Palbociclib in hormone receptor positive advanced breast cancer: A cost-utility analysis.

INTRODUCTION: The addition of palbociclib to letrozole improves progression-free survival in the first-line treatment of hormone receptor positive advanced breast cancer (ABC). This study assesses the cost-utility of palbociclib from the Canadian healthcare payer perspective. METHODS: A probabilistic discrete event simulation (DES) model was developed and parameterised with data from the PALOMA 1 and 2 trials and other sources. The incremental cost per quality-adjusted life-month (QALM) gained for palbociclib was calculated. A time horizon of 15 years was used in the base case with costs and effectiveness discounted at 5% annually. Time-to- progression and time-to-death were derived from a Weibull and exponential distribution. Expected costs were based on Ontario fees and other sources. Probabilistic sensitivity analyses were conducted to account for parameter uncertainty. RESULTS: Compared to letrozole, the addition of palbociclib provided an additional 14.7 QALM at an incremental cost of $161,508. The resulting incremental cost-effectiveness ratio was $10,999/QALM gained. Assuming a willingness-to-pay (WTP) of $4167/QALM, the probability of palbociclib to be cost-effective was 0%. Cost-effectiveness acceptability curves derived from a probabilistic sensitivity analysis showed that at a WTP of $11,000/QALM gained, the probability of palbociclib to be cost-effective was 50%. CONCLUSION: The addition of palbociclib to letrozole is unlikely to be cost-effective for the treatment of ABC from a Canadian healthcare perspective with its current price. While ABC patients derive a meaningful clinical benefit from palbociclib, considerations should be given to increase the WTP threshold and reduce the drug pricing, to render this strategy more affordable.

Course of preeclamptic glomerular injury after delivery.

We evaluated the early postpartum recovery of glomerular function over 4 wk in 57 women with preeclampsia. We used physiological techniques to measure glomerular filtration rate (GFR), renal plasma flow, and oncotic pressure (pi(A)) and computed a value for the two-kidney ultrafiltration coefficient (K(f)). Compared with healthy, postpartum controls, GFR was depressed by 40% on postpartum day 1, but by only 19% and 8% in the second and fourth postpartum weeks, respectively. Hypofiltration was attributable solely to depression, at corresponding postpartum times, of K(f) by 55%, 30%, and 18%, respectively. Improvement in glomerular filtration capacity was accompanied by recovery of hypertension to near-normal levels and significant improvement in albuminuria. We conclude that the functional manifestations of the glomerular endothelial injury of preeclampsia largely resolve within the first postpartum month.

Long-term blood pressure control in a cohort of peritoneal dialysis patients and its association with residual renal function.

BACKGROUND: Hypertension is the prime contributor for cardiovascular mortality in the dialysis population. Peritoneal dialysis (PD) has been thought to improve blood pressure (BP) control in the short term, but the long-term benefits are not conclusively proven. We aimed to evaluate the degree of BP control in PD patients in the long term and analyse the factors associated with poor control. METHODS: Data of all patients who were initiated on PD at one centre between July 1994 and July 1998 and completed at least 1 year of PD were analysed retrospectively at initiation of PD, at 6 months, and annually thereafter until 5 years or until discontinuation of therapy. Hypertension was defined as per WHO/ISH criteria. A 'Blood Pressure Control Index' was empirically defined to account for the effect of antihypertensives on measured BP. Factors associated with poor BP control were analysed. RESULTS: Out of 207 patients (age 57.0+/-16.0 years, 103 male, 104 female) 91.3% were hypertensive at the start of PD. About 33.8% had diabetic nephropathy. Systolic and mean arterial pressure index improved in early phase reaching a nadir between 6 months and 1 year followed by steady progressive worsening through out the rest of follow up. On multiple linear regression analysis age (P<0.001), duration of hypertension prior to dialysis (P<0.001), and declining residual renal function, expressed as both average of urea and creatinine clearance (P=0.002) and residual urine output (P<0.001) were independently associated with poor BP control. Diabetes (P=0.836), peritoneal transport (D/P 4 of creatinine at start) (P=0.218), peripheral oedema (P=0.479) and dose of erythropoetin (P=0.488) were not associated. CONCLUSIONS: Initiation of PD results in early improvement of hypertension in end-stage renal disease (ESRD). BP control thereafter deteriorates steadily with time and this is associated with age, duration of hypertension, and declining residual renal function. This suggests that hypertension in ESRD patients is a progressive disease primarily related to falling glomerular filtration rate, the preservation of which might improve BP control and possibly modify cardiovascular risk.

A comparison of four treatment strategies for ductal carcinoma in situ using decision analysis.

BACKGROUND: The goals of the current study were to compare four treatment approaches in the management of ductal carcinoma in situ (DCIS), to determine the conditions where mastectomy may be preferred to breast-conserving therapy (BCT), and to determine conditions where the addition of tamoxifen produces better results than BCT alone. METHODS: A decision analysis model was used to compare four treatment approaches after local excision for DCIS: mastectomy, irradiation, irradiation plus adjuvant tamoxifen, or observation. The model weighed the potential benefits of each treatment approach (reduction of ipsilateral and/or contralateral breast carcinoma) against the potential risks of treatment-related toxicities. In addition, the model adjusted for the potential detrimental impact of local recurrence or treatment-related toxicity on health-related quality of life (HRQOL). Base-case estimates were obtained from published randomized trial data. One-way and two-way sensitivity analyses were performed. RESULTS: According to the model, the optimal treatment for DCIS was strongly dependent on the individual's risk of local recurrence and the patient's attitudes toward mastectomy. Mastectomy was preferred in patients whose estimated 10-year risk of local recurrence was > 15%, provided that mastectomy resulted in a very low reduction in quality of life (i.e., utility estimate > 0.97). Conditions where the addition of tamoxifen was preferred to breast-conserving therapy alone included the following: estimated 10-year risk of local recurrence > 38%, estimated 10-year risk of developing a contralateral breast carcinoma > 6%, or a significant decrement in HRQOL associated with the development of an invasive local recurrence or salvage mastectomy (utility estimates < 0.85). CONCLUSION: Based on this quality-adjusted model, BCT appeared to be the preferred treatment for DCIS. The most important determinants of optimal management for DCIS included the risk of local recurrence and the utility of mastectomy. Formal evaluation of utilities in the context of DCIS and more accurate determination of the risk of recurrence are required.

Application of probabilistic neural network analysis to a disease with complex inheritance: the GAW11 simulated data.

A probabilistic neural network analysis was applied to the simulated GAW11 data. Six replicates drawn at random from one of the simulated populations were used to generate training and test vectors for pairs of siblings. The vectors incorporated two environmental indicators as well as identical-by-descent allele sharing scores from each of 300 genetic markers. The performance of a 'naïve' probabilistic neural network (PNN) was fair. However, by combining a traditional linkage analysis with a PNN which incorporated gene x environment interaction, the performance was considerably enhanced.

Genetic anticipation and breast cancer: a prospective follow-up study.

Genetic anticipation is characterized by an earlier age of disease onset, increased severity, and a greater proportion of affected individuals in succeeding generations. The discovery of trinucleotide repeat expansion (TRE) mutations as the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders has led to a resurgence of interest in this phenomenon. Because of the difficulties presented to traditional genetics by complex diseases, the testing for genetic anticipation coupled with TRE detection has been proposed as a strategy for expediting the identification of susceptibility genes for complex disorders. In the case of breast cancer, a number of previous studies found evidence consistent with genetic anticipation. It is known that a proportion of such families are linked to either BRCA1 or BRCA2, but no TRE mutations have been identified. It has been shown that the typical ascertainment employed in studies purporting to demonstrate genetic anticipation combined with unadjusted statistical analysis can dramatically elevate the type I error. We re-examine the evidence for anticipation in breast cancer by applying a new statistical approach that appears to have validity in the analysis of anticipation to data ascertained from a recent follow-up of a large prospective cohort family study of breast cancer. Using this approach, we find no statistically significant evidence for genetic anticipation in familial breast cancer. We discuss the limitations of our analysis, including the problem of adequate sample size for this new statistical test.

The analysis of parental origin of alleles may detect susceptibility loci for complex disorders.

The phenomenon of genomic imprinting describes the differential behavior of genes depending on their parental origin, and has been demonstrated in a few rare genetic disorders. In complex diseases, parent-of-origin effects have not been systematically studied, although there may be heuristic value in such an approach. Data from a genome scan performed using 356 affected sibling pair families with type 1 diabetes were examined looking for evidence of excess sharing of either maternal or paternal alleles. At the insulin gene (IDDM2), evidence for excess sharing of alleles transmitted from mothers was detected, which is consistent with transmission disequilibrium results published elsewhere. We also identified additional loci that demonstrate allele sharing predominantly from one parent: IDDM8 shows a paternal origin effect, IDDM10 shows a maternal effect, and a locus on chromosome 16q demonstrates a paternal effect. We have also evaluated these loci for confounding by differences in sex-specific meiotic recombination by performing linkage analysis using sex-specific genetic maps. The analysis of the parental origin of shared alleles from genome scans of complex disorders may provide additional evidence for linkage for known loci, help identify regions containing additional susceptibility loci, and assist the cloning of the genes involved.