NEW YORK (Reuters Health) – In advanced renal cell cancer, targeted inhibitors of the vascular epithelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways improve progression-free survival in both first-line and second-line settings.

However, these treatments rarely yield complete responses and thus are not curative and no placebo-controlled trial has reported a health-related quality of life benefit.

These are the conclusions of a Cochrane systematic review of data from randomized trials published through June 2011 published online September 27 in BJU International.

“Targeted agents have greatly changed the therapeutic landscape in RCC,” Dr. Christian Kollmannsberger, of the division of medical oncology, BC Cancer Agency and Vancouver Cancer Centre, Vancouver, British Columbia, and colleagues note in their report.

Interferon-alpha, the former standard cytokine therapy, was associated with “substantial subjective toxicities and poor effectiveness,” they point out. “Targeted therapies represent a new class of drugs that have much more specific sites of cellular action than chemotherapy or immunotherapy, with potential for improved effectiveness with fewer harmful effects.”

Twenty-eight studies met the study team’s inclusion criteria and they eventually selected 21 for review. Fifteen studies involving a total of 5,587 patients tested the anti-VEGF agents bevacizumab, sorafenib, sunitinib, pazopanib, tivozanib, or axitinib.

Three studies in a total of 1,147 patients tested the mTOR inhibitors temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors and one tested the combination of temsirolimus plus bevacizumab.

Most of the studies required RCC with a clear cell component; data on non-clear cell RCCs was limited, the authors note.

First-Line Options

In studies, sunitinib or bevacizumab plus interferon-alpha have been validated against prior standard interferon in good-intermediate-risk patients for multiple outcomes including overall survival, the authors report. There is some evidence to suggest a higher rate of grade 3/4 toxicities for bevacizumab plus interferon-alpha than sunitinib (27% vs 14%).

The data also suggest that pazopanib yields similar progression-free survival as sunitinib but it was compared with placebo rather than interferon-alpha. For poor-prognosis patients, mTOR temsirolimus improves progression-free survival and overall survival.

Second-Line Options

After cytokine therapy, one trial with sorafenib and one with pazopanib showed prolonged progression-free survival over placebo. A preliminary report of the investigational VEGF receptor inhibitor axitinib showed superior progression-free survival with this agent over sorafenib after either prior cytokine or prior sunitinib treatment. There is also evidence that after cancer progression on sunitinib and/or sorafenib, everolimus may prolong survival.

As for adverse effects of targeted agents, the authors say, “The practical supervision and detailed monitoring of targeted agents in the clinic is central to the safety of the individual patient but beyond the scope of this article.”

In general, toxicities seen with VEGF inhibitors include cardiotoxicity, bleeding, impaired wound healing, sarcopenia, hepatoxicity, stomatitis and diarrhea. Some common toxicities with mTOR inhibitors include elevation of serum cholesterol, glucose and triglycerides. Immunosuppression, atypical infections and non-infectious pneumonitis are others.

As for costs, Dr. Kollmannsberger told Reuters Health, “In Canada all of these agents are about the same with regards to pricing; I would think that also applies to the US and Europe. The one exception is the combination of bevacizumab and interferon, which is substantially more expensive.”

Reference:

BJU Intern 2011.