Action to Cure Kidney Cancer

Paul de Souza from the St. George Hospital in Kegorah, Austria presented a Wyeth Pharmaceuticals-sponsored study on the occurrence of hyperglycemia (high blood sugar), hypertriglyceridemia (high blood levels of triglycerides) and hypercholesterolemia (high blood levels of cholesterol) in RCC patients as a side effect of treatment with temsirolimus (Torisel) compared to Interferon-a (IFN). Temsirolimus inhibits the mTor (or rapamycin) pathway, a signaling mechanism by which cancer cells are able to proliferate and spread throughout the body. Specifically, mTor is involved in cellular division and angiogenesis. Temsirolimus has been approved in the US for treatment against RCC, but compared to IFN treatment, instances of metabolic derangements such as hyperglycemia,, hypertryglyceridemia, and hypercholesterolemia appear in much greater frequency in patients undergoing treatment and were reported by Gary Hudes in his Phase 3 trial report on temsirolimus versus INF. Dr. de Souza's study sought to examine the prevalence of these side effects and determine if there was any correlation between the severity of the metabolic changes and the efficacy of treatment. Fortunately, though these side effects are problematic, they appear to be unlinked to drug response and are treatable with secondary medications.

Methodology

Patients in the trial were randomized to receive one of three treatments: one group received 3 million units of IFN subcutaneously 3x weekly, eventually increased to 18 million units; another received temsirolimus at 25 mg via IV infusion weekly; the last group received 15 mg of temsirolimus via IV and in addition 6 million units of IFN subcutaneously 3 times a week. Patients were characterized as diabetic or not, since hyperglycemia is known to appear in non-diabetic patients undergoing temsirolimus treatment.

Results

Dr. de Souza's study confirmed the link between temsirolimus and hyperglycemia, with 16% of non-diabetic patients undergoing temsirolimus treatment developing grade 2 or higher hyperglycemia, compared to 3% of patients treated with IFN. 100% of diabetic patients receiving temsirolimus developed grade 2 or higher hyperglycemia versus 36% of those who received INF. A less profound link was observed between temsirolimus and hypercholesterolemia, with 8% of temsirolimus patients developing the condition at grade 2 severity or worse, compared to 1% of IFN patients. As far as hypertriglyceridemia was concerned, patients receiving temsirolimus generally fared no worse than those receiving IFN. 7% of temsirolimus patients developed grade 2 or higher hypertriglyceridemia, compared to 6% of IFN patients. For patients undergoing either form of therapy, the durations of the blood side effects were comparable. The median duration for hyperglycemia in temsirolimus patients and IFN patients alike was 15 days; the median duration for hyperglyceridemia was 15 days for both as well; the median duration for hypercholesterolemia was the only one significantly different between the two groups, lasting 71 days for two IFN patients compared to 15 days for seventeen temsirolimus patients.

The fortunate and more important news that comes from Dr. de Souza's study is that though there may be a link between temsirolimus and some of these side effects, there is no evidence that these side effects decrease the drug's efficacy. The numbers may even suggest a positive association between the presence of metabolic side effects and longer overall survival, for both groups. However, the differences do not reach statistical significance. The relative survival rates are listed in the tables below:

Note: NA means data not available.

Discussion

With or without the development of metabolic side effects, survival rates are distinctly higher among patients treated with temsirolimus than with IFN, with temsirolimus patients surviving nearly 6 months longer than IFN patients. The patients in the trial were in the poor risk category (for survival) and did not have previous systemic therapy for their disease. There is even a slight correlation between the development of these side effects and increased survival, though the connection, pointed out only with the utmost care as the researchers themselves do not even mention it, was not statistically significant. Nevertheless, advanced RCC patients with poor prognosis treated with temsirolimus face much better odds of survival than those treated with IFN, regardless of the development of hyperglycemia or hypercholesterolemia, although the patient's oncologist should be prepared to treat hyperglycemia, especially in diabetic patients.