Bruno Gagnon

Randomized, Double-Blind, Placebo-Controlled Trial of Erythropoietin in Non–Small-Cell Lung Cancer With Disease-Related Anemia

PURPOSE Previous trials have suggested a quality-of-life (QOL) improvement for anemic cancer patients treated with erythropoietin, but few used QOL as the primary outcome. We designed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung (NSCLC). PATIENTS AND METHODS A multicenter, randomized, double-blind, placebo-controlled trial was conducted. The proposed sample size was 300 patients. Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks. RESULTS Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm). This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 v 129 days; hazard ratio, 1.84; P = .04). The Steering Committee closed the trial. Patient numbers compromised the interpretation of the QOL analysis, but a positive Hgb response was noted with epoetin alfa treatment. CONCLUSION An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.

Pattern of Care at the End of Life: Does Age Make a Difference in What Happens to Women With Breast Cancer?

PURPOSE In the last 40 years, palliative care has become the standard of care at the end of life. However, there are limited data about the degree of access to such care at the population level. METHODS Using administrative databases, a care-oriented profile score was created to describe the care received during the last 6 months of life for 2,291 women who were dying of breast cancer in the province of Quebec, Canada, during the years 1992 to 1998. The care received was described through indicators of care that would reflect a palliative care philosophy. An ordinal score was developed for comparisons among age groups of women using a proportional odds ordinal regression model. RESULTS We found that only 6.9% of women died at home, while 69.6% of them died in acute care beds. While most women (75%) had few indicators indicating provision of palliative care during the last 6 months of life, younger women (< 50 years) were even less likely (odds ratio, 0.70; 95% CI, 0.54 to 0.90) to receive such care compared with middle aged women (50 to 59 years; serving as the reference group), while older women (> 70 years) were more likely (odds ratio, 1.85; 95% CI, 1.49 to 2.29). CONCLUSION Our study indicates that a sizeable proportion of women terminally ill from breast cancer do not have access to palliative care-an issue that health care policy makers may wish to explore further.

Flexible modeling improves assessment of prognostic value of C-reactive protein in advanced non-small cell lung cancer

Background:C-reactive protein (CRP) is gaining credibility as a prognostic factor in different cancers. Coxs proportional hazard (PH) model is usually used to assess prognostic factors. However, this model imposes a priori assumptions, which are rarely tested, that (1) the hazard ratio associated with each prognostic factor remains constant across the follow-up (PH assumption) and (2) the relationship between a continuous predictor and the logarithm of the mortality hazard is linear (linearity assumption).Methods:We tested these two assumptions of the Coxs PH model for CRP, using a flexible statistical model, while adjusting for other known prognostic factors, in a cohort of 269 patients newly diagnosed with non-small cell lung cancer (NSCLC).Results:In the Coxs PH model, high CRP increased the risk of death (HR=1.11 per each doubling of CRP value, 95% CI: 1.03–1.20, P=0.008). However, both the PH assumption (P=0.033) and the linearity assumption (P=0.015) were rejected for CRP, measured at the initiation of chemotherapy, which kept its prognostic value for approximately 18 months.Conclusion:Our analysis shows that flexible modeling provides new insights regarding the value of CRP as a prognostic factor in NSCLC and that Coxs PH model underestimates early risks associated with high CRP.

A prospective evaluation of an interdisciplinary nutrition-rehabilitation program for patients with advanced cancer

BACKGROUND Cancer can affect many dimensions of a patients life, and in turn, it should be targeted using a multimodal approach. We tested the extent to which an interdisciplinary nutrition-rehabilitation program can improve the well-being of patients with advanced cancer. METHODS Between January 10, 2007, and September 29, 2010, 188 patients with advanced cancer enrolled in the 10-12-week program. Body weight, physical function, symptom severity, fatigue dimensions, distress level, coping ability, and overall quality of life were assessed at the start and end of the program. RESULTS Of the enrolled patients, 70% completed the program. Patients experienced strong improvements in the physical and activity dimensions of fatigue (effect sizes: 0.8-1.1). They also experienced moderate reductions in the severity of weakness, depression, nervousness, shortness of breath, and distress (effect sizes: 0.5-0.7), and moderate improvements in Six Minute Walk Test distance, maximal gait speed, coping ability, and quality of life (effect sizes: 0.5-0.7) Furthermore, 77% of patients either maintained or increased their body weight. CONCLUSIONS Interdisciplinary nutrition-rehabilitation can be advantageous for patients with advanced cancer and should be considered an integrated part of standard palliative care.

Treating an Established Episode of Delirium in Palliative Care: Expert Opinion and Review of the Current Evidence Base With Recommendations for Future Development

CONTEXT Delirium is a highly prevalent complication in patients in palliative care settings, especially in the end-of-life context. OBJECTIVES To review the current evidence base for treating episodes of delirium in palliative care settings and propose a framework for future development. METHODS We combined multidisciplinary input from delirium researchers and other purposely selected stakeholders at an international delirium study planning meeting. This was supplemented by a literature search of multiple databases and relevant reference lists to identify studies regarding therapeutic interventions for delirium. RESULTS The context of delirium management in palliative care is highly variable. The standard management of a delirium episode includes the investigation of precipitating and aggravating factors followed by symptomatic treatment with drug therapy. However, the intensity of this management depends on illness trajectory and goals of care in addition to the local availability of both investigative modalities and therapeutic interventions. Pharmacologically, haloperidol remains the practice standard by consensus for symptomatic control. Dosing schedules are derived from expert opinion and various clinical practice guidelines as evidence-based data from palliative care settings are limited. The commonly used pharmacologic interventions for delirium in this population warrant evaluation in clinical trials to examine dosing and titration regimens, different routes of administration, and safety and efficacy compared with placebo. CONCLUSION Delirium treatment is multidimensional and includes the identification of precipitating and aggravating factors. For symptomatic management, haloperidol remains the practice standard. Further high-quality collaborative research investigating the appropriate treatment of this complex syndrome is needed.

Identification in Administrative Databases of Women Dying of Breast Cancer

PURPOSE Palliative care is an essential component of cancer care, and population-based research is needed to monitor its impact. Administrative databases are the cornerstone of health services research. Their limitation is that cause of death is not sufficient to readily classify decedents as terminally ill for the study of the health services they received at the end of life. The study purpose is to develop and test the validity of an algorithm allowing the classification of the decedents as dying of breast cancer (BC), using administrative data. METHODS Validation was carried out through a chart review of 119 BC decedents extracted from hospital-based databases. This algorithm was applied to 3,384 deceased women with BC representative of the whole population. The effect of the classification by the algorithm was illustrated by the shift in the distributions of age and place of death. RESULTS The validation showed a sensitivity of 95%, a specificity of 89%, a positive predictive value of 98%, and negative predictive value of 77% for the classification of women dying of BC. Of the 3,384 decedents, 2,293 were classified as dying of, and 1,091 as not dying of BC. Women dying of BC were younger, died less often at home (6.9% v 17.9%), and in chronic care institutions (4.1% v 14.8%), and more often in acute-care beds (69.9% v 57.1%). CONCLUSION This novel way to classify decedents is conceptually based and empirically validated through chart review and impact on distribution of age and place of death.

Independent contributors to overall quality of life in people with advanced cancer

Background:The definition of health for people with cancer is not focused solely on the physiology of illness and the length of life remaining, but is also concerned with improving the well-being and the quality of the life (QOL) remaining to be lived. This study aimed to identify the constructs most associated with QOL in people with advanced cancer.Methods:Two hundred three persons with recent diagnoses of different advanced cancers were evaluated with 65 variables representing individual and environmental factors, biological factors, symptoms, function, general health perceptions and overall QOL at diagnosis. Three independent stepwise multiple linear regressions identified the most important contributors to overall QOL. R2 ranking and effect sizes were estimated and averaged by construct.Results:The most important contributor of overall QOL for people recently diagnosed with advanced cancer was social support. It was followed by general health perceptions, energy, social function, psychological function and physical function.Conclusions:We used effect sizes to summarise multiple multivariate linear regressions for a more manageable and clinically interpretable picture. The findings emphasise the importance of incorporating the assessment and treatment of relevant symptoms, functions and social support in people recently diagnosed with advanced cancer as part of their clinical care.

Ranking hospitals according to acute myocardial infarction mortality: should transfers be included?

Objective:The objective of this population-based observational cohort study was to estimate the extent to which the inclusion/exclusion of transferred patients with acute myocardial infarction (AMI) impacts on hospital performance rankings. Subjects:The authors studied 91,633 adult patients admitted to 116 acute care hospitals in Quebec, Canada, with a primary diagnosis of AMI between 1992 and 1999. Main Outcome Measure:Hospital performance ranks, based on 30-day AMI mortality rates, were estimated with hierarchical models and compared using 3 different methods for handling transferred patients (exclude all transfers; include transfers and assign outcome to the referring hospital; include transfers and assign outcome to the receiving hospital). The explanatory variable of interest was the hospital to which the patients outcome was attributed. Results:Using the 3 methods, 4 hospitals were ranked “best performers” once, and 1 hospital ranked among the best in 2 of the 3 analyses performed. Nine hospitals were ranked “worst performers” at least once (4 of which ranked among the “worst” once only, 2 ranked among the “worst” twice, and 3 were consistently ranked “worst performers” in all analyses). There was significant variation in mortality rates among hospitals, and the difference in the rates between the highest and lowest ranking hospitals exceeded the clinically relevant benchmark of 1%. Conclusions:Performance evaluation studies that compare hospital mortality rates typically exclude transferred patients. However, methods used to deal with AMI patient transfers influenced hospital ranks when comparing 30-day mortality rates. Excluding transfers may lead to an inaccurate depiction of the quality of healthcare services in regionalized healthcare systems that call for the timely interhospital transfer of patients with AMI.

Effect of Oral Bisphosphonates for Osteoporosis on Development of Skeletal Metastases in Women With Breast Cancer: Results From a Pharmaco-Epidemiological Study

BACKGROUND Treatment with bisphosphonates in women with breast cancer and established bone metastasis delays further skeletal-related events. Evidence is emerging that bisphosphonates are beneficial for secondary prevention of bone metastasis. The study aimed to estimate the effect of oral bisphosphonates for treatment or prevention of osteoporosis on development of bone metastasis in a population of women with breast cancer. METHODS A historical cohort of 21664 women diagnosed with breast cancer was created from health administrative data in Quebec, Canada. The primary outcome was time to develop bone metastasis; exposure was bisphosphonate use prediagnosis, postdiagnosis, both, or neither and a cumulative index of drug exposure. The sample was stratified according to stage (0-II or III) at time of diagnosis. Cox proportional hazards tested the effect of bisphosphonate use on time to develop bone metastases. RESULTS Taking bisphosphonates postdiagnosis of breast cancer only or continuing bisphosphonates started prior to diagnosis after diagnosis was associated with a reduction in risk of bone metastasis from 45% to 28% in women with local disease at diagnosis. In women with regional disease, postdiagnosis bisphosphonate use, with or without prediagnosis use, reduced risk by almost 50%. A statistically significant dose-response trend was observed relating increased use to lower risk (slope = 0.94, 95% confidence interval = 0.90 to 0.99). Bisphosphonates were also associated with a decreased risk of all-cause mortality similar to that of the development of bone metastasis. CONCLUSION Low-dose oral bisphosphonates administered for prevention or treatment of postmenopausal osteoporosis were associated with lower risk of skeletal metastasis in patients with early- or more advanced-stage breast cancer.

Montreal prognostic score: estimating survival of patients with non-small cell lung cancer using clinical biomarkers.

Background:For evidence-based medical practice, well-defined risk scoring systems are essential to identify patients with a poor prognosis. The objective of this study was to develop a prognostic score, the Montreal prognostic score (MPS), to improve prognostication of patients with incurable non-small cell lung cancer (NSCLC) in everyday practice.Methods:A training cohort (TC) and a confirmatory cohort (CC) of newly diagnosed patients with NSCLC planning to receive chemotherapy were used to develop the MPS. Stage and clinically available biomarkers were entered into a Cox model and risk weights were estimated. C-statistics were used to test the accuracy.Results:The TC consisted of 258 patients and the CC consisted of 433 patients. Montreal prognostic score classified patients into three distinct groups with median survivals of 2.5 months (95% confidence interval (CI): 1.8, 4.2), 8.2 months (95% CI: 7.0, 9.4) and 18.2 months (95% CI: 14.0, 27.5), respectively (log-rank, P<0.001). Overall, the C-statistics were 0.691 (95% CI: 0.685, 0.697) for the TC and 0.665 (95% CI: 0.661, 0.670) for the CC.Conclusion:The MPS, by classifying patients into three well-defined prognostic groups, provides valuable information, which physicians could use to better inform their patients about treatment options, especially the best timing to involve palliative care teams.