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BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.
Asunto(s)
Antieméticos , Antineoplásicos , Cannabidiol , Cannabis , Náusea , Vómitos , Adulto , Anciano , Anciano de 80 o más Años , Antieméticos/uso terapéutico , Antineoplásicos/uso terapéutico , Australia , Cannabidiol/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Dronabinol/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológicoRESUMEN
BACKGROUND: Potentially platinum sensitive recurrent ovarian cancer (PPS ROC) is defined by a platinum-free interval of >6 months, and usually treated with platinum-based chemotherapy with variable response and benefit in women who have had 3 or more lines of chemotherapy(≥3). We identified baseline characteristics (health-related quality of life[HRQL] and clinicopathological factors), associated with PFS, OS and early progression (within 8 weeks). The goal is to improve patient selection for chemotherapy based on a nomogram predicting PFS. METHODS: HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with PFS and OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis were included in multivariable analyses using backward elimination to select those significant. Associations with stopping chemotherapy early were assessed with logistic regression. RESULTS: 378 women were enrolled, with median(m)OS and PFS of 16.6 months and 5.3 months, respectively. The majority had ECOGPS 0-1. Chemotherapy was stopped early in 45/378 participants (12%); with mOS 3.4 months (95% CI: 1.7-7.2). Physical function(PF), role function(RF), cognitive function(CF), social function(SF), Global Health Status(GHS) and abdominal/GI symptoms(AGIS) were significant univariable predictors of PFS(p < 0.030). SF remained significant after adjusting for clinicopathological factors; p = 0.03. PF, RF, CF, SF, GHS and AGIS were significant univariable predictors of OS (p < 0.007); PF, RF, SF and GHS remained significant predictors of OS in multivariable models; p < 0.007. Poor baseline PF and GHS were significant univariable predictors of stopping chemotherapy early (p < 0.007) but neither remained significant after adjusting for clinicopathological factors. CONCLUSION: Baseline HRQL is simple to measure, is predictive of PFS and OS and when used in conjunction with clinicopathological prognostic factors, can assist with clinical decision making and treatment recommendations for women with PPSROC≥3.
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Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/sangre , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Calidad de Vida , Tasa de SupervivenciaRESUMEN
PURPOSE: To compare estimates of expected survival time (EST) made by patients with advanced cancer and their oncologists. METHODS: At enrolment patients recorded their "understanding of how long you may have to live" in best-case, most-likely, and worst-case scenarios. Oncologists estimated survival time for each of their patients as the "median survival of a group of identical patients". We hypothesized that oncologists' estimates of EST would be unbiased (~ 50% longer or shorter than the observed survival time [OST]), imprecise (< 33% within 0.67 to 1.33 times OST), associated with OST, and more accurate than patients' estimates of their own survival. RESULTS: Twenty-six oncologists estimated EST for 179 patients. The median estimate of EST was 6.0 months, and the median OST was 6.2 months. Oncologists' estimates were unbiased (56% longer than OST), imprecise (27% within 0.67 to 1.33 times OST), and significantly associated with OST (HR 0.88, 95% CI 0.82 to 0.93, p < 0.01). Only 41 patients (23%) provided a numerical estimate of their survival with 107 patients (60%) responding "I don't know". The median estimate by patients for their most-likely scenario was 12 months. Patient estimates of their most-likely scenario were less precise (17% within 0.67 to 1.33 times OST) and more likely to overestimate survival (85% longer than OST) than oncologist estimates. CONCLUSION: Oncologists' estimates were unbiased and significantly associated with survival. Most patients with advanced cancer did not know their EST or overestimated their survival time compared to their oncologist, highlighting the need for improved prognosis communication training. Trial registration ACTRN1261300128871.
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Neoplasias/mortalidad , Oncólogos/normas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
Since the publication of this paper, the authors noticed an error in Fig. 1. The X-axis on all the figure panels should read 'Time (years)', not 'Time (months)'. The corrected Fig. 1 is shown below.
RESUMEN
Background: We sought to determine the survival benefits that patients judged sufficient to warrant adjuvant therapy with sorafenib for 1 year, or for 3 years after resection of renal cell carcinoma in the SORCE trial. Methods: SORCE participants from all sites in Australia and New Zealand, and selected sites in the UK, completed a validated preferences questionnaire at months 0, 3, 15, and 42 to elicit the minimum survival benefits they judged sufficient to warrant adjuvant sorafenib for 1 year (versus observation), or for 3 years (versus 1 year). The questionnaires used reference survival times of 5 and 15 years; and reference survival rates at 5 years of 65% and 85%. Results: The 233 participants had a median age of 57 years (range 29-78) and 71% were male. For 1 year of sorafenib versus no adjuvant therapy, the median benefits in survival times judged sufficient to warrant treatment were an extra 9 months beyond 5 years and an extra 1 year beyond 15 years; the median benefit in survival rates were an extra 4% beyond 65% and an extra 3% beyond 85% at 5 years. For 3 years of sorafenib versus 1 year of sorafenib, the median benefit in survival time judged sufficient to warrant extended treatment was an extra 1 year beyond both 5 and 15 years. Participants randomly allocated to treatment with sorafenib judged larger benefits necessary than those allocated to placebo. Participants' preferences were not associated with their baseline characteristics or the interval from randomisation. Conclusion: Most participants judged an extra year of survival necessary to warrant 1 year of adjuvant sorafenib worthwhile, and an additional year of survival to warrant extending the duration of sorafenib from 1 to 3 years. Patients' preferences are important in shared decision making. SORCE trial clinical trials number: NCT00492258.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Prioridad del Paciente , Sorafenib/uso terapéutico , Adulto , Anciano , Carcinoma de Células Renales/mortalidad , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/mortalidad , Femenino , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Health-related quality of life (HRQOL) in melanoma is affected by cancer stage. Previous studies have reported limited data on utility-based HRQOL. OBJECTIVES: To determine pooled estimates of utility-based HRQOL (utilities) for people with American Joint Cancer Committee stage I/II, III or IV melanoma for use in economic evaluations. METHODS: We performed a systematic review, meta-analysis and metaregression of utilities for patients with melanoma. HRQOL scores reported with the QLQ-C30, SF-36, SF-12, FACT-G and FACT-M instruments were converted to utilities using published mapping algorithms. Meta-analysis was used to calculate mean utilities. Metaregression was used to examine the effects of baseline patient and study characteristics. RESULTS: We identified 33 studies reporting 213 utilities. From meta-analyses, the mean utility for stage I/II melanoma was 0·97 [95% confidence interval (CI) 0·90-0·98]; for stage III melanoma it was 0·77 (95% CI 0·70-0·83); for stage III/IV 0·76 (95% CI 0·76-0·77); and for stage IV melanoma 0·76 (95% CI 0·71-0·81). The difference in utility between stage III and stage IV was not statistically significant (P = 0·52). For patients with stage I/II, the utility estimate at the time of surgery was 0·77 (95% CI 0·75-0·79), and at 3-12 months postsurgery it was 0·85 (95% CI 0·84-0·86). Utility estimates for patients with stage IV melanoma were 0·65 (95% CI 0·62-0·69) during the first 3 months of treatment and 0·83 (95% CI 0·81-0·86) at 4-12 months on treatment. For patients with stage IV melanoma treated with chemotherapy, the utility estimate was 0·52 (95% CI 0·51-0·52), while for those treated with targeted therapy it was 0·83 (95% CI 0·82-0·85). CONCLUSIONS: These robust, evidence-based estimates of health state utility can be used in economic evaluations of new treatments for patients with early-stage or advanced-stage melanoma.
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Melanoma/terapia , Calidad de Vida , Neoplasias Cutáneas/terapia , Adulto , Antineoplásicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Posoperatorios/estadística & datos numéricos , Años de Vida Ajustados por Calidad de VidaRESUMEN
BACKGROUND: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present a multi-centre collaborative study to validate this association. METHODS: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between 1 January 2000 to 31 December 2014. The primary endpoint was time to development of RIS. RESULTS: We identified 419 patients with RIS. Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1.37; 95% CI: 1.08-1.72; P=0.009). In the multi-variable model, older age (HR 2.11; 95% CI 1.83-2.43; P<0.001) and chemotherapy for the first malignancy (HR 1.61; 95% CI 1.26-2.05; P<0·001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect. CONCLUSIONS: This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of RIS.
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Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias Inducidas por Radiación/etiología , Neoplasias Primarias Secundarias/etiología , Sarcoma/etiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antraciclinas/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic. PATIENTS AND METHODS: Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic. RESULTS: In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively. CONCLUSIONS: Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making. CLINICAL TRIAL REGISTRATION: NCT00976911.
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Compuestos Organoplatinos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Humanos , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/fisiopatología , Análisis de SupervivenciaRESUMEN
e-TC is an online intervention designed to address common psychosocial concerns of testicular cancer survivors. It aims to reduce anxiety, depression and fear of cancer recurrence by providing evidence-based information and psychological intervention. This paper details the development and pilot testing of e-TC. During pilot testing, 25 men (with varying psychological profiles) who had completed treatment for testicular cancer, 6 months to 5 years ago (which had not recurred), used e-TC over a 10-week period and provided quantitative and qualitative feedback on the feasibility and acceptability of the programme. Six men also completed a qualitative interview to provide detailed feedback on their experiences using e-TC. Fourteen men (56%) completed at least 80% of the programme. Participants reported a high level of satisfaction with the programme. Men's limited time was a barrier to programme use and completion, and participants suggested that men with a more recent diagnosis and a higher level of distress may be more likely to engage with the programme. e-TC appears to be a feasible and acceptable online intervention for survivors of testicular cancer. Findings from this study are currently being used to refine e-TC and guide the design of a larger efficacy study.
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Ansiedad/terapia , Supervivientes de Cáncer/psicología , Terapia Cognitivo-Conductual/métodos , Depresión/terapia , Estrés Psicológico/terapia , Neoplasias Testiculares/psicología , Adulto , Ansiedad/psicología , Depresión/psicología , Estudios de Factibilidad , Humanos , Internet , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud , Proyectos Piloto , Estrés Psicológico/psicología , Terapia Asistida por Computador/métodosRESUMEN
PURPOSE: Psychological responses to cancer are widely believed to affect survival. We investigated associations between hope, optimism, anxiety, depression, health utility and survival in patients starting first-line chemotherapy for metastatic colorectal cancer. METHODS: Four hundred twenty-nine subjects with metastatic colorectal cancer in a randomised controlled trial of chemotherapy completed baseline questionnaires assessing the following: hopefulness, optimism, anxiety and depression and health utility. Hazard ratios (HRs) and P values were calculated with Cox models for overall survival (OS) and progression-free survival (PFS) in univariable and multivariable analyses. RESULTS: Median follow-up was 31 months. Univariable analyses showed that OS was associated negatively with depression (HR 2.04, P < 0.001) and positively with health utility (HR 0.56, P < 0.001) and hopefulness (HR 0.75, P = 0.013). In multivariable analysis, OS was also associated negatively with depression (HR 1.72, P < 0.001) and positively with health utility (HR 0.73, P = 0.014), but not with optimism, anxiety or hopefulness. PFS was not associated with hope, optimism, anxiety or depression in any analyses. CONCLUSIONS: Depression and health utility, but not optimism, hope or anxiety, were associated with survival after controlling for known prognostic factors in patients with advanced colorectal cancer. Further research is required to understand the nature of the relationship between depression and survival. If a causal mechanism is identified, this may lead to interventional possibilities.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Esperanza , Optimismo , Anciano , Trastornos de Ansiedad/etiología , Neoplasias Colorrectales/psicología , Trastorno Depresivo/etiología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Encuestas y CuestionariosRESUMEN
AIMS: Current patient-reported measures (PROMs) do not specifically address radiotherapy (RT) related inconvenience. We conducted, as per guidelines of the European Organization for Research and Treatment of Cancer (EORTC), the initial (issue generation) phase of development of a RT inconvenience PROM. Specifically, we aimed to develop a conceptual framework for RT inconvenience and generate a comprehensive list of issues pertaining to it. METHODS: We reviewed existing PROMs and literature and gathered qualitative and quantitative data from consumers and health professionals, in order to generate a comprehensive list of issues pertaining to RT inconvenience. A framework for the consideration of RT inconvenience was defined and used to ensure all possible issues were explored and to list the issues into conceptual domains. RESULTS: Qualitative data from 26 consumers and 30 health professionals, and quantitative data from 1191 consumers and 253 health professionals resulted in the identification of 38 issues grouped into five conceptual domains: (1) inconvenience of RT opportunity, (2) inconvenience of decision-making, (3) inconvenience of treatment, (4) inconvenience of side effects, and (5) inconvenience of follow-up. CONCLUSIONS: This list of RT inconvenience issues will, in future work, be operationalized into a set of items for pretesting and then large-scale field testing as per the EORTC guidelines.
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Medición de Resultados Informados por el Paciente , Calidad de Vida/psicología , Toma de Decisiones , Humanos , Percepción , RadioterapiaRESUMEN
BACKGROUND/AIM: The utility of pulmonary function testing (PFT) to detect bleomycin-induced pneumonitis is controversial. We describe its impact on bleomycin dosing in a phase 2 trial of accelerated BEP (bleomycin, etoposide, cisplatin) for advanced germ cell tumours. METHODS: There were 12 planned weekly bleomycin doses for intermediate-risk and poor-risk disease and nine for good-risk disease. Clinical assessments, chest X-ray, diffusing capacity of lung for carbon monoxide (DLCO) and forced vital capacity (FVC) were performed bi-weekly. Bleomycin was ceased for predefined clinical/radiological evidence of pulmonary toxicity and a >25% reduction in DLCO or FVC. We determined doses planned, received and omitted and patients receiving all, ≥two-thirds, two-thirds of planned bleomycin doses. RESULTS: Of 43 eligible patients, 30% had lung metastases. Of 471, 375 (80%) of planned bleomycin doses were received, and 30% received Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación
, Bleomicina/administración & dosificación
, Neoplasias Pulmonares/epidemiología
, Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico
, Neoplasias Testiculares/tratamiento farmacológico
, Adolescente
, Adulto
, Antibióticos Antineoplásicos/efectos adversos
, Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación
, Australia
, Bleomicina/efectos adversos
, Monóxido de Carbono/análisis
, Cisplatino/administración & dosificación
, Relación Dosis-Respuesta a Droga
, Etopósido/administración & dosificación
, Femenino
, Humanos
, Neoplasias Pulmonares/secundario
, Masculino
, Neoplasias de Células Germinales y Embrionarias/patología
, Pronóstico
, Radiografía Torácica
, Pruebas de Función Respiratoria
, Neoplasias Testiculares/patología
, Capacidad Vital
, Adulto Joven
RESUMEN
BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, â¼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1ß, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.
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Citocinas/sangre , Resistencia a Antineoplásicos , Calicreínas/sangre , Macrófagos/metabolismo , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Línea Celular Tumoral , Técnicas de Cocultivo , Docetaxel , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/farmacologíaRESUMEN
BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.
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Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/administración & dosificación , Indoles/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirroles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Australia , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Everolimus/efectos adversos , Estudios de Factibilidad , Femenino , Humanos , Indoles/efectos adversos , Neoplasias Renales/enzimología , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/efectos adversos , Pirroles/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Riesgo , Sunitinib , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Nitroglicerina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Little is known about the relative importance that oncologists attribute to the benefits and harms of anti-cancer drugs when considering treatment options with their patients. AIM: To quantify the trade-offs made between overall survival, progression-free survival and adverse effects. METHODS: A web-based survey elicited importance weights for the benefits and harms of bevacizumab or everolimus. Combining the importance weights with trial-based probabilities produced a score and ranking for each treatment option. RESULTS: A total of 40 responses was received for the bevacizumab scenario and 32 for the everolimus scenario. All respondents regarded overall survival and progression-free survival as the most important attributes - more important than avoiding the potential harms regardless of drugs. Among the potential harms, respondents allocated the highest mean importance weight to gastrointestinal (GI) perforation and rated absolute improvement in overall survival as 1.6 times and 2.3 times as important as avoiding GI perforation in the two versions of the bevacizumab scenario respectively. For the everolimus scenario, stomatitis and pneumonitis were allocated the highest mean importance weights with absolute improvement in overall survival rated as 2.2 times as important as avoiding stomatitis/pneumonitis. All 40 respondents (100%) favoured treatment option with bevacizumab to no bevacizumab based on respondents' determined weights for treatment attributes. The converse was found for everolimus with 22 (69%) of respondents preferring the 'no everolimus' option. CONCLUSION: Oncologists' preferences over the benefits and harms of treatment do, when combined with evidence of effect, influence treatment decisions for anti-cancer drugs.
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Inhibidores de la Angiogénesis/administración & dosificación , Antineoplásicos/administración & dosificación , Actitud del Personal de Salud , Bevacizumab/administración & dosificación , Everolimus/administración & dosificación , Oncología Médica , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Toma de Decisiones Clínicas , Supervivencia sin Enfermedad , Femenino , Encuestas de Atención de la Salud , Encuestas Epidemiológicas , Humanos , Internet , Masculino , Persona de Mediana Edad , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Shared understanding of prognosis is vital for optimal, multidisciplinary, clinical decision making. AIMS: This study aims to determine the frequency and nature of prognostic information in medical oncologists' letters to referring doctors for patients with metastatic cancer. METHODS: We reviewed all consultation letters (to June 2014) for new patients with metastatic cancer presenting to medical oncologists at Concord and Macarthur Cancer Centres between June 2012 and June 2013. We recorded the presence and nature of prognostic information in the letters, patients' characteristics and survival. Characteristics associated with inclusion of prognostic information were explored. RESULTS: We analysed 1344 letters pertaining to 272 patients with a median survival of 13 months. The median number of letters per patient was 4 (interquartile range 1-7), with 50% written by trainees. The terms 'metastatic' or 'stage IV cancer' were included in letters for 253 patients (93%), treatment was described as 'palliative' for 174 patients (64%) and the word 'incurable' was included for 93 (34%). Only 31 patients (11%) had a quantitative estimate of prognosis in any correspondence: median or average survival in 14, general time frame in 12 and, best case, typical and worst case scenarios in 5. Inclusion of quantitative prognostic information was not associated with patient age, cancer type, treatment plan, trainee authoring letter or shorter survival. CONCLUSION: Inclusion of quantitative prognostic information in written correspondence from medical oncologists regarding patients with metastatic cancer was infrequent. Encouraging oncologists to include quantitative prognostic information in their letters could improve communication between oncologists, referring doctors and patients.
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Oncología Médica/estadística & datos numéricos , Neoplasias , Médicos/estadística & datos numéricos , Derivación y Consulta/organización & administración , Anciano , Toma de Decisiones Clínicas , Correspondencia como Asunto , Femenino , Humanos , Relaciones Interprofesionales , Masculino , Neoplasias/mortalidad , Neoplasias/patología , Neoplasias/terapia , Guías de Práctica Clínica como Asunto , Pronóstico , Derivación y Consulta/normasRESUMEN
BACKGROUND: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). METHODS: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. RESULTS: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). CONCLUSIONS: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Metilación de ADN , ADN de Neoplasias/genética , Epigenómica , Gutatión-S-Transferasa pi/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Islas de CpG , ADN de Neoplasias/sangre , Estudios de Seguimiento , Gutatión-S-Transferasa pi/sangre , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Tasa de Supervivencia , Estudios de Validación como AsuntoRESUMEN
BACKGROUND: Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are â¼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study. METHODS: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. RESULTS: Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together. CONCLUSIONS: Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.
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Adenocarcinoma/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Biomarcadores de Tumor/sangre , Resistencia a Antineoplásicos/genética , MicroARNs/sangre , Neoplasias de la Próstata/tratamiento farmacológico , ARN Neoplásico/sangre , Taxoides/uso terapéutico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Docetaxel , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Curva ROC , Factores de Riesgo , Taxoides/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS: Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS: Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION: Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.