Platinum Priority – Kidney CancerEditorial by Camillo Porta on pp. 1171–1172 of this issueSequence Therapy in Patients with Metastatic Renal Cell Carcinoma: Comparison of Common Targeted Treatment Options Following Failure of Receptor Tyrosine Kinase Inhibitors
Introduction
During the last few years, efficacious therapeutic options have been developed for patients with metastatic renal cell carcinoma (mRCC). Most patients are treated with receptor tyrosine kinase inhibitors (rTKIs), particularly sunitinib (Sun), based on the results obtained in two meta-analyses [1], [2]. Inevitably, most of the patients develop tumour resistance to the first rTKI therapy and therefore require further sequential therapy.
Based on a phase 3 trial, everolimus (EV) is an efficacious treatment option after failure of vascular endothelial growth factor receptor (VEGFr) targeted therapy, particularly rTKI treatment [3]. Current guidelines for the treatment of mRCC have adopted EV as the treatment of choice after VEGF failure [4], [5]. However, some limited evidence suggests that following failure of one VEGFr targeted agent, patients may still have the potential to respond to another VEGFr inhibitor. Particularly rTKIs such as Sun and sorafenib (Sor) have been applied in sequence, although the data of a phase 2 study suggested limited efficacy of this sequencing regimen [6]. Largely retrospective data form the basis for the sequential use of Sun and Sor or vice versa [7], [8], [9], [10], [11], [12]. However, studies sufficiently comparing different sequence options are still lacking.
In the context of insufficient comparative data on the best sequence of targeted treatments in mRCC patients, we collected the data of patients treated with two common sequence options: rTKI therapy followed by EV (rTKI-EV) versus rTKI therapy followed by another rTKI (rTKI-rTKI) in two treatment centres. The aim of our retrospective study was to compare these sequence options in terms of efficacy and toxicity.
Section snippets
Patients and methods
We retrospectively reviewed patients treated with first rTKI therapy (Sun or Sor) at two large academic centres between 2005 and 2010. Patients receiving the sequence rTKI-EV or rTKI-rTKI were included in this study. Either Sun or Sor was allowed as first rTKI treatments, so the rTKI-rTKI sequence subgroup included patients treated with Sun-Sor or vice versa, and the rTKI-EV subgroup included Sun-EV or Sor-EV. Further therapy lines were individualised and included EV, temsirolimus, dovitinib,
Patient characteristics
A total of 108 patients with first rTKI treatment were included in the study. Of these 46 received the rTKI-rTKI sequence, and 62 individuals received the rTKI-EV sequence. The rTKI-rTKI group included Sun-Sor (n = 35) and Sor-Sun (n = 11); the rTKI-EV group consisted of Sun-EV (n = 50) and Sor-EV (n = 12). All patients underwent nephrectomy before targeted therapy. Table 1 depicts the main patient characteristics of the study population and by sequence group. There were no statistical significant
Discussion
Despite significant improvements in the efficacy of systemic treatment of mRCC patients, the best strategy of sequencing targeted therapies remains a matter of debate. Literally all patients with mRCC inevitably experience tumour progression during first-line treatment necessitating sequential therapy.
In this study we compared frequent sequence strategies. Our data support the notion that both efficacy and safety of the most frequently applied sequential targeted therapies (ie, switching rTKI
Conclusions
EV remains the preferred option in rTKI-resistant mRCC according to the evidence available to date. Sequential rTKI therapy with Sun or Sor may provide similar efficacy in terms of PFS and response rate. The trend towards superior OS for the rTKI-EV sequence needs further confirmation in prospective randomised trials. Results from such trials comparing different sequence options are urgently needed to better define the treatment algorithms in rTKI-resistant disease.
References (28)
- et al.
Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial
Lancet
(2008) - et al.
EAU guidelines on renal cell carcinoma: the 2010 update
Eur Urol
(2010) - et al.
Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis
Eur Urol
(2008) - et al.
Sequential sorafenib and sunitinib for renal cell carcinoma
J Urol
(2009) - et al.
Clinical outcome in metastatic renal cell carcinoma patients after failure of initial vascular endothelial growth factor-targeted therapy
Urology
(2010) - et al.
Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma
Eur Urol
(2010) - et al.
Toxicities of targeted therapy and their management in kidney cancer
Eur Urol
(2011) - et al.
Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma
Eur Urol
(2008) - et al.
Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited
Cancer Cell
(2009) - et al.
Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis
Cancer Cell
(2009)
Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis
Cancer Cell
Metastatic renal cell cancer treatments: an indirect comparison meta-analysis
BMC Cancer
Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness
Br J Cancer
NCCN clinical practice guidelines in oncology: kidney cancer
J Natl Compr Canc Netw
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Both authors contributed equally to this work.