Results from the first phase II trial-conducted to test the effects of erlotinib on patients with bladder cancer that has invaded the muscle layer-revealed that 16 of 25 patients are still alive 25 months after being treated with the drug before a surgical procedure, and 10 of these patients have no evidence of disease.
These survival statistics are better than those achieved with standard treatment for invasive bladder cancer, which involves surgical removal of the bladder as well as involved muscle [radical cystectomy], the researchers reported. "Bladder cancer is an unforgiving disease. Surgery represents our best chance at controlling and curing invasive bladder cancer, but still only 50 percent of patients undergoing definitive surgical therapy will experience long-term disease-free survival. In those patients who recur after surgery, survival benefits with standard chemotherapy are limited and many patients ultimately succumb to the disease-often within two years. In our study, six patients did die of the disease, but that is much less than 50 percent," according to Angela Smith, MD, a surgical resident in the division of urologic surgery at the University of North Carolina, Chapel Hill.
After treatment with erlotinib, 75 percent of the patients in the clinical trial had organ-confined disease. All patients had muscle invasive disease at the outset of the study. Following a four-week course of oral erlotinib, 25 percent of the patients were pathologically free of disease and 35 percent were pathologically down-staged to indicate they now had super-ficial cancer involvement of the bladder-numbers typically higher than observed with surgery alone. "Fifteen out of 20 patients ended up with disease that was confined to the bladder, and this [result] is very positive because patients have the best chance of cure if the disease is organ-confined," explained Dr. Smith.
Erlotinib inhibits the action of epidermal growth factor receptor (EGFR), which is found naturally in the body on the surface of cells but leads to cancer when mutations cause over-expression or up-regulation of the receptor. EGFR is over-expressed in many cancers, including colon and lung cancer. The receptor is also overly expressed in more aggressive forms of bladder cancer. "EGFR expression can be correlated with tumors of higher stage and grade of bladder cancer and also correlated with the increased likelihood of spread of bladder cancer and decreased overall survival. Erlotinib has been effective in the treatment of lung and colon cancer. Based on that evidence, we thought, let''s try this [approach] in bladder cancer," Dr. Smith said.
"It''s too early to tell exactly what the outcome of treatment will be, especially with such a small sample size of patients in the study and lack of a control group. But these preliminary results are encouraging," she emphasized. The researchers are currently evaluating the effect of erlotinib on EGFR expression on bladder cancer cells at the molecular level. Ultimately, they will pursue a phase III clinical trial for their research, "where we can test the drug in larger numbers of patients and compare its effects to randomized controls," she explained.
"Bladder cancer can be a deadly disease, even if you seemingly catch it early. Once it spreads, patients do not fare well. So if the drug can limit the spread of disease before cystectomy, if patients can be down-staged or have organ-confined disease at the time of cystectomy, their chances of survival go up dramatically. If that can happen with erlotinib, then we may ultimately be able to alter survival in a positive way," Dr. Smith added.
The research team included Robert Matthew Coward, MD; William Kim, MD; Matthew E. Nielsen, MD; Eric M. Wallen, MD, FACS; and Raj S. Pruthi, MD, FACS.