxiety. CONCLUSION: The COST measure of financial toxicity demonstrated acceptable validity parameters in an Australian outpatient population. Greater financial toxicity was associated with worse psychological well-being and with certain patient demographics.
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Neoplasias , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Australia , Costo de Enfermedad , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVES: In response to the COVID-19 pandemic there have been significant developments in research, its conduct and the supporting ethical framework. While many protocols have been delayed, halted or modified, other research efforts have been accelerated, generating controversy. The goal of this paper is to determine the rates of references surrounding the ethical oversight of research as reported in current COVID-19-related research publications. DESIGN: Scoping review. SETTING: Population-based observational or interventional studies from December 2019 to May 2020 with sample size of two or more. Studies were searched through electronic databases including Medline, EMBASE, and Cochrane CENTRAL Register of Controlled Trials. PARTICIPANTS: Eligibility criteria included participants within published studies who tested positive for COVID-19. MAIN OUTCOMES AND MEASURES: Data were extracted and charting methods included taking note of references to ethical frameworks, institutional review board (IRB), ethics committee (EC) or research ethics board (REB) involvement, consent processes, and other variables. RESULTS: 11 556 articles were screened, with 656 included in the final analysis. References to ethics were present in 530 (80.8%) studies, with 491 (74.8%) involving IRB/ECs/REBs and 126 (19.2%) not referencing ethics. Consent processes were outlined in 201 (30.6%) studies, with 198 (30.2%) reporting that they obtained consent waivers, however, 257 (39.2%) did not mention consent at all. Differences (p<0.001) in ethics-related references were apparent when analysed by continent, publication type, sample size and IF. CONCLUSIONS: The majority of published articles pertaining to COVID-19 research made mention of ethical considerations, however, national and regional variations in research ethics review requirements introduce heterogeneity between studies and raise important questions about the conduct of scientific research during global public emergencies. TRIAL REGISTRATION NUMBER: Open Science Framework: https://osfio/z67wb.
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COVID-19 , Comités de Ética en Investigación , Ética en Investigación , Humanos , Pandemias , SARS-CoV-2RESUMEN
Background: Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients.Methods: 31 Patients received pemetrexed ± cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4+ T-cells, with doses tailored to target Treg nadir <4%.Results: Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. Seventeen percent of patients ceased cyclophosphamide due to toxicity.Conclusions: Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies.Trial registration: Clinical trial registration: www.anzctr.org.au identifier is ACTRN12609000260224.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino , Ciclofosfamida/administración & dosificación , Ciclofosfamida/toxicidad , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed , Platino (Metal)/uso terapéutico , Linfocitos T ReguladoresRESUMEN
PrOTYPE is a locked down assay validated to Institute of Medicine standards, using NanoString technology to classify high-grade serous ovarian cancer into four defined subgroups. Future directions will include prospective-retrospective analysis and prospective clinical validation to define the predictive role of this assay and its role in influencing treatment decisions.See related article by Talhouk et al., p. 5411.
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Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Femenino , Expresión Génica , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.
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The COVID-19 global pandemic has drastically impacted cancer care, posing challenges in treatment and diagnosis. There is increasing evidence that cancer patients, particularly those who have advanced age, significant comorbidities, metastatic disease, and/or are receiving active immunosuppressive therapy may be at higher risk of COVID-19 severe complications. Controlling viral spread from asymptomatic carriers in cancer centers is paramount, and appropriate screening methods need to be established. Universal testing of asymptomatic cancer patients may be key to ensure safe continuation of treatment and appropriate hospitalized patients cohorting during the pandemic. Here we perform a comprehensive review of the available evidence regarding SARS-CoV-2 testing in asymptomatic cancer patients, and describe the approach adopted at Princess Margaret Cancer Centre (Toronto, Canada) as a core component of COVID-19 control.