KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: A systematic literature review and meta-analysis.

KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation detected in patients with non-small cell lung cancer (NSCLC). However, the role of KRAS as either a prognostic factor or predictive factor (modifier of treatment effects) in NSCLC is not well established at this time. This systematic literature review (SLR) and meta-analysis synthesized the available evidence regarding the role of KRAS mutation as a predictive factor and/or prognostic factor of survival and response outcomes in patients with advanced/metastatic (stage IIIB-IV) NSCLC. Relevant clinical trials and observational studies were identified by searching MEDLINE, Embase and Cochrane Register of Controlled Trials. Meta-analyses were performed using data extracted from multivariable and univariable analyses from clinical studies to assess the empirical evidence of KRAS mutation status as a prognostic or/and predicitive factor. 43 selected studies were identified by the SLR and included in this meta-analysis. Pairwise meta-analyses of hazard ratios (HRs) reported in randomized controlled trials (RCTs) did not demonstrate a significant prognostic effect of mutant KRAS on overall survival (OS) (HR=1.10; 95% CI [0.88, 1.38]) or progression free survival (PFS) (HR=1.03; 95% CI [0.80, 1.33]). However, when conducting meta-analyses on HRs reported in observational studies, a statistically significant negative prognostic effect of mutant KRAS was observed (OS HR=1.71; 95% CI [1.07, 2.84]; PFS HR=1.18; 95% CI [1.02, 1.36]). Meta-analyses of objective response rate (ORR) in RCTs demonstrated a negative prognostic effect of mutant KRAS (RR=0.38; 95% CI [0.16, 0.63]). Limited data were available to evaluate the role of KRAS mutation as a predictive factor. In conclusion, this research offers evidence that KRAS mutation may be a negative prognostic factor for survival and response outcomes in patients with advanced/metastatic NSCLC, but further research is needed to address conflicting results on the importance of KRAS mutations as a predictive factor.

A cost-effectiveness analysis of first-line induction and maintenance treatment sequences in patients with advanced nonsquamous non-small-cell lung cancer in France.

BACKGROUND: Comparative effectiveness and cost-effectiveness data for induction-maintenance (I-M) sequences for the treatment of patients with nonsquamous non-small-cell lung cancer (nsqNSCLC) are limited because of a lack of direct evidence. This analysis aimed to compare the cost-effectiveness of I-M pemetrexed with those of other I-M regimens used for the treatment of patients with advanced nsqNSCLC in the French health-care setting. MATERIALS AND METHODS: A previously developed global partitioned survival model was adapted to the France-only setting by restricting treatment sequences to include 12 I-M regimens most relevant to France, and incorporating French costs and resource-use data. Following a systematic literature review, network meta-analyses were performed to obtain hazard ratios for progression-free survival (PFS) and overall survival (OS) relative to gemcitabine + cisplatin (induction sequences) or best supportive care (BSC) (maintenance sequences). Modeled health-care benefits were expressed as life-years (LYs) and quality-adjusted LYs (QALYs) (estimated using French EuroQol five-dimension questionnaire tariffs). The study was conducted from the payer perspective (National Health Insurance). Cost- and benefit-model inputs were discounted at an annual rate of 4%. RESULTS: Base-case results showed pemetrexed + cisplatin induction followed by (→) pemetrexed maintenance had the longest mean OS and PFS and highest LYs and QALYs. Costs ranged from €12,762 for paclitaxel + carboplatin → BSC to €35,617 for pemetrexed + cisplatin → pemetrexed (2015 values). Gemcitabine + cisplatin → BSC, pemetrexed + cisplatin → BSC, and pemetrexed + cisplatin → pemetrexed were associated with fully incremental cost-effectiveness ratios (ICERs) of €16,593, €80,656, and €102,179, respectively, per QALY gained versus paclitaxel + carboplatin → BSC. All other treatment sequences were either dominated (ie, another sequence had lower costs and better/equivalent outcomes) or extendedly dominated (ie, the comparator had a higher ICER than a more effective comparator) in the model. Sensitivity analyses showed the model to be relatively insensitive to plausible changes in the main assumptions, with none increasing or decreasing the ICER by more than ~€20,000 per QALY gained. CONCLUSION: In the absence of direct comparative trial evidence, this cost-effectiveness analysis indicated that of a large number of I-M sequences used for the treatment of patients with nsqNSCLC in France, pemetrexed + cisplatin → pemetrexed achieved the best clinical outcomes (0.28 incremental QALYs gained) versus paclitaxel + carboplatin → BSC.

Bayesian Model Assessment in Joint Modeling of Longitudinal and Survival Data with Applications to Cancer Clinical Trials.

Joint models for longitudinal and survival data are routinely used in clinical trials or other studies to assess a treatment effect while accounting for longitudinal measures such as patient-reported outcomes (PROs). In the Bayesian framework, the deviance information criterion (DIC) and the logarithm of the pseudo marginal likelihood (LPML) are two well-known Bayesian criteria for comparing joint models. However, these criteria do not provide separate assessments of each component of the joint model. In this paper, we develop a novel decomposition of DIC and LPML to assess the fit of the longitudinal and survival components of the joint model, separately. Based on this decomposition, we then propose new Bayesian model assessment criteria, namely, ΔDIC and ΔLPML, to determine the importance and contribution of the longitudinal (survival) data to the model fit of the survival (longitudinal) data. Moreover, we develop an efficient Monte Carlo method for computing the Conditional Predictive Ordinate (CPO) statistics in the joint modeling setting. A simulation study is conducted to examine the empirical performance of the proposed criteria and the proposed methodology is further applied to a case study in mesothelioma.

JMFit: A SAS Macro for Joint Models of Longitudinal and Survival Data.

Joint models for longitudinal and survival data now have a long history of being used in clinical trials or other studies in which the goal is to assess a treatment effect while accounting for a longitudinal biomarker such as patient-reported outcomes or immune responses. Although software has been developed for fitting the joint model, no software packages are currently available for simultaneously fitting the joint model and assessing the fit of the longitudinal component and the survival component of the model separately as well as the contribution of the longitudinal data to the fit of the survival model. To fulfill this need, we develop a SAS macro, called JMFit. JMFit implements a variety of popular joint models and provides several model assessment measures including the decomposition of AIC and BIC as well as ΔAIC and ΔBIC recently developed in Zhang et al. (2014). Examples with real and simulated data are provided to illustrate the use of JMFit.

First-Line Pemetrexed Plus Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in East Asian Never-Smoker Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-cell Lung Cancer: Quality of Life Results From a Randomized Phase III Trial.

BACKGROUND: The efficacy results from an open-label, randomized, multicenter study found no significant difference in progression-free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and unknown epidermal growth factor receptor (EGFR) mutation status (hazard ratio favored PC/G). The present report describes the quality of life (QoL) results from that trial. PATIENTS AND METHODS: Chemotherapy-naive, East Asian, light ex-smokers or never-smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status (n = 236) were randomly assigned (1:1) to PC/G or G. EGFR mutation status was subsequently determined for 74 patients. The symptoms and QoL were assessed using the Lung Cancer Symptom Scale (LCSS). The time to worsening of symptoms (TWS) was analyzed using the Kaplan-Meier method. RESULTS: In the overall population, the TWS was generally longer in the G group (n = 109) than in the PC/G group (n = 109) for the LCSS symptoms classified as treatment-related (loss of appetite, fatigue) and tumor-related (cough, dyspnea, hemoptysis, pain). In the subgroup of patients with wild-type EGFR, the TWS was generally longer in the PC/G group (n = 13) than in the G group (n = 8) for the tumor-related LCSS symptoms. CONCLUSION: In this study population clinically selected to respond to gefitinib, the LCSS scores were more favorable in the G group than in the PC/G group. Patients with wild-type EGFR tended to show greater improvement in tumor-related LCSS symptoms with chemotherapy than with gefitinib alone. These LCSS outcomes provide further evidence that patients with wild-type EGFR might not benefit from first-line treatment of advanced NSCLC with gefitinib.

Cost-effectiveness of first-line induction and maintenance treatment sequences in non-squamous non-small cell lung cancer (NSCLC) in the U.S.

OBJECTIVES: Due to the lack of direct head-to-head trials, there are limited data regarding the comparative effectiveness of induction-maintenance sequences. The objective of this study was to develop a cost-effectiveness model to compare induction-maintenance sequences in the US for the treatment of advanced non-squamous NSCLC. MATERIALS AND METHODS: Decision analytic modelling was used to synthesize the treatment effect and baseline risk estimates for nine induction and maintenance treatment sequences, reflecting treatments used in the US. The model was structured using an area-under-the-curve approach and sensitivity analyses were conducted. Model validation was conducted by an independent third party. RESULTS: All active maintenance therapy-containing regimens, with the exception of gemcitabine+cisplatin (first-line)→erlotinib (maintenance), were more costly than induction-only regimens. Concerning treatments that may be cost effective, the incremental costs per life-year gained were $121,425, $148,994, and $191,270 for gemcitabine+cisplatin→erlotinib versus gemcitabine+cisplatin→best supportive care (BSC), pemetrexed+cisplatin→BSC versus gemcitabine+cisplatin→erlotinib, and for pemetrexed+cisplatin→pemetrexed versus pemetrexed+cisplatin→BSC, respectively. All other regimens were found to be dominated (carboplatin+paclitaxel→BSC; carboplatin+paclitaxel→erlotinib; carboplatin+paclitaxel→pemetrexed; bevacizumab+carboplatin+paclitaxel→bevacizumab) or extendedly dominated (cisplatin+gemcitabine→pemetrexed). Sensitivity analyses demonstrated stability. CONCLUSIONS: Depending on the specific cost-effectiveness threshold used by a decision maker, the most cost-effective treatment sequence may include the referent comparator gemcitabine+cisplatin and the studied regimens of gemcitabine+cisplatin→erlotinib, pemetrexed+cisplatin→BSC, or pemetrexed+cisplatin→pemetrexed.

Can bundled payment improve quality and efficiency of care for patients with hip fractures?

The current Medicare reimbursement for hip fractures lacks accountability and promotes cost cutting. A bundled payment system-analogous to the Medicare Acute Care Episodes Demonstration for Orthopedic and Cardiovascular Surgery-may help curtail costs, foster communication among health care providers, and improve their accountability for patient outcomes. In hip fracture care, bundled payment may spur development of multidisciplinary best practice guidelines, quality assessment, and reporting, and result in benchmarking and best practices sharing. However, its implementation may face challenges: the need for quality assessment criteria and risk adjustment methods and possible risks of pushing costs outside of Medicare boundaries.

Joint modeling of survival and longitudinal non-survival data: current methods and issues. Report of the DIA Bayesian joint modeling working group.

Explicitly modeling underlying relationships between a survival endpoint and processes that generate longitudinal measured or reported outcomes potentially could improve the efficiency of clinical trials and provide greater insight into the various dimensions of the clinical effect of interventions included in the trials. Various strategies have been proposed for using longitudinal findings to elucidate intervention effects on clinical outcomes such as survival. The application of specifically Bayesian approaches for constructing models that address longitudinal and survival outcomes explicitly has been recently addressed in the literature. We review currently available methods for carrying out joint analyses, including issues of implementation and interpretation, identify software tools that can be used to carry out the necessary calculations, and review applications of the methodology.

Assessing model fit in joint models of longitudinal and survival data with applications to cancer clinical trials.

Joint models for longitudinal and survival data now have a long history of being used in clinical trials or other studies in which the goal is to assess a treatment effect while accounting for longitudinal assessments such as patient-reported outcomes or tumor response. Compared to using survival data alone, the joint modeling of survival and longitudinal data allows for estimation of direct and indirect treatment effects, thereby resulting in improved efficacy assessment. Although global fit indices such as AIC or BIC can be used to rank joint models, these measures do not provide separate assessments of each component of the joint model. In this paper, we develop a novel decomposition of AIC and BIC (i.e., AIC = AICLong + AICSurv|Long and BIC = BICLong + BICSurv|Long) that allows us to assess the fit of each component of the joint model and in particular to assess the fit of the longitudinal component of the model and the survival component separately. Based on this decomposition, we then propose ΔAICSurv and ΔBICSurv to determine the importance and contribution of the longitudinal data to the model fit of the survival data. Moreover, this decomposition, along with ΔAICSurv and ΔBICSurv, is also quite useful in comparing, for example, trajectory-based joint models and shared parameter joint models and deciding which type of model best fits the survival data. We examine a detailed case study in mesothelioma to apply our proposed methodology along with an extensive set of simulation studies.

Direct medical costs for complications among children and adults with diabetes in the US commercial payer setting.

BACKGROUND: Complications associated with diabetes are a major contributor to the burden of the disease. To better inform decision modelling, there is a need for cost estimates of specific diabetes-related complications, stratified by diabetes type and patient age group. OBJECTIVE: To obtain direct medical costs of managing and treating diabetes-related complications over a 2-year period, for adults and children with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM), using data from a large commercially insured US subscriber database. METHODS: We examined records from a large US multi-payer claims database to identify patients with any diabetes-related complications included in nine pre-specified categories, filed between January 2009 and September 2010, and with pre-index evidence of T1DM or T2DM. Patients were required to have continuous health plan enrolment 12 months before and 24 months after each index complication. Patients were classified into cohorts based on their diabetes type and age status at the time of the complication. The direct medical cost associated with each complication was calculated for the 12- and 24-month follow-up periods. Mean paid and allowed total costs were calculated and inflation-adjusted to the year 2011. RESULTS: Of the 119,715 patients who met the inclusion criteria, 211 (0.2 %) were categorized as children with T1DM, 55 (0.05 %) as children with T2DM, 6,227 (5.2 %) as adults with T1DM and 113,222 (94.6 %) as adults with T2DM. The respective mean cohort ages were 13.5, 14.9, 48.5 and 58 years. Proteinuria/albuminuria was the most common complication for T1DM and T2DM child cohorts, with this complication occurring in almost one third of these children. Among the child cohorts, renal disease accounted for the highest mean paid cost for T1DM patients (US$6,053) whereas for T2DM patients, the complication associated with the highest mean paid cost was lactic acidosis (US$25,053). For the adult T1DM cohort, the complications with the highest occurrence and highest mean total paid cost were non-proliferative retinopathy (40.3 %) and renal disease (US$28,076), respectively. Similarly, for the adult T2DM cohort, these complications were neuropathy (26.8 %) and peritoneal dialysis (US$32,826). CONCLUSION: With the continuing and increasing interest in child and adult T1DM and T2DM, stakeholders will need relevant and timely information to guide treatment decision making. This cost research may directly inform the economic models that are often developed to better identify, understand and manage key economic considerations that drive the costs of this chronic disease.

Joint modeling of longitudinal outcomes and survival using latent growth modeling approach in a mesothelioma trial.

Joint modeling of longitudinal and survival data can provide more efficient and less biased estimates of treatment effects through accounting for the associations between these two data types. Sponsors of oncology clinical trials routinely and increasingly include patient-reported outcome (PRO) instruments to evaluate the effect of treatment on symptoms, functioning, and quality of life. Known publications of these trials typically do not include jointly modeled analyses and results. We formulated several joint models based on a latent growth model for longitudinal PRO data and a Cox proportional hazards model for survival data. The longitudinal and survival components were linked through either a latent growth trajectory or shared random effects. We applied these models to data from a randomized phase III oncology clinical trial in mesothelioma. We compared the results derived under different model specifications and showed that the use of joint modeling may result in improved estimates of the overall treatment effect.

Joint modeling of multiple longitudinal patient-reported outcomes and survival.

Researchers often include patient-reported outcomes (PROs) in Phase III clinical trials to demonstrate the value of treatment from the patient's perspective. These data are collected as longitudinal repeated measures and are often censored by occurrence of a clinical event that defines a survival time. Hierarchical Bayesian models having latent individual-level trajectories provide a flexible approach to modeling such multiple outcome types simultaneously. We consider the case of many zeros in the longitudinal data motivating a mixture model, and demonstrate several approaches to modeling multiple longitudinal PROs with survival in a cancer clinical trial. These joint models may enhance Phase III analyses and better inform health care decision makers.

Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma.

This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related.

The economic burden of metastatic breast cancer: a systematic review of literature from developed countries.

OBJECTIVE: Breast cancer, the most common malignant cancer among women in Western countries, has poor prognosis following metastasis. New therapies potentially extend survival, but their value is questioned when benefits are incremental and expensive. The objective of our study was to understand the economic impact of metastatic breast cancer (MBC) and its treatment, and to evaluate the designs of these studies. METHODS: We systematically reviewed the MEDLINE-indexed, English-language literature, identifying 31 articles on the economic evaluation of MBC in 10 developed countries, including studies of per-patient costs, gross national costs, and cost-effectiveness models. We also included health technology assessments (HTAs) from government and regulatory agencies. RESULTS: Total per-patient costs of MBC are only available for Sweden ($17,301-$48,169 annually, depending on patient age (2005 USD)). Most economic analyses of per-patient direct costs originate from the US; across all countries, data indicate that this burden is substantial. Gross national costs of MBC are available only for the UK (cost of incident MBC cases is estimated to be $22 million annually (2002 GBP)). Many cost-effectiveness analyses suggest that a number of new and established treatments are cost-effective compared to standard care in various countries, but many offer small increments in survival. The cost-effectiveness of trastuzumab, capecitabine, and nab-paclitaxel has been evaluated in many recent studies. CONCLUSION: Most economic evaluations of MBC have utilized secondary rather than primary data, and have used scenarios and assumptions which may be inaccurate or outdated. The quality of evidence disseminated to decision-makers could be improved by adherence to best practices in cost-effectiveness analyses.

Economic burden of follicular non-Hodgkin's lymphoma.

Follicular non-Hodgkin's lymphoma (FNHL), a slow-growing cancer of the immune system, constitutes about 15-30% of all incident non-Hodgkin's lymphoma in developed countries. Its incidence is rising worldwide. Patients can live many years, but FNHL is considered incurable. We systematically reviewed the English-language MEDLINE-indexed and non-indexed economic literature published in the past 10 years on FNHL, identifying 23 primary economic studies. The economic burden of FNHL is significant, but available data are generally limited to retrospective considerations of hospital-based direct treatment costs, with little information available regarding societal cost of illness. Most direct cost information originates from the US, with one estimate of $US36 000 for the per-patient incremental cost of FNHL care during the first year following diagnosis. The most studied treatment is rituximab, which may offer similar overall costs to fludarabine considering higher resource use with fludarabine complications. Nearly all cost-effectiveness models identified by this review evaluated rituximab for relapsed/refractory FNHL responding to chemotherapy induction. Rituximab is supported as a cost-effective addition to standard chemotherapy by two models in the UK and one in the US, as maintenance therapy instead of stem-cell transplant by one UK model, and as maintenance therapy instead of observation alone by one model each in France, Spain and Canada. The UK National Institute for Health and Clinical Excellence updated guidance on rituximab in February 2008, concluding that it is cost effective when added to induction chemotherapy, and when used as maintenance therapy. No studies of per-patient or national indirect costs of illness were identified, with the only study of indirect costs a Canadian survey documenting lost work productivity. Across all study types identified by our review, the most common focus was on the direct costs of rituximab. As new treatments for FNHL come to market, more real-life cost data are imperative to calculate their relative cost effectiveness.

Validity of 24-h recall ratings of pain severity: biasing effects of "Peak" and "End" pain.

Despite the frequent use of pain recall ratings in clinical research, there remains doubt about the ability of individuals to accurately recall their pain. In particular, previous research indicates the possibility that the most pain experienced during a recall period and the most recent pain experienced (known as peak and end effects, respectively) might bias recall ratings. The current study used data from a published clinical trial to determine the relative validity of a 24-h recall rating of average post-operative pain and the nature and extent of any biasing influence of peak and end effects on nine separate 24-h recall ratings. The results supported a statistically significant but small biasing influence of both peak and end pain. Also, the influence of peak pain was stronger than that of end pain. However, the biasing impact of both peak and end pain together was very small, suggesting that 24-h recall ratings are adequately valid indicants of average pain for patients participating in post-surgery clinical pain trials.

Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery.

BACKGROUND: Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. METHODS: The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. RESULTS: Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). CONCLUSIONS: Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.

Medical visits among adults with symptoms commonly associated with an overactive bladder.

OBJECTIVES: To examine nationally representative data and thus obtain estimates of the use of healthcare providers associated with the overactive bladder (OAB) symptoms, a condition characterized by frequency, urgency and nocturia, with or with no urge incontinence, as although it is ranked among the 10 most common chronic medical conditions in the USA, the level of OAB-associated medical treatment remains largely unknown. METHODS: To estimate the number of annual OAB-associated medical visits among patients aged > or =18 years, three national databases in the USA (year 2000) were examined: the National Ambulatory Medical Care Survey, the National Hospital Ambulatory Medical Care Survey, and the National Hospital Discharge Survey. Population estimates were constructed using design-based statistical analyses to account for the complex survey designs of data. RESULTS: During 2000, adult Americans made 1.4 million (95% confidence interval 1.1-1.8 million) ambulatory visits to non-Federal office-based physicians with International Classification of Disease (ICD-9) coding indicative of OAB symptoms. Accounting for emergency and outpatient department visits, as well as non-Federal short-stay hospital discharges, the estimated number of medical visits with OAB-associated ICD-9 coding was <1.5 million. CONCLUSION: The prevalence of OAB was estimated to be 34 million adult Americans. When 1.4 million ambulatory visits were compared with this prevalence, as few as 4% of adult Americans with OAB sought medical treatment during the year 2000. The present results therefore suggest a large unmet medical need among the population of adult Americans with OAB.