Helge Bischoff

Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity‐modulated RT radiotherapy and cetuximab

The aim of this study was to evaluate efficacy and toxicity of radioimmunotherapy with intensity‐modulated radiation (IMRT) and cetuximab in stage III nonsmall cell lung cancer (NSCLC).

Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518)

BackgroundEven today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone.Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment.It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux®) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects.Methods/designThe NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combinations efficacy and rate of development of distant metastases with an accrual of 30 patients.Patients receive weekly infusions of cetuximab (Erbitux®) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles.DiscussionThe primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux®) and IMRT loco-regional irradiation.Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.

Cross-market cost-effectiveness analysis of erlotinib as first-line maintenance treatment for patients with stable non-small cell lung cancer

Background Platinum-doublet, first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) is limited to 4–6 cycles. An alternative strategy used to prolong the duration of first-line treatment and extend survival in metastatic NSCLC is first-line maintenance therapy. Erlotinib was approved for first-line maintenance in a stable disease population following results from a randomized, controlled Phase III trial comparing erlotinib with best supportive care. We aimed to estimate the incremental cost-effectiveness of erlotinib 150 mg/day versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease. Methods An economic decision model was developed using patient-level data for progression-free survival and overall survival from the SATURN (SequentiAl Tarceva in UnResectable NSCLC) study. An area under the curve model was developed; all patients entered the model in the progression-free survival health state and, after each month, moved to progression or death. A time horizon of 5 years was used. The model was conducted from the perspective of national health care payers in France, Germany, and Italy. Probabilistic sensitivity analyses were performed. Results Treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care. In the base-case analysis, the cost per life-year gained was €39,783, €46,931, and €27,885 in France, Germany, and Italy, respectively. Conclusion Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

Comparison of treatment costs of grade 3/4 adverse events associated with erlotinib or pemetrexed maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) in Germany, France, Italy, and Spain

Objective of this indirect economic comparison was to estimate and compare management costs of grade 3/4 adverse events (AEs) reported for first-line erlotinib or pemetrexed maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC). The economic analysis was performed for Germany, France, Italy and Spain. Types and incidences of reported grade 3/4 AEs observed with erlotinib or pemetrexed maintenance therapy were retrieved from two recently published placebo-controlled trials. Country-specific estimates on standard treatment algorithms and incremental medical resource utilization associated with each of the reported grade 3/4 AEs have been obtained from clinical oncologists practicing in the four countries and co-authoring this article. The resource use items were subsequently assigned country-specific tariffs to estimate total per-patients costs associated with the AE profiles of the two compared maintenance regimens. For the economic analysis a customized economic spreadsheet model was employed. Our comparison shows lower total average per-patient AE management costs for erlotinib than for pemetrexed maintenance therapy in all four studied countries. Total estimated cost savings per patient in favour of erlotinib amount to € 121, € 237, € 106, and € 119 for Germany, France, Italy and Spain, respectively. These AE cost savings for erlotinib when compared to pemetrexed represent a decrease by 80%, 71%, 94%, and 82%, respectively. The study also discovered considerable differences in AE management costs across countries which are primarily due to differences in clinicians estimates of hospitalization referral rates. Erlotinib maintenance therapy in patients with advanced NSCLC causes lower AE management costs than pemetrexed maintenance therapy indicating a potentially superior tolerability profile.

A cross-market cost comparison of erlotinib versus pemetrexed for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer

Erlotinib and pemetrexed were approved by the European Medicines Agency for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) to prolong overall survival after first-line therapy. An adjusted, matched, indirect comparison of erlotinib and pemetrexed suggested that survival benefits were not statistically significantly different between treatments. We conducted a cost-comparison analysis of erlotinib versus pemetrexed in first-line maintenance treatment of locally advanced or metastatic, non-squamous NSCLC in France, Germany, Italy and Spain, performed from the perspective of national health-care decision-makers or purchasers. The analysis was limited to direct costs and comprised drug-acquisition costs, administration costs and costs of treating adverse events (AEs). A one-way sensitivity analysis on administration, acquisition and AE costs was also performed. Total monthly per-patient treatment costs for erlotinib in France, Germany, Italy and Spain were €2140, €2732, €1518 and €2048, respectively, and for pemetrexed €3453, €5534, €2921 and €3164, respectively. AE cost was greater for pemetrexed in all countries, as was administration cost. As an oral treatment, erlotinib is not associated with any administration costs, except in Germany, where the cost is lower than for pemetrexed. The sensitivity analysis showed acquisition costs to be the main driver of total monthly per-patient costs. Erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable survival benefits, based on an indirect comparison, at a lower cost.

Effectiveness of bevacizumab- and pemetrexed-cisplatin treatment for patients with advanced non-squamous non-small cell lung cancer

The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third generation chemotherapy, pemetrexed, combined with cisplatin, are approved as first-line treatment for patients with advanced nonsquamous non-small cell lung cancer (NSCLC). As no head-to-head comparison of these treatments exists, this study aimed to compare the effectiveness of the two treatments using an indirect treatment comparison approach. An indirect comparison on progression-free survival (PFS) was performed for two relevant randomised controlled trials using a well-accepted adjusted indirect comparison method. The results were used in a statistical disease model (Markov model) to extrapolate the long-term effectiveness of the two treatments. A hazard ratio of 0.83 for PFS for bevacizumab plus cisplatin and gemcitabine, was calculated suggesting that this treatment is associated with a 17% lower risk of disease progression and death compared with pemetrexed plus cisplatin treatment. The Markov model predicted that bevacizumab plus cisplatin and gemcitabine resulted in 2.5 months additional PFS and overall survival compared with pemetrexed plus cisplatin. Based on this analysis bevacizumab plus cisplatin and gemcitabine is more effective than pemetrexed plus cisplatin for patients with advanced non-squamous NSCLC and should be considered as one of the preferred targeted treatments of choice for these patients.

Maintenance erlotinib in advanced nonsmall cell lung cancer: cost-effectiveness in EGFR wild-type across Europe

Background First-line maintenance erlotinib in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) has demonstrated significant overall survival and progression-free survival benefits compared with best supportive care plus placebo, irrespective of epidermal growth factor receptor (EGFR) status (SATURN trial). The cost-effectiveness of first-line maintenance erlotinib in the overall SATURN population has been assessed and published recently, but analyses according to EGFR mutation status have not been performed yet, which was the rationale for assessing the cost-effectiveness of first-line maintenance erlotinib specifically in EGFR wild-type metastatic NSCLC. Methods The incremental cost per life-year gained of first-line maintenance erlotinib compared with best supportive care in patients with EGFR wild-type stable metastatic NSCLC was assessed for five European countries (the United Kingdom, Germany, France, Spain, and Italy) with an area-under-the-curve model consisting of three health states (progression-free survival, progressive disease, death). Log-logistic survival functions were fitted to Phase III patient-level data (SATURN) to model progression-free survival and overall survival. The first-line maintenance erlotinib therapy cost (modeled for time to treatment cessation), medication cost in later lines, and cost for the treatment of adverse events were included. Deterministic and probabilistic sensitivity analyses using Monte Carlo simulation (1000 iterations) were performed. Results According to the model simulations, first-line maintenance erlotinib compared with best supportive care in EGFR wild-type stable metastatic NSCLC resulted in 4.57 months of life gained (17.82 months for erlotinib versus 13.24 months for best supportive care) and 1.14 months of life without progression gained (erlotinib 4.29 versus best supportive care 3.15), and incremental total costs of erlotinib from €7897 (UK) to €9580 (Germany). The corresponding mean incremental cost per life-year gained of erlotinib ranged between €20,711 (UK) and €25,124 (Germany). Sensitivity analyses confirmed these results. Conclusion First-line erlotinib maintenance treatment is cost-effective compared with best supportive care in EGFR wild-type stable metastatic NSCLC, irrespective of the country setting.

Costs of bevacizumab and pemetrexed for advanced non-squamous NSCLC in Italy and Germany

The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third-generation chemotherapy pemetrexed in combination with cisplatin, have been approved as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC). An indirect comparison between bevacizumab plus cisplatin and gemcitabine and pemetrexed plus cisplatin showed that bevacizumab (plus cisplatin and gemcitabine) achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the monthly cost of these treatments for advanced non-squamous NSCLC in Italy and Germany. The comparison used country specific cost data and adopted the payer perspective in Italy and Germany. The monthly cost of bevacizumab, including administration cost, as a single agent was 1,509 euro and 2,564 euro less than pemetrexed in Italy and Germany, respectively. The monthly treatment cost of bevacizumab plus cisplatin and gemcitabine was 1,001 euro and 446 euro less than pemetrexed plus gemcitabine in Italy and Germany, respectively. Results indicate that clinical benefits with bevacizumab plus cisplatin and gemcitabine therapy are achieved at a lower monthly cost than pemetrexed plus gemcitabine doublet therapy. Therefore, from a budget perspective, bevacizumab should be considered as a preferred targeted treatment of choice for advanced non-squamous NSCLC.

Societal cost savings through bevacizumab-based treatment in non-small cell lung cancer (NSCLC).

Bevacizumab in combination with platinum-based chemotherapy is associated with increased survival outcomes compared to chemotherapy alone in patients with non-squamous metastatic non-small cell lung cancer (mNSCLC). The objective of this study was to estimate potential economic benefits from a societal perspective in patients returning to work when treated with bevacizumab-based combination therapy. These economic benefits were assessed with respect to reduced productivity losses and described in terms of per patient cost savings. The analysis was conducted for France, Germany, Italy and Spain. Clinical outcomes in terms of progression-free survival (PFS) were based on two phase III clinical trials (E4599 and AVAiL) comparing bevacizumab + chemotherapy vs. chemotherapy alone. Potential cost savings due to reduction in productivity losses were assessed in progression-free patients who return back to work (human capital approach). It was assumed that 20% of all progression-free patients with performance status 0 or 1 and below 55 years of age would return back to work after the induction therapy maintaining their prior employment status (60% part-time, 40% full-time). Savings were calculated over 1 and 1.5 year time horizons. Mean savings, per progression-free patient ranged from 12,401 euro in Spain at year 1 to 39,001 euro in France at year 1.5. Respective findings proved to be fairly sensitive to the change of employment patterns and labour costs. This analysis shows that bevacizumab-based treatment can result in substantial cost savings in progression-free patients with mNSCLC.

Observation of the treatment and outcomes of patients receiving chemotherapy for advanced NSCLC in Europe (ACTION study)

Abstract Objective: The ACTION (Assessment of Cost and ouTcomes of chemotherapy In an Observational setting) study investigated associations between chemotherapy, patient/disease characteristics and outcomes in advanced non-small cell lung cancer (NSCLC) patients in clinical practice. Research design and methods: Chemonaïve NSCLC patients from five European countries were observed for 18 months from initiation of first-line chemotherapy; care was at the physician’s discretion. Main outcome measures: Survival and associated prognostic factors were estimated using Kaplan–Meier methods and a Cox proportional hazards model, respectively. Cluster analyses of baseline patient characteristics were also performed. Toxicity data were not considered in these analyses. Results: A total of 975 eligible patients with NSCLC (Stage IIIb/IV) were enrolled and provided baseline and response data; cluster analysis was performed on 829 patients and survival data were available from 906 patients. In first-line treatment, a 39.8% response rate, a 39.5% 1-year survival rate and unadjusted median survival of 9.3 months were observed. Prognostic factors for survival included performance status (PS), number of metastatic organs, gender and age. Five patient clusters were identified, highlighting patient heterogeneity in terms of baseline condition and age. PS was maintained or improved throughout first-line and second-line chemotherapy in half the patients receiving these treatments. Conclusions: ACTION provides valuable information about patient population, disease characteristics, treatment choices, prescribing patterns and outcomes in routine clinical practice in advanced NSCLC in Europe. Our findings suggest that maintenance of PS after first and subsequent lines of chemotherapy, and survival rates may both be higher than previously anticipated. Our results also showed an association between age and survival, which suggests that age should not exclude patients from receiving chemotherapy if they meet all other eligibility criteria.