Treatment of lung cancer: will financial issues become a criterion of choice?

Keywords::

• clinical decision
• economics
• lung cancer

By 2020, the cost of cancer care in the USA is predicted to almost double from US$90 billion to 160 billion [1]. Treatment costs for lung cancer (LC) have risen massively in recent years, with new targeted therapies accounting for 11% of the increase [2]. Maintenance treatments based on either chemotherapy or targeted drugs have also had a significant impact.

In Europe, the total annual cost of cancer care is approximately €124 billion, or €240 per citizen per year, of which €84 (36%) is supported by healthcare insurance [3]. In France, targeted therapeutics currently cost approximately €945 million annually. The advent of new drugs such as crizotinib will also weigh heavily on public finances.

Economic issues are thus becoming a major factor in the decision-making process [4]. However, economic studies are rare and are mostly based on mathematical models that are tightly linked to the particularities of national healthcare systems [2]. Microeconomic analyses will become increasingly important as treatment is tailored to the individual patient and specific treatments are used in relatively small patient populations.

Are consolidation treatments becoming unaffordable?

Many articles have been published on this subject, with different drugs. For pemetrexed, all the articles gave the same conclusion. Tsuchiya et al. [5] constructed an economic model based on the results of the clinical trial conducted by Culieanu et al. [6]. The payer’s perspective was adopted, and the cost–effectiveness figures thus obtained were far higher than any national health system could possibly accept. For Bongers et al. [7] with the same database [6], pemetrexed was not cost effective from a Switzerland healthcare perspective (€106,222/quality-adjusted life year [QALY]). The two main drivers in the sensitivity analysis were utility value and palliative care costs in the pemetrexed group. For bevacizumab, Goulart and Ramsey [8] constructed a model based on a single clinical trial [9] and concluded that consolidation therapy was not cost effective for the US healthcare system. For erlotinib, the UK NICE conducted an analysis of erlotinib maintenance therapy and found that it was not cost effective [10], although thresholds are often lower in the UK. Walleser et al. found a cost–effectiveness ratio of less than €30,000 in several European countries when they analyzed patients included in the SATURN trial [11]. At this threshold, probability of a cost-effective ratio were 93.6% in the UK, 91% in Germany, 91.7% in France, 92.1% in Spain and 92.9% in Italy. The same conclusions were reached in the subgroup of the SATURN trial (stable diseases) in terms of cost per life years saved [12]. Overall, consolidation treatments have not yet been validated, and further studies are therefore needed.

Do we have the means to prescribe targeted therapeutics?

Gefitinib

Gefitinib was the first tyrosine-kinase inhibitor to be approved for the treatment of non-small-cell LC. Previous data showed an average treatment cost per patient of approximately US$46,000 during the first 2 years [13]. The impact of gefitinib is difficult to analyze because of the paucity of studies. Chouaid et al. performed a model-based study of compassionate-use gefitinib therapy between 2002 and 2004 in France, based on the data of 106 patients [14]. The total cost for each of these patients was €40,000 ± 20,729, with gefitinib representing approximately 10.7% of the overall cost (€4241 ± 1424). However, this study included only highly selected patients. A second study conducted in Thailand examined the cost–utility of second-line gefitinib for non-small-cell LC [15]. The comparators were docetaxel, erlotinib and pemetrexed. Gefitinib proved to be the most cost-effective second-line treatment. This study adopted the perspective of the Thai healthcare system, and most of the costs were based on expert estimates. Horgan et al. based their study on the data set from the INTEREST clinical trial [16]. In this cost–utility study based on prospective data, the marginal cost–effectiveness of gefitinib versus docetaxel was CAN$5161, which was considered acceptable for the North American healthcare system. Adverse effects and quality of life also favored the use of gefitinib rather than chemotherapy. Brown et al. conducted a study for the UK NICE [17]. Patients were not selected for EGF receptor (EGFR) mutations. Costs were considered too high for the British system, despite the fact that this was a selected population (IPASS trial). The costs calculated by NICE ranged from GB£25,000 to 65,000 per additional QALY. The recently published study by de Lima Lopes et al., adopting the perspective of Asian health systems, analyzed first-line gefitinib use in patients with EGFR mutations by comparison with chemotherapy [18]. The results favored gefitinib, as confirmed by sensitivity analyses.

Erlotinib

Erlotinib was first validated in second line. Among the many studies conducted, only one French study took EGFR mutation status into account [19]. The use of targeted therapies did not reduce the overall cost of treatment [20,21]. Bradbury et al. conducted an economic analysis of the BR21 registration trial [22]. They showed that marginal cost–effectiveness was close to US$100,000 per year of life saved, which was still just acceptable for the Canadian healthcare system. Other studies compared erlotinib with chemotherapeutic agents such as docetaxel and pemetrexed. Carlson et al. showed that erlotinib dominated the other two products [23]. Lewis et al. compared erlotinib with docetaxel in a cost–utility study. Although the results were very similar, they tended to favor erlotinib [24].

The answer is very different according to whether or not the population is selected. Used as second-line treatments in the general patient population, Bradbury et al. found that these treatments were not cost effective compared with chemotherapy, although in some cases, based on clinical end points, tyrosine kinase inhibitors were cost effective in selected populations [16]. Borget et al. showed that cost–effectiveness increased as the patient population was more strictly selected [19]. Note that such analyses also need to take the cost of the necessary selection tests into account.

There are no published data on first-line erlotinib. An exploratory study conducted by Carlson et al. in 2009 showed that a pharmacogenomic test could reduce the cost per QALY [25]. Many clinical trials taking EGFR mutations into account have now been published [26], but economic analyses are still needed. It is very likely that erlotinib wil prove to be cost effective in selected populations.

Antiangiogenic agents: bevacizumab

Bevacizumab is the most extensively studied anti-EGFR antibody in terms of health economics, notably through a general review [27]. Two studies showed that bevacizumab had an acceptable cost–effectiveness ratio from the perspective of Italian or German society [28,29], while another three studies suggested it was not cost effective. However, all these publications were based on models rather than on clinical trial data. In addition, some assumed a dose of 7.5 mg/kg and others 15 mg/kg.

Conclusion

Certain methodological adjustments are necessary when considering targeted therapies. In particular, both direct and indirect costs must be taken into account from the point of view of society. Indeed, these treatments are often much lengthier than chemotherapy protocols, and some patients may be able to resume employment [7,30]. The financial burden will always be a heavy one because, even though patients are willing to support part of the cost of these drugs, it is generally limited to only 5 or 10% [31,32].

The need for cost–effectiveness and cost–utility studies has increased in recent years for cancer management, owing to international budgetary restrictions and also to the multiplication of these new therapies. Clinical trials should now include economic analyses, possibly backed up by modeling. Giving ‘the right treatment to the right patient’ is probably the best option, as this will make these expensive treatments more cost effective. Only in this way can patients expect to benefit from prolonged, high-quality survival at an acceptable cost. This is a major challenge we now face for most cancers, and especially LC. The number of publications on this issue is likely to explode in coming years.

Financial & competing interests disclosure

A Vergenegre has received honoraria from Roche, Amgen and Lilly and has received funding for clinical research from AstraZeneca, Chugaï, Lilly, Amgen, Roche and Boehringer Ingelheim. In the past 5 years, C Chouaid received fees for attending scientific meetings, speaking, organizing research or consulting from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman la Roche, AstraZeneca, Sanofi-aventis, Lilly, Novartis and Amgen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.