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OBJECTIVE: Nuanced distress screening tools can help cancer care services manage specific cancer groups' concerns more efficiently. This study examines the sensitivity and specificity of a tool specifically for women with gynaecological cancers (called the Gynaecological Cancer Distress Screen or DT-Gyn). METHODS: This paper presents cross-sectional data from individuals recently treated for gynaecological cancer recruited through Australian cancer care services, partner organisations, and support/advocacy services. Receiver operating characteristics analyses were used to evaluate the diagnostic accuracy of the DT-Gyn against criterion measures for anxiety (GAD-7), depression (patient health questionnaire), and distress (IES-R and K10). RESULTS: Overall, 373 individuals aged 19-91 provided complete data for the study. Using the recognised distress thermometer (DT) cut-off of 4, 47% of participants were classified as distressed, while a cut-off of 5 suggested that 40% had clinically relevant distress. The DT-Gyn showed good discriminant ability across all measures (IES-R: area under the curve (AUC) = 0.86, 95% CI = 0.82-0.90; GAD-7: AUC = 0.89, 95% CI = 0.85-0.93; K10: AUC = 0.88, 95% CI = 0.85-0.92; PHQ-9: AUC = 0.85, 95% CI = 0.81-0.89) and the Youden Index suggested an optimum DT cut-point of 5. CONCLUSIONS: This study established the psychometric properties of the DT-Gyn, a tool designed to identify and manage the common sources of distress in women with gynaecological cancers. We suggest a DT cut point ≥5 is optimal in detecting 'clinically relevant' distress, anxiety, and depression in this population.
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Neoplasias dos Genitais Femininos , Neoplasias , Humanos , Feminino , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/epidemiologia , Austrália , Sensibilidade e Especificidade , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Neoplasias/epidemiologia , Psicometria , Neoplasias dos Genitais Femininos/diagnóstico , Inquéritos e Questionários , Programas de RastreamentoRESUMO
AIMS: To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high-grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context. METHODS: Data were collected from 25 consecutive patients undergoing CRS and HIPEC from December 2018 to July 2022 at the Peritoneal Malignancy Service at the Mater Hospital Brisbane, Australia. Data collected included demographics, clinical variables, surgical procedures and complications and intra-operative and post-operative indexes of morbidity. RESULTS: Twenty-five women who underwent CRS and HIPEC from December 2018 to July 2022 were included in analysis. Findings indicate that CRS with HIPEC is associated with low morbidity. CONCLUSION: While judicious patient selection is imperative, HIPEC during CRS was well tolerated by all patients and morbidity was comparable to results from the previously reported OVHIPEC-1 trial. HIPEC appears to be a safe and feasible addition to CRS for the treatment of advanced ovarian cancer in Australian practice.
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BACKGROUND: The primary aim of this study was to evaluate the activity of intraperitoneal bevacizumab (IP-bev) in delaying re-accumulation of malignant ascites in women with chemotherapy-resistant epithelial ovarian cancer (CR-EOC) who have ceased chemotherapy. Secondary outcomes were safety and quality of life. METHODS: Women with CR-EOC and malignant ascites that reaccumulated within 28 days of their last paracentesis (P-1) were administered IP-bev 5 mg/kg following their first therapeutic paracentesis on study (P0). Additional doses of IP-bev were allowed at each subsequent paracentesis (P1, P2, etc) provided the interval from the last dose was 42 days or greater (median time from first to second therapeutic ascitic drainage). RESULTS: 24 participants (median age 67 years [range 38-86]; median 4.5 lines prior systemic treatment [range 1-12]; ECOG performance status of 0 in 1, 1 in 8, and 2-3 in 15) were recruited. The doses of IP-bev administered were 1 in 13 participants, 2 in 5, 3 in 2, 4 in 1, and 5 in 1. The proportion with a TTP of >42 days using competing risk analysis was 77% (95% CI 58-92). Median time from P0 to P1 or death was 48 days (range 8-248). Median paracentesis-free interval (P0-P1 or death) was 4.29-fold (95% CI 2.4-5.8) higher following a first dose of IP-bev compared with the time between paracenteses prior to study entry (P-1-P0). CONCLUSION: IP-bev was safe, active, and warrants further study as a palliative intervention for recurrent ascites in CR-EOC patients receiving best supportive care.
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Antineoplásicos Imunológicos/uso terapêutico , Ascite/tratamento farmacológico , Bevacizumab/uso terapêutico , Carcinoma Epitelial do Ovário/complicações , Neoplasias Ovarianas/complicações , Cuidados Paliativos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ascite/etiologia , Ascite/cirurgia , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Injeções Intraperitoneais , Pessoa de Meia-Idade , Paracentese , Segurança do Paciente , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Áustria/epidemiologia , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias das Tubas Uterinas/patologia , Feminino , França/epidemiologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Platina/administração & dosagem , Platina/efeitos adversos , Polietilenoglicóis/administração & dosagemRESUMO
BACKGROUND: Recent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors. METHODS: We developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease. RESULTS: Higher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939). CONCLUSIONS: This study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Thus, the cause of most fluorouracil toxicity cases remains unexplained. METHODS: For this small cohort study, thymine (THY) 250 mg was administered orally to 6 patients who had experienced severe toxicity during treatment with 5FU or capecitabine. Plasma and urine were analyzed for THY and its catabolites dihydrothymine (DHT) and ß-ureidoisobutyrate. RESULTS: Of the 6 patients, 2 had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, 3 patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared with a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these 3 patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these 3 patients as "enhanced thymine absorption". Only 1 of the 6 cases of toxicity had a normal postdose plasma profile for THY and its catabolites. Postdose urine collections from all 6 patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. CONCLUSIONS: This small cohort provided evidence for a hypothesis that fluorouracil toxicity cases may include a previously undescribed pyrimidine absorption variant, "enhanced thymine absorption," and elevated THY/DHT ratios in urine may predict fluorouracil toxicity. A prospective study is currently being conducted.
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Timina/farmacocinética , Adulto , Idoso , Amidoidrolases/genética , Capecitabina/efeitos adversos , Di-Hidrouracila Desidrogenase (NADP)/genética , Feminino , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/urina , Fenótipo , Timina/análogos & derivados , Timina/sangue , Timina/urinaRESUMO
BACKGROUND: Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer. METHODS: CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined. Three patient-derived xenograft (PDX) mouse models were developed and characterised for CDCP1 expression. The effect of a monoclonal anti-CDCP1 antibody on PDX growth was examined. Src activation was assessed by western blot analysis. RESULTS: Elevated CDCP1 was observed in 77% of HGSC cases. Silencing of CDCP1 reduced migration and non-adherent cell growth in vitro and tumour burden in vivo. Expression of CDCP1 in patient samples was maintained in PDX models. Antibody blockade of CDCP1 significantly reduced growth of an HGSC PDX. The CDCP1-mediated activation of Src was observed in cultured cells and mouse xenografts. CONCLUSIONS: CUB-domain containing protein 1 is over-expressed by the majority of HGSCs. In vitro and mouse model data indicate that CDCP1 has a role in HGSC and that it can be targeted to inhibit progression of this cancer.
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Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Cistadenocarcinoma Seroso/patologia , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/patologia , Animais , Antígenos CD/genética , Antígenos de Neoplasias , Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Cistadenocarcinoma Seroso/metabolismo , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Camundongos , Gradação de Tumores , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Análise de SobrevidaRESUMO
PURPOSE: This study aims to investigate the prevalence and factors predictive of vitamin D deficiency in patients with malignancy in Brisbane, Australia (latitude 27° S). METHODS: This is a prospective cross-sectional study measuring serum levels of 25-hydroxyvitamin D (25-OHD) in 100 subjects with non-haematological cancer at least 18 years of age not taking vitamin D supplements attending a day oncology unit and oncology/palliative care inpatient ward in Brisbane, Australia. RESULTS: Thirty-seven per cent of outpatient and 49 % of inpatient subjects respectively were vitamin D deficient. Functional status was predictive of low vitamin D levels. CONCLUSION: There was a high prevalence of vitamin D deficiency in patients with cancer in Brisbane, Australia.
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Neoplasias/sangue , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Adulto , Idoso , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Prevalência , Estudos Prospectivos , Vitamina D/sangue , Deficiência de Vitamina D/epidemiologiaRESUMO
BACKGROUND: There is substantial interest in the role of ginger as an adjuvant therapy for chemotherapy-induced nausea and vomiting (CINV). However, available evidence lacks robust methodology. OBJECTIVE: To assess the effect of adjuvant ginger compared with placebo on chemotherapy-induced nausea-related quality of life (QoL) and CINV-related outcomes. DESIGN: A parallel, double-blind, placebo-controlled randomized trial with 1:1 allocation was conducted. PARTICIPANTS/SETTING: One hundred three chemotherapy-naïve adults scheduled to receive moderately to highly emetogenic chemotherapy at two hospitals in Australia were enrolled and analyzed. INTERVENTION: Four standardized ginger capsules (totaling 84 mg/day active gingerols/shogaols), or placebo, were administered commencing the day of chemotherapy and continuing for 5 days for chemotherapy cycles 1 through 3. MAIN OUTCOME MEASURES: The primary outcome was chemotherapy-induced nausea-related QoL. Secondary outcomes were vomiting- and CINV-related QoL; anticipatory, acute, and delayed nausea and vomiting; fatigue; nutritional status; depression and anxiety; health-related QoL; and adverse events. STATISTICAL ANALYSES PERFORMED: Intention-to-treat analysis was performed. Mixed analysis of variance with repeated measures determined differences between groups. The null hypothesis was no difference between groups. After applying a Bonferroni multiple testing correction, evidence against the null hypothesis was considered at P= 0.003. RESULTS: One hundred three participants (ginger: n = 52; placebo: n = 51) were enrolled and analyzed. There was clinically relevant evidence against the null hypothesis, favoring ginger, in change scores for nausea-related QoL (F[df] = 9.34[1,101]; P = 0.003; partial η2 = 0.09), overall CINV-related QoL (F[df] = 12.26[1,101]; P < 0.001; partial η2 = 0.11), delayed nausea severity (F[df] = 9.46[1,101]; P = 0.003; partial η2 = 0.09), and fatigue (F[df] = 10.11[1,101]; P = 0.002; partial η2 = 0.09). There was a clinically meaningful lower incidence of delayed nausea and vomiting in the ginger group at Cycle 2 (53% vs 75%; P = 0.020 and 4% vs 27%; P = 0.001, respectively) and Cycle 3 (49% vs 79%; P = 0.002 and 2% vs 23%; P = 0.001, respectively). There was a clinically meaningful lower incidence of malnutrition in the ginger group at Cycle 3 (18% vs. 41%; P = 0.032) and in change scores for Patient-Generated Subjective Global Assessment (F[df)] = 4.32[1,100]; P = 0.040; partial η2 = 0.04). Change scores between groups favored ginger for vomiting-related QoL and number of vomiting episodes; however, findings were not clinically meaningful. There was no effect of ginger on anticipatory or acute CINV, health-related QoL, anxiety, or depression. No serious adverse events were reported. CONCLUSIONS: Ginger supplementation was a safe adjuvant to antiemetic medications for CINV that enhanced QoL during chemotherapy treatment. Future trials are needed to examine dose-dependent responses to verify optimal dosing regimens.
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Antineoplásicos , Neoplasias , Extratos Vegetais , Zingiber officinale , Adulto , Humanos , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Fadiga/induzido quimicamente , Fadiga/tratamento farmacológico , Fadiga/prevenção & controle , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Náusea/prevenção & controle , Pós , Qualidade de Vida , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/prevenção & controleRESUMO
OBJECTIVE: To investigate cell-free DNA (cfDNA) in plasma and ascites and its association with clinical outcomes (paracentesis-free interval, overall survival) and CA125 level in participants with advanced ovarian cancer, treated with palliative intraperitoneal bevacizumab to delay re-accumulation of ascites. METHODS: cfDNA was extracted from 0.3 to 1 mL samples from 20/24 participants of the REZOLVE trial. Standard and methylation-specific PCRs were performed to measure 3 biomarkers: total cfDNA (Alu), tumour-derived cfDNA (ctDNA, methylated IFFO1 promoter) and endothelium-derived cfDNA (ec-cfDNA, unmethylated CDH5 promoter). Values were correlated to clinical outcomes. RESULTS: cfDNA was detected in all samples, with higher yield in ascites (mean 669 ng/mL) than plasma (mean 75 ng/mL, p < 0.0001). Ascites had a higher ctDNA proportion than plasma (74 % vs. 20 %, p < 0.0001) and plasma had a higher ec-cfDNA proportion than ascites (24 % vs. 16 %, p < 0.002). High ctDNA proportion (>75 %) in ascites was associated with a significantly shorter paracentesis-free interval (median interval 47.5 versus 84 days, hazard ratio (HR) 2.21, 95 % confidence interval (CI) 0.85 to 5.73, p = 0.039) and ctDNA presence in plasma was unfavourable for survival (median survival 56 versus 242 days, HR 3.21, 95 % CI 1.15 to 9.00, p = 0.008). A significant positive correlation was observed between ctDNA proportion in plasma and CA125 level (p = 0.012). No significant difference in total cfDNA, ctDNA nor ec-cfDNA was observed between participants who were responders versus non-responders. CONCLUSION: Sufficient cfDNA was detected in both plasma and ascites to study three biomarkers. These samples can provide useful information and should be considered in the design of future ovarian cancer trials.
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INTRODUCTION: The benefits of exercise in reducing treatment-related morbidity and improving quality of life following a primary diagnosis of cancer have been well documented and have led to exercise being recommended by oncology societies for all people with a cancer diagnosis. However, these recommendations are derived from research typically involving cohorts with more common cancers and relatively good prognosis, such as breast and prostate. Evidence from these cancers may not apply to women with recurrent ovarian cancer. Therefore, the primary objective of this trial is to evaluate the feasibility and safety of a home-based, telephone-delivered exercise intervention for women undergoing chemotherapy for recurrent ovarian cancer. METHODS AND ANALYSIS: The Exercise During Chemotherapy for Recurrent Ovarian Cancer (ECHO-R) trial is a single-arm, phase II, pre/postintervention trial of a 6-month, telephone-delivered exercise intervention (consistent with recommended exercise oncology prescription). The target sample size is 80 women who are currently undergoing (or are scheduled to receive) chemotherapy for recurrent ovarian cancer. Recruitment is through participating hospital sites in Queensland, Australia, or via self-referral. The exercise intervention comprises 12 telephone sessions over a 6-month period delivered by trial-trained exercise professionals and supplemented (where feasible) by five sessions face to face. Exercise prescription is individualised and works towards an overall goal of achieving a weekly target of 150 min of moderate-intensity, mixed-mode exercise. Assessments via self-administered survey and physical fitness and function tests occur at baseline and then at 6 and 9 months postbaseline. Data to inform feasibility and safety are recorded as case notes by the exercise professional during each session. ETHICS AND DISSEMINATION: Ethics approval for the ECHO-R trial was granted by the Metro North Human Research Ethics Committee (HREC/2020/QRBW/67223) on 6 November 2020. Findings from the trial are planned to be disseminated via peer-reviewed publications and both national and international exercise and oncology conferences. TRIAL REGISTRATION NUMBER: ACTRN12621000042842.
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Neoplasias Ovarianas , Qualidade de Vida , Feminino , Humanos , Masculino , Carcinoma Epitelial do Ovário , Terapia por Exercício/efeitos adversos , Estudos de Viabilidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/etiologia , TelefoneRESUMO
This study aimed to investigate nutritional status, body composition, dietary protein intake, handgrip strength, 6 min or 4 m walk tests, self-reported physical activity, physical function, and quality of life (QoL-EORTC-QLQc30) at commencement of chemotherapy; to detect changes over time (from commencement of chemotherapy, and after 3, 6, 12, 26 and 52 weeks) in women with metastatic breast cancer (MBC); and to investigate the relationship between nutritional variables. 'Sarcopenia' was defined as low muscle mass and strength, 'myosteatosis' as muscle fat-infiltration (CT scan). Continuous variables were analysed using paired t-tests between baseline and follow-ups. Fifteen women (54y, 95% CI [46.3;61.2]) were recruited. At baseline, malnutrition was present in 3 (20%) participants, sarcopenia in 3 (20%) and myosteatosis in 7 (54%). Thirteen (87%) participants had low protein intake; low handgrip strength was observed in 0, and low walk test distance and physical activity in four (27%) participants. Physical function and QoL were low in 10 (67%) and 9 (60%), respectively. QoL between baseline and 52 weeks decreased by 11.7 (95% CI [2.4;20.9], p = 0.025). Other variables did not significantly change over time. In this small study sample, myosteatosis, low dietary protein intake, low exercise levels and impaired quality of life and physical function are common.
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Neoplasias da Mama , Sarcopenia , Humanos , Feminino , Qualidade de Vida , Força Muscular/fisiologia , Força da Mão , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas Alimentares/uso terapêutico , Seguimentos , Sarcopenia/etiologia , Exercício Físico , Músculos/patologiaRESUMO
Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
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PURPOSE: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. PATIENTS AND METHODS: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. RESULTS: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. CONCLUSIONS: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
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Neoplasias da Mama , Inibidores de Proteínas Quinases , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes , Classe I de Fosfatidilinositol 3-Quinases/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Fulvestranto/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , SulfonamidasRESUMO
BACKGROUND: In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)-mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR). METHODS: A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics. RESULTS: Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1-2. CONCLUSION: Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR. TRIAL REGISTRATION NUMBERS: ANZGOG1601, ACTRN12617000106336, and NCT03015129.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias do Endométrio/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Reparo de Erro de Pareamento de DNA , Esquema de Medicação , Neoplasias do Endométrio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Olaparib was originally formulated as 50 mg capsules with a recommended dose of 400 mg twice daily which requires patients to take 16 capsules a day. More recently, a tablet formulation with equivalent efficacy has become available and reduces the pill burden for patients to two tablets twice daily which is more convenient for patients. However, it is important to understand the key differences between the olaparib capsule and tablet formulations as they are not bioequivalent, and the doses are not interchangeable. Educating patients when transitioning from capsules to tablets is critical to avoid dosing errors and maintain both safety and efficacy of olaparib maintenance therapy. MAIN RECOMMENDATIONS: There are no established guidelines on transitioning patients from capsules to tablets. Patients taking 400 mg of the capsules twice daily should be switched to 300 mg of the tablets twice daily. In patients on a reduced dose of 200 mg capsules twice daily, consider switching to 250 mg twice daily of the tablet formulation. In patients on 100 mg capsules twice daily, consider 200 mg tablets twice daily. Particular care should be taken in transitioning patients who are on a reduced dose due to anemia and who have a low hemoglobin (9 g/dL) where a lower dose of the tablets should be considered initially. Close monitoring of patients for the first 3 months with further dose reductions based on tolerability is recommended. The tablet dose can be escalated or de-escalated depending on tolerance.
Assuntos
Cápsulas/administração & dosagem , Neoplasias/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Guias de Prática Clínica como Assunto/normas , Comprimidos/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Distribuição TecidualRESUMO
AIMS: Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (-) breast cancer could provide more accurate prognostic information. METHODS: The retrospective cohort included 229 patients from a single institution with ER+, HER2- breast cancer who had synchronous ALN metastatic disease (2005-2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. RESULTS: One patient had an ER+ primary tumour, which was ER- in the ALN metastasis. 27 (11.3%) were PR- in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR- in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR- metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR- metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). CONCLUSIONS: Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Linfonodos/química , Recidiva Local de Neoplasia , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Queensland , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
PURPOSE: The rare association between breast cancer and pregnancy means that few oncologists gain an expertise in this area. In particular, there are few published data concerning the use of chemotherapy for breast cancer during pregnancy. In this retrospective case series, we describe the experiences of five hospitals in London, United Kingdom, and how they manage this condition. PATIENTS AND METHODS: Retrospective searches were performed at five London hospitals in order to identify women who received chemotherapy for breast cancer while pregnant. RESULTS: Twenty-eight women were identified who had received chemotherapy for breast cancer during pregnancy. Twenty-four women received adjuvant or neoadjuvant chemotherapy for early breast cancer, and four women received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy. Sixteen women were treated with anthracycline-based chemotherapy and 12 received cyclophosphamide, methotrexate, and fluorouracil. All but one of the women were treated after the first trimester. One spontaneous abortion occurred in the woman treated during her first trimester; otherwise, there were no serious adverse consequences for the mothers or neonates. CONCLUSION: These data provide evidence that in terms of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Adulto , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Londres , Metotrexato/administração & dosagem , Terapia Neoadjuvante , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/cirurgia , Resultado da Gravidez , Estudos RetrospectivosRESUMO
Olaparib is the first oral poly(ADP-ribose) polymerase inhibitor to be approved as maintenance monotherapy for treatment of patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) serous ovarian cancer. This review provides practical guidance on the use of olaparib (capsule formulation) in the maintenance setting. The article focuses on the key toxicities that can arise with olaparib therapy and recommendations for their management. Nausea, vomiting, fatigue and anemia are the most commonly reported adverse events in olaparib clinical trials and are generally mild to moderate and transient in nature in most patients. Implementation of an effective and timely management plan can control many of the side effects. It is vital that health care providers effectively communicate the potential side effects of olaparib, as well as educate patients on management strategies to combat these symptoms. To this end, realistic expectations regarding the potential side effects need to be set, with an understanding that dose interruptions and modifications may be required to allow patients to continue receiving treatment.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/efeitos adversos , Ftalazinas/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Feminino , Humanos , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagemRESUMO
The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and ß-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30-45min) in plasma to a maximum concentration of 170±185µg/L (mean±SD). Clearance was high (mean 57.9L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (<1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma ß-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.