Since 2006, several new targeted therapies for mRCC have entered the market and randomised controlled trial (RCTs) have shown that these therapies improve survival [4, 5, 9, 16–27]. This study examined the uptake and use of targeted therapies in The Netherlands. Not unexpected, targeted therapies, sunitinib in particular, have largely replaced IFN-a as first-line standard of care. Few patients were treated with bevacizumab (combined with IFN-a) or temsirolimus in the 2008–2013 period, even though these therapies were added to the ESMO guidelines in 2009 [6], and to Dutch guidelines in 2010 [6]. Pazopanib has only been recommended since 2010 [8], which partly explains why an increase in its use was only seen from 2012. Furthermore, there was a shift in the use of second-line therapies, where sorafenib was replaced by everolimus as the most frequent choice from 2010 onwards.
The median OS of patients with an intermediate prognosis treated with sunitinib in Dutch daily practice and fulfilling the SUTENT trial eligibility criteria was shorter than the median OS of patients in the SUTENT trial with an intermediate prognosis, i.e. 14.8 months (95 % C.I. 10.8–16.1) in the 2008–2010 Cohort compared to 20.7 months (95 % C.I. 18.2–25.6) in the SUTENT trial [5]. However, the difference was much smaller for the 2011–2013 Cohort (median OS, 18.0 months (95 % C.I. 10.1-NR)) compared to the SUTENT trial patients. Median OS of patients with a poor prognosis fulfilling the SUTENT trial eligibility criteria was similar to the median OS found in the SUTENT trial, i.e. 6.8 months (95 % C.I. 5.3–10.7) in the 2008–2010 Cohort and 6.6 months (95 % C.I. 3.8-NR) in the 2011–2013 Cohort compared to 5.3 months (95 % C.I. 4.2–10.0) in the SUTENT trial [5].
The median OS of patients with an intermediate prognosis treated with sunitinib in Dutch daily practice (regardless of their SUTENT trial eligibility status) was shorter than the OS in the expanded-access trial [7]. Median OS of patients with a poor prognosis was in line with the results of the expanded-access trial. The median OS of patients with an intermediate prognosis treated with sunitinib in Dutch daily practice was also shorter than the OS in a retrospective, non-interventional study in Australia [28]. These findings may indicate that the patients in the PERCEPTION registry with an intermediate risk had a worse prognosis than the patients with an intermediate risk in other studies.
While previous studies suggest that patients fulfilling SUTENT trial eligibility criteria have a survival benefit from first-line sunitinib [5], many eligible patients did not receive sunitinib (or any other targeted therapy) in daily practice. This was also seen in England where one in three patients with mRCC eligible for either sunitinib or pazopanib did not receive the drug [29]. Patients aged 65+ years were less likely to receive targeted therapy than younger patients after adjustment for other factors. This age factor was found in patients with an intermediate prognosis (2011–2013 Cohort) and in patients with a poor prognosis (2008–2010 Cohort and 2011–2013 Cohort). There are several explanations for this association, including medical contraindications, other grounds for physician reluctance, and patient refusal. Additionally, patients with one metastatic site were less likely to receive sunitinib (according to the 2008–2010 Cohort results), which might be explained by patients with low volume but unresectable metastases whose targeted therapy is delayed. Nevertheless, most of these patients died within the follow-up period without receiving targeted therapy at any point in time. The reasons for apparent underutilisation of targeted therapies should be examined more carefully. While hospital-level factors may also affect utilisation and lead to between-hospital variation, we found no significant differences in the prescription of targeted therapy between hospitals, except for the patients with a poor prognosis in the 2008–2010 Cohort. However, the sample size per hospital was small and the statistical power to show a difference was therefore limited.
Although this study mainly focussed on patients fulfilling SUTENT trial eligibility criteria, we found that many patients in daily clinical practice are different from patients included in RCTs. In the total study population, only 42 % and 58 % fulfilled the SUTENT trial eligibility criteria in the 2008–2010 Cohort and 2011–2013 Cohort, respectively. This was partly caused by the inclusion criteria of the PERCEPTION registry, which consisted of a diagnosis of mRCC (i.e. metastases at initial presentation in the 2008–2010 Cohort) of any histological subtype. Since many patients are excluded from clinical trials, such as patients with a non clear-cell subtype, patients with a WHO performance status of 2 to 4 and patients with brain metastases, one could argue that the results of these trials only apply to a subgroup of patients.
A limitation of this study is the amount of missing data in baseline characteristics, which is inherent to an observational study. To overcome this problem, multiple imputations by chained equations were conducted, which ensure that all patients are included in the analysis but simultaneously ensure that the uncertainties from missing data are retained [15]. Additionally, eligibility criteria, such as the presence of measurable disease and adequate organ function were not taken into account when determining whether patients fulfilled the SUTENT trial eligibility criteria, since data on these criteria were lacking in the PERCEPTION registry. As a consequence, some of the patients that we labelled as eligible in this study were not in fact eligible for targeted therapy. However, since we used WHO performance status to classify patients, and since we expect a relationship between WHO performance status and organ function, we believe that this could only have had a limited effect on our conclusions about the uptake and use of targeted therapies. Furthermore, the follow-up length of the 2011–2013 Cohort was limited. As a consequence, patients might have received targeted therapy after the follow-up period, leading to an underestimate of actual targeted therapy use. However, this limitation is only relevant for patients treated later in the 2011–2013 period who did not die. Lastly, OS was calculated from the date of diagnosis (i.e. metastatic disease) for patients not receiving any targeted therapy and from the start of therapy for patients treated with targeted therapy; as a consequence a comparison between the two is impossible. This approach was based on the one used in other studies to enable comparisons between the OS of patients treated with sunitinib in our study with the OS of patients treated with sunitinib in other studies [5, 7, 28].