Management and interpretation of novel toxicities of molecular targeted therapies: Renal toxicities

Over the past years the benefits and risks associated with pharmaceutical agents have received increasing attention from the medical community.

Some doubts have arisen concerning the current approach of drug approval based on clinical trials. In most cases these studies include relatively small numbers of patients, which can lead to an incomplete safety profile assessment of these drugs at the time of approval. In addition, safety profile and effectiveness may change when these drugs are used in a wider, less carefully selected population than patients included in clinical trials.

This phenomenon has been discussed in detail by Giezen and colleagues [1] in a recent publication. In this study of 174 biological products (antibodies, hormones, enzymes) approved from January 1995 through June 2007, including 136 agents approved in the US, 105 approved in the European Union, and 67 approved in both regions, the authors found 82 safety-related regulatory actions. The probability of a biological agent having a first safety-related regulatory action was 14% at 3 years and 29% at 10 years after approval.

This is very important in cancer treatment in which major advances have been made in recent years with new targeted molecules such as antibodies (ABs) and tyrosine kinase inhibitors (TKIs). Most patients will be treated with these compounds for a long period of time and in such circumstances cumulative toxicities will appear. In our opinion, one has to be alert for new signs and symptoms reported by patients who are treated with these drugs.

As an example, kidney cancer treatment has evolved in the last 3 years, and this change has been made thanks to the development of new drugs. During 2006 and 2007, four drugs were approved to treat kidney cancer: bevacizumab, sorafenib, sunitinib and temsirolimus.

Bevacizumab toxicity is better known because many patients have been treated with it for other indications like colon, breast and lung cancer before its approval in renal cell cancer.

However, the approval by the US Food and Drugs Administration (FDA) and the European Medicines Agency (EMEA) of sorafenib, sunitinib and temsirolimus was based on less than 3000 patients. Surprisingly, only 1242 patients have been treated with sorafenib (137 patients in phase I; 202 patients in phase II and 903 patients in one phase III study); 884 patients with sunitinib (28 patients in phase I, 106 in phase II and 750 in phase III studies) and 761 patients with temsirolimus (24 in a phase I study, 111 in phase II and 626 patients in the phase III study). Under such circumstances, little is known about the chronic toxicities of these drugs.

In a recent study, Bhojani and colleagues [2] reviewed the main toxicities reported in phase I, II and III studies of three drugs approved, in different settings, for kidney cancer. The authors found that renal toxicities were rare and included proteinuria and oedema. However, proteinuria may occur after prolonged exposure. Other molecules included were bortezomib, erlotinib and lapatinib.

As previously mentioned, the approval of different inhibitors that target the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) has changed the treatment of cancer patients. However, because the same growth factors are expressed in the kidney, these therapeutic agents have renal side effects. In this paper, we will review renal toxicities related to molecular targeted therapies according to their different nephron structural damage. We will also point out the probable pathogenesis, early diagnosis and treatment.