Our study should be of interest to patients and clinicians alike. Until only recently, mRCC patients had few treatment options beyond cytokine therapies. Our study demonstrates consistent PFS benefits with the new targeted therapies. Insights into the histology of RCC appear to now result in considerably improved PFS and response rates. Our study represents a first step at determining the relative effectiveness of each new intervention.
We sought out all randomized controlled trials of targeted drugs for mRCC. In the end, five papers and two abstracts met our inclusion criteria. Analysis of the populations from those studies revealed there to be three distinct groups of patients: treatment naïve patients of favorable to intermediate risk, refractory patients of favorable to intermediate risk, and refractory patients of intermediate to poor risk. As we hoped to measure the overall treatment effect of targeted therapy, we included both the treatment naïve and refractory patients of favorable to intermediate risk. While the refractory group were likely to be enrolled later after their time of diagnosis, and hence at risk for shorter PFS by definition, we felt that PFS was still a reasonable outcome measure based on their favorable (and similar) prognostic risk. In a pooled analysis this would likely bias the results in a negative direction that would make a statistically positive result more likely to be true. For patients with a poorer prognosis, PFS (our a priori
primary endpoint) is likely shorter whether or not previous treatment has been tried. Interestingly, as can be seen in Additional Files 1
[See additional Files 1
], median duration of treatment and hazard ratios for PFS and investigator assessed response rate were comparable between the poor-risk patients and favorable-risk ones.
Establishing prognosis of mRCC is difficult as there are a variety of patient, tumour, and biochemical factors that have been shown to influence prognosis [33
]. Some of these include, among other variables, prior nephrectomy, tissue pathology, tumour stage (nodes and number of metastatic sites), serum calcium, alkaline phosphatase, and hemoglobin values, and scores of performance such as Eastern Co-operative Oncology Group (ECOG) performance status or Karnofsky score. We accepted individual study authors' assessment of prognosis into favorable-risk, intermediate, and poor-risk patients. While some criteria varied between papers, measures of ECOG or Karnofsky scores were also used by authors and we accepted risk stratification based upon them. From Additional Files 1
[See Additional Files 1
], however, the PFS, and clinician determined response to therapy was similar between the other groups included in our statistical models. While they are not perfectly matched groups from a prognostic point of view, we felt they are similar enough for inclusion into our analysis. Further limitations of included trials based on more specific prognostic factors would have made any analysis impossible given the variety of different prognostic scores available for metastatic renal cell carcinoma.
There are several important strengths and limitations to consider when interpreting our analysis. Strengths include our extensive searching and successful contact with authors for clarifications and in one case, access to individual patient data. Our data analysis approach used a strategy that permits strong inferences about the relative effectiveness of interventions in the absence of head-to-head direct evidence. While head-to-head trials remain the highest level of evidence of therapeutic effectiveness, the method we employed has demonstrated comparatively consistent findings between this indirect method and head-to-head trials [36
]. Limitations of our review include the absence of head-to-head trials, the potential that other trials exist that we were unable to identify, and the small number of included studies, thus negating the possibility of exploring possible sub-group analyses and exploring heterogeneity among study populations. Indeed, such analyses can only be undertaken when there are a large number of included studies.
Our method of analysis employed the adjusted indirect comparisons meta-analysis method. This method may be unfamiliar to some readers. Strengths of this method are that it borrows strength from each trial and maintains the benefits of randomization. Clinical, as well as statistical, rationale is required for combining treatments. Head-to-head (direct comparisons) trials remain the highest level of evidence of therapeutic effectiveness and in our review the only head-to-head trials compared these new therapies versus cytokine therapy, IFN-α. While our comparative data is hypothesis generating, it highlights the need for appropriate new clinical trials that examine the direct relative effectiveness of these interventions and also examine the combined effectiveness of these interventions.
There has been a recent public outcry over access to these mRCC interventions in the UK. The UK National Institute for Clinical Excellence (NICE) has issued provisional guidance not to recommend any of the drugs on the National Health Service due to their cost [11
]. Our review finds that the clinical benefits of these interventions are clear. However, NICE evaluated the cost of the drugs per quality adjusted life year (QALY) and found all four treatments exceeding the Institute's £30,000 threshold (bevacizumab £171,301, sorafenib tosylate £102,498, sunitinib £71,462, temsirolimus £94,385). This troubling finding indicates two important public health challenges: 1) drugs need to be available at reduced costs; and 2) thresholds for cost-effectiveness need to be adjusted according to relative clinical efficacy [38
]. In May 2009, NICE will issue final guidance that will take into account new supplementary criteria to be applied in drugs used at 'End of Life', and because of this it is expected that one or more of the reviewed drugs will be recommended. It is difficult to envision our own clinical decision-making, if cost alone were the deciding factor.