Search

Objectives Older adults constitute the majority of patients with lung cancer. However, they are under-represented in clinical trials as eligibility criteria often restrict enrolment based on comorbidities that are common with aging. We aimed to describe comorbidities relating to trial exclusion criteria in older adults with lung cancer, determine the proportion that would typically be excluded from trials, and examine the impact on treatment uptake. Materials and Methods We conducted a population-based study of people aged ≥65 years diagnosed with metastatic lung cancer using linked data for clients of the Australian Government Department of Veterans' Affairs (2005–2015). We defined trial-typical patients based on the absence of comorbidities related to the following: inadequate organ (cardiac, renal, hepatic, marrow) function; cognitive dysfunction; poor performance status (PS); prior malignancy within 5 years. We report systemic therapy uptake within 3 months of diagnosis. Results Our study included 677 patients (median age 84). Over half (53.4%) were not trial-typical, with the most common reasons being poor PS (37.5%), cardiac disease (19.2%), and prior cancer (12.9%). Eighty-two (12.1%) received systemic therapy. Patients with poor PS, cardiac disease, and dementia had lower treatment uptake rates. However, there was no significant difference in treatment uptake between trial-typical and non-trial-typical patients (13.4 vs 11.0%). Conclusion More than half of older adults with advanced lung cancer would be typically excluded from trial participation. Future clinical trials of older adults need to consider broader eligibility criteria to better reflect this population to gain the best evidence for their care.

Cardiac function assessment is important for detecting and managing trastuzumab-associated cardiotoxicity. Our study estimates rates and predictors of cardiac assessment among patients receiving trastuzumab for HER2-positive early breast cancer (HER2+EBC) in Australia. We conducted a retrospective cohort study of Australians initiating (neo)adjuvant trastuzumab for HER2+EBC between 1 January 2015 and 15 April 2019. We used administrative claims to determine the number of patients receiving guideline-recommended assessment, i.e. evidence of baseline cardiac assessment (between 120 days before and 30 days after trastuzumab initiation) and regular on-treatment cardiac assessments (at least every 120 days). We examined factors associated with baseline and regular on-treatment cardiac assessment. Our study includes 5621 patients (median age 56 years), of whom 4984 (88.7%) had a baseline cardiac function test. Among 4280 patients with at least 12 months of follow-up, 2702 (63.1%) had guideline-recommended cardiac assessment. Rates of guideline-recommended assessment increased with later year of diagnosis (60.9% in 2015 vs 68.3% in 2018, OR 1.34, 95% CI 1.06–1.69). Patients with higher baseline comorbidities and greater socioeconomic disadvantage were less likely to have guideline-recommended cardiac assessment. Cardiac assessment practices varied by State/Territory. There was no association between baseline cardiac risk or anthracycline use and the likelihood of receiving guideline-recommended cardiac assessment. The majority of patients receiving (neo)adjuvant trastuzumab had guideline-recommended baseline and on-treatment cardiac assessment. Variations in cardiac assessment predominantly related to system-level factors, such as year of diagnosis and geography, rather than individual patient factors.

Background Randomised clinical trials (RCTs) demonstrate that trastuzumab improves survival in patients with human epidermal growth factor 2-positive early breast cancer (HER2 + EBC), but real-world patients and clinical practice often differ from RCTs. We examine real-world treatment patterns and outcomes associated with trastuzumab for HER2 + EBC. Methods We identified all Australians dispensed trastuzumab for HER2 + EBC between 1/1/2007 and 30/6/2016. We estimated the proportion of patients completing 12 months of treatment (defined as ≥350 days of exposure within 540 days of initiation). We estimated overall survival (OS) and recurrence-free survival (RFS) by using trastuzumab dispensing for metastatic breast cancer as a surrogate for recurrence. Results Our study included 14,644 patients. Among patients with ≥540 days of follow-up (n = 11,903), 67.4% completed 12 months of trastuzumab. OS rates at 5 and 9 years were 92.7 and 87.9%, and RFS rates at 5 and 9 years were 86.8 and 81.4%, respectively. Patients who completed 12 months of trastuzumab had a 9-year OS rate of 90.2% compared with 86.2% among patients receiving Conclusions Real-world HER2 + EBC patients are less likely to complete 12 months of trastuzumab than some clinical trial counterparts but have survival outcomes comparable to those reported in landmark RCTs.

International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing treatments in diverse populations and facilitating the study of rare tumours or specific molecular subtypes. However, a number of challenges continue to hinder the efficient and productive conduct of both commercial and non-commercial international clinical trials. These challenges include complex and burdensome regulatory requirements, the high cost of conducting trials, and logistical challenges associated with ethics review, drug supply and biospecimen collection and management. We propose solutions to promote oncology trial collaboration, such as regulatory reform, harmonisation of trial initiation and management processes and greater recognition and funding of academic (non-commercial) clinical trials. It is only through coordinated effort and leadership from researchers, regulators and those responsible for health systems that the full potential of international trial collaboration can be realised.

Objectives We evaluated how well phase II trials in locally advanced and metastatic pancreatic cancer (LAMPC) meet current recommendations for trial design. Methods We conducted a systematic review of phase II first-line treatment trial for LAMPC. We assessed baseline characteristics, type of comparison, and primary end point to examine adherence to the National Cancer Institute recommendations for trial design. Results We identified 148 studies (180 treatment arms, 7505 participants). Forty-seven (32%) studies adhered to none of the 5 evaluated National Cancer Institute recommendations, 62 (42%) followed 1, 31 (21%) followed 2, and 8 (5%) followed 3 recommendations. Studies varied with respect to the proportion of patients with good performance status (range, 0%-80%) and locally advanced disease (range, 14%-100%). Eighty-two (55%) studies concluded that investigational agents should progress to phase III testing; of these, 24 (16%) had documented phase III trials. Three (8%) phase III trials demonstrated clinically meaningful improvements for investigational agents. One of 38 phase II trials that investigated biological investigational agents was enriched for a biomarker. Conclusions Phase II trials do not conform well to current recommendations for trial design in LAMPC.

The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy. This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life. In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity. For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy. Australian Clinical Trials Registry registration number ACTRN12605000478617.

Objectives The objective of this study was to determine the prevalence of trial registration in health research, whether trial registration status and timing vary depending on trial characteristics, and the relationship between trial registration status and risk of bias. Study Design and Setting We systematically reviewed all clinical trials published from January to June 2017 in 28 high- and low-impact factor general and specialty medicine journals. Results We identified 370 trials and assessed risk of bias in 183 trials. Trial registration rates were high; 95% of trials were registered prospectively or retrospectively before enrollment completion. Larger sample size, multiple recruitment countries, and primary industry funding were all predictors of earlier trial registration. Prospectively registered trials had a significantly lower risk of bias compared to unregistered trials across all domains. Prospectively registered trials had a similar risk of bias compared to retrospectively registered trials across four out of six domains, and a lower risk of bias across the remaining two domains. Conclusion Trial registration is an imperfect proxy for risk of bias. Systematic reviewers should assess risk of bias on a case-by-case basis and conduct sensitivity analyses excluding high risk of bias studies. In the longer term, mechanisms should be implemented to facilitate prospective registration of all trials.

Background We sought to compare the effect sizes hypothesized in the trial design, observed in the trial results, and considered clinically meaningful by the American Society of Clinical Oncology (ASCO) 2014 recommendations, in phase III trials of targeted and immunological therapies. Methods We studied phase III, superiority trials of targeted and immunological therapies in advanced cancers published from 2005 to 2015. We recorded the characteristics, design parameters, and observed results for the primary endpoint of each trial. The effect sizes hypothesized in the trial design were compared with the ASCO 2014 recommendation that phase III trials be designed to detect overall survival (OS) benefits that are clinically meaningful (hazard ratio ≤0.8). Results All critical elements of the trial design (effect sizes hypothesized, estimated survival in the control group, power, and significance level) were identified in 165 of 213 included trials (77%). Of trials with a statistically significant result for the primary endpoint, 16 of 30 (53%) with a primary endpoint of OS and 20 of 53 (38%) with a primary endpoint of progression free survival (PFS) had an observed effect size less extreme than hypothesized; and 7 of 30 trials (23%) reported an observed effect size for OS that was statistically significant but not clinically meaningful (HR > 0.80) according to the ASCO 2014 recommendations. Conclusion Many trials were designed such that an observed benefit in OS or PFS that was not clinically meaningful would be statistically significant. Phase III trials should be designed to provide results that are statistically significant for observed effects that are clinically meaningful but not for observed results that are of dubious clinical importance.

Importance There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. Exposures Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score Results A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P Conclusions and Relevance In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Background Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine). Patients and methods Pharmacy records were used to identify patients receiving raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing raltitrexed. Results Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil ± leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity. Conclusion Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.

Breast cancer treatment recommendations will often require an appraisal of likely benefits in relation to likely side effects on survival and quality of life end points, and possibly also an evaluation of the size of the anticipated net clinical benefit against financial costs. Quality-adjusted survival (QAS) analysis methods provide a formal approach for deriving an estimate of net clinical benefit to facilitate this appraisal process. QAS analysis methods have been applied in trials with breast cancer patients of adjuvant therapies as well as treatments for advanced/metastatic disease. QAS analyses based solely on trial data may fail to capture plausible longer-term benefits; thus, methods to explore the possible outcomes of treatment beyond the limits of trial data have been developed. These modeling approaches can help researchers gain insights and identify future research priorities, but do not replace the need for long-term evidence from randomized trials.

Loss of phosphatase and tensin homologue (PTEN) expression may be prognostic in colorectal cancer (CRC) and may have a correlation with vascular endothelial growth factor (VEGF) expression via hypoxia-inducible factor 1 (HIF-1) alpha, and the PI3K/mTOR pathways. We therefore have explored the prognostic association of PTEN loss and the potential that PTEN loss may be predictive of outcome with bevacizumab. Patients enrolled in the AGITG MAX trial, a randomized Phase III trial of capecitabine (C) +/− bevacizumab (B) (+/− mitomycin C [M]) with available tissues were analyzed for PTEN expression (loss vs. no loss) as assessed using a Taqman® copy number assay (CNA). Of the original 471 patients enrolled, tissues from 302 (64.1%) patients were analyzed. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. PTEN status was not prognostic for progression-free survival (PFS) or overall survival (OS) in multivariate analyses adjusting for other baseline factors; loss versus no loss PFS hazard ratio (HR) 0.9 (0.7–1.16), OS HR 1.04 (0.79–1.38). PTEN was not prognostic when assessed by KRAS and BRAF status. By using the comparison of C versus CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS. PTEN status was not prognostic for survival in advanced colorectal cancer, irrespective of KRAS or BRAF status. PTEN status did not significantly predict different benefit with bevacizumb therapy.

Objective: To adjust patients' time trade-off (TTO) scores using information on their utility functions for survival time to derive a measure of health state utility equivalent to the standard gamble (SG).Methods: A sample of 199 cardiovascular patients were asked three TTO and SG questions (to assess their own health state), and three certainty equivalent questions (to assess their utility function for survival time) in an interview.Results: Patients' utility functions for time were increasingly concave, but being unable to model this successfully, a constant function with an averaged level of concavity was used. The raw TTO scores were significantly higher than SG scores, while the adjusted TTO scores were equivalent to the SG.Conclusions: Raw time trade-off scores will give biased estimates of health state utility when patients' utility functions for time are not linear, but these can be adjusted to yield true utilities. The constant proportional risk-posture assumption of the conventional QALY model, on which previous attempts to adjust time trade-offs have been based, was not supported by the data.

In an ageing population, a greater proportion of geriatric patients will be considered for systemic chemotherapy. Colorectal cancer (CRC) is a common malignancy and will be a major health issue in geriatrics. We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy.MAX, a three arm study of Capecitabine (C) versus CBevacizumab (CB) versus CBMitomycin C (CBM), found an improvement in progression-free survival (PFS), with addition of B [+/- mitomycin C (MMC)] to C. This analysis assesses the effect of adding B (+/- MMC) to C on PFS, overall survival (OS), response rate (RR), toxicity and dose intensity in geriatric patients (age ≥ 75 years).Ninety-nine patients (21%) were aged 75-86 years. Baseline characteristics were well balanced. Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day; days 1-14, q21 (61% for75 years) and 88% were Eastern Cooperative Oncology Group 0-1. Co-morbidities were as expected in this population. The addition of B significantly improved PFS in geriatric patients(C 5.8 months versus CB 8.8 months, Hazard ratio (HR) 0.65 and C versus CBM 10.4 months HR 0.38). The interaction test for OS, RR and PFS revealed no impact of age. Dose intensity was maintained90% in all patients. There were no major differences in toxicity patterns between age cohorts.Addition of B to C significantly improved PFS in this geriatric population, with similar benefits to those aged75 years. Treatment was well tolerated with no signal of increased toxicity (including thromboembolism) when compared with those aged75 years.

OBJECTIVE Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. RESULTS Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. CONCLUSIONS Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.

Background Bevacizumab is an antiangiogenic mAb with efficacy against several cancers, but it is associated with risk of arterial thromboembolism (ATE). Further data are needed to determine the safety of bevacizumab. Patients and methods We recorded grade 3, 4, or 5 ATE events and other data (including age, baseline cardiovascular risk factors, history of ATE, and aspirin use) from 471 patients with metastatic colorectal cancer in the MAX (Mitomycin, Avastin, Xeloda) trial of capecitabine monotherapy versus capecitabine with bevacizumab with or without mitomycin C. Results Bevacizumab-treated patients had 12 grade 3, 4, or 5 ATEs (3.8% incidence). ATEs occurred in 2.1% of patients >65 years, 5% of those with a history of ATE, and 5% of those with cardiac risk factors. Age, history of ATE, or vascular risk factors did not increase risk. Aspirin users had a higher incidence than nonusers (8.9% versus 2.7%) but had higher rates of vascular risk factors. Conclusions Bevacizumab was associated with a modestly higher risk of ATE, but safety was not significantly worse in older patients or patients with a history of ATE or vascular risk factors. The effect of aspirin in preventing ATE in patients receiving bevacizumab could not be determined from this study.

Background: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin–paclitaxel (CP) or carboplatin–liposomal doxorubicin (CPLD). Methods: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell

Women starting first-line chemotherapy for advanced breast cancer have differing baseline character- istics and survival times. We sought to develop and vali- date a pragmatic prognostic nomogram to predict overall survival (OS) by using available clinical and laboratory data. The prognostic model was developed in a training cohort (n = 693) from two first-line chemotherapy trials (ANZ8101 and ANZ8614) and validated in two other trials (ANZ0001 and ANZ9311) with 324 and 233 patients, respectively. The proportional-hazards model was con- structed from pretreatment demographic and disease char- acteristics. Patients were classified into good (score \88), medium (88-157), and poor ((157) prognostic groups. A nomogram was constructed (n = 1250) from the combined datasets of all four trials, based on the predictors identified in the training cohort. The nomogram predicted OS with a concordance index of 0.65 (95%CI, 0.62-0.67). Factors in the nomogram were age, performance status, estrogen receptor status, number of involved organs (lung, liver and brain), hemoglobin concentration, neutrophil count, and serum alkaline phosphatase. The median survival for good, medium, and poor prognosis was 15.4 months (95%CI, 12.7-19.1), 10.2 months (95%CI, 9.0-11.6), and 6.1 months (95%CI, 4.4-6.7), respectively. The actual and model-predicted probabilities of 18-month survival agreed well, after recalibration for the new baseline survival functions for each validation cohort. A nomogram com- bining seven readily available baseline characteristics enabled stratification of advanced breast cancer patients into three groups with significantly different survival times. This nomogram could be useful for individualising treat- ment and for stratifying patients in future randomized trials.

Background/Aims: Treatment with high-dose cisplatin (HDC) previously required inpatient (IP) admission with overnight hospitalization, but recently practice has shifted to outpatient (OP) therapy. We aimed to determine whether it is preferable to give HDC as an IP or OP using a two-period cross-over trial. Methods: Eligible patients were starting chemotherapy with ≥2 cycles of HDC (≥100 mg/dose) and were suitable for OP treatment. All patients received an IP cycle and OP cycle: the order was randomly allocated. Pre-hydration, anti-emetics and chemotherapy were identical for IP and OP. Post-hydration varied by group (3 L normal saline (NS) for IP, 2 L NS for OP). The primary outcome was patient preference for IP versus OP treatment. Secondary outcomes included aspects of health-related quality of life, adverse events (dose delays and reductions, elevated creatinine and unplanned readmissions) and resource use. Results: Fifty-nine patients were randomized, 53 completed two cycles of HDC. Most patients preferred OP treatment (36 vs 13, P= 0.002). There were no significant differences in patients' ratings of nausea, vomiting, fatigue, anxiety, depression or overall quality of life. Adverse events were few and unrelated to IP versus OP treatment. Nursing time was longer for IP than OP (163 vs 104 min, P < 0.001). Conclusion: OP treatment was preferred by most patients, appeared safe and used less resources.

Фоновое лазерное лечение диабетической ретинопатии часто ассоциируется с сужением полей зрения и другими офтальмологическими и побочными явлениями. Нашей целью было оценить, может ли длительное гиполипидемическое лечение фенофибратом уменьшить прогрессию ретинопатии и необходимость лазерного лечения у пациентов с сахарным диабетом 2 типа. Методы. Исследование (FIELD) было мультинациональным рандомизированным исследованием на 9795 пациентах в возрасте от 50 до 75 лет, страдающих сахарным диабетом. Подходящие пациенты были рандомизированы для получения фенофибрата 200 мг/день (п=4895) или соответствующего плацебо (п=4900). На каждом клиническом визите проводился сбор информации, касающейся лазерного лечения диабетической ретинопатии - предопределенной конечной точки основного исследования. Вопросы лазерного лечения макулярного отека, пролиферативной ретинопатии оценивались офтальмологом, не имеющим информации в отношении распределения по группам. В субисследовании на 1012 пациентах проводилось стандартизованное фотографирование сетчатки и фотографии распределялись согласно критериям Исследования Раннего Лечения Диабетической Ретинопатии (ETDRS) для определения объединенной частоты возникновения диабетической ретинопатии и очагов, являющихся ее компонентами. Анализ проводился у всех рандомизированных пациентов. Это исследование зарегистрировано, как Международное Стандартное Рандомизированное Контролируемое Исследование номер ISRCTN64783481. Результаты. Лазерное лечение требовалось чаще у пациентов с худшей гликемией или с худшим артериальным давлением, чем у пациентов с хорошим контролем над этими факторами. Кроме того, оно требовалось чаще у пациентов с более тяжелым поражением микрососудов, однако, концентрация липидов в плазме не влияла на необходимость такого лечения. Необходимость первого лазерного лечения для всех случаев ретинопатии была значительно меньше в группе фенофибрата в сравнении с группой плацебо (164 [3. 4%] пациента в группе фенофибрата против 238 [4.9%] пациентов в группе плацебо; соотношение рисков [HR] 0.69,95% CI 0.56-0.84; р=0.0002; снижение абсолютного риска 1.5% [0.7-2.3]). В офтальмологическом субисследовании первичная конечная точка, двуступенчатая прогрессия степени ретинопатии, не различалась значительно между двумя группами (46 [9.6%] пациентов в группе фенофибрата в сравнении с 57 [12.3%] в группе плацебо; р=0.19) или в субпопуляции пациентов без ретинопатии в анамнезе (43 [П.4%] против 43 [11.7%]; р=0.87). С другой стороны, среди пациентов, имеющих ретинопатию в анамнезе, значительно меньшее количество пациентов в группе фенофибрата имели двуступенчатую прогрессию в сравнении с таковыми в группе плацебо (три [3.1%] пациента против 14 [14.6%]; р=0.004). Объясняющая составная переменная двуступенчатой прогрессии степени ретинопатии, макулярного отека или лазерного лечения была значительно ниже в группе фенофибрата в сравнении с группой плацебо (HR 0.66, 95% CI 0.47-0.94; р=0.022). Интерпретация. Лечение фенофибратом лиц с сахарным диабетом 2 типа снижает потребность в лазерном лечении диабетической ретинопатии несмотря на то, что механизм этого эффекта скорее всего не связан с концентрацией липидов в плазме.

Background Patients who suffer re-infarction during initial hospitalization for ST-elevation myocardial infarction (STEMI) have decreased survival compared to patients without re-infarction, so treatment of re-infarction may influence survival. Methods and results To determine whether the utilization of reperfusion therapies varied within 12 h of re-infarction and was associated with 30-day mortality, we studied 552 patients with re-infarction of 17 073 patients with STEMI enrolled in HERO-2 in five regions (Russia, Eastern Europe, Western Countries, Asia, and Latin America). Patients presenting within 6 h of symptom-onset were randomized to receive either bivalirudin or unfractionated heparin intravenously just prior to streptokinase. Re-infarction occurred in 2.8 and 3.6% of bivalirudin and heparin treated patients, respectively ( P = 0.004), but treatment assignment did not influence mortality after re-infarction. Patients with re-infarction had a higher 30-day mortality than those without re-infarction (24 vs. 10%; P < 0.001 by Cox model). Within 12 h of re-infarction, fibrinolytic therapy was administered to 12.0 and 8.2% underwent percutaneous coronary intervention (PCI); these two treatments were more frequently utilized in patients from Western countries ( n = 112), compared to patients from other countries ( n = 440) (34.8 and 16.1% compared to 6.1 and 6.1%, respectively, P < 0.001). Mortality was 15% in patients receiving reperfusion therapy for re-infarction and 27% for those with conservative management, hazard ratio (HR) 0.53 (95% CI 0.32–0.88), P = 0.01. In multiple Cox regression analysis which included adjustment for clinical variables and randomized treatment assignment, 30-day mortality after re-infarction varied by region (highest Latin America 29%, lowest Western countries 15%; P = 0.01). Other independent prognostic factors included age, time from randomization to re-infarction, and Killip class at randomization. The HR for PCI treatment of re-infarction was 0.18 [(95% CI 0.04–0.76), P = 0.02] in analyses which excluded deaths within 12 h. Conclusion Treatment of re-infarction with reperfusion therapies was markedly under-utilized, especially in non-western countries. PCI for re-infarction, in particular, was associated with a lower 30-day mortality, which may reflect both patient selection and effects of treatment.

Background: Studies of women who had adjuvant chemotherapy for early breast cancer 10–20 years ago showed that many judged small benefits sufficient to make it worthwhile. Indications, regimens and supportive care have changed. We sought the preferences of contemporary women who received similar chemotherapy. Patients and methods: Ninety-seven consecutive consenting women who completed adjuvant chemotherapy for early breast cancer 3–34 months previously were interviewed. Preferences were elicited with a structured, scripted interview using the trade-off method. Women were presented with four hypothetical scenarios based on known life expectancies (5 and 15 years) and survival rates (65% and 85% at 5 years) without adjuvant chemotherapy. Results: Improvements of an additional year in life expectancy or 3% in survival rates were judged sufficient to make adjuvant chemotherapy worthwhile by 68–84% of women. Half the women judged 1 day or 0.1% sufficient to make adjuvant chemotherapy worthwhile. Recollections of better well-being during adjuvant chemotherapy, having dependants and having a friend or relative who died from cancer were independently associated with judging smaller benefits sufficient to make adjuvant chemotherapy worthwhile (all P Conclusions: Preferences were highly variable, but the benefits judged sufficient to make adjuvant chemotherapy worthwhile were even smaller than those found in previous studies. Preferences were influenced by factors other than direct benefits and harms of chemotherapy.

Objective: To measure the cost-effectiveness of cholesterol-lowering therapy with pravastatin in patients with established ischaemic heart disease and average baseline cholesterol levels. Design: Prospective economic evaluation within a double-blind randomised trial (Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID]), in which patients with a history of unstable angina or previous myocardial infarction were randomised to receive 40 mg of pravastatin daily or matching placebo. Patients and setting: 9014 patients aged 35-75 years from 85 centres in Australia and New Zealand, recruited from June 1990 to December 1992. Main outcome measures: Cost per death averted, cost per life-year gained, and cost per quality-adjusted life-year gained, calculated from measures of hospitalisations, medication use, outpatient visits, and quality of life. Results: The LIPID trial showed a 22% relative reduction in all-cause mortality (P < 0.001). Over a mean follow-up of 6 years, hospital admissions for coronary heart disease and coronary revascularisation were reduced by about 20%. Over this period, pravastatin cost $A4913 per patient, but reduced total hospitalisation costs by $A1385 per patient and other long-term medication costs by $A360 per patient. In a subsample of patients, average quality of life was 0.98 (where 0 = dead and 1 = normal good health); the treatment groups were not significantly different. The absolute reduction in all-cause mortality was 3.0% (95% CI, 1.6%-4.4%), and the incremental cost was $3246 per patient, resulting in a cost per life saved of $107730 (95% Cl, $68626-$209881) within the study period. Extrapolating long-term survival from the placebo group, the undiscounted cost per life-year saved was $7695 (and $10 938 with costs and life-years discounted at an annual rate of 5%). Conclusions: Pravastatin therapy for patients with a history of myocardial infarction or unstable angina and average cholesterol levels reduces all-cause mortality and appears cost effective compared with accepted treatments in high-income countries.

BACKGROUND: The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that pravastatin therapy over 6 years reduced mortality and cardiovascular events in patients with previous acute coronary syndromes and average cholesterol concentrations. We assessed the longer-term effects of initial treatment with pravastatin on further cardiovascular events and mortality over a total follow-up period of 8 years. METHODS: In the main trial, 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol concentration of 4.0-7.0 mmol/L were randomly assigned pravastatin 40 mg daily or placebo and followed up for 6 years. Subsequently, all patients were offered open-label pravastatin for 2 more years. Major cardiovascular events and adverse events were compared according to initial treatment assignment. FINDINGS: 7680 (97% of those still alive) had 2 years of extended follow-up. 3766 (86%) of those assigned placebo and 3914 (88%) assigned pravastatin agreed to take open-label pravastatin. During this period, patients originally assigned pravastatin had almost identical cholesterol concentrations to those assigned placebo, but a lower risk of death from all causes (219 [5.6%] vs 255 [6.8%], p=0.029), coronary heart disease (CHD) death (108 [2.8%] vs 137 [3.6%], p=0.026), and CHD death or non-fatal myocardial infarction (176 [4.5%] vs 196 [5.2%], p=0.08). Over the total 8-year period, all-cause mortality was 888 (19.7%) in the group originally assigned placebo and 717 (15.9%) in the group originally assigned pravastatin, CHD mortality was 510 (11.3%) versus 395 (8.8%), myocardial infarction was 570 (12.7%) versus 435 (9.6%; each p < 0.0001), and stroke was 272 (6.0%) versus 224 (5.0%; p=0.015). Stronger evidence of separate treatment benefits than in the main trial was seen in important prespecified subgroups (women, patients aged > or = 70 years, and those with total cholesterol < 5.5 mmol/L). Pravastatin had no significant adverse effects. INTERPRETATION: The evidence of sustained treatment benefits and safety of long-term pravastatin treatment reinforces the importance of long-term cholesterol-lowering treatment for almost all patients with previous CHD events.

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. 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. Median follow-up was 31 months. Univariable analyses showed that OS was associated negatively with depression (HR 2.04, P

Adjuvant chemotherapy for early-stage breast cancer has been shown to delay recurrence and improve survival. However, the benefits are modest and must be balanced against the adverse treatment effects. We assessed the size of the survival benefit needed to justify the toxicity of chemotherapy, based on the preferences of women who had previously received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We also attempted to identify circumstances in which larger survival gains would be needed. In semistructured interviews, 104 women who had received adjuvant CMF chemotherapy were asked to rate the survival benefit that would justify 6 months of such treatment, using a series of hypothetical trade-offs between shorter survival without treatment and longer survival with treatment. Similar preferences were sought for a greater probability of 5-year survival. Most patients considered 6 months of adjuvant CMF chemotherapy worthwhile for relatively modest survival gains: 77% considered an increase of from 5 to 6 years worthwhile, 74% thought an increase of from 15 to 17 years worthwhile, and more than 70% considered such treatment justified for a 5% greater chance of living 5 or more years. Smaller survival benefits were needed for women who had experienced less toxicity (P =.01), had not received initial radiotherapy (P =.01), had better social support (P =.02), and had others at home dependent on their support (P =.0001). Modest survival benefits are sufficient to justify adjuvant cytotoxic chemotherapy for most women with early-stage breast cancer. Individual preferences are important when weighing trade-offs between survival and adverse treatment effects.

Summary Background Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours. Methods Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m 2 cisplatin on days 1–5, 100 mg/m 2 etoposide on days 1–5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m 2 cisplatin on day 1, 120 mg/m 2 etoposide on days 1–3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat. Findings 166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0·22 [95% CI 0·06–0·77], p=0·008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0·25 [0·07–0·88], p=0·03). Interpretation In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.

Methods for combining measurements on multiple dimensions of quality of life can reduce the dimensionality of the data and increase the precision of estimation. When the dimensions are weighted according to their importance to patients, the resulting estimate is clinically useful and provides a step towards a true utility estimate. We derive two such weighting methods using linear regression on a measure of overall quality of life and demonstrate their usefulness in the analysis of quality of life data from two clinical trials of cancer therapies. Procedures for transforming the quality of life measures into utility measures are demonstrated.

The Utility-based Quality of Life – Heart Questionnaire (UBQ-H) is a cardiovascular extension of the Health Measurement Questionnaire. It is a multidimensional instrument that can be scored to yield a utility estimate using the Rosser Index and a classification algorithm developed for the Health Measurement Questionnaire. The aim of this study was to employ a statistical modelling approach to devise an improved scoring system. A sample of 201 cardiovascular patients completed the UBQ-H and assessed the utility of their own health state using standard gamble and time trade-off questions in an interview. Two new scoring methods were devised by regressing the UBQ-H data against patients' self-assessed utilities. The new methods gave utility estimates that correlated with angina/dyspnoea grades, life satisfaction scores and General Health Questionnaire (GHQ) scores. In a second sample of 1,112 cardiovascular patients, the UBQ-H utilities were able to distinguish between patients who had/had not experienced an adverse event (e.g. myocardial infarction) and were responsive to changes in health over time. The new scoring methods were not particularly more sensitive to quality of life effects than the original method based on the Rosser Index. However, they produced significantly lower estimates and more accurately reflected patients' self-assessed utilities.

In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain.In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease.Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin.Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

The patterns of revoscularisation with percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery in the GUSTO I trial patients in Australia are described. In comparison with rates documented in earlier trials of thrombolytic therapy in Australia the rates of revascularisation post-thrombolysis increased by 50%, primary due to a doubling in the rate of use of PTCA. However, the rates were low by international comparisons. There were marked variations in the rates of revascularisation between States, but no correlation with differences in mortality between States. The main predictors of post thrombolysis PTCA were prior angina, mild infarction and access to PTCA facilities.

Objectives: To determine the extent to which publication is influenced by study outcome. Design: A cohort of studies submitted to a hospital ethics committee over 10 years were examined retrospectively by reviewing the protocols and by questionnaire. The primary method of analysis was Cox9s proportional hazards model. Setting: University hospital, Sydney, Australia. Studies: 748 eligible studies submitted to Royal Prince Alfred Hospital Ethics Committee between 1979 and 1988. Main outcome measures: Time to publication. Results: Response to the questionnaire was received for 520 (70%) of the eligible studies. Of the 218 studies analysed with tests of significance, those with positive results (P v 8.0 years). This finding was even stronger for the group of 130 clinical trials (hazard ratio 3.13 (1.76 to 5.58), P=0.0001), with median times to publication of 4.7 and 8.0 years respectively. These results were not materially changed after adjusting for other significant predictors of publication. Studies with indefinite conclusions (0.05 P Conclusions: This study confirms the evidence of publication bias found in other studies and identifies delay in publication as an additional important factor. The study results support the need for prospective registration of trials to avoid publication bias and also support restricting the selection of trials to those started before a common date in undertaking systematic reviews. Key messages This retrospective cohort study of clinical research projects confirms the findings of publication bias found in previous studies Delay in the publication of studies with negative results has been identified as an additional important factor in publication bias With the recognised importance of evidence based medicine, these results have important implications for the selection of studies included in systematic reviews Prospective registration of clinical research projects will avoid many of the problems associated with publication bias However, it is also important to restrict inclusion in systematic reviews to studies started before a certain date to allow for the delay in completing studies with negative results

PURPOSE To determine whether a strategy of adding medroxyprogesterone acetate (MPA) to tamoxifen (TAM) is superior to the substitution of MPA for TAM among women with advanced breast cancer and disease progressing on TAM. To assess the patterns or response and subsequent progression in sites and tissues according to prior involvement and treatment. PATIENTS AND METHODS Two-hundred-fifteen postmenopausal women with advanced breast cancer progressing on TAM after receiving TAM for at least six months were randomized: 109 to add MPA 500 mg/day orally (TAM + MPA), and 106 to stop TAM and to substitute MPA. RESULTS There were no significant differences between the groups with respect to complete plus partial response rates: TAM + MPA 10%, MPA 9%, median time to progression TAM + MPA 3.0 months, MPA 4.5 months, or median overall survival, TAM + MPA 17.2 months, MPA 18.4 months. In a multivariate model, prognostic factors significant for a shorter time to disease progression were worse for performance status, involvement of more than one tissue, prior radiotherapy, and shorter time from recurrence after primary therapy to randomization. Adjusting for these factors, treatment with TAM + MPA was associated with a higher relative risk for disease progression, with a hazards ratio of 1.31, but this was not significant (95% confidence interval, 0.98 to 1.74; P = .067). However, in an exploratory analysis, the time to disease progression, among patients with progesterone receptor positive (PR+) tumors, was 6.3 months with MPA versus 2.9 months with TAM + MPA, with a hazards ratio of 1.92 (95% confidence interval, 1.12 to 3.32; P = .02). There was a significant interaction, P = .04, between PR status and treatment, indicating an advantage to treatment substitution for those who have PR+ tumors. Tumor response occurred in 14% of assessed metastatic sites. Subsequent progression occurred in a new tissue alone in 13% of patients, in both new and previously involved (old) tissues in 76%, and in old tissues only in 11%. In 23% of patients, progression occurred only at a new site, in 50% at both old and new sites, and in 27% only at old sites. No significant differences in the patterns of response or progression were seen in the different treatment groups. CONCLUSION Among women with breast cancer whose disease is progressing after at least six months of treatment with TAM, there is no advantage to maintaining TAM when MPA is to be given. An overall effect of treatment on the pattern of failure at old sites or at new sites or tissues cannot be discerned.

Summary Purpose: To investigate the effect of two doses of megestrol acetate (MA) compared with placebo on quality of life (QoL) and nutritional status (NS) in patients with advanced endocrine-insensitive cancer. Patients and methods: Two hundred forty patients were randomised to double-blind MA 480 mg/day, MA 160 mg/ day, or matching placebo for 12 weeks. Nutritional status (including weight, skinfold thickness and midarm circumference) and QoL (using 6 linear analogue self-assessment (LASA) scales) were assessed at randomisation and after four, eight and 12 weeks. A QoL ranking incorporating QoL and death was also used ranging from 1 = dead to 5 = much better QoL. Results: One hundred seventy-four patients were assessable at week four, 136 at week eight and 103 patients at week 12. Patients receiving MA reported substantially better appetite (P = 0.001), mood (P = 0.001) and overall quality of life (P < 0.001), and possibly less nausea and vomiting (P = 0.08) than patients receiving placebo, based on a test for trend. A larger benefit was seen with the higher dose which (unlike the lower dose) was significantly better in pairwise comparisons with placebo for appetite, mood and overall QoL (each P ^ 0.001). Despite some missing data on QoL scores, QoL ranking was available on 227 (95%) of patients with significantly higher QoL ranking associated with MA (P = 0.002). Improvements in QoL occurred early within four weeks and were sustained. No statistically significant differences were observed in NS measurements, including weight (P = 0.29). Side effects of therapy were minor and did not differ significantly across treatments. Conclusion: Megestrol acetate given at 480 mg/day is useful palliation in patients with endocrine-insensitive advanced cancer. It improves appetite, mood and overall quality of life in these patients, although not through a direct effect on nutritional status.

Background: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy–refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. Methods: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment–biomarker interaction. Results: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status (‘co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P

Background Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. Patients and methods The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). Results The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65–0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). Conclusions This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.

Objective: To assess and compare quality of life of patients six months after an acute myocardial infarction treated with one of two thrombolytic agents, streptokinase (SK) or recombinant tissue plasminogen activator (tPA). Design: A cohort study of consecutive patients randomly allocated to thrombolytic therapy and treated in hospitals participating in the Australian arm of the International tPA/SK Mortality Trial (AUS-TASK). Patients and setting: 776 patients with acute myocardial infarction were asked to complete questionnaires at their follow-up clinic visit six months after the infarct. Main outcome measures: Two measures were used: (i) the York Health Measurement Questionnaire, which measures activities and distress and provides basic descriptors of quality of life; and (ii) a time trade-off question about the number of years a person would be willing to give up in exchange for returning to full health. Results: The quality of life of the 714 respondents (92%) was generally high, with a mean index of 0.98. The five main areas causing distress were: lack of energy; breathlessness; anxiety; difficulty sleeping; and pain. In the time trade-off question, the mean number of years respondents were willing to forgo, out of 15 years, was 0.87 years; while 76% did not think it worthwhile to forgo any time. The 8% of patients who declined to answer the questionnaire were in significantly poorer health (New York Heart Association classification, P=0.01; and Karnofsky index, P< 0.001). There were no significant differences in quality of life or time trade-off answers between patients allocated to streptokinase or tPA (P= 0.96 and 0.73, respectively). Conclusions: Quality of life six months after myocardial infarction is generally high, and most patients are able to return to normal activities. However, it is significantly impaired in a small group of patients, mainly those with a subsequent stroke or re-infarction. There was no significant difference in quality of life between those treated with tPA and those with streptokinase.

Group V interdiffusion of strained and unstrained InGaAsP/InGaAs(P) quantum wells induced by thermal anneals at 650 °C with phosphorus gas pressure using photoluminescence spectroscopy and x‐ray diffraction measurements have been investigated. The blueshift of the annealed quantum well photoluminescence peak exhibits large variations with the phosphorus pressure, with a minimum around 0.1 atm. Samples capped with a SiO2 layer only exhibit minor blueshifts, thus demonstrating the possibility of spatially selective control of the intermixing. A differential blueshift as large as 80 meV is presently obtained between capped and uncapped areas. The interdiffusion of the quantum well interfaces is shown to be dependent on the layer strain.

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n = 955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n = 340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.

AIMS/HYPOTHESIS: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. METHODS: Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. RESULTS: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min(-1) 1.73 m(-2) annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min(-1) 1.73 m(-2), p = 0.065) than on placebo (6.9 ml min(-1) 1.73 m(-2), p < 0.001), sparing 5.0 ml min(-1) 1.73 m(-2) (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥ 0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). CONCLUSIONS/INTERPRETATION: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. TRIAL REGISTRATION: ISRCTN64783481.

Treatment with high-dose cisplatin (HDC) previously required inpatient (IP) admission with overnight hospitalization, but recently practice has shifted to outpatient (OP) therapy. We aimed to determine whether it is preferable to give HDC as an IP or OP using a two-period cross-over trial.Eligible patients were starting chemotherapy with ≥2 cycles of HDC (≥100 mg/dose) and were suitable for OP treatment. All patients received an IP cycle and OP cycle: the order was randomly allocated. Pre-hydration, anti-emetics and chemotherapy were identical for IP and OP. Post-hydration varied by group (3 L normal saline (NS) for IP, 2 L NS for OP). The primary outcome was patient preference for IP versus OP treatment. Secondary outcomes included aspects of health-related quality of life, adverse events (dose delays and reductions, elevated creatinine and unplanned readmissions) and resource use.Fifty-nine patients were randomized, 53 completed two cycles of HDC. Most patients preferred OP treatment (36 vs 13, P = 0.002). There were no significant differences in patients' ratings of nausea, vomiting, fatigue, anxiety, depression or overall quality of life. Adverse events were few and unrelated to IP versus OP treatment. Nursing time was longer for IP than OP (163 vs 104 min, P0.001).OP treatment was preferred by most patients, appeared safe and used less resources.

A new mechanism, injection induced electrostatic confinement of the electron gas, is proposed to explain the origin of the laser effect in tensile strained GaInAs/GaInAsP quantum well lasers.

Quantum well structures and separate confinement heterostructure lasers based on strained quaternary Ga 1− x In x As 1− y P y well material were grown by gas source molecular beam epitaxy. The substitution of As for P allows a simultaneous control of wavelength, well width and strain in the structure. Single strained layers in InP show photoluminescence with narrow linewidth (4 to 8 meV). Broad area lasers with strained and unstrained layers have been grown with five quantum wells and identical optical confinement. The strained quaternary structure has a threshold current density of 760 A/cm 2 for L = 400 μm, an internal quantum efficiency of nearly 100%, a waveguide loss of 10 cm -1 and a high T 0 value ( T 0 = 91 K). Single-well structures have a lowest value of 240 A/cm 2 for 3 mm long devices.

Purpose Randomised controlled trials (RCTs) provide optimal evidence to assess the benefits of new treatments. However, clinicians routinely rely on cross-trial comparisons to assess competing treatments when head-to-head randomised comparisons are unavailable. We investigate the validity of cross-trial comparisons using individual patient data (IPD) where patients received the same treatment protocol. We also examine the extent to which statistical adjustment for baseline characteristics can account for inter-trial differences in outcomes. Patients and methods We used pooled IPD of 378 women with advanced breast cancer assigned to oral cyclophosphamide, intravenous methotrexate and 5-fluorouracil (CMF) in the control arms of three first-line treatment RCTs (ANZ8101, ANZ8614 and ANZ0001) conducted between 1982 and 2001. The Kaplan–Meier method was used to compare progression-free survival (PFS) and overall survival (OS) across trials. Proportional hazard models were constructed to estimate the hazard rates across trials after adjustment for baseline characteristics. Results The distribution of baseline characteristics varied across trials. There was a statistically significant difference in survival among women treated with CMF in these trials (logrank p = 0.009). The median OS were 17.7, 10.3 and 10.1 months for 0001, 8101 and 8614, respectively. The hazard ratios for survival, adjusted for baseline characteristics differences, were 1.44 (8614) and 1.45 (8101) compared to 0001 ( p = 0.03). PFS did not differ across trials (logrank p = 0.38). Conclusions Caution should be exercised when interpreting results from historical cross-trial comparisons even if the adjustment of baseline prognostic characteristics can be performed. Cross-trial comparisons have some role in hypothesis-generating, identifying and prioritising promising treatments for further investigation; however RCTs are still essential to guide sound clinical practice.

MBE grown quantum devices for the detection of infrared light are introduced. These structures are based on photon-assisted resonant tunnelling and will have a projected tuning range of 5 to 30 mu m. Two structures are discussed: a single quantum well device with large initial population for high adsorption, and a double quantum well structure with promise of sharper detection linewidth and wider tuning range. Optical and electrical measurements of material properties are presented, and their implications on the devices discussed.

People affected by cancer want information about their prognosis but clinicians have trouble estimating and talking about it. We sought to determine the nature and accuracy of medical oncologists' estimates of life expectancy in newly referred patients with incurable cancer. With reference to each patient, medical oncologists estimated how long they thought 90, 50, and 10% of similar patients would live. These proportions were chosen to reflect worst case, predicted, and best case scenarios suitable for discussions. After a median follow-up of 35 months, 86 of the 102 patients had died with an observed median survival of 12 months. Oncologists' estimates of each patient's worst case, predicted and best case scenarios were well-calibrated: 10% of patients lived for fewer months than estimated for the worst 10% of similar patients; 50% lived for at least as long as estimated for 50% of similar patients (predicted survival), and 17% lived for more months than estimated for the best 10% of similar patients. Oncologists' estimates of each patient's predicted survival were imprecise: 29% were within 0.67–1.33 times the patient's actual survival, 35% were too optimistic (>1.33 times the actual survival), and 39% were too pessimistic (

BACKGROUND: Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. METHODS: We did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481). FINDINGS: Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p