Professor Ziya Kirkali (Dokuz Eylül University, School of Medicine, Izmir, Turkey) discussed the past, present and possible future treatment options for advanced RCC. Novel strategies for treating advanced RCC indicate that there may be new treatment options for patients with this previously ‘difficult to treat’ cancer. Indeed ongoing studies with targeted therapies in the adjuvant treatment may even follow the option to cure the disease. “Historically, treatment choices for advanced RCC have been limited” stated Professor Kirkali. Since RCC is highly resistant to chemotherapy the mainstay of treatment has been immunotherapy, which can be highly effective in a limited number of patients but is unsuitable for the majority because of substantial toxicities.

The key decision for the physician used to be whether or not his patient was suitable for immunotherapy. However, over the past few years the arrival of targeted therapies involved in inhibiting tumour angiogenesis (blood supply) has dramatically changed this situation. In addition to immunotherapy, physicians now have the choice of four targeted agents for the treatment of advanced RCC (Nexavar® [sorafenib], Sutent® [sunitinib], Avastin® [bevacizumab] +interferon and Torisel® [temsirolimus]) with a fifth agent (everolimus) in advanced clinical development.

Professor Kirkali outlined how different targeted agents act on different molecules in order to achieve their effect. Sorafenib and sunitinib for example are tyrosine kinase inhibitors (TKIs) which target a range of kinases including vascular endothelial growth factor (VEGF) receptors. Sorafenib also inhibits Raf-1, interfering with cell growth as well as angiogenesis. Temsirolimus and everolimus have a different mode of action, targeting the mammalian target of rapamycin (mTOR) pathway, another important determinant of cell growth.

The challenge that physicians now face is how to make the best use of the range of treatments available in order to maximize the overall benefit to the patient in terms of both quality and duration of life. However, as every patient is different, no single targeted therapy will likely benefit everyone. This means that therapy should be tailored to suit each individual patient needs. Phase III studies (the data from which all medications are FDA/EMEA approved and on which guidelines are often based) have exclusion criteria that often include comorbidities that are common in patients with advanced RCC. This means that for many patients these data may not be directly applicable and therefore additional sources of evidence, such as expanded access ‘real-life’ clinical studies should also be considered.

Professor Jürgen Gschwend (Rechts der Isar Medical Center, Technical University of Munich, Germany) highlighted that in patients with advanced RCC the underlying disease means that even on therapy disease progression is inevitable. This may be combated by considering the long-term ‘overall treatment plan’; meaning that by optimizing the sequence in which patients receive therapy they can remain stable for a prolonged period of time. Although complete responses (cures) are rare, patients with advanced RCC can live for months or even years longer than patients did less than a generation ago.

However, in order to achieve this, physicians must consider important treatment decisions such as which VEGF targeted agent should be used first. “Current retrospective data suggests that there is no cross-resistance between TKIs, which means that they can effectively be given in sequence” stated Professor Gschwend. These data also suggest that if sorafenib is used prior to sunitinib in sequence the overall progression-free survival period may be longer compared with using sunitinib prior to sorafenib.

Furthermore, evidence supports the notion that no switch in the mode-of action is necessary after disease progression on the first VEGF targeted agent. Indeed, data from the phase III RECORD trial showed that the mTOR inhibitor everolimus, is as effective after two VEGF targeted agents as after one VEGF targeted agent (hazard ratio for disease progression 0.32 after sorafenib and sunitinib vs. 0.25 after sorafenib monotherapy; p<0.001).

“Optimizing each individual therapy within the treatment pathway can be achieved by considering individual patient needs for any particular treatment”, suggested Professor Bellmunt (Autonomous University of Barcelona & Hospital del Mar, Barcelona, Spain). The patient-focused schema, developed by a group of experts encompassing experienced urologists and oncologists from across Europe, was designed to identify specific disease- (e.g. histology), patient- (e.g. age) and treatment-related (e.g. to maintain quality of life) factors that should be considered when selecting treatment for individual patients.

To illustrate how to employ the ‘patient-focused’ approach Professor Bellmunt gave examples on how to use the schema. For example, based on the expert consensus there is a high level of evidence to support the use of sorafenib in elderly patients*, patients with clear-cell RCC and those with a history of hypertension. Consensus also demonstrated an intermediate level of evidence to support the use of sorafenib in patients complaining of fatigue.

It has been suggested that this schema may also be applied to patients with other types of cancer. In the meantime, this may serve to be an invaluable tool to help physicians across the disciplines (e.g. urologists, oncologists) make complex treatment decisions for their patients.

About sorafenib (Nexavar®)
In Europe Nexavar is approved for the treatment of patients with advanced RCC who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy. Nexavar is currently approved in more than 70 countries for the treatment of patients with advanced RCC and more than 60 countries for the treatment of hepatocellular carcinoma. The recommended dose of sorafenib in adults is 400 mg (two tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg). The most common adverse reactions were diarrhoea, rash, alopecia and hand-foot-skin reaction.

About Bayer Schering Pharma
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* The experience with the use of Nexavar® is limited. Cases of renal failure have been reported. Monitoring of renal function should be considered (EU SmPC Nexavar® November 2008).