The present study suggests that concomitant use of angiotensin system inhibitors may improve the outcome of sunitinib treatment in metastatic renal cell carcinoma. In this retrospective study, patients receiving angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, before or within one month of sunitinib treatment, had a a significant (HR 0.537, p
= 0.0055) 7months increase of the progression free survival, after adjustment for other known risk factors for poorer outcome. At present, progression free survival is considered to be a valid measure of clinical benefit in patients with metastatic renal cell carcinoma treated with targeted compounds.23,24
Patients using angiotensin system inhibitors also had an increase in response rate (47% versus 37%), a decrease of primary treatment refractoriness (progressive disease at first imaging evaluation within the first 3 months, 14% versus 28%), and better overall survival (HR 0.688), although these were not statistically significant at 0.05 significance level (might have been in a larger patient cohort). Furthermore, subgroups analysis of patients according to the Heng prognostic model22
and those with clear cell variety that were naïve to systemic targeted treatment, revealed a better progression free survival and hazard ratio of patients using angiotensin system inhibitors, although this was not statistically significant at 0.05 significance level in some of the subgroups representing a relatively small cohort. Finally, in amultivariate analysis for the entire group, which included the clinicopathologic prognostic factors mentioned before, the use of angiotensin system inhibitors was independently associated with progression free survival (HR = 0.54, p
The present study observation is supported by existing preclinical and clinical data suggesting that blockade of the renin–angiotensin pathway with angiotensin system inhibitors may inhibit tumour growth in several cancer types, by inhibiting the activation of angiotensin II type 1 receptors, and therefore tumour cell proliferation, migration, and angiogenesis. Some of these effects may be mediated by mechanisms that are independent of sunitinib action as decreasing the level of the vascular endothelial growth factor, modulating matrix metalloproteinases activity, reducing the activation of the epidermal growth-factor receptor, and inhibiting the mitogen-activated protein kinase/signal transducers and activators of transcription (MAPK/STAT) pathway.6–16
Therefore angiotensin system inhibitors may be additive or synergistic with VEGF inhibition therapy, and not be specific to sunitinib treatment.
Our study has some limitations. This is a retrospective study that represents a heterogeneous group of patients, including all histological variants of renal cell carcinoma, and patients who were treatment naïve and those with a history of prior therapy. This is because the study was designed to generate an initial hypothesis, and to evaluate a potential signal of antitumour activity and benefit of angiotensin inhibitors in patient’s metastatic renal cell carcinoma that are treated with sunitinib. Therefore we included an unselected cohort of all patients that were treated with sunitinib. Furthermore, previous data suggests that progression-free survival is not necessarily affected by targeted therapy administered as first- or second-line22
, and although sunitinib has been less extensively studied in patients with non-clear cell carcinoma, data suggests that it may be active in patients with non-clear cell histology.20,25
The median progression free survival in the group not receiving angiotensin system inhibitors is shorter than expected.5
We are unable to exclude the possibility that unequal distribution of unidentified clinicopathologic parameters in our patient cohort may have biased the observed results. In addition, the total number of 44 patients treated with angiotensin system inhibitors is relatively small. Other clinicopathologic factors that were not found to be significantly associated with disease progression in the present study might have been important in a larger patient cohort, as the Heng risk stratification, time from initial kidney cancer diagnosis to sunitinib treatment initiation, the presence of more than two metastatic sites, and the presence of anaemia and corrected (for albumin) serum calcium level above 10mg/dL. Finally, all users in the present study started angiotensin system inhibitors before (95%, n
= 42/44) or shortly after (within a month, 5%, n
= 2/44) initiation of sunitinib treatment. Therefore, the benefit of adding angiotensin system inhibitors after this period of time remains an open question.
Despite these limitations, our clinical observation that angiotensin system inhibitors seem to improve the outcome of sunitinib treatment in metastatic renal cell carcinoma might contribute to treatment decisions, patient selection, and clinical trials design. There were no inadvertent interactions observed in patients receiving angiotensin system inhibitors concurrently with sunitinib. Because of little side-effects and relatively low costs, further studies may be warranted, to test and confirm our hypothesis generating observation in larger patient cohorts, to elucidate the underlying molecular mechanisms, and to define which subgroup of patients (e.g. according to risk by prognostic models, clear cell versus non-clear cell histology, and first line versus advanced line treatment) will benefit. These may include retrospective subgroup analysis of previously completed large randomised trials of sunitinib or other VEGF inhibitors therapy in metastatic renal cell carcinoma, as well as prospective studies with addition of angiotensin system inhibitors to standard anti-neoplastic targeted therapies.