by Ron Shinkman The mere mention of bladder cancer worries patients: they fear for what lies ahead and, at the most personal level, they fear for the loss of their dignity.
For decades the typical treatment regimen for bladder cancer usually caused extreme discomfort, punctuated by concerns that it could recur and necessitate removal of the bladder. In such a scenario patients faced the possibility of having one of life's common functions irreparably altered.
But in recent years physicians have vastly improved their ability to anticipate the progression of bladder cancer and assign the proper treatment. Even if the bladder is removed, many patients still retain the ability to urinate normally. Much of the research behind these advances has been conducted at the USC/Norris Comprehensive Cancer Center.
"We now have a much better understanding of the disease at the molecular level than we did a decade ago," says Derek Raghavan, M.D., Ph.D., chief of medical oncology at the Keck School of Medicine of USC and associate director for clinical research at USC/Norris.
Raghavan's research has focused on minimizing the toxicity of chemotherapy given to bladder cancer patients. Chemotherapy is often used to suppress multiple recurrences of superficial cancer, which are known as transitional cell carcinomas. In advanced cases of bladder cancer, when tumors have breached the bladder wall, removal of the bladder is the typical course of treatment (in advanced stages of the disease, the cancer may appear in nearby lymph nodes and eventually metastasize in the lungs).
The standard chemotherapy regimen for bladder cancer patients is a four-drug cocktail of the cancer drugs methotrexate, vinblastine, adriamycin and cisplatin. Called MVAC, the treatment has been in use for bladder cancer patients since the mid-1980s. "It's extremely toxic," Raghavan says, adding that it can take its toll on older patients.
With the help of a series of studies sponsored by the National Cancer Institute and the Institute for Aging, USC/Norris is striving to gauge the efficacy of a regimen that calls for a single drug called gemcitabine. Manufactured by Eli Lilly and Co. and marketed under the name Gemzar, gemcitabine is used to treat lung and pancreatic cancer but has not received approval from the U.S. Food and Drug Administration for bladder tumors. Raghavan, who is the principal investigator on the gemcitabine study, says initial research performed by Lilly suggest that there is less than a 5 percent differential in outcomes for patients who are treated with gemcitabine versus MVAC.
New regimens are also being developed for the superficial form of bladder cancer. According to the American Cancer Society, up to 90 percent of the 54,000 cases of the disease diagnosed in the United States every year are superficial, meaning they can be removed in the first occurrence with minor surgery.
Patients are initially diagnosed and treated at this stage of the disease through cystoscopy-inserting a thin instrument called a cystoscope through the urethra into the bladder to identify and remove tumors. Removing them, called a transurethral resection, is done either with a wire loop attached to the cystoscope to scrape away the tumors or through fulguration-using an electric current to burn the cancer away.
Along with USC urology faculty members Eila Skinner, M.D., and John Stein, M.D., Raghavan is researching a new treatment using cytotoxic, or cell-killing, compounds that could be used to treat superficial tumors. Raghavan says that research is "still on the drawing board."
Even as work is being done to increase the efficacy of chemotherapy for bladder cancer patients, research on the disease's genetic drivers could reduce both the need for chemotherapy and increase its efficiency when it is used. USC/Norris researchers are focusing on the behavior of three genes: p53, p21, and Rb, which play key roles in the progression of bladder cancer.
Alterations in the p53 gene have been linked to the development of many forms of cancer, including bladder cancer. If mutated, the gene directs production of a protein that can become incorrectly manufactured, leading to outbreaks of cancerous cells. The long-held notion is that patients with a mutated p53 gene who contract bladder cancer have about a 45 percent likelihood the disease will progress, versus a 15 percent chance among patients without the mutated gene. Patients with the mutated gene were also thought to be less likely to respond to chemotherapy.
But research at the Keck School of Medicineand USC/Norris suggests otherwise. The research is being done by Richard Cote, M.D., professor of pathology and urology, USC/Norris Director Peter Jones, Ph.D., the H. Leslie and Elaine S. Hoffman Chair in Cancer Research, John Stein, M.D., assistant professor of urology, and Donald Skinner, M.D., the Hanson-White Chair in Medical Research and chair of the Aresty Department of Urology. Although their work concludes that patients with a mutated p53 gene have a bleaker prognosis for bladder cancer, they also believe they may be more likely to respond to chemotherapy than patients without the mutated gene. USC/Norris is currently enrolling 700 bladder cancer patients in a clinical trial to prove that theory. It will be conducted jointly with some 40 institutions, including Johns Hopkins University, the University of Chicago, the Cleveland Clinic and various research institutions in Europe. Cote is the principal investigator at USC/Norris.
"The study is a unique effort in that it will be the first to use a molecular determinant to select therapy," Cote says. "It's a groundbreaking trial from that point of view."
If the trial is successful, Cote hopes it will alter the treatment strategy for invasive bladder cancer. Currently, only those patients with the most advanced disease receive chemotherapy. This study may indicate that select patients with less advanced bladder cancer could benefit from chemotherapy, based on the p53 status of the tumor.
However, only about a third of the candidates required have enrolled to date. Cote admits that it is a difficult trial, mainly because so many bladder cancer patients are reluctant to undergo chemotherapy. To address that issue, Cote has helped establish a support group for the clinical trial candidates called the p53 MVAC Trial Patient Advocate Group. "It's one of the first patient advocacy groups for bladder cancer, and may become the model for others," Cote says.
In another study, Cote and Stein examined the p21 gene and its ability to suppress bladder cancer after the bladder has been removed. Patients whose p21 genes express low levels of a protein that suppresses tumor growth often have bleaker outcomes following surgery versus patients with p21 genes that express higher protein levels. Cote and other USC/Norris researchers are examining the interactions between p21 and p53 as well as the p14 gene, which regulates the p53 gene.
In previous years, patients who had bladder removal surgery experienced diminished lifestyles. They were catheterized in the abdominal region and their urine collected in a bag either outside or just inside their body. But more than a decade of work by Donald Skinner has vastly improved the construction of an artificial bladder using a portion of the small intestine, a procedure called an orthotopic diversion.
Although such procedures have been in use since the early 1980s, they were prone to complications. Staples used in the procedure sometimes protruded through the interior wall mucosa in the bladder's valve area, encouraging the formation of stones. "It's much like a grain of sand in an oyster," Skinner says. And in as much as 6 percent of reconstructed bladders, urine flow was restricted or partially blocked due to a fibrotic stenosis or narrowing of the new bladder's nipple-like valve mechanism. This stenosis formed because of the lack of blood flow to the valve. Restricted urine flow or obstruction puts the patient at risk for kidney damage.
A new orthotopic construction, devised by Skinner, Stein and other USC/Norris researchers, called a t-pouch is an improvement over the previous construction, called the Kock ilieal reservoir, and addresses most of the previous complications. The procedure preserves more of the patient's original tissue in the valve area, ensuring a better blood supply and eliminating the fibrotic growths. The use of staples has also been refined, reducing the occurrence of stones.
Although reconstructed bladders generally have the same capacity as the old bladder, patients lack many of the sensations that once signaled a need to urinate, according to Skinner. They also must empty the new bladder by using pressure from muscles in their abdominal area. Still, the vast majority of patients are pleased with the reconstructive surgery. "They're surprised at how well they can work," Skinner says.
USC/Norris researchers are also examining ways people can minimize their risk for contracting bladder cancer - jump-starting anew what little research had been done about bladder cancer over the past several decades. "For a long time a lot of people thought it wasn't an interesting disease," says Ronald K. Ross, M.D., the Flora L. Thornton Chair in Preventive Medicine, head of the Department of Preventive Medicine, and USC/Norris' associate director. "We only started getting interested in bladder cancer in the 1980s, and we started taking it on with a passion in the 1990s."
Before then, what was generally known about the risk factors for bladder cancer were that it occurs mostly to people in their 60s and older, and that men were about four times more likely to contract the disease than women. Smokers were more than twice as likely to contract the disease than non-smokers because of the exposure to arylamines, carcinogens expelled from the body through urination. Workers in the synthetic dye and rubber industries were also at a greater risk because of their exposure to arylamines.
Although women are less likely than men to get bladder cancer, work by USC/Norris researchers show that some can significantly increase their risk by engaging in certain behaviors. According to a study conducted by Mimi C. Yu, Ph.D., professor of preventive medicine, preventive medicine researcher J. Esteban Castelao, M.D., Ph.D., and Ross, women who use permanent hair dye once a month for a year or more double their risk for contracting bladder cancer. Hair dyes represent another source of arylamines. Those who use it for 15 years or more triple their risk. This study also indicates that women smokers are twice as likely to get bladder cancer for the same amount of smoking as male smokers. The USC/Norris team is investigating why this is true. The hair dye and smoking research was based on a recently completed study of 1,514 bladder cancer patients in Los Angeles who were compared to a control population who lived in similar neighborhoods.
Along with a gender divide among bladder cancer victims there is also an ethnic divide. According to Ross, whites contract the disease at about twice the rate of blacks and four times that of Asians. As ethnic groups are subdivided further, Ross notes, even greater disparities occur in the incidence of bladder cancer. "Probably the most extreme situation I can think of are the Maoris (a Pacific Islander ethnic group) who have one of the highest smoking rates in the world, a high lung cancer rate but very low rates of bladder cancer," Ross says. "That sort of thing got our attention." The USC/Norris group is currently completing a study that will examine 600 people with bladder cancer in Shanghai, China, to try to understand why certain populations with high smoking rates do not have high bladder cancer rates.
The studies on how bladder cancer strikes by gender and race is pushing further research on the disease at the molecular level, particularly the study of genes that regulate the enzymes responsible for metabolizing arylamines, Ross says.
"Overall, the research being done on bladder cancer is a far cry from what was being done just a few years ago," Ross says. "It's a disease that deserves everyone's attention."