Cancer originating in the kidney in adults, known as renal cell carcinoma, is an important health problem (childhood Wilms’ tumour is a different condition not covered in this review). The condition is rarely curable if it has spread to other organs at the time of diagnosis, if spread appears after initial removal of the affected kidney, or the kidney tumour is too extensive for surgery. Kidney cancer is resistant to conventional chemotherapy. The observation that these tumours can occasionally shrink without therapy, especially when spread to the lungs, suggested that drugs that work through the patient’s immune system might be a useful approach. Because the course of kidney cancer is very variable between patients, studies were only included if patients consented to be randomly allocated to have the immunotherapy of interest or a control therapy. Any type of immunotherapy was accepted for inclusion in this survey.
A systematic search of reports published between 1966 and 2005 identified 58 different studies of immunotherapy in 6880 patients with advanced renal cell cancer. Thirty-seven studies reported the main outcome of interest, the chance of surviving for one year for each treatment tested. One study provides useful information about the effect of placebo, with 6% of patients having a partial remission and 25% having stable disease for more than six months. Other studies used hormone pills as control therapy, probably inactive agents. Of the many types of immunotherapy that have been tested, only interferon-alfa has been shown to improve the chance of surviving for one year. Interferon-alfa is normally made by white blood cells in response to viral infections. Originally obtained from human blood in tiny impure amounts, interferon-alfa can now be made as a pure product and is given by injection under the skin, usually three times per week. Four studies tested interferon-alfa in 644 patients with advanced kidney cancer and, compared to control therapy, this agent reduced the risk of death at one year by 46% and risk of death over the course of two years by 36%. The treatment has a low chance of shrinking cancers with partial remission seen in only 12.5% of patients. These studies included a representative sample of patients as long as they were ambulatory and without spread to the brain. Interferon-alfa therapy is very safe but causes an unpleasant flu-like syndrome of variable severity that tends to improve as treatment continues, with fatigue and loss of appetite.
Attempts to enhance the benefit of interferon-alfa by adding other drugs have been unsuccessful with the possible exception of adding cis-retinoic acid, related to Vitamin A, and this approach resulted in worse quality-of-life than interferon-alfa alone. However, in patients whose kidney cancer has visibly spread at the time of diagnosis, removing the kidney before giving interferon-alfa prolonged average survival by six months (two studies, combined data), the most impressive effect of any treatment for advanced kidney cancer so far demonstrated including the new targeted agents (see separate review). It has been suggested that the removal of the primary kidney tumour works by unblocking the patient’s immune system but it is unknown if this procedure can be counted as an immune approach.
One goal of this review was to assess the benefit of high dose interleukin-2, an expensive and toxic treatment that was the only approved therapy for advanced kidney cancer in the United States at the time of the most recent review update in 2006. No studies of high dose interleukin-2 compared to a non-immunotherapy control were identified. High dose interleukin-2 gives equivalent survival to low dose interleukin-2 plus interferon-alfa, a combination known to have greater toxicity than interferon-alfa alone.
The main limitation of the studies surveyed in this review was their small size with consequent limited ability to demonstrate differences in efficacy between treatments tested. For example, three studies tested different doses of interferon-alfa but are too small to provide useful information on this point and consequently the optimal dose of this agent is unknown.