Treating invasive bladder cancer is rife with professional disagreement about the various current regimens and the likelihood of five-year survival.
“The primary goal is survival,” said Colin P.N. Dinney, MD, Professor of Urology and Cancer Biology at the University of Texas M. D. Anderson Cancer Center. “The secondary goal is bladder preservation.”
Invasive disease, he explained, means that the tumor(s) is less differentiated than a superficial one, and is larger and poses a greater risk of recurrence. In addition, adverse prognostic factors are associated with a greater risk of disease progression: the presence of multiple aneuploid cell lines, overexpression of p53, and expression of the Lewis-x blood group antigen.
Tumors confined to the bladder muscle are associated with a survival rate after radical cystectomy of about 75% to 80%. But more deeply invasive tumors (into adjacent organs) have a far lower survival rate (20% to 40%), and when the tumor invades pelvic viscera or when there is lymph node involvement or metastasis to distant sites, survival is unfortunately rare.
Cigarette smoking and exposure to certain chemicals are known risk factors, but it is not clear what actually triggers the cellular response.
Most bladder cancers (90%) are transitional cell carcinomas, and of these, 30% are invasive. Transitional cell carcinoma is especially difficult to treat, although it is chemosensitive, Dr. Dinney said. One problem is that early responses to treatment may not last, and recurrence is common. Of great significance to eventual outcome is the determination of pathologic grade, which is based on cell type, nuclear abnormalities, and the number of mitotic figures.
The disease is diagnosed by cystoscopy and imaging techniques, although staging underestimation is common. “It's very rough—a 20 to 35 percent error rate,” said Dr, Dinney.
The stage of bladder cancer is determined by the general appearance of the tumors(s), the depth of invasion of the bladder wall, the presence of extravesical extension, and invasion of adjacent organs.
“If the cancer is confined to the bladder, we can cure it about 80 percent of the time—with surgery alone,” he added.
Factors that Boost Stage at Diagnosis & Increase Risk that Surgery Will Be Insufficient
The more locally advanced the disease, the higher the stage and the greater the need for radical cystectomy and other treatment modalities. The factors that boost stage at diagnosis and increase the risk of failure for surgery alone (thus necessitating chemotherapy) include:
▪ The ability to palpate a three-dimensional mass during examination under anesthesia.
▪ Lymphovascular invasion.
▪ Histologic evidence of direct extension to adjacent organs.
“Bladder cancer should be treated only at a major center that deals with it regularly,” said Harry W. Herr, MD, an attending surgeon at Memorial Sloan-Kettering Cancer Center (MSKCC). “This is a potentially life-threatening disease for which you need an experienced multidisciplinary team and surgeons who know what they're doing.”
He noted that MSKCC has satellites in three states: Connecticut, New Jersey, and New York—and Pennsylvania in the future. “I can't imagine anyone living in this area who can't get to one of our satellites. Also, many fellows who have trained at MSKCC practice all over the northeast United States and bring our treatment protocols with them.”
M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) is the current standard of care, but it is toxic (myelosuppression, mucositis, drug-related mortality) and difficult to tolerate. Some toxicities are dose limiting but may be ameliorated by granulocyte colony-stimulating factor.
GC (gemcitabine and cisplatin) also is effective, Dr. Herr said, although less so than M-VAC, and less toxic. GC is often used in the elderly or those with poor performance status. GC may become a new standard of care in some cases, although it is not equivalent to M-VAC.
Because kidney dysfunction and advanced age make cisplatin-based therapy problematic, carboplatin is sometimes substituted, he noted. It is not as effective as cisplatin while being almost as toxic.
Dr. Herr said that carboplatin is a substandard drug in this instance and should never be given in place of cisplatin, regardless of the patient's ability to tolerate it.
AG-ITP (doxorubicin/gemcitabine followed by ifosfamide, paclitaxel, and cisplatin) is a dose-dense sequential regimen used in transitional cell carcinoma. It can produce a high overall response rate, although to date the number of patients so treated has been too small to be definitive.
Treating invasive bladder cancer with adjuvant chemotherapy following surgery can extend survival in patients at high risk of recurrence, although in patients with concurrent medical problems, the morbidity associated with aggressive use of drugs has to be taken into consideration when assessing overall advantages, Dr. Herr said.
Patients who are at low risk of recurrence and who have no comorbidity have a better chance of long-term survival with aggressive adjuvant chemotherapy.
Bacillus Calmette-Guerin (BCG) can be used as intravesical therapy or given systemically. It can delay recurrence and tumor progression, improve bladder preservation, and increase survival.
Whether given systemically or intravesically, two nonconsecutive six-week courses of treatment is the usual approach, he noted. If the disease persists after the second course of BCG, the patient should have a cystectomy.
Should Neoadjuvant Chemotherapy Be Offered to All Patients?
Neoadjuvant chemotherapy is designed to debulk bladder tumors prior to surgery. The controversy lies in whether or not it increases survival and should therefore be offered to all patients.
An 11-year Southwest Oncology Group trial of 307 patients, published in the August 28, 2003 issue of The New England Journal of Medicine, showed that patients who received neoadjuvant chemotherapy had a survival time of 77 months compared with 46 months for patients treated with surgery alone.
David Wood, MD, Professor of Urology at the University of Michigan, said that neoadjuvant chemotherapy does indeed increase survival.
“If you give three or four cycles of M-VAC, depending on the patient's ability to tolerate it, and taking into account the risk of disease progression, it's possible to shrink bulky local tumors. It should be used only in small-volume invasive disease. I don't think, however, that it's appropriate to offer it routinely to all patients.”
Dr. Herr said it confers a 15% reduction in mortality and a two-year increase in survival. When asked if he would offer it to all patients, his unhesitating response was, “Yes, absolutely.”
Dr. Dinney also concurred, citing a 2002 article in Lancet, based on a meta-analysis of 10 series, which showed a 5% increase in survival, despite the significant toxicity of M-VAC, which in itself has a 4% to 10% treatment mortality, higher than usual for cancer drugs.
The hard part, he said, is identifying the subset of patients whose cancer will continue to progress after surgery alone and would therefore benefit from neoadjuvant chemotherapy.
“We have studies going on that will create a molecular profile for such patients, but that's in the future,” Dr. Dinney said. “For right now, I think the survival results are about the same for chemo before and after surgery. Afterward is more difficult for patients to tolerate, so there's some advantage to giving it before.”
But Anthony Zietman, MD, Professor of Radiation Oncology at Harvard Medical School and Massachusetts General Hospital (MGH), had a different view: “There is no survival advantage to neoadjuvant chemotherapy. You have to give it for at least three months prior to surgery, and that's much too long a time to risk disease progression.”
If the tumor has invaded the muscle or if there are regional or distant metastases, transurethral resection (TUR) is insufficient. Radical cystectomy is the surgery of choice, with removal of the bladder, perivesical tissues, prostate and seminal vesicles in men; and the uterus, fallopian tubes, ovaries, anterior vaginal wall, and urethra in women. It also may include pelvic lymph node dissection.
Cystectomy no longer means resorting to an external ureterostomy bag, which is anathema to most patients, Dr. Wood noted.
Rather, a faux bladder is created by fashioning a loop of small bowel into a reservoir and attaching it to the ureters. Urine then reaches the outside in one of two ways, he explained: Preferably, the bladder is attached to the urethra so the patient can urinate relatively normally (although sometimes the patient must press on the bladder to express urine).
In a minority of cases, a small stoma is created in the abdominal wall, and every few hours, the patient inserts a catheter into the reservoir to release urine.
The surgery is successful in both men and women, Dr. Herr said, although the latter often have trouble urinating. No one knows why, and sometimes the trouble is so severe that women have to catheterize themselves.
Dr. Wood noted that some patients do refuse surgery altogether because they cannot face the prospect of not being able to urinate entirely normally. He described the case of a patient who has refused surgery for two years and now wants to change his mind.
“Unfortunately, it's too late for him,” Dr. Wood said. “His disease has progressed so far that nothing will help. He's not alone. Many patients refuse cystectomy.”
Some physicians discourage older patients from surgery, Dr. Wood added.
Dr. Herr, however, emphasized that age alone should never be a deterrent to surgery. “It should be offered to everyone who can benefit from it,” he said.
“Twenty percent of bladder cancer patients are over age 80, and with an aging population, that number will increase. Not treating invasive bladder cancer as aggressively as possible is wrong because it is fatal. The last six to 12 months of life with cancer in the pelvis is absolutely miserable.”
In the 1960s and '70s, radiation therapy was the only alternative to cystectomy, Dr. Zietman said. “It cured about 30% of the cases, and the other 70% either had cystectomy or palliative care. But at least there was that one third chance that you'd keep your bladder.”
This remained the standard of care in Great Britain and Scandinavia until the late 1990s when low-dose cisplatin chemotherapy was discovered to potentiate radiotherapy.
Radiation is effective for small tumors, Dr. Wood said. “It provides about a 50% chance of five-year disease-free survival. However, patient selection is the critical factor in choosing patients for radiotherapy—or chemotherapy, for that matter.”
Dr. Dinney described the following patients as good candidates for radiation and chemotherapy:
▪ Those with small well-circumscribed lesions.
▪ Those who have a visually complete TUR—that is, where no residual tumors are seen.
▪ Those who do not have hydronephrosis.
Only about 5% to 10% of all bladder cancer patients meet these criteria, but 70% to 80% of them survive five years or more, he said.
Dr. Herr partially agreed: “Radiation is used only in combination with other treatment modalities. It can spare the bladder but does not confer an increase in survival.”
Clinical trials conducted by Dr. Zietman and his partner William Shipley, MD, Head of the Genitourinary Oncology Unit at MGH, in conjunction with the Radiation Therapy Oncology Group, demonstrated the benefit of trimodality treatment.
“We use limited surgery [TUR], low-dose chemotherapy [begun one month before surgery], and low-dose radiation to the bladder,” Dr. Zietman explained, adding that 80% of patients on this regimen have a complete response, and 65% ultimately keep their bladder. Superficial relapse occurs in about 20% of the cases, but it responds to treatment with BCG.
“This response rate is identical to treatment with immediate cystectomy,” he said. “Halfway through initial chemotherapy and radiation, we do a cystoscopy to see if the tumors are debulking. If they are, we go on as planned. If not, we take the bladder out right away and continue with low-dose chemo to eliminate micrometastases. The very close evaluation lets us keep tabs on the pre-op treatment so we can get more aggressive if necessary.”
Dr. Zietman said he is “very strict” with patients who undergo this regimen: “They have to be extremely responsible in following through with all the prescribed treatments and interim cystoscopies. If they can't or won't, I don't want them in the program.”
There's a reward for sticking to it. More than 70% of all patients void normally, and about half the men can have an erection.
If this regimen has such a high response rate and is so successful in preserving the bladder, why isn't it used more often? “This disease is treated mainly by surgeons who want to take out the bladder first and think later,” said Dr. Zietman. “They hate to turn over any part of the treatment to radiation oncologists, who they perceive as delaying a cure.
“In addition, bladder cancer therapy is way out of step with all other oncologic treatment. We're still back in the old days when radical mastectomy was the only cure for breast cancer and all prostate cancer patients had radical surgery. But trimodality treatment is a move toward organ conservation, a goal of cancer therapy since the early 1990s. A combination of less aggressive modalities is as effective, or more so, than a single surgical bombshell. And patients like it better, because a preserved natural bladder is always preferable to an artificial one.”
What the Future Holds
Regarding possible biologic treatments on the horizon, Dr. Wood said there was nothing particularly earth-shattering, but that there is some research with trastuzumab because HER-2/neu overexpression is a factor in bladder cancer, as it is with breast and other cancers.
“We may see some small-molecule-targeted therapy in the not-too-distant future, but don't hold your breath waiting for a vaccine,” he said.
There is no accurate biomarker, nor is there likely to be one for a while, added Dr. Wood. But Dr. Dinney described a prospective randomized trial of the predictive features of EGF receptor and VEGF receptor inhibitors as possible biomarkers for bladder cancer, a paper scheduled for publication in the Journal of Urology.
Dr. Wood held out more hope for a chemopreventive agent for recurrent disease (approximately 75% percent of all cases recur): “The perfect model for surface tumors would be an oral agent, for example a COX-2 inhibitor, that would continually bathe the bladder.”
The prognosis for patients with recurrent or progressive invasive bladder cancer is unfortunately poor, but there is hope, Dr. Herr said. Giving up smoking is one of the best ways to decrease the incidence of recurrence, he said. “All our patients are sent to smoking-cessation programs—we have one here at MSKCC—and many succeed. Having had cancer once can scare them into quitting.”
When asked about a COX-2 inhibitor as a chemopreventive for recurrent bladder cancer, he said there is a Phase III trial at MSKCC to determine if celecoxib is an effective prophylactic agent. The trial began about a year ago and will last for at least two years.
“We need about 100 patients, but so far have enrolled only 50.” Dr. Dinney pointed to a celecoxib trial at M.D. Anderson as well.
SPORE at M. D. Anderson
The Specialized Program for Research Excellence (SPORE) at M. D. Anderson is at work on bladder cancer research, including:
▪ Using BCG to treat recurrent disease: The bacterium is administered intravesically and triggers an immune response. It is used mainly as maintenance therapy to prevent the next inevitable recurrence.
▪ Developing techniques to improve staging, detect recurrence earlier, improve chemotherapy regimens, and find genomic and proteomic biomarkers: The last approach has identified a series of protein peaks that appear sensitive and could identify patients who are good candidates for novel therapies, who are likely to have recurrent disease, and who might benefit from chemoprevention.
▪ Testing gefitinib to block EGF receptor, which is overexpressed in 80% of invasive cancer cases. Patients who respond to chemotherapy will receive gefitinib to determine its potentiating ability.
▪ Using adenoviral gene therapy with p53, which has so far been unsuccessful. But when combined with interferon alpha and an agent called Syn 3, administered intravesically, it could result in gene transfer across the bladder to regress tumors.
Bladder Cancers Marked by Defective Checkpoint Function
Both p53-dependent and p53-independent cell cycle checkpoints, which help to maintain genetic stability, are frequently defective in bladder cancer cell lines, a new study has found.
Compared with normal human uroepithelial cells, bladder cancer cell lines had severely attenuated checkpoint function, report a team led by Sharon C. Doherty, PhD, of the University of Ulster in Northern Ireland and William K. Kaufmann, PhD, of the University of North Carolina Comprehensive Cancer Center.
“These functional defects in the bladder [cell] lines suggest that cell cycle checkpoints may represent barriers to bladder carcinogenesis,” they said in their article, published in the Dec. 17 issue of the Journal of the National Cancer Institute.
Active Smoking Associated with Increased Breast Cancer Risk
Active smoking appears to play a larger role in the development of breast cancer than previously thought, according to a study in the January 7 issue of the Journal of the National Cancer Institute (2004;96:29–37).
As explained in a news release, although metabolites of cigarette smoke have been found in the breast fluid of smokers, studies examining the association between tobacco smoke and breast cancer risk have yielded inconsistent results. Many studies have not been able to independently assess the contributions of the timing of exposure, age of diagnosis, or genetic susceptibilities to the overall risk of breast cancer.
In addition, many of these studies did not consider passive smoking exposures, or exposure to secondhand smoke, among nonsmokers.
A team led by Peggy Reynolds, PhD, of the California Department of Health Services examined breast cancer risk among 116,544 women in the California Teachers Study who had reported their smoking status on a survey given to them when they enrolled in the study.
Between 1996 and 2000, a total of 2,005 of the women were diagnosed with invasive breast cancer. The incidence of breast cancer among current smokers was approximately 30% greater than that among women who had never smoked, irrespective of whether they were compared with women who had or had not been exposed to passive smoking.
Analysis of subgroups of active smokers revealed increased breast cancer risks among women who started smoking before age 20, who began smoking at least five years before their first full-term pregnancy, and who had a longer duration of smoking or who smoked 20 or more cigarettes per day.
Current smoking was associated with increased breast cancer risk in women without a family history of breast cancer but not among women with a family history of the disease.
There was no statistically significant increase in breast cancer risk among former smokers, and there was no evidence of an association between passive smoking exposure and breast cancer risk.
Online Bladder Cancer Information Often Outdated
Thirty-two percent of Web sites about bladder cancer contain inaccurate or outdated information, according to a study by researchers at the University of Michigan Health System. And of a list of 41 factors related to bladder cancer, 32% of sites covered fewer than half the issues.
The research team, Cheryl T. Lee, MD, Assistant Professor of Urology ad Director of the Bladder Cancer Program, searched the term “bladder cancer” on the eight most frequently used Internet search engines. They looked at the first 30 results retrieved from each search, for a combined 240 sites, eventually narrowing the list down to 38 unique, working Web sites.
“We found many of the same sites came up in different search engines,” Dr. Lee and her colleagues said. “The searches also returned broken links or pages that only linked to another site, so the whole search process could be frustrating to patients seeking information.” The study was published in the November issue of the Journal of Urology.
They developed a checklist rating system based on practice guidelines from consensus panels to assess the extent of information on each Web site, and two urologic oncologists used the checklist to evaluate each site.
No site included information on all 41 checklist items. Most sites contained information on signs and symptoms, tobacco and chemical exposure as risk factors, diagnostic tests, and treatments. Only one site accurately included more than 90% of the factors, while 12 sites covered fewer than half.
For example, 84% of sites mentioned tobacco use as a major risk factor for bladder cancer, but only 58% mentioned that quitting smoking could help prevent the disease.
Further, fewer than half the sites discussed follow-up care. Treatment information was also limited, with most sites describing cystectomy, but fewer sites also included information on urinary diversion.
Six factors were presented inaccurately on some sites: incidence, staging, tobacco as a risk factor, recurrence, treatment of muscle-invasive disease, and treatment of metastatic disease.
The inaccuracies were generally due to outdated information, not blatantly false statements. For example, information on incidence used statistics from 2001 or earlier, and staging explanations did not reflect a system put in place in 1997.
“Even though the inaccuracies seldom reflected flat-out false statements, a 32% inaccuracy rate is still disturbing,” Dr. Lee said in a news release. “Other studies have found that online information about melanoma is inaccurate only 14% of the time and for sarcoma, only 6% of the time.”
Doctors must be proactive to help their patients obtain quality information, she continued. This could include assessing Web site information, contributing materials for online publication, or offering patients a list of reliable Web resources.
She and her coauthors recommended four sites:
▪ The NCI: www.cancer.gov/cancer_information/cancer_type/bladder/
▪ All Refer Health: www.1uphealth.com/medical/disease/cancer-disease/bladder-cancer-1.html
▪ The Cancer Information Network: www.cancerlinksusa.com/bladder/home.html
▪ MEDLINEplus: www.nlm.nih.gov/medlineplus/
Congress Encourages Organ Donation
The Senate unanimously passed the Organ Donation and Recovery Improvement Act (S 573) in November. Sponsored by Senator Bill Frist (R-TN), the bill aims to increase the number of organs available for transplants.
HHS estimates that there are more than 83,000 people waiting for an organ transplant. On the other hand, an AMA report about a year ago pointed out that one quarter of the families of eligible donors are not asked about organ donation—and over half of those asked refuse donation.
The $25 million bill will provide grants for travel and subsistence costs to living donors, establish organ donation programs at eligible hospitals, and create a public education campaign to encourage donation.