Metastatic renal cell carcinoma: How to make the best sequencing decision after withdrawal for intolerance to a tyrosine kinase inhibitor, "Beyond the Abstract," by Roberto Sabbatini, MD, et al

BERKELEY, CA (UroToday.com) - Treatment of metastatic renal cell carcinoma (mRCC) represents one of the most rapidly evolving fields in oncology. From 2005 to 2012, seven novel targeted agents (sorafenib, sunitinib, everolimus, bevacizumab combined with interferon alpha, pazopanib, and axitinib) have been approved and are now entered in clinical practice. In the last decade, the approval of these new agents has represented a progress that has completely changed the approach to the disease. Despite this important development, discussion on the optimal therapeutic strategies is still open. In particular, the extreme heterogeneity of the disease and the plethora of therapeutic options now available make precise recommendations difficult. Characteristics and comorbidities of the patients and the toxicity profile of each treatment could provide useful tools to plan the most appropriate sequence of treatment.

The aim of our review was to describe the safety profiles reported in pivotal studies of novel targeted agents recently introduced in clinical practice. Moreover, our purpose was also to provide suggestions to establish the most appropriate second-line (or later) treatment on the basis of toxicities observed during each therapy.

The toxicity profile of new targeted agents represents an important issue, since it is crucial to find the best possible balance between the minimization of the risk of adverse events and the need to maintain the drug dosage able to induce clinical benefit. On this basis, proper recognition and management of side effects are fundamental to avoid unnecessary dose reduction. This concept is particularly important in patients at increased risk for toxicities or in those with comorbidities. The optimal management of toxicities consists of patient education about prevention and early detection of adverse events, accurate periodic clinical examinations, and application of emerging management strategies. However, although targeted agent related toxicities are rarely of high grade, they could be extremely distressing for the patient. On these bases, treatments chosen in the successive lines should have a safety profile different to the previously used drug. Particularly from second line, when the quality of life is a crucial issue, treatment should be tailored to the needs of the patient (considering characteristics of patient, of disease, treatment aim, and previous toxicities).

Finally, to maximize the efficacy of novel targeted agents, several further issues should be faced in the future -- in particular, the identification of molecular biomarkers predictive of response or toxicity, the identification of the optimal sequence of targeted therapies, the benefits of combining targeted agents with different mechanisms of action in order to better inhibit one or more pathways, and the strategies for overcoming resistance to a given drug.

Written by:
A. Toss, C. Masini, and R. Sabbatini as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Medical Oncology Division
Azienda Ospedaliero Universitaria,
Policlinico di Modena
41125 Modena, Italy

Metastatic renal cell carcinoma: How to make the best sequencing decision after withdrawal for intolerance to a tyrosine kinase inhibitor - Abstract

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