Management and interpretation of novel toxicities of molecular targeted therapies: Renal toxicities
Introduction
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.
Section snippets
Glomerular lesions
Glomerulonephritis and proteinuria
Different drugs have been reported to cause glomerulonephritis and proteinuria through glomerular damage. Most of the toxicity is related to VEGF inhibition. VEGF is very important in maintaining normal glomerular endothelial function. In an elegant study, Guan and colleagues showed that VEGF can act as a survival factor for podocytes and thereby prevent glomerulonephritis [3]. Shulman and colleagues [4] performed renal biopsies on patients with various glomerular diseases to evaluate the
Renal thrombotic microangiopathy
Thrombotic microangiopathy (TMA) had been previously described after treatment with sirolimus in transplanted patients, preferentially in kidneys with concomitant endothelial injury. Analysis of VEGF has shown that renal VEGF expression during sirolimusinduced TMA was significantly lower than VEGF expression in normal transplanted kidneys, and this decreased expression of VEGF seemed to be a consequence of sirolimus treatment since analysis of biopsies performed after removal of sirolimus
Combinations and interactions with other neprohotoxic drugs
Most of the experience of targeted therapies in combination with chemotherapy has been gained with bevacizumab and cetuximab.
In a recent phase III study, bevacizumab when combined with cisplatin in non-small cell lung cancer (NSCLC) prolongs survival and the incidence of grade 3 or greater adverse events was similar between both arms [36]. Safety results are also very similar to that observed in prior clinical studies of bevacizumab in NSCLC [37, 38].
Cetuximab has also been combined with a
Patients with renal impairment
Different antibodies have been approved in recent years for cancer treatment. These include beva-cizumab, cetuximab, trastuzumab, panitumumab and palifermin. Renal insufficiency per se is not a contraindication to receive different monoclonal antibodies for cancer treatment.
Haemodialysis does not influence cetuximab and bevacizumab clearance. Inauen and colleagues [46] observed no effect of haemodialysis on cetuximab concentrations but the small number of blood samples did not allow them to
Conclusion
Although the incidence of kidney injury among patients receiving VEGF inhibitors and other molecular targeted therapies has not been fully described, it is prudent to monitor patients receiving these new drugs closely for possible renal toxicity.
Conflict of interest statement
None declared.
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