Ingolf Griebsch

The Economic Burden of Head and Neck Cancer: A Systematic Literature Review

BackgroundThis systematic literature review aimed to evaluate and summarize the existing evidence on resource use and costs associated with the diagnosis and treatment of head and neck cancer (HNC) in adult patients, to better understand the currently available data. The costs associated with HNC are complex, as the disease involves multiple sites, and treatment may require a multidisciplinary medical team and different treatment modalities.MethodsDatabases (MEDLINE and Embase) were searched to identify studies published in English between October 2003 and October 2013 analyzing the economics of HNC in adult patients. Additional relevant publications were identified through manual searches of abstracts from recent conference proceedings.ResultsOf 606 studies initially identified, 77 met the inclusion criteria and were evaluated in the assessment. Most included studies were conducted in the USA. The vast majority of studies assessed direct costs of HNC, such as those associated with diagnosis and screening, radiotherapy, chemotherapy, surgery, side effects of treatment, and follow-up care. The costs of treatment far exceeded those for other aspects of care. There was considerable heterogeneity in the reporting of economic outcomes in the included studies; truly comparable cost data were sparse in the literature. Based on these limited data, in the US costs associated with systemic therapy were greater than costs for surgery or radiotherapy. However, this trend was not seen in Europe, where surgery incurred a higher cost than radiotherapy with or without chemotherapy.ConclusionsMost studies investigating the direct healthcare costs of HNC have utilized US databases of claims to public and private payers. Data from these studies suggested that costs generally are higher for HNC patients with recurrent and/or metastatic disease, for patients undergoing surgery, and for those patients insured by private payers. Further work is needed, particularly in Europe and other regions outside the USA; prospective studies assessing the cost associated with HNC would allow for more systematic comparison of costs, and would provide valuable economic information to payers, providers, and patients

Analysis of patient-reported outcomes from the LUME-Lung 1 trial: A randomised, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer

INTRODUCTION The LUME-Lung 1 trial (NCT00805194; Study 1199.13) demonstrated a significant overall survival (OS) advantage for nintedanib plus docetaxel compared with placebo plus docetaxel as second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and adenocarcinoma histology. Patient-reported outcomes (PROs) for symptoms and health-related quality of life (QoL) are reported here. METHODS PROs were assessed at screening, on Day 1 of each 21-day treatment cycle, at the end of active treatment, and at the first follow-up visit. PRO instruments were the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 supplement, and the EuroQol disease-generic questionnaire (EQ-5D and EQ-VAS). Analyses of PRO items for lung cancer-specific symptoms of cough, dyspnoea and pain were prespecified. RESULTS Rates of questionnaire completion were high. There was no significant difference in time to deterioration of global health status/QoL, or symptoms of cough, dyspnoea or pain, between the treatment groups for both the overall study population and the adenocarcinoma population. Time to deterioration of some gastrointestinal events was shorter with nintedanib versus placebo. Longitudinal analysis for the adenocarcinoma population showed comparable changes between the groups in symptom scores over time, with numerical differences in favour of nintedanib for cough and pain scales, and significant reductions in some pain items with nintedanib versus placebo. There was no statistically significant difference in EQ-5D or EQ-VAS between the groups. CONCLUSION The significant OS benefit observed with the addition of nintedanib to docetaxel therapy was achieved with no detrimental effect on patient self-reported QoL.

Afatinib in the treatment of EGFR mutation-positive NSCLC - A network meta-analysis

OBJECTIVES Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA). MATERIALS AND METHODS A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods. RESULTS The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population. The estimated PFS HR (95% credible interval, CrI) for afatinib compared with gefitinib was 0.70 (0.40-1.16) and compared with erlotinib was 0.86 (0.50-1.50) in the total population. The estimated probability of being best for afatinib over all other treatments for PFS was 70% versus 27% for erlotinib and 3% for gefitinib; the estimated probability of chemotherapy being the best treatment was 0%. Estimated HR (95% CrI) in patients with common mutations was 0.73 (0.42-1.24) for afatinib compared with erlotinib and 0.60 (0.34-0.99) for afatinib compared with gefitinib. OS findings were not significantly different between treatments. CONCLUSIONS In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, our analysis suggests that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS. A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits.

Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer: a network meta-analysis

BACKGROUND Nintedanib plus docetaxel has proven an overall survival benefit over docetaxel monotherapy in second-line treatment of non-small-cell lung cancer of adenocarcinoma histology in the LUME-Lung 1 pivotal trial. No published trials have previously compared nintedanib plus docetaxel with agents – other than docetaxel – that are approved second-line treatments for non-small-cell lung cancer. METHODS The relative efficacy of nintedanib plus docetaxel versus second-line agents was evaluated by conducting a network meta-analysis of progression-free survival and overall survival. RESULTS Nine suitable studies were identified. The estimated probability of nintedanib plus docetaxel being the best treatment with regard to overall survival was 70% (versus 16% for pemetrexed, 10% for docetaxel and 3% for erlotinib). Results for progression-free survival were similar. CONCLUSION In patients with advanced non-small-cell lung cancer of adenocarcinoma histology, results suggest that nintedanib plus docetaxel offers clinical benefit compared with docetaxel alone, when used as second-line treatment, and suggests that this combination may also add clinical benefit compared with erlotinib in this patient group.

Patient-reported outcome labeling claims and measurement approach for metastatic castration-resistant prostate cancer treatments in the United States and European Union

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) and its treatment significantly affect health-related quality of life (HRQOL). Our objectives were to evaluate and compare patient-reported outcome (PRO) claims granted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for 5 recently approved mCRPC treatments and to examine key characteristics, development, and measurement properties of the PRO measures supporting these claims against current regulatory standards.MethodsFive products approved for treatment of mCRPC by the FDA and the EMA (2010–2013) were examined: enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and radium Ra 223 dichloride. United States (US) drug approval packages and European Public Assessment Reports were reviewed. PRO claims in the US labels and European Summaries of Product Characteristics and supporting measures were identified. For PRO measures supporting claims, a targeted literature review was conducted to identify information on key characteristics and measurement properties; this information was compared against FDA PRO guidance criteria.ResultsNine PRO “claims” were granted across 4 of 5 products reviewed. The EMA granted more claims (7 claims—4 for pain, 3 for HRQOL) than the FDA (2 claims, both for pain). The Brief Pain Inventory–Short Form (BPI-SF) worst pain item supported most pain claims and was the only measure supporting US claims. EMA pain claims were supported by BPI-SF worst pain (n = 2) and average pain (n = 1) items and the McGill Pain Questionnaire Present Pain Intensity component (n = 1). EMA HRQOL claims were supported by the Functional Assessment of Cancer Therapy–Prostate Module (n = 2) and the EuroQol 5 Dimensions with visual analogue scale (n = 1). Pain and prostate cancer–specific HRQOL measures supporting claims met US regulatory standards for construct validity, reliability, and responsiveness; these properties were strongest for the BPI-SF worst pain item. Only the BPI-SF worst pain item has documented content validity in mCRPC.ConclusionsPRO label claims were commonly granted across the mCRPC products reviewed. Among the measures reviewed, only the BPI-SF worst pain item supported US label claims. The BPI-SF worst pain item is recommended for pain assessment for the evaluation of new mCRPC treatments.

Is progression-free survival associated with a better health-related quality of life in patients with lung cancer? Evidence from two randomised trials with afatinib

Objective Progression-free survival (PFS) is frequently used as an efficacy end point in oncology clinical trials. However, there is limited evidence to support a positive association between improvement in PFS and improvement in health-related quality of life (HRQoL). The association between PFS and HRQoL was evaluated in two randomised trials. Materials and methods Data from two randomised controlled trials in patients with non-small cell lung cancer (NSCLC; LUX-Lung 1 and LUX-Lung 3) were used to investigate HRQoL in patients to determine whether tumour progression is accompanied by worsening HRQoL. HRQoL was assessed using the cancer-specific European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30, the EuroQol EQ-5D overall utility and EuroQol EQ visual analogue scale. In both studies, progression was evaluated by independent review using RECIST criteria (primary end point) and also by investigator assessment. The relationship between tumour progression and HRQoL was evaluated using analysis of covariance and a longitudinal model. Results Compliance with HRQoL questionnaire completion was high. In both studies, patients with progression consistently experienced numerically poorer HRQoL at the time of progression than patients without progression. Differences in mean scores were statistically significant (p<0.05) between patients with and without progression at week 4 in all analyses in LUX-Lung 1 and at multiple time points in LUX-Lung 3. Results from the longitudinal analysis showed that progression (by independent review and investigator assessment) appears to have consistent negative impact on all three HRQoL measures (all p<0.0001). Conclusions Tumour progression in patients with NSCLC was associated with statistically significant worsening in HRQoL. These findings confirm the value of PFS as a patient-relevant end point.

Model-Based Cost-Effectiveness Analyses for the Treatment of Chronic Lymphocytic Leukaemia: A Review of Methods to Model Disease Outcomes and Estimate Utility

Assessing the economic value of treatments for chronic lymphocytic leukaemia (CLL) is necessary to support healthcare decision makers; however, it poses a number of challenges. This paper reviews economic models of CLL treatment to learn the lessons from this experience and support ongoing model efforts. A search of databases and submissions to key health technology assessment agencies identified nine models. The modelling approaches adopted across these studies were fairly similar, with most models adopting a cohort Markov structure, though one example of a discrete event simulation was identified. While the cohort Markov approach has been acceptable to the National Institute for Health and Care Excellence, the review identifies a number of key uncertainties with these models, including the extrapolation of survival outcomes beyond the period observed by the trial, the effectiveness of second-line therapies, and estimates of health state utility. Further work is required to overcome these uncertainties, including comprehensive sensitivity analysis, systematic review of the evidence on the natural progression of CLL, and the collection of longer-term trial and registry data.

Model-Based Cost-Effectiveness Analyses for the Treatment of Chronic Myeloid Leukaemia: A Review and Summary of Challenges

Assessing the economic value of treatments for chronic myeloid leukaemia (CML) is important but poses a number of challenges. This paper reviews economic models of CML treatment to learn lessons from this experience and support ongoing efforts to model CML. A search of databases and submissions to key health technology assessment agencies identified 12 studies that reported 22 models. Common practice included the use of cohort Markov models—most models used health states organised around the key stages in CML: chronic phase, accelerated phase and blast phase—and the use of utility estimates in the literature that correspond with the National Institute for Health and Care Excellence reference case. Two key areas of uncertainty were the extrapolation of survival outcomes beyond the period observed by the trial; and the effectiveness of second-line therapies. Further work is required to overcome these uncertainties in existing models, such as longer-term trial data collection, including trials of second-line therapies; validation of health-related quality-of-life instruments; and the testing of alternative modelling approaches. In the meantime, it is important that the impact of uncertainties is tested through the use of sensitivity and scenario analysis.

Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer of adenocarcinoma histology: a network meta-analysis vs new therapeutic options

PATIENTS & METHODS We provide an update to a network meta-analysis evaluating the relative efficacy of nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. RESULTS Overall similarity of nintedanib + docetaxel versus ramucirumab + docetaxel, and versus nivolumab. Comparing nintedanib + docetaxel with nivolumab, hazards ratio (HR) of overall survival and progression-free survival (PFS) pointed in opposite directions (overall survival: HR: 1.20 [95% credible interval: 0.92-1.58]; PFS: HR: 0.91 [0.68-1.21]). Exploratory subgroup analysis indicated superiority of nivolumab in high PD-L1 expression level subgroups; results were more favorable for nintedanib in all subgroups with low (<1%, <5%, <10%) PD-L1 expression levels - in particular, with regard to PFS. CONCLUSION Results demonstrated similar efficacy of nintedanib + docetaxel compared with the new therapeutic options ramucirumab + docetaxel and nivolumab, with potential differences in subgroups according to PD-L1 expression level.

Treatments for EGFR Mutation-Positive (M+) NSCLC Patients – A Network Meta-Analysis (NMA) by Mutation Type

1Royal Marsden Hospital, London, UK; 2National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; 3Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 5Guangdong Lung Cancer Institute, Guangzhou, China Treatments for EGFR Mutation-positive (M+) NSCLC Patients – A Network Meta-Analysis (NMA) by Mutation Type PCN8