Individualising treatment choices in a crowded treatment algorithm

Metastatic renal-cell cancer (mRCC) is considered incurable, and systemic therapy is the foundation of patient management. Historically, hormonal therapy was used for palliation of symptoms but had little anti-cancer effect [1]; cytotoxic chemotherapy is beneficial for only a small proportion of patients [2–7]. Immunotherapy, generally interferon-alpha (IFNa), was standard treatment until 2005, when it was replaced by the first inhibitor of the vascular endothelial growth factor receptors (VEGFRs), sunitinib [8]. Since then, another six agents which target either the VEGF or the mammalian target of rapamycin (mTOR) pathways have been developed and approved for use in advanced RCC [9–15]. Notably, cytoreductive nephrectomy was proven in two randomised trials to improve survival in combination with IFN, compared with drug treatment alone [16]. Despite a significant change in the systemic agents utilised in mRCC, this has remained an integral aspect of the treatment approach. The prognosis for patients with mRCC has improved markedly with the introduction of agents targeting cell signalling pathways [17,18]. The expected survival time for an individual patient can be highly variable, but it is standard practice to categorise patients with mRCC into prognostic groups, originally defined by the Memorial Sloan Kettering Cancer Center (MSKCC) in the immunotherapy era of treatment [19]. This model, which uses clinical and pathological factors to group patients into favourable, intermediate and poor-risk groups, has now been updated and validated in patients treated with VEGFR–tyrosine kinase inhibitors (VEGFR–TKIs) [20] and is an important consideration in the current standards of care. The treatment algorithm for mRCC in 2013 includes seven targeted agents and cytokine therapy, used in a sequential fashion [21]. This algorithm is becoming increasingly complex as clinical trials attempt to define the optimal treatment regimen to improve progression-free and overall survival and response rates, and to preserve quality of life. Combinations of targeted drug therapy remain experimental; to date, no combination has proved to be superior to monotherapy, and it is frequently poorly tolerated [22]. This educational chapter will summarise the treatment algorithm for advanced RCC and will provide details on how treatments may be individualised within the algorithm. The potential impact of new agents, future trial results and developments in translational research in mRCC will also be discussed.