Bladder cancer, which gets little public attention compared with high-profile cancers like those of the breast and prostate, made news recently when a study suggested drinking lots of fluid may help prevent the disease.
At the same time, some experts hesitate to endorse this seemingly simple prevention approach, partly because other studies suggest that chemicals sometimes found in drinking water may increase the risk of this type of cancer.
That paradox is one of several unusual facets of the struggle to control a disease diagnosed in 55,000 Americans each year. Bladder cancer is the fourth most common malignancy in men, eighth in women. No one knows why it is nearly four times more common in men: Smoking and occupation play roles, but after these factors are accounted for, the male excess persists. While squamous cell bladder cancer is prevalent in geographic areas plagued by schistosomiasis infection, the most common type in Western industrialized countries about 90% is transitional cell carcinoma. Incidence has risen modestly in the United States (about 6% in men and 13% in women since 1973) and more dramatically in parts of Europe.
Scientists believe most cases are caused by chronic exposure to carcinogens in urine. The major risk is tobacco smoking, which is thought to exert its effect by introducing aromatic amines into the urine. Smokers have a two to five times higher risk than nonsmokers.
Many occupational groups have elevated risk as well, from leather workers to painters. For some, such as workers exposed to certain aromatic amines, the culprit compound has been identified and in many cases, banned but for others there is no solid explanation, said Debra Silverman, Sc.D., of the National Cancer Institute's Occupational Epidemiology Branch.
Dietary Links
Dietary links have been proposed, but they are relatively weak. As with many cancers, fruits and vegetables may lower risk, while the bracken fern one of a group of plants eaten as "fiddleheads" and used to make beer in some countries contains suspected bladder carcinogens.
One potential bladder cancer threat to the general population may come from chemicals in drinking water, although it is unclear how great a risk these pose in most places. Parts of Taiwan, Chile, and Argentina have extremely high arsenic levels in their drinking water, which have been linked to bladder cancer deaths there. Public water supplies in most of the United States have levels hundreds of times lower and pose little risk. But recently, some have speculated that modest elevations in arsenic ingestion might be hazardous, and might explain geographic hot spots in the United States, said Silverman particularly in northern New England, where NCI cancer atlases show excess mortality from bladder cancer in both men and women.
"This is a pattern that's been there since we began doing maps . . . and arsenic is the leading suspect."
NCI is conducting two case-control studies, one in New England and one in the area of Barcelona, Spain, that will assess a wide variety of exposures, including arsenic and chlorination, other environmental exposures, and genetic susceptibilities. The New England study aims to include every bladder cancer diagnosed over a 3-year period in people aged 30 to 79 in Maine, New Hampshire, and Vermont an estimated 2,100 cases.
Flip Side
The flip side of this watery issue is that high fluid intake in general appears beneficial. In the study published in the May 6 New England Journal of Medicine, Dominique S. Michaud, Sc.D., and colleagues at the Harvard School of Public Health in Boston used data from the massive Health Professionals Follow-up Study to assess the effects of total fluid intake on bladder cancer risk.
Michaud and co-authors found that men who drank the most fluids (above 2.5 liters per day) had about half the risk of bladder cancer compared with those who drank less than 1.3 liters.
In an editorial, Peter A. Jones, Ph.D., and Ronald K. Ross, M.D., of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, nevertheless cautioned that tainted water may compromise the effect. "The quality of what you drink may therefore be as important as what you imbibe," they wrote.
Research in bladder cancer treatment has been scarce, and progress relatively slow, said Arie Belldegrun, M.D., chief of urologic oncology at the University of California, Los Angeles, in part because most urologic oncology researchers have focused on prostate cancer instead.
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Superficial bladder cancer has a strong tendency to recur locally after treatment, and can become invasive. Much research in this disease is directed either at more effectively preventing recurrence or detecting it earlier.
TB Strain
A unique aspect of bladder cancer treatment is that the best adjuvant treatment for superficial tumors is direct injection into the bladder of Bacille Calmette-Guérin, a non-virulent cultured strain of the tuberculosis bacterium. Also used as a TB vaccine, BCG was unimpressive in tests against other tumors but apparently activates cytokines or other immune modulators. Its precise mechanism is unknown.
Most clinical trials are now focused on using cytotoxic or immunotherapeutic agents in combination with BCG, to reduce BCG dose, or to replace BCG for patients unable to tolerate its side effects, which include urinary problems and bladder inflammation. One agent being tested extensively is interferon-alfa. In a Phase II trial planned to include 660 patients at 100 centers nationwide, researchers are testing a combination of BCG and interferon alfa.
"By casting a large net, we are trying to put together different subgroup profiles," to study which patients do best with the combination treatment, said lead investigator Michael A. O'Donnell, M.D., of Beth Israel Deaconess Medical Center in Boston. "For instance, how does the patient with high-grade disease respond versus the patient with nuisance, low-grade recurrent disease?"
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Several chemoprevention trials are aimed at thwarting recurrence of superficial bladder cancer. The Southwest Oncology Group has a randomized trial of fenretinide in which patients take the synthetic retinoid or a placebo for a year after surgery. And a trial planned by the North Central Cancer Treatment Group aims to determine whether multivitamins reduce risk.
Investigators are probing the molecular genetics of bladder cancer in an attempt to discover genetic factors associated with tumor recurrence and progression. One of the first molecular prognostic factors identified was the p53 gene. About 50% of bladder tumors have abnormal p53 expression, and researchers at several cancer centers have shown they can identify high-risk patients, using p53 mutations to single out tumors most likely to invade, O'Donnell said.
A trial at USC/Norris will compare survival after radical surgery of patients with alterations in the p53 gene who are treated with the chemotherapy regimen methotrexate, vinblastine, doxorubicin, and cisplatin versus those receiving no further treatment. O'Donnell said p53 testing should become more clinically useful as the techniques become standardized. "Right now, the problem is in achieving uniformity," he said.
The makers of several commercially available assays claim their products are useful in monitoring bladder cancer patients for recurrence. These include BTA (bladder tumor antigen) marketed by C. R. Bard, Inc., in Covington, Ga., and NMP22 (a nuclear matrix protein) from Matritech in Newton, Mass.
O'Donnell said the tests' high false positive and false negative rates make them impractical as a replacement for the "gold standard" of cystoscopy, but newer and better assays are in the pipeline.
Other researchers hope to target p53 with gene therapy. Lance C. Pagliaro, M.D., at the University of Texas M. D. Anderson Cancer Center in Houston, is conducting a trial of p53 with an adenovirus vector in patients with advanced bladder cancer. Another trial, set to begin this year at UCLA, will test an adenovirus-p53 conjugate made by Schering-Plough Pharmaceuticals of Madison, N.J., Belldegrun said.
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