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Intermediate-Stage Bladder CancerBy Sunni Hosemann Introduction When bladder cancer is suspected, an in-office cystoscopy is usually done to detect and document the presence of lesions. If lesions are found, the patient then undergoes a transurethral resection (TUR), which is a cystoscopic procedure usually done under general anesthesia. During a TUR, the surgeon examines the bladder wall, removes all possible tumor for pathologic study, and takes biopsy samples from any other suspicious areas. The bladder neck, areas around the openings of both ureters, and the urethra are examined. A TUR also includes a bimanual examination of the bladder (rectal exam in men, rectovaginal exam in women) to detect palpable tumor masses. Imaging studies are done (computed tomography or magnetic resonance imaging of the abdominal and pelvic areas, depending on the pathologic findings from the TUR). Imaging should determine whether the ureters are dilated (hydronephrosis). Hydronephrosis caused by tumor obstruction is clinically very significant. Clinical staging of bladder cancer is important for treatment decisions. Standard treatment for early cancers (sometimes considered “superficial” lesions) does not usually include systemic therapy, whereas systemic therapy is standard for advanced (deeply invasive) cancers. But for intermediate (or minimally invasive) cancers, whether systemic therapy should be used is a question that has not been resolved by clinical studies. Early bladder cancers—those that have not penetrated beyond the subepithelium—are most often treated by resection of the lesion by TUR. For carcinomas in situ and some noninvasive papillary cancers (specifically, those with multiple or recurrent tumors or those that cannot be completely excised), intravesical therapy is added as a prophylaxis against recurrence. Intravesical therapy involves administering a drug into the bladder via a urinary catheter, usually weekly over a period of weeks. Bacille Calmette-Guérin (BCG) is the most commonly administered agent. Tumors that invade the subepithelial tissue without invading deep muscle can be treated with BCG if repeat resection indicates no evidence of residual invasive tumor. Advanced tumors are those that have macroscopically invaded the bladder wall or nearby organs (prostate, uterus, or vagina) or have spread to the abdominal or pelvic wall. Standard treatment for advanced tumors includes radical cystectomy and systemic chemotherapy. Intermediate bladder cancers are those that have microscopically invaded the bladder muscle or have begun to penetrate perivesical tissue. Radical cystectomy with concomitant urinary diversion is the standard treatment for these cancers, either alone or with preoperative (neoadjuvant) chemotherapy. Based on pathologic analysis of the resected bladder, postoperative (adjuvant) chemotherapy is sometimes recommended. Two questions arise in the treatment of intermediate-stage bladder cancer. The first is, which patients should receive neoadjuvant chemotherapy? The second is, which option for urinary diversion after cystectomy is best? Whether to give neoadjuvant chemotherapy Because the potential for benefit must be weighed against the risk of adding toxic chemotherapy to a major surgical operation, experts have not agreed on whether all patients with intermediate-stage bladder cancer should receive systemic chemotherapy prior to radical cystectomy. Fifty percent of patients with muscle-invasive tumors experience a recurrence, commonly at distant sites. However, recent large studies and meta-analyses demonstrated only a modest survival benefit in groups that received neoadjuvant chemotherapy, and most accepted guidelines today list cystectomy with neoadjuvant systemic therapy and cystectomy without neoadjuvant systemic therapy as equivalent standards of care.
However, bladder cancer specialists at M. D. Anderson do not view the two approaches as equivalent, because the large studies and meta-analyses so far have considered the group of patients with intermediate cancers to be homogeneous. “But in fact, this group is not homogeneous,” said Randall E. Millikan, M.D., Ph.D., an associate professor in the Department of Genitourinary Medical Oncology. “We believe an identifiable subset of this group are at a higher risk of recurrence than the average and can benefit from neoadjuvant therapy, an idea that has been supported by smaller studies at M. D. Anderson.” Based on his experience and the studies done at M. D. Anderson, Dr. Millikan believes strongly that when larger studies are done in which the higher-risk subset is separated from the overall group, the benefit for some patients will be proven and a new standard will emerge. What is concerning is that some patients may be getting chemotherapy unnecessarily, while others who need it are not. “The size of the group at high risk—those who benefit from neoadjuvant therapy—is hard to know for sure,” Dr. Millikan said. “It may be 20%–30%.” According to H. Barton Grossman, M.D., deputy chairman of the Department of Urology and a professor in the Departments of Urology and Cancer Biology, patients who have a greater chance of being cured if they receive neoadjuvant therapy (and a higher risk of death if they do not) have adverse characteristics that indicate a higher risk of occult disease. The chief characteristics used by M. D. Anderson (and recommended that colleagues in the community use) to identify this group are:
Aggressive pathologic features “Bladder cancers with such characteristics are considered to have a high risk of lymph node involvement,” Dr. Millikan said. Thus, at M. D. Anderson, patients with such cancers receive neoadjuvant chemotherapy. However, Dr. Millikan points out that patients who do not have the characteristics listed above have been shown to be cured 80% of the time with surgery alone, and therefore chemotherapy has a different risk-benefit ratio for them. “There is no chemotherapy so non-toxic that it can be ethically given to patients with an 80% chance of cure from surgery alone—in essence, you’d be treating many people to help a few, which is unacceptable,” he said, underscoring the fact that both groups benefit from proper staging of their tumors. For the lower-risk group, receiving chemotherapy may have an additional downside: unnecessarily delaying surgery, in some cases by as many as 12 weeks. Choosing urinary diversion after radical cystectomy When the bladder is removed, the urinary flow must be rerouted. According to Colin P. N. Dinney, M.D., chairman of the Department of Urology and a professor in the Departments of Urology and Cancer Biology, there are basically three types of diversions, each with advantages for particular patients:
Treatment decisions Primary treatment The decision about whether to use neoadjuvant chemotherapy is largely a medical one. It is strongly recommended for the subset of patients who by identified criteria more likely harbor occult disease and therefore are at a high risk for recurrence. “For those patients, it’s a major determinant of survival,” said Dr. Millikan. For patients who do not have adverse indicators, neoadjuvant therapy can still be considered by the physician and patient. Some patients and physicians prefer to use chemotherapy along with surgery to minimize risk of recurrence. When a patient’s physiologic reserve is adequate to tolerate both approaches, this is a reasonable decision. “Because chemotherapy provides a small advantage, it must be weighed against the side effects,” said Dr. Grossman. “This is significant therapy, and chemotherapy and surgery back-to-back can be quite intensive, so comorbidities are a significant factor.” If the patient is expected to tolerate only one of the two treatments well, surgery alone should be chosen, as it offers the best chance of cure. Another approach for some patients is to proceed with the surgery and decide afterward about adjuvant chemotherapy, based on the operative findings and postoperative pathologic examination of the bladder. However, response to chemotherapy—often a strong prognostic indicator—cannot be observed if the chemotherapy is given after the bladder and tumor are removed. According to Dr. Grossman, bladder cancer is a very lethal disease when it becomes advanced, so it is crucial to undertake treatment with a view to minimizing that possibility. Where there are treatment choices to be made, it is important to help patients understand all of their risks and options, to help them arrive at the best choice for their individual situation. Urinary diversion The surgeon discusses all options for diversion with the patient preoperatively and learns the patient’s preferences. While patient preferences can usually be met, the final decision is usually made intraoperatively by the surgeon, based on the extent of surgery necessary to remove the cancer. “For example, the creation of a neo-bladder is not among the options for patients in whom we’re not able to spare the urethra,” Dr. Dinney said. According to Ouida Lenaine Westney, M.D., a reconstructive surgeon and an associate professor in the Department of Urology, other medical factors may also preclude the creation of a neo-bladder. Renal insufficiency and compromised liver function are two contraindications because the neo-bladder is constructed from intestine, which (unlike bladder tissue) reabsorbs toxins such as creatinine. Likewise, the bowel segment that will be used must be healthy, and therefore patients with extensive bowel disease such as celiac disease or inflammatory bowel disease may not be able to have a neo-bladder or Indiana pouch. Beyond medical considerations, Dr. Westney said the patient’s lifestyle and desires play a big part in the diversion decision as well. For example, many patients do not want to deal with urostomy’s external urine collection bag, which can be embarrassing for them. On the other hand, some patients are very averse to the idea of a catheter, which is the method of emptying an Indiana pouch (4–6 times per day) and which may have to be used on occasion with neo-bladders, especially in the early months. Some degree of hand-eye coordination and manual dexterity are required to handle a catheter, and Dr. Westney suggests that such capacities be assessed preoperatively. For both types of continent diversion, patients must be able to catheterize and irrigate the internal pouch to prevent mucus buildup and stone formation. Neo-bladders may not be the best option for patients who feel unable (or do not want) to undertake bladder training, which is necessary for continence and normal voiding with neo-bladders. Patients who have significant comorbidities or physical limitations are examples. According to Dr. Millikan, an important consideration regarding radical cystectomy and urinary diversion is the available surgical experience. Ultimately, the patient will benefit most if such an operation is performed by a surgeon with a great deal of experience doing it. Even though bladder cancer is relatively common (the U.S. National Cancer Institute estimates more than 68,000 new cases and 14,000 deaths in 2008), invasive tumors are rare, so the surgery is uncommon outside of major cities and treatment centers.
For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, November 2008 issue:
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