October 10, 2011

Questions Raised About Bladder Cancer Care
By Carolyn Gutierrez
For The Record
Vol. 23 No. 18 P. 24

Study results show patients are not receiving guideline-recommended care. The reason remains unclear.

Researchers following more than 4,500 patients with high-grade non–muscle-invasive bladder cancer found that only one patient received the guideline-recommended care to prevent the disease’s recurrence.

Karim Chamie, MD, postdoctoral fellow in urologic oncology health services research at UCLA and lead study author, says, “If you look at the last 15 years, clearly we haven’t made significant headway with regard to bladder cancer care. If you look at the mortality rate associated with bladder cancer in the last 15 years, there’s been about a 5% relative risk reduction in bladder cancer-related deaths. You have to compare it to the big four—prostate, breast, lung, and colon cancer—where we’ve made significant advances, where we’ve had 20% to 40% relative risk reduction during that time frame.

“What people have historically thought is that we haven’t made any headway in bladder cancer because we haven’t come up with any new chemotherapy drugs, or we haven’t come up with better operations, or we haven’t come up with new biomarkers that help us detect bladder cancer at an earlier stage,” Chamie adds. “However, in the literature, you’ll see a plenitude of studies that have been published that show that part of the reason may be quality of care—but no one’s really put it together into one comprehensive measure.”

Facts and Figures
It’s estimated that 70,000 cases of bladder cancer will be diagnosed in the United States in 2011, with 15,000 of those cases being fatal. Men are almost four times as likely as women to be diagnosed with bladder cancer, and whites are more than twice as likely as blacks and Hispanics to develop the disease. Exposure to arsenic and the cancer drug cyclophosphamide, along with certain dyes, rubber, textiles, paints, and hairdressing supplies, are thought to increase a person’s risk for the cancer. Also, smokers have a two to three times greater risk than nonsmokers.

Symptoms include blood in the urine, either visible (gross hematuria) or found during urinalysis (microscopic hematuria). Frequent urination or pain while urinating can also be indicative of bladder cancer. However, these symptoms are found in an array of other diseases and conditions, making it necessary to perform urine cytology to identify any abnormal bladder cells. An internal exam to feel for masses in the rectum or vagina and an MRI or CT scan (with or without an injected contrast medium) can help determine possible signs of cancer.

If bladder cancer is suspected, a transurethral bladder tumor resection (TURBT) is performed using a cystoscope, a long flexible tube with a lens at the end that is inserted through the urethra, allowing the urologist to visualize the bladder. During this procedure, the urologist can remove a tumor or collect a sample of bladder muscle for biopsy. Once bladder tissue is removed, a pathologist can evaluate whether the cells are malignant and measure the grade, or severity, of the cancer cells. Grading the bladder cancer can aid a urologist in determining how rapidly the cancer may grow and spread. The aggressiveness and location of the cells in the bladder tissue determine a patient’s disease classification within the cancer staging system.

Urothelial carcinoma (also known as transitional cell carcinoma) is the most common form of bladder cancer. The urothelium is the innermost layer of cells lining the urethra. Between this layer and the bladder muscles is a thin, fibrous band known as the lamina propia. When bladder cancer is noninvasive, it has not spread through the lamina propia to the bladder muscle tissue, and cancerous cells can be removed through TURBT, chemotherapy, and immunotherapy.

Less common forms of bladder cancer include squamous cell carcinoma, which begins in thin, flat cells and is possibly brought on by chronic inflammation or a parasitic infection, and adenocarcinoma, which starts in the glandular cells that release mucus or fluids.
All three types can metastasize into surrounding tissues and organs.

Research Details
To determine what percentage of patients were receiving guideline-recommended care, the researchers studied a cohort of individuals aged 66 or older who had high-grade bladder cancer that had not yet invaded the muscle wall. Although this particular form of cancer is curable, follow-up care is essential since these patients have a 50% to 70% chance of recurrence following treatment and a 30% to 50% chance of the cancer invading the muscle wall. When this happens, the bladder and surrounding organs must be removed, which severely impacts a patient’s prognosis and quality of life.

The research team sought patients who had lived at least two years after their diagnosis, had intact bladders, and had not received any systemic chemotherapy or radiation therapy. In addition, the patients must have had Medicare claims for at least two years after their diagnosis of bladder cancer. The final sample was comprised of 4,545 patients, approximately 75% of whom were male.

In a July article in Cancer, the researchers consolidated the clinical practice guidelines set forth by the National Comprehensive Cancer Network, the American Urological Association, and the European Association of Urology, determining the general consensus that “because patients with high-grade non–muscle-invasive bladder cancer have high rates of disease recurrence and progression, they should undergo frequent surveillance (to detect recurrence and progression) and be treated with intravesical agents (to minimize recurrence and progression).”

Surveillance methods recommended by all guidelines include cystoscopy and urine cytology every three months for the first two years following diagnosis, along with a CT scan every other year.

 “When the patient gets diagnosed with bladder cancer or when they have a recurrence and the tumor is resected—anytime a tumor is resected—the physician should instill a chemotherapy in the bladder which would prevent the cancer from reimplanting,” says Chamie. Instillation of perioperative mitomycin C, an intravesical chemotherapeutic, is recommended after TURBT, as well as a postoperative course of the immunotherapy Bacillus Calmette-Guérin (BCG).

“BCG was a vaccine we used to use for tuberculosis,” says Chamie. “It’s a weakened virus. Now we instill it in the bladder and it creates this massive inflammatory response, which then tries to kill whatever cells are in there.”

The guidelines recommend that during a two-year period after diagnosis, high-grade non-muscle-invasive bladder cancer patients should get a total of eight cystoscopies and eight cytologies, along with two upper-tract imaging studies. Patients should also get at least six instillations of BCG and one instillation of an intravesical chemotherapeutic after any TURBT.

Eye-Opening Findings
The study results showed that only one high-grade non–muscle-invasive bladder cancer patient out of 4,545 patients received comprehensive care. Alarmed by these results, the researchers played devil’s advocate, according to Chamie, and significantly relaxed their definition of compliance, assessing how many patients had received a single cystoscopy, cytology, and BCG after diagnosis. “What we found,” he says, “was two-thirds of patients didn’t get one cystoscopy, one cytology, and one instillation of BCG during the indicated period of time. That’s really the surprising point.”

Age, race, ethnicity, and socioeconomic status seemed to have no bearing on the lack of patient compliance, Chamie adds.

Focusing on the providers, the researchers calculated the number of urologists who were compliant with a measure on at least one patient. “We found that 42% of urologists have never once, for any of their patients, instilled one BCG, one chemotherapy, and one cytology,” says Chamie. To the researchers, this result confirmed that noncompliance with guideline-recommended care could not be solely attributed to the patients.

The research team was unable to pinpoint exactly why providers were not adhering to the guidelines for care. Although bladder cancer is one of the most expensive diseases to treat, the researchers do not believe that noncompliance is cost related. However, reimbursement incentives for urologists to follow guidelines may be a possible solution to the problem.

Raising awareness of the guidelines and a heightened collaboration between academic medical institutions and surrounding community hospitals may help educate physicians and patients alike about comprehensive care for bladder cancer, they add.

“Providing doctors with the guidelines and telling them the importance of them and helping triage patients if the care can’t be delivered at the community practices—knowing that the academic medical center is close to the community practices—you can build a triage network,” Chamie says. “If a doctor can’t give BCG or doesn’t have access to it, referring the patient to the academic institution may obviate that barrier.”

Technology’s Role
The growing use of EHRs may streamline any miscommunications and maintain contact with bladder cancer patients otherwise lost to follow-up, Chamie says.

“If you can put the guidelines into an electronic health record system that sets up clinical reminders so that when a patient comes in with a diagnosis of bladder cancer, it would guide you, tell you, ‘He’s here for his three-month cystoscopy and his three-month cytology. Make sure to order his CT scan, because he’s due for one now.’ Or it says, ‘He’s here for his fifth out of sixth BCG installation,’ and so forth,” Chamie says. “Obviously, doctors treat a lot of patients with many diseases. To keep track of every single patient with every disease process and make sure they’re all getting guideline-recommended care is difficult. That’s something that computers are great at doing—being able to incorporate guidelines into routine care.”

Less invasive state-of-the-art imaging technologies are being designed that may also help bladder cancer patients and their providers stay compliant. At the University of Washington (UW) in Seattle, researchers have developed an ultrathin laser endoscope—at 1.5 mm, it resembles a single strand of spaghetti—that when combined with UW software can produce a 3D panorama of the bladder’s interior.

By piecing together a mosaic of the endoscopic images of the bladder with the software, Timothy Soper, PhD, a UW research scientist in mechanical engineering at the Human Photonics Laboratory, has developed a 3D digital reconstruction that he refers to as the “Google Earth view of the bladder.”

“This endoscope is unique because it fundamentally images differently than conventional endoscopes,” says Soper. “There are a lot of procedures that are limited because endoscopy is performed with large endoscopes—and they are large because they typically have a bundle of fiber optics or they have a CCD [charge-coupled device] array. Basically, to try to get an alternate endoscope, you have to reduce the size of these fiber optic bundles or the size of that array. You end up having a trade-off between the size of your endoscope and the resolution—the more pixels you remove from the image, the worse that image gets.”

Using a single fiber, the ultrathin endoscope (which is awaiting FDA approval for use in human bladders) constructs an image of the bladder’s interior by scanning a laser beam in a circular-spiral path over the bladder’s surface, which collects pixel data needed to form an image at a rate of 30 frames per second. “The benefit is that by using just this one fiber that can be scanned, you can remove a large number of elements that are necessary in some of the larger endoscopes,” Soper says.

The advantages in using an ultrathin endoscopic device in medical procedures are clear—since it is minimally invasive and flexible, scientists anticipate it will reduce the discomfort and complications typically associated with urological exams as well as minimize bleeding and tissue damage. In using a small endoscope, anesthesia may not even be necessary.

The superior imaging capabilities make the ultrathin endoscope an ideal tool for cancer screening. “Because we use laser light,” says Soper, “there are a number of other image enhancements that could be performed that could potentially improve contrast and the detection of early cancer in the bladder.”

Scientists are also developing these devices to be used for surveillance in the lung, pancreas, bile ducts, and esophagus. “The technology is being used for a lot of different applications, of which the bladder is just one,” Soper explains.

— Carolyn Gutierrez is a freelance writer based in New York City.