Commentary (Soloway): Management of Patients With Muscle-Invasive and Metastatic Bladder Cancer

High-grade urothelial cancer of the bladder is not only relatively common but unfortunately, is frequently lethal. These tumors are often diagnosed when the tumors have already invaded the wall of the bladder. Even when they are diagnosed at a time when they are confined to the mucosa or lamina propria, patients may not respond to a bladder-preservation approach. Often a radical cystectomy with urinary diversion is either not offered at all or not considered until the cancer has invaded deep into the muscularis propria and local treatment fails. What would it require to improve the prognosis for patients with highgrade bladder cancer? I believe two critical components would be an education program directed at primary care providers regarding the need for prompt investigation of hematuria and an early detection trial directed at current and former cigarette smokers. It is very unfortunate to see so many men and women with locally advanced bladder cancer relate how they had either hematuria or voiding symptoms weeks or months prior to their eventual correct diagnosis. Guidelines and Prognostic Factors
Most patients with bladder cancer present with either microscopic or gross hematuria. All too often, however, the initial treatment is antibiotics with the presumptive diagnosis of a urinary tract infection. If one follows current guidelines, any patient who has smoked cigarettes or is older than 50 should have a cystoscopy and a urine cytology to determine whether the hematuria is related to a urinary tract malignancy. In addition to the evaluation of the lower urinary tract by endoscopy, upper-tract imaging is also required. Once a diagnosis of bladder cancer is established, each patient can be categorized by the degree of risk, based primarily on tumor grade and stage. Following the initial tumor resection, patients with lowgrade, low-stage bladder cancer are at little risk for progression; however, those who have a high-grade urothelial malignancy must be carefully evaluated and closely observed even if disease is initially confined to the mucosa or lamina propria. As I have stated already, we need some poster boys to help us educate the public about the signs and symptoms of bladder cancer.[1,2] Look at what Katie Couric has done for the awareness of colon cancer. I have yet to find any television program even mentioning bladder cancer much less discussing the warning signs and indicating the risk factors. Once a diagnosis of a high-grade urothelial cancer that has invaded the muscularis propria is established, other prognostic factors should be considered to determine whether systemic chemotherapy should be incorporated into the initial treatment plan. If there is lymphovascular invasion, a clinical stage of T3 or T4, invasion of the prostatic stroma or upper-tract obstruction, I believe one should consider beginning treatment with chemotherapy. The authors established a nice case for neoadjuvant chemotherapy in this circumstance. Completed randomized trials are consistent with a 5% survival advantage for neoadjuvant chemotherapy. Evidence from a single institutional trial has shown that if perioperative chemotherapy is to be used, it is not critical for it to be introduced prior to and then subsequent to cystectomy, but five cycles adjuvant to cystectomy provides a similar result.[ 3] Nevertheless, there is a rationale in my view to initiate treatment with systemic chemotherapy. The two most compelling reasons are that
(1) the blood supply to the tumor is not interrupted prior to surgery; and
(2) the 20% perioperative complication rate related to radical cystectomy and urinary diversion poses the risk that the initiation of adjuvant chemotherapy may be delayed. As we have learned from adjuvant trials, many patients who may benefit from chemotherapy after major surgery such as a radical cystectomy either refuse chemotherapy or experience delays in the planned treatment due to a prolongation of the postoperative convalescence. Limitations of Radical Cystectomy
One of the major dilemmas in discussing the management of patients with locally advanced urothelial cancer of the bladder is why more patients who have locally advanced bladder cancer are not offered radical cystectomy. First of all, radical cystectomy is a lengthy, technically demanding operation with, as mentioned, a rather high perioperative complication rate. Although the majority of its morbidity is related to fairly minor complications such as postoperative ileus or wound infection, there can be serious complications requiring intensive postoperative monitoring and 24-hour vigilance. Many of these patients, because of their smoking history, have compromised cardiac or pulmonary reserve. Thus, urologists and their patients are likely to be wary of undertaking this major surgery. Although a bladder-preservation approach consisting of a "complete" transurethral tumor resection followed by systemic chemotherapy and external- beam radiation therapy can be a reasonable alternative, this requires the expertise and coordination of three specialists (urology, radiology, and medical oncology). It is more expensive than surgery and has morbidities related to both the radiation and the chemotherapy. In addition, the vast majority of patients I evaluate are not candidates for this approach because the extent of the tumor in the bladder does not allow for a "complete" transurethral resection (TUR), which is one of the prerequisites. Most patients with cT2-T3 bladder cancer should be referred to a major medical center. This is not always possible, as many patients are unwilling to travel to a "strange" environment for their medical care. For those who consent to bladder removal, the neobladder has dramatically improved the acceptance of radical cystectomy. Most patients are able to void per urethra without intermittent catheterization, and the complication rate is no higher than for a diversion with a stoma. Role of Systemic Chemotherapy
Although there is obviously a need for improvement in the effectiveness of systemic chemotherapy, it is important to recognize that up to 40% of patients who undergo a radical cystectomy following a TUR and neoadjuvant chemotherapy have no residual cancer. The pT0 rate is about 10% with no prior chemotherapy (TUR only) prior to cystectomy. Although some of these patients who are pT0 still relapse, their prognosis is far better than those who have residual cancer after two or three cycles of neoadjuvant systemic chemotherapy. One of the goals for future exploration is to find a molecular marker to identify patients who can avoid either cystectomy or external-beam radiation therapy after chemotherapy. Unfortunately, a repeat TUR is not 100% accurate when no tumor is identified. When such patients undergo a cystectomy, some of them who had no tumor evident by TUR still have residual tumor found in the removed bladder. Henry et al have written a terrific review of the current role of chemotherapy for locally advanced and metastatic urothelial cancer of the bladder. There has been progress in treating patients in this setting-better drugs, better surgery, better perioperative care. One of our challenges is to encourage the media to help us educate the public about this cancer.

Disclosures:

Dr. Hussain receives research support from and is a consultant for Bristol-Myers Squibb, and has received research support from Genentech.

References:

1. Soloway MS: Where are the ‘poster boys’ for bladder cancer? BJU Int 91:769-770, 2003.
2. Soloway MS: Editorial: Bladder cancer. How can we make a difference? J Urol 170:1781- 1782, 2003 .
3. Millikan R, Dinney C, Swanson D, et al: Integrated therapy for locally advanced bladder cancer: Final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 19:4005-4013, 2001.