Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Real-world treatment patterns in resectable (stages I-III) non-small-cell lung cancer: a systematic literature review.

Aim: The aim of this systematic literature review was to describe treatment patterns in nonmetastatic non-small-cell lung cancer. Methods: A search was conducted in MEDLINE and EMBASE. Eligible studies were multicentered (>50 patients) and conducted after 2000 in North America, Europe and Asia. Results: Twenty studies met the eligibility criteria. Based on US and Canadian studies in the resectable population, the proportion of patients who received neoadjuvant chemotherapy/chemoradiotherapy and adjuvant chemotherapy/chemoradiotherapy increased with increasing stage (i.e., from <3% in stage I to about 40% in stage III and from 15% in stage I to 30% in stage III, respectively). Within the resectable population, the breakdown between bimodal and trimodal therapy was variable, suggesting that clinical practice is not uniform. Conclusion: Overall, studies were heterogeneous, precluding data extrapolation across regions. Despite heterogeneity and limited evidence, this review suggested an increase in neoadjuvant and adjuvant chemotherapy with increasing stage, generally in line with treatment guidelines.

This literature review aimed to describe the treatment patterns in nonmetastatic non-small-cell lung cancer. This review was performed according to the highest methodological standards and searched published and unpublished records of stages I­III non-small-cell lung cancer treatment in North America, Europe and Asia. A limited number of studies were identified showing that in North America treatment with neoadjuvant and adjuvant chemotherapy (with or without radiotherapy) increased with stage. Identified studies in all regions showed that the treatment received, such as bimodal with surgery and chemotherapy compared with trimodal with surgery, chemotherapy and radiotherapy, was quite variable and that practice was not uniform. Overall, the studies were heterogeneous and data could not be extrapolated to practice across all regions. However, the studies suggested an increase in neoadjuvant and adjuvant usage with increasing stage, which is generally in line with treatment guidelines.

Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one-step and two-step methods.

OBJECTIVE: To conduct a cost minimisation analysis of three methods of gestational diabetes mellitus (GDM) screening and diagnosis. DESIGN: Prospective randomised controlled trial. SETTING: University teaching hospital. POPULATION: Pregnant women (n = 1594) presenting for GDM screening. METHODS: Women presenting for GDM screening, who consented to participate, were randomised to GR1 [1-hour, 50-g glucose screen (GS) +/- 3-hour, 100-g oral glucose tolerance test (OGTT)], GR2 (50-g GS +/- 2-hour, 75-g OGTT) or GR3 (2-hour, 75-g OGTT). Demographics, health and time/travel cost information were assessed for each glucose testing visit. MAIN OUTCOME MEASURES: Costs (direct and indirect) and prevalence of GDM diagnosis. RESULTS: The direct sampling costs of the glucose tests per woman were as follows: GS, CAN$12.57; 75-g OGTT, $36.10; 100-g OGTT, CAN$48.13. Among women in the two-step method groups diagnosed with GDM, 39% of the GR1 and 61% of the GR2 groups were diagnosed at the first step by GS > or = 10.3 mmol/l, according to the Canadian Diabetes Association recommendations, contributing to a lower total cost in these groups. The total costs per woman screened were as follows: GR1, CAN$91.61; GR2, CAN$89.03; GR3, CAN$108.38. The GDM prevalence was similar (3.7%, 3.7% and 3.6%, respectively). The higher costs of GR3 were related to more blood draws and the time required for all women to undergo the 2-hour OGTT. CONCLUSIONS: Careful consideration should be given to an internationally recommended method of universal screening for GDM which minimises the burden and cost for individual women and the healthcare system, yet provides diagnostic efficacy. The two-step method (GS +/- OGTT) accomplished this better than the one-step method (75-g OGTT).

Cost-effectiveness of mandibular two-implant overdentures and conventional dentures in the edentulous elderly.

Implementation of new therapies is usually governed by financial considerations, so efficacy studies should also include cost comparisons. The cost and effectiveness of mandibular conventional dentures (CD, n = 30) and two-implant overdentures (IOD, n = 30) were compared in elderly subjects. Effectiveness (Oral Health Impact Profile, OHIP-20) and cost were measured up to one year post-treatment. Data for subsequent years were estimated by the Delphi method. Using an average life expectancy of 17.9 years, the equalized annual costs (in Canadian dollars) were dollar 399 for CD and dollar 625 for IOD (p < 0.001), and the equalized annual values for the outcome (OHIP-20) were 47.0 for CD and 31.3 for IOD treatment (p < 0.05). These values translate into a yearly additional cost for IOD treatment of dollar 14.41 per OHIP-20 point. These results are key to the implementation of programs to provide this form of therapy for edentulous adults.

The systemic lupus erythematosus tri-nation study: longitudinal changes in physical and mental well-being.

OBJECTIVE: We have shown that SLE patients in Canada and the UK incurred 20% and 13% lower health costs than those in the US, respectively, but did not experience worse outcomes as expressed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We now compare change in quality of life in these patients. PATIENTS AND METHODS: Seven hundred and fifteen SLE patients (Canada 231, US 269, UK 215) completed the SF-36 annually over four years. The annual change in the SF-36 Physical and Mental Component Summary (PCS and MCS) scores over the course of the study were summarized by estimating a linear trend for each individual patient using hierarchical modelling. Cross-country comparison of the slopes in the PCS and MCS scores was then performed using simultaneous regressions. RESULTS: The estimated mean annual changes (95% credible interval [CrI]) in the PCS scores in Canada, the US, and the UK were 0.18 (-0.07, 0.43), -0.05 (-0.27, 0.17), and 0.03 (-0.20, 0.27), respectively; the mean annual changes in the MCS scores were 0.15 (-0.04, 0.34), 0.23 (0.09, 0.37), and 0.08 (-0.10, 0.27), respectively. Regression results showed that the mean annual changes in PCS and MCS scores did not substantially differ across countries. CONCLUSION: Quality of life remained stable across countries. Despite Canadian and British patients incurring lower health costs, on average, patients experienced similar changes in physical and mental well-being.

Co-morbidity and physician use in fibromyalgia.

OBJECTIVE: To describe comorbidity in women with FM, and to examine the effects of different types of comorbidity on physician use. METHODS: Women (n = 180) with primary FM were evaluated at baseline and 6 months later for self-reported health resource use and covariates. Reported comorbidity was classified into 4 categories: medical, psychiatric, "functional", and unknown. The category for "functional" conditions included disorders that have been classified by previous authors as medically unexplained symptoms such as the irritable bowel and chronic fatigue syndromes. Logistic regression models were developed to examine associations between types of comorbidity and physician use. RESULTS: Comorbid conditions were reported by over 90% of the sample. Total number of comorbid complaints was associated with high number of physician visits. In logistic regression models (controlling for age, ethnicity, education, disability, pain, and psychological vulnerability) medical comorbidity was a much stronger determinant of high number of physician visits than was "functional" comorbidity. CONCLUSIONS: Comorbidity with other disorders, both functional and medical, was high in this sample. Medical and psychiatric comorbidity were stronger determinants of high physician use than "functional" comorbidity.

Measurement error in prenatal care utilization: evidence of attenuation bias in the estimation of impact on birth weight.

OBJECTIVE: Errors in the measurement of the timing and number of prenatal care visits may produce downward bias in estimates of the impact of prenatal care use on birth outcomes. This paper examines the extent of attenuation bias from measurement error in the estimation of the effect of prenatal care use on birth weight. METHODS: Data were analyzed from the 1980 National Natality Survey, a nationally representative sample of live births with information on prenatal care utilization from three sources: birth certificates, medical provider surveys, and maternal surveys. The extent of attenuation bias in estimates of the impact of different measures of prenatal care use on birth weight was examined by comparing estimates robust to measurement error (including instrumental variables) with ordinary least squares results. RESULTS: There is considerable disagreement in measures of prenatal care across the three data sources, with correlations in the utilization measures computed from different sources around 0.5. The results also show evidence of attenuation bias from measurement error in estimates of the impact of prenatal care on birth weight for both White and Black mothers. Attenuation bias was least severe for information from the birth certificate report of prenatal care. CONCLUSIONS: Because of measurement error, previous studies may have underestimated the effect of prenatal care utilization on birth weight. Corrected estimates, however, do not suggest that prenatal care is a major predictor of birth weight. In addition, part of what previous analyses have interpreted as adverse selection bias may in fact be attenuation bias due to measurement error.