We are now in the wonderful era where we have a number of new agents for the treatment of renal cell carcinoma (RCC), but the honeymoon may be over as we come to realize that with these agents comes a price in terms of toxicity, asserted Eric Jonasch, MD, of The University of Texas M. D. Anderson Cancer Center in Houston. “RCC is a disease of older people, who have multiple medical problems and are on polypharmacy, and it behooves us to know what the different side effects are and how best to manage them,” Dr. Jonasch cautioned.
The toxic effects of the tyrosine kinase inhibitors (TKIs) in question—sunitinib (Sutent), sorafenib (Nexavar), bevacizumab (Avastin), and temsirolimus (Torisel)—have been described in several phase III studies. Among the more common adverse effects linked to TKIs are fatigue, hypertension, hand-foot syndrome, and diarrhea. Fatigue appears to be a concern with all four of these agents, Dr. Jonasch reported, whereas hand-foot syndrome and diarrhea seem to be more of a problem with sorafenib and sunitinib. Hypertension has been associated with all the drugs except for temsirolimus. Rarer and potentially more serious effects of TKIs include cardiac toxicity, intestinal perforation, interstitial lung disease, hypertriglyceridemia, and hypothyroidism, he added.
In a phase III study of sunitinib (Motzer RJ et al. N Engl J Med 2007;356:115–124), approximately half of the patients experienced fatigue, diarrhea, and nausea. Hypertension was noted in nearly 25% of treated patients. Although the left ventricular ejection fraction (LVEF) declined in 10% of these patients, Dr. Jonasch warned about drawing any definitive conclusions regarding its occurrence with sunitinib. This adverse event was more extensively studied with this agent, unlike other studies of the other drugs. “So this does not mean that this is an exclusive toxicity to this particular agent,” he cautioned.
Based on the findings of a phase III trial of sorafenib (Escudier B et al. N Engl J Med 2007;356:125−134), diarrhea, rash, fatigue, hand-foot syndrome, alopecia, and nausea were noted as adverse events occurring in at least 20% of treated patients. “Although hypertension was not listed here, it does exist with this agent,” Dr. Jonasch mentioned.
There is a lack of data on the toxicity of bevacizumab as a single agent, but investigators of a phase III study evaluated selected grade 3 or 4 adverse events of bevacizumab and interferon (Escudier B et al. J Clin Oncol 2007;25[18S]:3). Fatigue was the most common effect, followed by proteinuria and hypertension. Dr. Jonasch offered two points to consider in interpreting these findings. First, the combination of the two study drugs makes it difficult to determine what effects are linked to bevacizumab alone. Second, the fact that proteinuria appears here but not in the other studies previously discussed may be simply because it was not evaluated elsewhere. “If you don’t look, you don’t find it,” he emphasized. “Proteinuria may be significantly more of a problem with bevacizumab, but in our experience it does occur at lower rates with sorafenib and sunitinib,” Dr. Jonasch said.
In a phase III study of temsirolimus (Hudes G et al. N Engl J Med 2007;356:2271−2281), adverse events reported included asthenia, which occurred in 51% of patients; nausea (37%); rash (47%); dyspnea (28%); diarrhea (27%); and peripheral edema (27%). Among the laboratory abnormalities observed were anemia, hyperlipidemia, hyperglycemia, and hypercholesterolemia. “The hyperglycemia and hypertriglyceridemia are fairly unique to this agent,” stated Dr. Jonasch.
In terms of the rare, but dangerous, side effect of cardiotoxicity, a decrease in LVEF appears to be more of a problem with sunitinib than with other TKIs. Predisposing factors include uncontrolled hypertension, with a meta-analysis of data from 61 large cardiology studies (Lewington S et al. Lancet 2002;360:1903–1913) showing that a rise in blood pressure increased cardiac morbidity and mortality. Although aggressive management of hypertension was not conducted in the subgroup of cancer patients, it suggests that “if we control blood pressure strictly, we might decrease some of these [cardiac] side effects,” Dr. Jonasch predicted. Furthermore, practice guidelines from the Heart Failure Society of America recommend that patients receiving TKIs should have their blood pressure controlled fairly aggressively and checked regularly, he added.
Intestinal perforation represents a rare but serious and potentially fatal side effect of all four TKIs. Dr. Jonasch urged oncologists to have a high index of suspicion and intervene early when patients treated with these agents report abdominal discomfort.
Another rare but potentially fatal side effect is interstitial lung disease. However, this problem tends to be specific to temsirolimus, he explained. “If there is any evidence of progressing dyspnea or interstitial infiltrates, dose reduction or discontinuation should be considered,” Dr. Jonasch advised. In extreme cases, he added, anecdotal evidence suggests a course of corticosteroids may be beneficial.
Another toxicity linked particularly to temsirolimus is hypertriglyceridemia. When it is associated with pancreatitis, it can be severe, Dr. Jonasch warned and recommended closely following triglyceride levels in patients receiving temsirolimus. “Generally speaking, when the triglyceride level exceeds 500 mg/dL, it’s time to start thinking about…intervention,” he added.
Hypothyroidism, specific to sunitinib, is also potentially serious, so frequent monitoring of the thyroid-stimulating hormone level is recommended. Hypothyroidism is very simple and straightforward to deal with if it happens. But failure to follow it might result in some big surprises,” he warned.
Although there is little category 1 evidence on options for managing TKI toxicities, Dr. Jonasch offered some practical approaches gleaned from a compilation of experiences from a large number of clinics, as well as from first- or second-hand accounts. For treating fatigue, the best remedy is dose reduction. However, concerns regarding the decrease in TKI efficacy of taking such an approach clearly highlight the need to develop “strategies that may aid individuals in keeping the same dose but [providing a] better quality of life,” he urged. Anecdotal experience with some patients seems to show that administration of methylphenidate or modafinil may provide some benefit.
Prior to starting patients on TKIs at M. D. Anderson Cancer Center, a blood pressure of 140/90 mm Hg is the acceptable baseline blood pressure. According to Dr. Jonasch, echocardiography or multiple-gated acquisition (MUGA) scans are performed prior to initiating sorafenib or sunitinib to assess overall cardiac status. Although no single agent or class of agents is superior, he mentioned that angiotensin-converting enzyme inhibitors are reasonable front-line choices.
For managing diarrhea, loperamide is a good starting point. When loperamide is ineffective, diphenoxylate and atropine may be worth a try. Stool-bulking agents may also be worthwhile.
Patients being treated with sorafenib or sunitinib who experience hand-foot syndrome may find relief from frequent use of emollients. For corns and calluses, any type of over-the-counter corn and callus removers, as well as frequent pedicures, may be beneficial.
Temsirolimus-induced stomatitis, manifested as mouth ulcers, can be effectively alleviated by dose reduction or lidocaine-containing mouthwash solutions. For mucosal rawness associated with sunitinib, sucralfate coatings may benefit some patients.
Finally, rash appears to be more of a concern with temsirolimus and less of a problem with sorafenib and sunitinib. Good hydration and treatment with diphenhydramine or hydroxyzine provide some relief, Dr. Jonasch suggested.