Advances in Bladder Cancer Treatment Around the Corner

In October 2010, Pat Boumansour completed a half marathon. But it was no ordinary 13.1 miles for this long-time runner; it was 65-plus laps around the corridors of the University of Michigan hospital. And Boumansour was no ordinary marathoner. Days earlier she had undergone radical surgery to remove her bladder after she received a diagnosis of stage 3 bladder cancer.

Boumansour’s diagnosis came after she suffered for nearly two years with common bladder cancer symptoms, including a frequent urge to urinate and feeling a burning sensation whenever she did. When she noticed blood in her urine after a race, she consulted her gynecologist, who attributed the symptoms to runner’s bladder, or exercise-induced hematuria.

When Boumansour, a former smoker, finally received a diagnosis of bladder cancer, she was initially shocked. “I felt like the universe was playing a huge joke on me,” she says.

Boumansour handled the pre-surgery with relative ease. But when her surgery revealed that the cancer had spread to a lymph node, putting her at high risk for recurrence, she enrolled in a clinical trial for Sutent (sunitinib), a drug that is approved for the treatment of advanced kidney cancer, gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. “So far, so good,” says Boumansour, 66, who has had four cancer-free scans since completing the trial.

Sutent is only one up-and-coming treatment being examined in bladder cancer, a disease that hasn’t seen a new treatment in more than a decade. And an observational study published in a recent issue of Cancer found that most patients don’t receive optimum treatment anyway, even though patients who received at least half of the recommended care experienced a survival advantage.

Most of the 70,000 new cases of bladder cancer that occur in the U.S. each year affect people such as Boumansour—current or prior smokers over age 55. People exposed to certain environmental chemicals in the workplace are also at higher risk. The disease poses a unique challenge compared with other forms of cancer, such as breast and prostate, because there is no routine screening test for the disease. And despite ongoing research into the biology and potential new therapies, the standard treatment remains unchanged, and no new drugs have been approved for bladder cancer since 1998.

If a patient’s symptoms raise a red flag, the urine is examined microscopically for signs of cancerous cells (cytology). The patient also undergoes a cystoscopy, a procedure in which a flexible fiberoptic tube is inserted via the urethra to visualize the inner bladder surface, and biopsies of suspicious areas can be taken.

Several non-invasive tests designed to detect tumor markers in the urine have been approved by the FDA but are not widely used. One test, called ImmunoCyt, detects proteins commonly expressed on cancerous cells. “The problem is that these assays have a lower specificity than urine cytology, so there are falsepositives,” says Elizabeth Guancial, MD, a genitourinary oncology fellow at the Dana-Farber Cancer Institute in Boston. “The tests that are on the market now are not good enough to replace routine cystoscopy,” adds Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center. “If you have to do both, there’s no point.”

Once cancer is diagnosed, prognosis and treatment options depend on the extent of disease. “Bladder cancer is actually two very different diseases,” Guancial explains. The good news is that 70 to 80 percent of newly diagnosed patients have superficial, early-stage tumors (stage 0 or 1) that are confined to the inner lining and connective tissue of the bladder and can be surgically removed.

View Illustration: Staging and Treating Bladder Cancer

The situation is more complicated for patients whose cancer has invaded the muscle wall of the bladder (stage 2) or has reached beyond the muscle layer into the surrounding tissues and reproductive organs (stage 3). If the disease has spread to distant sites, such as the bones, liver and lungs (stage 4), it is generally regarded as incurable. Some patients with stage 4 disease are eligible for a radical cystectomy along with lymph node removal, but most are treated with platinum-based chemotherapy and/or are enrolled in a clinical trial.

The stage of the disease determines the approach to treatment, but staging is no simple feat. “Fifty percent of patients who have muscle-invasive disease have more advanced disease than anticipated in the initial workup,” says Colin Dinney, MD, chairman of the department of urology at M.D. Anderson Cancer Center in Houston, referring to a problem known as understaging.

The first step in treating any stage of bladder cancer is getting rid of the tumor. For those with superficial disease, this is fairly straightforward. Early-stage tumors are removed in a procedure called transurethral resection of the bladder tumor (TURBT). And although these early-stage cancers recur frequently, they can be removed with repeat TURBTs and rarely develop into metastatic disease.

In patients with early-stage disease at higher risk of recurrence, TURBT is often followed by treatment with bacillus Calmette-Guérin (BCG)—most commonly used as a vaccine against tuberculosis. When injected into the bladder through a catheter, BCG is thought to rev up the immune system, which then attacks the cancer. One study showed that BCG treatment combined with TURBT resulted in a disease-specific 10-year survival rate of 75 percent compared with 55 percent with TURBT alone.

A more aggressive approach is taken with patients who have more aggressive disease. Those with stage 2 or 3 bladder cancer typically have their entire bladder removed (along with nearby reproductive organs and lymph nodes) in a procedure called a radical cystectomy. To restore the body’s plumbing, some patients have a new internal bladder (or neobladder) constructed from part of the small intestine, which is then attached to the urethra and tubes that connect to the kidneys. With practice and muscle training, many patients can achieve nearly normal urinary control.

View Illustration: Creating a New Bladder

Boumansour was not a candidate for a neobladder because part of her urethra was removed during surgery. Instead she received an ileal conduit, in which a collection pocket is created from a piece of small intestine. The conduit is then drained into an external pouch through a small hole (stoma) in the abdomen. A lucky few are eligible for a partial or segmental cystectomy, which spares bladder function, provided the tumor is low-grade and confined to only one area of the bladder. But even for those whose entire bladders are removed, half will relapse with metastatic disease.

Cystectomy is often combined with cisplatin-based chemotherapy either before or after surgery to lower the risk of future recurrence—the most common regimens are gemcitabine and cisplatin, CMV (cisplatin, methotrexate, vinblastine) and M-VAC (methotrexate, vinblastine, Adriamycin [doxorubicin], cisplatin). Although cisplatin-based regimens are the most effective against bladder cancer, patients with kidney dysfunction or heart problems often can’t tolerate the drugs, which can cause damage to these organs. For these patients, the standard cisplatin is often replaced by another platinumcontaining agent, carboplatin.

“It’s clear that carboplatin combos are inferior to cisplatinbased combos,” says Harry Herr, MD, a urologic surgeon at Memorial Sloan-Kettering Cancer Center in New York. “It’s a debate whether it’s worth giving the chemo for a lesser response rather than just doing the surgery itself.” For patients who are too sick to undergo surgery or decide against radical cystectomy, radiation is an option.

Recent studies have shown that the most successful approach for patients with muscle-invasive disease is to administer cisplatin-based chemotherapy regimens prior to surgery (neoadjuvant chemotherapy), which may decrease the tumor mass and eliminate not-yet-visible metastases.

In a recent study of nearly 1,000 patients with muscleinvasive bladder cancer, three cycles of CMV prior to cystectomy or radiation therapy improved the 10-year survival rate by 6 percent compared with not receiving neoadjuvant chemo. And the risk of death from bladder cancer was reduced by 16 percent in the CMV group. But despite its success, this chemo-first approach is debated among physicians and is surprisingly underutilized, with only 12 percent of patients at leading academic institutions in the U.S. having received this treatment from 2003 to 2008.

Both Boumansour and 48-year-old Lisa Hunt, who received a diagnosis of stage 3 bladder cancer in August 2010, were treated with neoadjuvant chemotherapy before undergoing radical cystectomy. Both tolerated the treatment well. But although Hunt’s three-month scan post-surgery was clear, by six months the cancer had spread to her lungs, liver and pelvis.

“There is an argument that chemotherapy will increase the morbidity of the [surgery],” Dinney says, “so many urologists prefer to do a cystectomy and reserve chemotherapy for those patients who have higher risk features identified after surgery.”

“One argument that drives the bias [against neoadjuvant chemotherapy] is that many people do not benefit,” notes Theodorescu. So the trick is to predict who will and who won’t benefit from pre-surgery chemotherapy.

“There’s no marker yet that can differentiate responders from nonresponders,” says Herr. “This requires evaluation in prospective trials and is kind of the Holy Grail, but we’re not close yet.”

Theodorescu, on the other hand, feels that the Holy Grail is closer at hand. He has developed a prediction model (called COXEN, for CO-eXpression ExtrapolatioN) that will soon be tested in a multi-institutional clinical trial. His approach is to identify gene expression patterns in the tumor that distinguish drug-responsive tumor cells from drug-resistant ones. If a patient’s tumor has a gene expression pattern associated with non-responsiveness, the patient is not likely to benefit from chemotherapy. Consequently, that patient can be spared the toxic effects of treatment and undergo surgery without delay.

In initial retrospective tests, the COXEN model accurately predicted which patients would respond to M-VAC chemotherapy. The model has also proven successful for predicting responses in other types of cancer. Others, including Guancial from Dana-Farber, are also trying to identify specific genetic markers (biomarkers) to recognize patients who are most likely to respond to chemotherapy.

The COXEN model has also shown promise for predicting which patients will respond to radiation and certain targeted anticancer therapies, as well as which patients will have lymph node involvement (and thus be at high risk for recurrence) at the time of cystectomy.

Many targeted drugs that have been successful in other cancers have thus far shown little success in patients with bladder cancer. But there’s still hope for these agents. Dinney’s group recently completed a clinical trial in high-risk bladder cancer patients comparing dose-dense M-VAC with M-VAC plus Avastin (bevacizumab), a drug that binds to the vascular endothelial growth factor (VEGF) protein and inhibits the growth of blood vessels to the tumor. “The reason we did this trial was that in our previous neoadjuvant trials with cisplatin-based regimens, we found that the overexpression of VEGF was associated with a poor outcome,” Dinney explains. The trial results are expected this year.

A vaccine, lapuleucel-T, is also in phase 2 trials for highrisk bladder cancer patients who have undergone radical cystectomy and whose tumors express a common breast cancer antigen called HER2. In this approach, the patient’s own immune cells are taken out, taught to recognize the HER2 antigen and then infused back into the patient. A similar vaccine, Provenge (sipuleucel-T), that targets prostatic acid phosphatase, was approved by the FDA in 2010 for patients with advanced prostate cancer.

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After her six-month scan, Hunt received more chemotherapy with gemcitabine and cisplatin but with limited success. Her most recent scan showed that some of the tumors had gotten smaller, but new ones had appeared in her right hip. Her next step: radiation. As for Boumansour, despite having “every side effect under the sun” from Sutent, including mouth sores, food aversions and anemia, the treatment seems to be working. “With each scan, it’s very scary,” says Boumansour. But judging by the 100-mile bike ride she finished shortly after the clinical trial, her cancer isn’t slowing her down.

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