From OncoLog, October 2003, Vol. 48, No. 10
‘Hitting Bladder Cancer on All Fronts’: Researchers Focus on Improving Therapies and Identifying Biomarkers
by Katie Prout Matias
Bladder cancer has an image problem. In truth, it is one of the most common cancers in the United States, has a high rate of recurrence, and kills more than 12,000 people each year. But the disease has developed a reputation for being nonlethal. This misperception, according to Colin P.N. Dinney, M.D., a professor in the Department of Urology at The University of Texas M. D. Anderson Cancer Center, is to blame for the longtime dearth of funding for bladder cancer research.
In recent years, however, the National Cancer Institute (NCI) has taken steps to reverse this trend. NCI funding for bladder cancer research increased from $15.5 million in 1997 to $32.3 million in 2002. And in 2001, the NCI awarded a $13.9 million Specialized Program for Research Excellence (SPORE) grant for bladder cancer research to M. D. Anderson. Within the program, five core research projects will study everything from prevention to detection and treatment. “We’re hitting bladder cancer on all fronts,” said Dr. Dinney, who directs the bladder cancer SPORE.
One of the chief goals of researchers at M. D. Anderson is to improve on the current standards of care for superficial and muscle-invasive bladder cancer, which are far from perfect. Patients with superficial bladder cancer are often treated with transurethral resection and, in some cases, intravesical chemotherapy. Nevertheless, 50% to 75% of superficial bladder cancers recur, and these recurrent tumors are treated with bacille Calmette-Guérin (BCG), an attenuated tuberculosis bacterium that is used as immunotherapy. In this treatment, a saline solution containing the bacteria is deposited into the bladder via a catheter, where it triggers the body’s immune response, destroying cancer cells. BCG is used more or less as a maintenance therapy, to delay the next recurrence that is likely to come.
“Even though we have effective therapies for the treatment of superficial disease, most bladder cancers over time will recur,” said Dr. Dinney. “And the salvage therapies that we have today are not very effective.” Up to 30% of patients in whom superficial bladder cancer recurs will die within 15 years.
Approximately 25% of bladder cancers will invade the muscle, requiring a cystectomy, or total removal of the bladder. Cystectomy can have many troubling side effects, including impotence resulting from nerve damage and urinary incontinence. The prostate, ovaries, uterus, and part of the vagina are also commonly removed. Sadly, in many of the patients who choose to go through a cystectomy, the cancer will recur. “Up to 50% of patients who present with muscle-invasive disease will die of metastasis, as will a small percentage of patients who have superficial disease. So there is a real need to develop better therapies,” said Dr. Dinney.
Researchers are investigating many different treatment approaches, including better chemotherapeutic strategies for metastatic, chemotherapy-resistant bladder cancer. One such strategy, still considered controversial by many, is neoadjuvant chemotherapy before cystectomy. According to Dr. Dinney, neoadjuvant chemotherapy not only is the first step toward bladder preservation but also allows physicians to observe whether the chemotherapy is working.
“If you take out the bladder and then give them chemotherapy after the fact, you really don’t know if that chemotherapy has been effective because there’s nothing to watch. If you leave the bladder tumor inside, you can actually evaluate it during the course of chemotherapy and determine how effective the therapy is,” said Dr. Dinney. “And if it’s not effective, you can change the course of treatment in the midst of it and not wait to see the cancer recur at the end of it all.”
In patients with locally advanced bladder cancer, the survival benefit of neoadjuvant chemotherapy was recently confirmed by an 11-year study of 307 patients conducted by the Southwest Oncology Group and led by H. Barton Grossman, M.D., a professor in the Department of Urology at M. D. Anderson. The study’s results, which were published in the August 28, 2003, issue of The New England Journal of Medicine, showed that patients treated with chemotherapy followed by surgery lived a median of 77 months, compared with 46 months for patients treated with surgery alone.
“This is an important advance, because the study shows a significant and clinically meaningful improvement in survival among patients who received chemotherapy before surgery,” said Dr. Grossman. “Treatment of this disease varies across the country, but we believe neoadjuvant chemotherapy should be used more frequently.”
Also being investigated to improve chemotherapeutic treatments is interferon, which has so far not been successful alone in treating muscle-invasive bladder cancer. In one study, patients will receive interferon systemically, and biopsies will be performed before and after treatment to see if the interferon is indeed killing cancer cells and enhancing the response to the chemotherapy. In patients for whom the treatment does not work, the researchers will study the biological mechanisms behind the resistance and use the results to select patients for interferon treatment.
Another agent being combined with chemotherapy is ZD-1839 (Iressa), an epidermal growth factor receptor (EGFR)–blocking agent. EGFR, which is overexpressed in more than 80% of advanced bladder cancers, is involved in many important aspects of tumor cell growth and invasion, including angiogenesis. Patients whose disease responds to chemotherapy will receive ZD-1839 in the hope that it will increase the efficacy of the treatment.
The bladder has long been thought to be ideal for gene therapy, but past trials using adenoviral p53 did not deliver enough of the gene to the tumor cells. As part of an ongoing investigation, researchers will be delivering the interferon-a gene, combined with a compound called Syn3, intravesically in patients with superficial bladder cancer. “In our animal models, Syn3 has led to tremendous gene transfer across the bladder and caused regressions of human bladder cancers growing in mice when given intravesically,” said Dr. Dinney.
In addition to looking for better therapies, the researchers are working to improve staging, detect recurrence earlier, and develop effective chemoprevention regimens. According to Dr. Grossman, who codirects the SPORE, several projects are under way to find genomic and proteomic biomarkers that would help physicians diagnose both primary and secondary bladder cancer earlier. Currently, cystoscopy is recommended every three to six months to test for bladder cancer recurrence. This invasive procedure can miss small tumors and carcinoma in situ lesions, however, and some patients do not return for their scheduled follow-up. If the biomarker studies are successful, physicians could instead test a patient’s urine for certain genes or proteins, saving them from the discomfort and expense of a cystoscopy.
“Both the genomic and proteomic approaches are yielding very exciting information,” said Dr. Grossman. “The proteomic approach has identified a series of protein peaks that appear to be very sensitive and specific for detecting bladder cancer.”
Using genetic or proteomic markers for bladder cancer, physicians also could identify patients who would be good candidates for novel therapies (in place of cystectomy), said Dr. Dinney, as well as patients who are likely to have recurrent or invasive cancer and whose disease should be treated more aggressively sooner. “These markers may help us identify those patients who actually respond to the chemotherapy and have a complete pathologic response, which is very hard to determine clinically before taking the bladder out. Your error is probably 30%, and that can be a very serious error,” he said. Physicians could also know if and when to perform a cystectomy on someone with superficial bladder cancer, thus resolving one of the bigger controversies in urologic oncology.
Finally, biomarkers could also help corroborate the efficacy of chemopreventive drugs. Two chemopreventive agents currently being evaluated at M. D. Anderson for bladder cancer prevention are fenretinide and celecoxib, which is intended to prolong the response to BCG. Both drugs are being investigated to prevent or delay recurrences.
“One of the problems with chemoprevention trials is that our ability to determine response is still very limited,” said Dr. Grossman. “If validated biomarkers were available that could be used as surrogate endpoints, you could assess chemoprevention in a much faster, more efficient way.”
The epidemiology of bladder cancer recurrence is another area of investigation. Cigarette smoking and exposure to certain chemicals are known causes of bladder cancer initially, but it is not clear what triggers recurrences. Variations in normal genes are being investigated, including those involved in DNA repair, nicotine addiction, and the ability to break down carcinogens into nontoxic byproducts. Researchers hope that the knowledge gained from these studies could one day be used to develop not only chemopreventive drugs to prevent recurrence but also primary prevention methods for people at high risk of bladder cancer, such as smokers, industrial workers, and those who carry certain genetic markers.
The knowledge researchers gain in their efforts to improve the prevention, diagnosis, and treatment of bladder cancer may also be applicable to other solid tumors that are more difficult to evaluate. “The bladder is an internal organ that is very, very accessible, so it provides a unique opportunity for developing therapies,” said Dr. Grossman.
For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.
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