It is estimated that, in 1995, about 50,500 new cases of urinary bladder cancer will be diagnosed and that 11,200 patients will die of the diease. The most common malignant tumor of the urinary tract, bladder cancer accounts for 6.5% of all cancers annually. It is the fifth most common cancer among American men , and approximately three quarters of all cases occur in men.
It is estimated that, in 1995, about 50,500 new cases of urinary bladder cancer will be diagnosed and that 11,200 patients will die of the diease. The most common malignant tumor of the urinary tract, bladder cancer accounts for 6.5% of all cancers annually. It is the fifth most common cancer among American men , and approximately three quarters of all cases occur in men.
Seventy-five percent of bladder cancers are superficial (confined within the lamina propria) at diagnosis. About 50% to 80% of superficial cancers recur, but only 15% to 20% progress to invasive disease (ie, tumors spreading beyond the lamina propria). Despite aggressive surgery or radiation, 50% of patients with muscle-invasive disease ultimately die of cancer . For patients with metastatic disease, cytotoxic chemotherapy is the only available option, and the chances of long-term survival are minimal.
Understanding the mechanism of tumor progression and improving the results of treatment remain the most important research and clinical management issues surrounding bladder cancer. This chapter will review the risk factors, molecular biology, pathology, diagnosis, and currently available options for and results of treatment of the disease.
Bladder cancer is predominantly a disease of the elderly male. The peak age of incidence is the seventh decade, and the male-to-female ratio is 3 to 1.
The incidence is higher in American whites than American blacks, higher in Western industrialized countries than African and Asian nations, and higher in urban areas than rural areas. These trends suggest a role for industrial substances in the development of bladder cancer . Chemical carcinogens that have been linked with bladder cancers, such as 2-naphthylamine, benzidine, and 4-aminobiphenyl, are associated with several occupations: aniline dye, rubber, and textile work; painting; leather processing; and hairdressing [3–5].
Cigarette smoking is the single greatest risk factor for bladder cancer; it is responsible for at least 50% of the cases in men. Compared with the nonsmoker, the smoker has twice the risk of developing the disease. Moreover, the risk is dose related; persons who stop cigarette smoking have an intermediate risk between those for the smoker and the nonsmoker. Among smokers, pipe and cigar smokers have a relatively low risk of developing the disease, and chewing tobacco does not predispose to bladder cancer at all [3,6,7].
Phenacetin-containing analgesics have been implicated in the pathogenesis of urothelial neoplasms. The effect of these analgesics is cumulative; women who have been taking phenacetin or one of its derivatives for 20 years or longer have an increased risk of developing urothelial cancer [8,9]. Chronic bladder infections or irritations, such as bilharziasis, bladder stones, and conditions requiring chronic indwelling catheterization, are associated with the development of squamous-cell carcinoma of the bladder [3,10,11]. Evidence suggesting that dietary factors such as coffee and artificial sweeteners are carcinogenic has been inconsistent [12-14]. On the other hand, milk and vitamin A have been associated with a decreased risk of bladder cancer .
Familial bladder cancer accounts for a very small population of the patients with bladder cancer. A large case-control study suggested that a combination of genetic and environmental factors contributes to the occurrence of bladder cancer in these families. The estimated relative risk of developing the disease is 1.45 for a person with a family member who developed bladder cancer before the age of 45 years .
Although information on genetic changes in bladder cancer has been emerging in recent years, it is still too early to routinely apply these biologic markers in clinical practice. However, the results are intriguing and have potential for facilitating the diagnosis and management of bladder cancer.
The chromosomal studies of bladder cancer, as for most of the solid tumors, are very complicated, and results have been inconsistent. Using molecular biologic techniques, investigators are able to examine structural and numerical chromosomal changes and allelic deletions. Deletion of part or all of chromosome 9 was found in all stages of bladder cancer, suggesting that these changes may be responsible for early bladder carcinogenesis [16,17]. An increasing copy number of chromosome 7 was found to correlate with high tumor grade and proliferation . Deletions of 3p, 11p, and 17p occurred predominantly in tumors of advanced stage; genes lost at these areas might be associated with tumor progression . However, despite the advances in genetic studies, most of the affected genes in bladder cancer and their biologic functions remain unknown. The potential clinical relevance of these altered genes should be further investigated.
The gene most frequently changed in bladder cancer and probably the most important gene in the progression of the disease is p53. The incidence of p53 mutations was 50% to 60% in the bladder tumors examined by DNA sequencing or by expression of the p53 protein [20-22]. Moreover, the presence of p53 mutation correlated with high-grade, invasive tumors [21-22].
A recent study conducted by Esrig et al showed that 42% of 243 cystectomy specimens containing bladder cancer of all stages had overexpression of the p53 protein; this overexpression independently predicted a significantly increased risk of disease recurrence and death in this population . Another study revealed that 48% of patients with carcinoma in situ (CIS) of the bladder had overexpression of the p53 protein; 86.7% of those with p53 overexpression subsequently developed progressive disease, compared with only 16.7% of patients without overexpression .
The presence of p53 mutation is probably the cause of the biologically aggressive behavior of CIS of the bladder. In contrast, the incidence of p53 mutation in low-grade, low-stage papillary bladder cancer is very low. Therefore, it has been hypothesized that there are dual molecular pathways in the tumor progression of superficial bladder cancer based on the presence of p53 mutation .
Allelic loss of the retinoblastoma (Rb) gene has been shown in 28 of 94 patients with transitional-cell carcinomas. Rb loss happened significantly more frequently in tumors of high grade and advanced stage . Altered expression of the Rb protein (total or partial absence of Rb expression), which represents losing all or part of the Rb gene, was reported in 34% of one series of patients with muscle-invasive disease  and in 37% of another such series . Altered Rb expression was associated with poor prognosis and shorter tumor-free survival [26,27].
The role of oncogenes in bladder cancer is not as significant as in other solid tumors. The incidence of overexpression of HER-2/neu in bladder cancer is one of the highest among all human malignancies, ranging from 9% to 34% of cancers tested [28,29]. It was more frequently found in tumors of high grade and advanced stage. About 7% to 20% of bladder tumors were reported to contain a ras mutation, but the clinical significance of this mutation is not known [30,31]. Expression of epidermoid growth factor receptor in bladder tumors has been associated with the progression of muscle-invasive disease .
The majority of bladder cancers originate in the urothelium, the characteristic transitional-cell epithelium lining the urinary tract from the renal pelvis to the proximal urethra. In the United States, 85% to 95% of bladder cancers are transitional-cell carcinomas. Mixed tumors containing squamous-cell carcinoma and adenocarcinoma elements are reported at various rates between 10% and 30%. Pure squamous-cell carcinoma occurs in less than 3% of bladder cancers in the United States, but in areas where bilharziasis is epidemic (eg, Egypt), squamous-cell carcinoma of the bladder is the most common malignancy . Adenocarcinoma accounts for 2% of bladder cancers; most occurs on the trigone of the bladder. A particular subset of adenocarcinomas arising from the urachus remnant locate over the dome of the bladder. About 70% to 80% of bladder cancers occur on the lateral or posterior walls of the bladder, and 20%, on the trigone. Thirty percent of tumors are multifocal at diagnosis [33,34].
The grading of transitional-cell carcinoma is based on the cellular atypia, nuclear abnormalities, and number of mitoses. At M.D. Anderson Cancer Center, bladder tumors are classified according to World Health Organization criteria into three categories: grades 1, 2, and 3. Low-grade (grade 1) tumors usually grow superficially with papillary patterns, whereas high-grade (grade 3) tumors are usually solid and invasive .
Carcinoma in situ is a histologically and biologically distinct cancer of the bladder. The tumor, by definition, is a superficial, nonpapillary, noninfiltrating flat neoplasia characterized by cellular anaplasia and nonspecific inflammatory changes. Brunn's nests (outpocketings of epithelium into the lamina propria) are a characteristic feature of this type of neoplasm . CIS frequently occurs in patients with other types of bladder tumors and can be close to the tumor (in 26% to 40% of cases) or remote from it .
Primary bladder tumors with CIS have a high frequency of recurrence and progression . A retrospective study showed that 40% of patients with CIS developed invasive disease within 5 years . Diffuse CIS in the absence of another type of tumor is a distinct subset of CIS; it usually involves 50% to 85% of the bladder mucosa. Presentation with bladder-irritative symptoms but nonspecific inflammatory cystoscopic findings are its characteristic features. Because the adhesion molecule is lost in CIS, the anaplastic cells easily shed into the lumen of the urinary tract; urine cytology tests yield positive results in over 90% of cases .
There are no pathognomonic symptoms or signs of bladder cancer. Painless intermittent gross hematuria or microscopic hematuria is the leading sign, occurring in over 75% of patients. About 30% of patients, particularly those with invasive disease or CIS, have irritative symptoms such as dysuria or urinary frequency. Pelvic pain and symptoms of rectal obstruction occur in locally advanced disease; flank pain often results from ureteral obstruction.
The standard procedure for diagnosis and staging of bladder cancer is cystoscopy and bimanual examination under anesthesia (EUA). All visible tumors should be removed, and multiple random biopsies of the bladder wall, including the trigone and prostatic urethra, should be performed to rule out the presence of CIS or dysplasia. Cold-cup biopsy is preferred to avoid the effects of cautery, and the biopsy should extend deep into the muscle layer to enable determination of the depth of tumor invasion. EUA should be performed immediately after cystoscopy to assess the extent of disease (the thickness of the tumor and its mobility) and to determine the clinical stage. However, the accuracy rate of staging by EUA is less than 50%, usually because the inflammatory reaction blurs the tumor margin .
Urine cytologic analysis and flow cytometry are useful for screening high-risk populations and for follow-up after tumor resection and the histologic diagnosis of CIS. The clinical application of flow cytometry is limited to patients who are known to have aneuploid chromosome numbers. Nonetheless, in these patients, this technique is more sensitive than cytologic analysis in detecting minimal or recurrent disease. The cell yield for these studies may be increased by brisk bladder lavage with normal saline during each cystoscopic examination.
Complete cell counts, biochemical survey, and urinalysis should be done prior to treatment. There is no serologic marker specific to bladder cancer, although elevation of serum levels of carcinoembryonic antigen and beta-human chorionic gonadotropin is not uncommon in cases of the disease. Radiographic studies are selected according to the clinical indication. Computed tomographic scans help in evaluating the tumor extent and metastasis. Intravenous pyelography is useful in detecting synchronous urothelial tumors of the upper urinary tract. Plain chest x-rays are routinely performed to evaluate pulmonary metastasis. Bone scan is indicated in patients with clinical symptoms suggestive of bone metastasis.
There are two staging systems for bladder cancer: the American Joint Committee on Cancer/International Union Against Cancer Tumor-Node-Metastasis (TNM) system and the Jewett-Marshall staging system. The latter was originated from the observation by Jewett that the depth of tumor invasion correlated with the tumor's clinical behavior and progression . The two systems are compared in Table 1. Generally, the TNM system is preferred and accepted universally.
|O||T0||No definitive tumor|
|Tis||Carcinoma in situ|
|A||Ta||Papillary tumor without invasion|
|T1||Lamina propria invasion|
|B-1||T2||Superficial muscle invasion|
|B-2||T3a||Deep muscle invasion|
|C||T3b||Perivesical fat invasion|
|D-1||T4||Prostate, vagina, uterus, or pelvis side wall invasion|
|D-2||N1-3||Pelvic lymph-node metastasis|
|D-3||M||Lymph-node metastasis beyond pelvis|
Table 2 summarizes the nodal classifications utilized in the TNM system.
|N1||Metastasis in single node, < 2 cm|
|N2||Metastasis in bilateral lymph nodes, or single node > 2 cm but < 5 cm|
|N3||Metastasis in any node > 5 cm|
|M||Lymph-node metastasis beyond pelvis, or distant metastasis|
Most patients with superficial disease do not die of bladder cancer. The goals of management in this group are to reduce the morbidity from recurrence and to prevent progression in the patients who are potentially at risk. In contrast, patients with invasive disease have a grave prognosis despite aggressive surgery or radiotherapy. The aims of management in this group are to improve the fraction of patients who achieve remission and to assure the best possible quality of life.
Transurethral bladder resection is the treatment of choice for superficial disease, which includes stages Ta, T1, and Tis (CIS). Other modalities include fulguration and photodynamic therapy. More than 80% of lesions can be controlled locally by surgery alone, but 30% to 80% of them will recur. Patients with the following conditions tend to have recurrences: high-grade tumor, multiple primary tumors, presence of cellular atypia, more than three previous recurrences, and endoscopically observed residual tumor .
A retrospective study of patients with low-grade tumors showed that 80% of the recurrences happened within 3 months of the first resection . The frequency of progression in stage and grade of the recurrences varied, ranging from 4% to 30% for stage and 10% to 30% for grade. Tumor stage and grade correlated with the incidence of recurrence and with survival. The NBCCGA study showed frequencies of progression of 4% for stage Ta tumors, 30% for stage T1 tumors, 2% for grade 1 tumors, and 45% for grade 3 tumors. The 10-year survival rates were 95% for patients with stage Ta, grade 1 tumors and only 50% for patients with stage T1, grade 3 tumors .
Carcinoma In Situ
Local CIS can be controlled by resection only. For multifocal or diffuse CIS, surgical resection and fulguration of the mucosal lesions plus intravesical therapy is the treatment of choice. Prognostic factors that indicate whether a patient is better suited for endoscopic resection or for cystectomy include the extent of disease, association with irritative symptoms, and a history of prior disease. Cystoprostatectomy is indicated when the lesions are not controlled by endoscopic resection, the bladder is severely contracted, intravesical therapy has been unsuccessful, or there is histologic evidence of persistent CIS of the prostatic duct or of stromal invasion . Panurothelial CIS, which involves the whole epithelium of the urinary tract, frequently recurs in either the upper urinary tract or the distal urethra despite radical surgery. The prognosis for patients with panurothelial CIS is dismal.
Intravesical therapy-the administration of cytotoxic agents or an immunomodulator through a catheter into the urinary bladder-has been empirically tried in patients with superficial disease as either primary or adjuvant treatment. The indications for intravesical therapy include a T1 tumor, multiple Ta tumors or a high-grade (grade 2 or 3) Ta tumor, CIS, and positive cytologic results after bladder tumor resection . Complete removal of all gross tumor is required before intravesical therapy to improve treatment results. The currently available agents for this type of therapy are doxorubicin (Adriamycin, Rubex), thiotepa, mitomycin (Mutamycin), and bacillus Calmette-Gurin (BCG); tumors that fail to respond to a full course of one drug often respond to another drug. Patients should receive follow-up with cystoscopic examination and urinary cytologic analysis every 3 months for 1 year, then every 6 months for the next 2 years, and then annually.
In patients with superficial disease, adjuvant intravesical mitomycin administration has been proven to decrease recurrence rates from 51% to 10% at 1.5-year follow-up . BCG was thought better than doxorubicin and thiotepa and at least as good as mitomycin in preventing recurrence and possibly in prolonging disease-free survival and avoiding the need for cystectomy . Although the optimal preparation, dose, and schedule of intravesical BCG therapy are not clear, 6-week consecutive therapy is preferred by most clinicians. In one study, maintenance therapy for longer than 6 weeks did not improve response and resulted in more complications than 6-week therapy . Schellhammer et al reported a complete response rate of 71% in 28 patients with superficial disease using a 6-week BCG schedule . A randomized study comparing transurethral bladder resection with resection followed by intravesical BCG showed significant differences in complete response rate (8% vs 65%) and in frequency of subsequent salvage cystectomy (35% vs 7%) . At Memorial Sloan-Kettering Cancer Center, long-term results in CIS patients who received BCG showed a 54% disease-free survival at 10 years; 33% of these patients retained a functional bladder .
The toxic effects of intravesical therapy include myelosuppression, local irritative symptoms, and systemic toxic effects. Mitomycin is associated with the least systemic toxicity because of its large molecule, but thiotepa has the highest incidence of myelosuppression. BCG induces local granulomatous inflammation over the bladder wall and results in irritative symptoms. Fever occurs in 20% to 30% of patients, and other systemic side effects, including pneumonitis, hepatitis, arthritis, arthralgia, skin rash, and sepsis, have been reported in 5% of patients. Only a small proportion of these patients need antituberculous treatment .
The treatment of choice for muscle-invasive disease is radical cystectomy with urinary diversion and bilateral pelvic lymph-node dissection. Many investigators have been attempting to preserve a functional bladder by limiting the extent of surgery when possible without compromising the results.
Conservative Management: For patients with superficial solitary muscle-invasive disease, a simple endoscopic resection may be curative. In a study at Memorial Sloan-Kettering Cancer Center, patients underwent secondary endoscopic resection after primary endoscopic resection of muscle-invasive bladder tumor. Those whose secondary resection showed no evidence of recurrence had a 65% disease-free survival rate (with a functioning bladder) and an 82% overall survival rate at 5 years .
For patients who have only one muscle-invasive tumor without CIS or dysplasia elsewhere, partial cystectomy is another alternative for attaining long-term disease control with less morbidity. The tumor should preferably be located on the dome or posterior wall of the bladder and should have at least a 2-cm surgical margin. Some surgeons also suggest preoperative radiotherapy to offer better regional control and prevent intraoperative seeding. However, the patients who are candidates for radiotherapy account for less than 5% of the total population of those with muscle-invasive bladder tumors .
Radical Surgery: Radical cystectomy with urinary diversion or construction of an internal reservoir and bilateral pelvic lymph-node dissection provide optimal control of muscle-invasive disease. This method enables the surgeon to prevent most local recurrences. Thus, the majority of recurrent tumors are distant metastases. Those patients who have multifocal primary tumors, diffuse CIS, or tumor in the prostatic urethra have significantly higher local recurrence rates. The overall survival rate of patients with muscle-invasive disease is about 50%; survival correlates with the depth of tumor invasion. The 5-year survival rate of patients with pathologic stage P2 and P3a tumors ranges from 60% to 80%. In patients with stage P3b or more advanced tumors, the 5-year survival rate drops to below 30% [2,54,55].
Other Treatment Modalities: Primary radiotherapy (usually 5,000 to 7,000 cGy) with or without salvage surgery has been used mostly in Great Britain and Canada. The complete response rate to this treatment is approximately 40% to 50%, and the 5-year survival rate ranges from around 30% to 45% [56,57]. In the United States, most primary radiotherapy is given to patients who have intercurrent disease or unresectable tumor. Therefore, the different patient populations preclude definitive comparison between primary radiotherapy and surgery. Local disease recurrence remains the major problem after radiotherapy. In one series, 25% of the cancer-related deaths resulted from local recurrence .
Preoperative radiotherapy (usually involving doses less than 4,000 cGy) followed by surgery has shown benefit in prolonging survival in both retrospective analyses and nonrandomized studies, but the only three prospective randomized trials have failed to confirm this result . The optimal schedule and dose of preoperative radiotherapy are undetermined, and the potential advantage remains controversial.
Neoadjuvant and Adjuvant Chemotherapy: The fact that the majority of recurrences of locally advanced bladder tumors are in the form of distant metastases suggests that subclinical micrometastases were present in these cases at the time of surgery. Integrating systemic cytotoxic chemotherapy and primary surgery using various schedules to prevent distant metastasis and prolong survival has been increasingly studied. Most of the reported results are from phase II studies. Although the response rates are promising, a survival benefit has not been confirmed .
Using the MVAC regimen (methotrexate, vinblastine, doxorubicin, and cyclophosphamide [Cytoxan, Neosar]) for preoperative chemotherapy, 27% of 71 patients (85% of whom had stage T3 or T4 tumors) had a complete response, and an additional 14% were downstaged to superficial in situ disease. With a median follow-up of 24 months, 58% of the complete responders remained free of disease . Another randomized study has not shown a survival difference by using cisplatin (Platinol) as neoadjuvant therapy . Currently there are several larger multi-institutional randomized neoadjuvant chemotherapy trials ongoing in North America and Europe.
Three single-institution trials have shown benefits of adjuvant chemotherapy. At M. D. Anderson Cancer Center, a three-arm trial compared low-risk patients who underwent surgery alone with high-risk patients (those with stage T3b or T4 tumor, nodal disease, and/or vascular and/or lymphatic invasion of primary tumor) who underwent surgery with or without adjuvant chemotherapy using the CISCA regimen (cisplatin, cyclophosphamide, and doxorubicin). The survival curve for high-risk patients receiving adjuvant chemotherapy was similar to that for low-risk patients. The 5-year survival rates for high-risk patients were 70% for the adjuvant group vs 35% for the nonadjuvant group .
At the University of Southern California, a delay in time to progression was found in 71 patients with pathologic stage T3 or T4 disease and/or positive nodal metastases treated with three cycles of CISCA; 70% of patients who received CISCA were free of disease at 3 years compared with only 46% of patients who did not receive CISCA. The difference in median survival (4.3 years with CISCA vs 2.4 years without CISCA) was statistically significant . Another trial using three cycles of MVAC as an adjuvant regimen was closed prematurely because of higher relapse rates in the nonadjuvant arm . Despite the positive results of the three trials, several inadequacies preclude a definite conclusion.
In summary, although the general belief is that the promising results of combination chemotherapy for bladder cancer in the adjuvant setting should translate into prolonged survival, the role of chemotherapy as an adjunct to primary therapy is still undefined. The difficulties in evaluating these trials include the varied criteria in patient selection, the lack of an effective regimen and optimal dose schedule, and the lack of a large-scale multi-institutional trial. Currently the recommended criteria for patients entering adjuvant trials are as follows: locally advanced primary tumor (stage T3b or T4), nodal disease, and vascular or lymphatic invasion by the primary tumor. Any form of adjunctive chemotherapy should be considered experimental.
Bladder Preservation: Endoscopic resection of the primary tumor with concurrent or sequential chemoradiotherapy has been shown to obtain long-term disease control while allowing the patient to retain a functioning bladder or to delay the cystectomy. In a nonrandomized trial of cisplatin-based regimens, the complete response rates were about 70% to 80%, with a 70% 2-year survival rate. Seventy percent of these patients did not require cystectomy at 2 years [64,65]. The patient population met highly selective criteria: stage T2 or T3a tumor, no evidence of CIS, and an adequate bladder capacity.
In patients with advanced localized disease, the ability to sterilize tumors by combined modalities is questionable. Because of the potential risk of local recurrence, continuous surveillance is mandatory . With the goal of maintaining a functioning bladder but not reducing long-term survival, primary treatment using combined modalities deserves further investigation in patients with superficial muscle-invasive disease.
Metastatic Bladder Cancer
Systemic cytotoxic chemotherapy remains the only option for treating patients with metastatic bladder cancer. With combination chemotherapy, a substantial frequency of tumor response has been achieved, including a significant proportion of complete responses. However, the disease continues to recur even with complete response, and long-term survival is rare. Further studies of new regimens or new modalities are urgent and ongoing.
Single-agent chemotherapy has been tested widely; complete response is uncommon, and responses last about 3 to 4 months. Cisplatin administered every 3 to 4 weeks is the most active regimen, producing an overall response rate of 30%. Methotrexate administered in a weekly or biweekly schedule has a pooled response rate of 29%. Response rates for other single agents are shown in Table 3 . A recent phase II trial of paclitaxel (Taxol) in 26 previously untreated patients showed an overall response rate of 42% and a complete response rate of 27%; the median response duration was 7 months . Nevertheless, this promising result needs to be confirmed.
|Agent||Response rate (%)|
Combination chemotherapy is currently the most accepted modality for metastatic bladder cancer and has shown significant antitumor activity. The initial study at M.D. Anderson Cancer Center of CISCA in patients with transitional-cell carcinoma of the bladder revealed an overall response rate of 70% and a complete response rate of 39%. The median response duration in complete responders was 100 weeks . Subsequently, other investigators have reported variable response rates to CISCA ranging from 13% to 70%, with a median rate of 46% .
The cisplatin, methotrexate, and vinblastine (CMV) regimen, first studied at Stanford University, was reported to have a 28% complete response rate and an additional 28% partial response rate. The median survival in complete responders was 11 months, compared with 6 months in nonresponders . The average response rates from other similar trials have ranged from 35% to 74%, with 20% to 30% complete response rates . Although there has not been a comparative study with single-agent chemotherapy, both combination regimens were thought to be promising and to have acceptable side effects in the early 1980s.
MVAC, the four-drug combination regimen developed in 1983 by Memorial Sloan-Kettering Cancer Center , has been the most popular regimen used in the United States. Response rates ranging from 40% to 72%, with approximately 25% to 30% complete responses, were reported . The response duration was reported to be as long as 38 months in patients with complete responses but only 11 months in partial responders . A randomized study comparing MVAC with cisplatin alone disclosed significant differences in terms of response rate (39% vs 12%) and median overall survival (12.5 vs 8.2 months) .
At M.D. Anderson Cancer Center, Logothetis et al conducted a prospective randomized study comparing MVAC with CISCA. The response rates were 65% and 46%, respectively, and median survivals were 48 and 36 weeks; thus, MVAC showed significant superiority over CISCA . Overall, the majority of complete responses occurred in patients with lymph-node metastases. Patients with liver metastases had the worst result. Pure transitional-cell carcinomas had a significantly higher response rate than mixed tumors [68,70].
About 15% of patients with metastatic disease achieve durable remission with combination chemotherapy. Long-term follow-up in patients treated with MVAC has shown a 6-year survival of 32% for patients with nodal disease and 17% for those with advanced metastatic disease .
The toxic effects of MVAC are significant; myelosuppression, sepsis, mucositis, nephrotoxicity, and neuropathy are not uncommon, and toxic death has been reported but is rare [53,70,72]. Patients with a long conduit or internal reservoir that can retain a significant amount of fluid may have decreased methotrexate clearance, leading to prolonged mucositis or myelosuppression .
Several modified MVAC regimens have been proposed, such as eliminating vinblastine and methotrexate on days 15 and 22, replacing doxorubicin with epirubicin (Farmorubicin), and replacing cisplatin with carboplatin . The purpose of these modifications is to reduce the toxicity without affecting the response rate. The results of phase II studies of these modified regimens are promising but still immature. Escalating the dose of MVAC with granulocyte-macrophage colony-stimulating factor rescue in 30 patients who had failed standard MVAC also produced a significant response rate of 40% . However, the modest increase in dosage of MVAC did not produce a substantially different response rate from that of front-line therapy in the subsequent phase II study .
Non-cisplatin-based regimens have increasingly been developed recently. A phase II study combining vinblastine, ifosfamide (Ifex), and gallium nitrite (Ganite) reported an overall response rate of 67%, with a 19% complete response rate . Other regimens, such as those using as analogs of methotrexate and taxanes, have been studied in various stages of clinical trials. Preliminary results are promising, and further combination trials are under investigation .
A biologic modifier combined with cytotoxic chemotherapy, ie, alpha interferon (IFN-alfa) plus flourouracil, produced a response rate of 30% in 32 patients who did not respond to previous cisplatin-based regimens . Moreover, a current study in patients with metastatic disease is comparing standard MVAC with a new combination, consisting of fluorouracil, cisplatin, and IFN-alfa.
In summary, current front-line chemotherapy for metastatic bladder cancer remains MVAC and CMV. The MVAC regimen has produced better response rates and survival than single-agent cisplatin or CISCA. Modifications of MVAC are indicated for those who cannot tolerate standard MVAC or for use in clinical research. The new non-MVAC regimens, which have shown significant antitumor activity in some clinical trials, may be another reasonable alternative if their efficacy is confirmed. However, in light of the fact that most patients with metastatic bladder cancer ultimately die of the disease, the ideal regimen or strategy for treatment has not yet been determined and warrants further investigation.
1. Wingo PA, Tong T, Bolden S: Cancer statistics, 1995. CA J Clin 45:8â30, 1995.
2. Fair WR, Fuks ZY, Scher HI: Cancer of the bladder, in Devita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practices of Oncology, 1052â1072. Philadelphia, JB Lippincott, 1993.
3. Silverman DT, Hartge P, Morrison AS, et al: Epidemiology of bladder cancer. Hematol Oncol Clin North Am 6:1â30, 1992.
4. Silverman DT, Levin LI, Hoover RN, et al: Occupational risk of bladder cancer in the United States: I. White men. J Natl Cancer Inst 81:1472â1480, 1989.
5. Hartge P, Harvey EB, Linehan MW, et al: Unexplained excessive risk for bladder cancer in men. J Natl Cancer Inst 82:1636â1640, 1990.
6. Augustine A, Hebert JR, Kabat GC, et al: Bladder cancer in relation to cigarette smoking. Cancer Res 48:4405â4408, 1988.
7. Burch JD, Rohan TE, Howe GR, et al: Risk of bladder cancer by source and type of tobacco exposure: A case-control study. Int J Cancer 44:622â628, 1989.
8. McCredie M, Stewart JH, Ford JM, et al: Phenacetin-containing analgesics and cancer of the bladder or renal pelvis in women. Br J Urol 55:220â224, 1983.
9. Piper JM, Tonocia J, Matanoski GM: Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. N Engl J Med 313:292â295, 1985.
10. Tawfik HN: Carcinoma of the urinary bladder associated with schistosomiasis in Egypt: The possible causal relationship. International Symposium of the Princess Takamatsu Cancer Research Fund 18:197â199, 1987.
11. Kantor AF, Hartge P, Hoover RN, et al: Urinary tract infection and risk of bladder cancer. Am J Epidemiol 119:510â515, 1984.
12. Hartge P, Hoover RN, West PW, et al: Coffee drinking and risk of bladder cancer. J Natl Cancer Inst 70:1021â1026, 1983.
13. Auerbach O, Garfinkel L: Histologic changes in the urinary bladder in relation to cigarette smoking and use of artificial sweeteners. Cancer 64:983â987, 1989.
14. Risch HA, Burch JD, Miller AB, et al: Dietary factors and the incidence of cancer of the urinary bladder. Am J Epidemiol 126:1179â1191, 1988.
15. Kantor AF, Hartge P, Hoover RN, et al: Familial and environmental interaction in bladder cancer. Int J Cancer 35:703â706, 1985.
16. Miyao N, Tsai YC, Lerner SP, et al: Role of chromosome 9 in human bladder cancer. Cancer Res 53:4066â4070, 1993.
17. Orlow I, Lianes P, Lacombe L, et al: Chromosome 9 allelic loss and microsatellite alternations in human bladder cancer. Cancer Res 54:2848â2851, 1994.
18. Walman FM, Carroll PR, Kerschmann R: Centromeric copy number of chromosome 7 is strongly correlated with tumor grade and labeling index in human bladder cancer. Cancer Res 51:3807â3813, 1991.
19. Presti JC Jr, Reuter VE, Galan T, et al: Molecular genetic alternation in superficial and locally advanced human bladder cancer. Cancer Res 51:5405â5409, 1991.
20. Sidransky D, von Eschenbach A, Tsai YC, et al: Identification of p53 gene mutations in bladder cancers and urine samples. Science 252:706â709, 1991.
21. Esrig DE, Elamjian D, Groshen S, et al: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331:1259â1264, 1994.
22. Cordon-Cardo C, Dalbagni G, Saez GI, et al: p53 mutation in human bladder cancer: Genotypic versus phenotypic pattern. Int J Cancer 56:347â353, 1994.
23. Sarkis AS, Dalbagni G, Cordon-Cardo C, et al: Association of p53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder. J Urol 152:388â392, 1994.
24. Spruck CH III, Ohneseit PF, Gonzalez-Zulueta M, et al: Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54:784â788, 1994.
25. Cairns P, Proctor AJ, Knowles MA: Loss of heterozygosity at the Rb locus is frequent and correlates with muscle invasion in bladder carcinoma. Oncogene 8:2305â2308, 1991.
26. Logothetis CJ, Xu H-J, Ro JY, et al: Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 84:1256â1261, 1992.
27. Cordon-Cardo C, Wartinger D, Petrylak D, et al: Altered expression of the retinoblastoma gene product: Prognostic indicator in bladder cancer. J Natl Cancer Inst 84:1251â1256, 1992.
28. Sato K, Moriyama M, Mori S, et al: An immunohistologic evaluation of c-erbB-2 gene product in patients with urinary bladder carcinoma. Cancer 70:2493â2498, 1992.
29. Coombs LM, Pigott DA, Sweeney E, et al: Amplification and overexpression of c-erbB-2 in transitional cell carcinoma of the urinary bladder. Br J Cancer 63:601â608, 1991.
30. Knowles MA, Willamson M: Mutation of H-ras is infrequent in bladder cancer: Confirmation by single-strand conformation polymorphism and direct sequencing. Cancer Res 53:133â139, 1993.
31. Agnantis NJ, Constantinidou A, Poulios C, et al: Immunohistological study of the ras oncogene expression in human bladder endoscopy specimens. Eur J Surg Oncol 16:153â160, 1990.
32. Ngugen PL, Swanson PE, Jaszez W, et al: Expression of epidermal growth factor receptor in invasive transitional cell carcinoma of the urinary bladder: A multivariate survival analysis. Am J Clin Path 101:166â176, 1994.
33. Pode D, Fair WR: The development of bladder cancer. AUA Update, vol 7, lesson 40. Bellaire, Texas, American Urological Associates, Office of Education, 1987.
34. Melicow MM: Tumor of the bladder: A multifaceted problem. J Urol 68:467â478, 1974.
35. Mostofi FA, Sobin LH, Torloni M: Histological typing of urinary bladder tumor, in International Histological Classification of Tumor, No. 10. Geneva, World Health Organization, 1973.
36. Friedell GH, Soloway MS, Hilgar AG, et al: Summary of workshop on carcinoma in situ of the bladder. J Urol 136:1047â1048, 1986.
37. Cooper PH, Waisman J, Johanston WH, et al: Severe atypia of transitional epithelium and carcinoma of the urinary bladder. Cancer 31:1055â1060, 1973.
38. Althausen AF, Prout GR Jr, Daly JJ: Noninvasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 116:575â579, 1976.
39. Tannenbaum M, Romas NA, Droller MJ: The pathobiology of early urothelial cancer, in Skinner DG, Lieskovsky G (eds): Genitourinary Cancer. Philadelphia, WB Saunders, 1988.
40. Farrow GM, Utz DC, Rife CC, et al: Clinical observation on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 37:2794â2798, 1977.
41. Lieskovsky G: The staging and classification of bladder cancer and the management of superficial disease, in Skinner G (eds): Urological Cancer. New York, Grune & Stratton, 1983.
42. Heney NM, Ahmed S, Flanagan MJ: Superficial bladder cancer: Progression and recurrence. J Urol 130:1083-1086, 1983.
43. Fitzpatrick JM, West AB, Butler MR: Superficial bladder tumors (stage pTa, Grade 1 and 2): The importance of recurrence pattern following initial resection. J Urol 135:920â922, 1986.
44. Skinner DG: Current perspective in the management of high grade invasive bladder cancer. Cancer 45:1886â1894, 1980.
45. Herr HW, Laudone VP, Whitmore WF Jr: An overview of intravesical therapy for superficial bladder tumor. J Urol 138:1363â1368, 1987.
46. Huland H, Otto U, Droese M, et al: Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma: Influence on recurrence, progression and survival. J Urol 132:27â29, 1984.
47. Badalament RA, Herr HW, Wong GY, et al: A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-GuÃ©rin for superficial transitional cell carcinoma of the bladder. J Clin Oncol 5:441â449, 1987.
48. Schellhammer PF, Ladaga LE, Fillion MB: Bacillus Calmette-GuÃ©rin for superficial transitional cell carcinoma of the bladder. J Urol 135:261â264, 1986.
49. Herr HW, Pinsky CM, Whitmore WF, et al: Long-term effect of intravesical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J Urol 135:265â267, 1986.
50. Herr HW, Wartingu DD, Fair WR, et al: Bacillus Calmette-GuÃ©rin therapy for superficial bladder cancer: A 10-year follow up. J Urol 147:1020â1023, 1992.
51. Lamm DL, van der Meyden APM, Morales A, et al: Incidence and treatment of complications of bacillus Calmette-GuÃ©rin intravesical therapy in superficial bladder cancer. J Urol 147:596â600, 1992.
52. Herr HW: Conservative management of muscle-infiltrating bladder muscle: Prospective experience. J Urol 138:1162â1163, 1987.
53. Bosl GJ, Fair WR, Herr HW, et al: Bladder cancer: Advanced in biology and treatment. Crit Rev Oncol Hematol 16:33â70, 1994.
54. Skinner DG, Lieskovsky G: Contemporary cystectomy with pelvic node dissection compared to preoperative radiation therapy plus cystectomy in management of invasive bladder cancer. J Urol 131:1069â1072, 1984.
55. Montie JE, Straffon RA, Stewart BH: Radical cystectomy without radiation therapy for carcinoma of the bladder. J Urol 131:477â482, 1984.
56. Davidson SE, Symonds RP, Snee HP, et al: Assessment of factors influencing the outcome of radiotherapy for bladder cancer. Br J Urol 66:288â293, 1990.
57. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: Failure analysis. J Urol 142:1448â1453, 1989.
58. Parsons JT, Million RR: Planned preoperative irradiation in the management of clinical stage B-C (T3) bladder carcinoma. Int J Radiat Oncol Biol Phys 14:797â810, 1988.
59. Scher HI, Herr HW, Sternbery C, et al: Neo-adjuvant chemotherapy for invasive bladder cancer: Experience with the MVAC regimen. Br J Urol 64:250â256, 1989.
60. Matinez-Piniero JA, Jimenez-Leon J, Gonzalez-Martin M, et al: Neo-adjuvant cisplatinum in locally advanced urothelial bladder cancer: A prospective randomized study of the group Cueto, in Splinter TAW, Scher HI (eds): Neoadjuvant Chemotherapy in Invasive Bladder Cancer, pp 95â103. Progress in Clinical and Biological Research. New York, Wiley-Liss, 1990.
61. Logothetis CJ, Johnson DE, Chong C, et al: Adjuvant cyclophosphamide, doxorubicin, and cisplatin chemotherapy for bladder cancer: An update. J Clin Oncol 6:1590â1596, 1988.
62. Skinner DG, Daniels JR, Russell CA, et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 145:459â464, 1991.
63. Stockle M, Meyenburg W, Wellek S, et al: Advanced bladder cancer (stage pT3b, pT4a, pN1 and pN2): Improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 148:302â307, 1992.
64. Shipley WU, Prout GR, Einstein AB, et al: Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA 258:931â935, 1987.
65. Prout GR Jr, Shipley WU, Kaufman DS, et al: Preliminary results in invasive bladder cancer with transurethral resection, neoadjuvant chemotherapy and combined pelvic irradiation plus cisplatin chemotherapy. J Urol 144:1128â1134, 1990.
66. Yogoda A: Chemotherapy of urothelial tract tumor. Cancer 60:574â585, 1987.
67. Roth BJ, Dreicer R, Einhorn LH: Significant activity of paclitaxel in advanced transitional cell carcinoma of the urothelium: A phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol 12:2264â2270, 1994.
68. Logothetis CJ, Dexeus FH, Chong C, et al: Cisplatin, cyclophosphamide and doxorubicin chemotherapy for unresectable urothelial tumors: The M.D. Anderson experience. J Urol 141:33â37, 1989.
69. Harker WG, Meyers FJ, Freiha FS, et al: Cisplatin, methotrexate, and vinblastine (CMV): An effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol 3:1463â1470, 1985.
70. Sternberg CN, Yogoda A, Acher HI, et al: Methotrexate, vinblastine, doxorubicin and cisplatin for advanced transitional cell carcinoma of the urothelium: Efficacy and pattern of response and relapse. Cancer 64:2448â2458, 1989.
71. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative study. J Clin Oncol 10:1066â1073, 1992.
72. Logothetis CJ, Dexeus FH, Finn F, et al: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumor. J Clin Oncol 8:1050â1055, 1990.
73. Kantoff PW, Scher HI: Chemotherapy for metastatic bladder cancer. Hematol Oncol Clin North Am 6:195â203, 1992.
74. Logothetis CJ, Dexeus FH, Sella A, et al: Escalated therapy for refractory urothelial tumor: Methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor. J Natl Cancer Inst 82:667â672, 1990.
75. Seidman AD, Scher HI, Gabrilove JL, et al: Dose-intensification of MVAC with recombinant granulocyte-colony stimulating factor as initial therapy in advanced urothelial cancer. J Clin Oncol 11:408â414, 1993.
76. Einhorn LH, Roth BJ, Ansari R, et al: Phase II trial of vinblastine, ifosfamide and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 12:2271â2276, 1994.
77. Logothetis CJ, Hossan E, Sella A, et al: Fluorouracil and recombinant human interferon alpha-2a in the treatment of metastatic chemotherapy-refractory urothelial tumors. J Natl Cancer Inst 83:285â288, 1991.