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1505 The American College of Surgeons Commission on Cancer and the American Cancer Society Address for reprints: Andrew K. Stewart, MA., Commission on Cancer, American College Of SW?ons, 55 E. Erie Street, Chicago, IL 60611. Received April 19,1996;revision received June 19,1996;accepted June 21,1996. 0 1996 American Cancer Society The National Cancer Data Base Report on Bladder Carcinoma Neil E. Fleshner, M.D.' Harry W. Herr, M.D.' Andrew K. Stewart, M.A? Gerald P. Murphy, M.D? Curtis Mettlin, P m . 4 Herman R. Menck, M.B.A? ' Department of Urology, Memorial Sloan. .._..-ring Cancer nter, New York, New York. Commission on Cancer, American College of Surgeons, Chicago, Illinois. Pacific Northwest Cancer Foundation, Northwest Hospital, Seattle, Washington. Roswell Park Cancer Institute, Buffalo, New York. BACKGROUND. Previous Commission on Cancer Data from the National Cancer Data Base (NCDB) have examined time trends in stage of disease, treatment patterns, and survival for selected cancers. The most current (1993)data relating to patients with bladder carcinoma are described here. METHODS. Five calls for data have yielded a total of 3,700,000cases for the years 1985 through 1993,including 447,679cases for 1988 and 608,593cases for 1993, from hospital cancer registries across the U.S.Data were received on 18,053bladder carcinoma cases in 1988 and 22,606cases in 1993. RESULTS. Interesting trends are 1) younger patients (49years of age and younger) present with earlier stages of disease than do older patients; 2)women are slightly more likely to be diagnosed with later stages (II,111, and IV)of bladder carcinoma than men; 3) African Americans are less likely to be diagnosed with Stage 0 or Stage I disease than either Hispanic or non-Hispanic whites; and 4) National Cancer Institute designated centers treat more patients with advanced disease than do other types of hospitals. CONCLUSIONS.The NCDB data are important for analyzing what cancer treatments and outcomes are used and occurring in the country. The data suggest that African Americans are diagnosed at later stages of disease progression. The relative survival rates among African Americans are lower than among Hispanics or non-Hispanic whites. Also, the decreasing utility of adjuvant chemotherapy is being recognized. Cancer 1996;781505-13. 0 1996 American Cancer Society. KEYWORDS bladder carcinoma, transitional cell carcinoma, treatment, surgery, radiotherapy, chemotherapy, transurethral resection, cystectomy, survival, National Cancer Data Base. Bladder carcinoma is an important public health problem. It is the fifth most common human cancer, with current estimates suggesting that more than 52,900 new cases will be diagnosed in 1996.' More than 11,000 individuals die in the U.S. annually from bladder carcinoma. Bladder carcinoma is also a preventable disease. Well defined risk factors accounting for approximately 80%of allcases have been described? These factors include cigarette smoking, indus- a P 1506 CANCER October 1,1996 I Volume 78 / Number 7 trial carcinogen exposure, and chronic infection with schistosomiasis hemat~bium.O~ ther less well ac- cepted risk factors for bladder carcinoma include past exposure to chemotherapeutic agents, pelvic irradia- tion, and human papilloma virus Changes in public health policy with regard to cigarette expo- sure coupled with a declining industrial work force may alter the epidemiology of bladder carcinoma. In addition, changes in health care delivery continue to unfold. The National Cancer Data Base (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons (ACOS) and the American Cancer Society, facilitates community, state, and national as- sessment of patient care by monitoring changes in the delivery of health care services to cancer patients and by following changing disease epidemiology. Data are currently being collected for a Patient Care Evaluation Studyof bladder carcinoma. The current report details the most recent NCDB data on bladder carcinoma. METHODS Sources of the Data Each year, the NCDB collects data for all forms of cancer from cancer registriesthroughout the country. The methods of the NCDB have been previously described.' Five calls for data have been issued. Mailings were routinely sent to approximately 2,100 hospitals (1,340 ACoS-Approved Programs and 760 others), and all known central/state registries and software vendors/ suppliers. Data were received on 18,053bladder carcinoma cases in 1988 and 22,606 cases in 1993. These data represent approximately39%and 43% of all bladder carcinomas diagnosed in the U.S. in 1988and 1993, respectively. These cases were used for the basic patterns of care time trend analysis presented in this article. For relative survival analysis, cases reported with 5-year follow-up information for 1985,1986,1987,and 1988 were grouped together, accounting for 25,198 cases of bladder carcinoma. SPSS (for Windows, Release 6.1, SPSS, Inc., Advanced Statistics, Chicago, IL, 1994), a standard statistical software package, was used to analyze the data. Data Definitions Bladder carcinoma cases include those reported for ICD-0-2 C67.0 through (268.0, according to the International Classification of Diseases for Oncology.8 Of the reported 1993 bladder carcinoma patients, most (91%) had their carcinomas diagnosed and also received all or part of their treatment at reporting hospitals: 8%received allor part of their treatment at reporting hospitals but had their carcinomas diagnosed elsewhere; TABLE 1 TNM Stagingfor Bladder Carcinoma - 0 Ta-Tis NO MO I T1 NO MO I1 T2-T3a NO MO III T3b-T4a NO MO N T4b,any T AnY N MO,M1 AICC American Joint Committee on Cancer; Ta: noninvasive papillary carcinoma; Ti: carcinomain situ; T1: tumor invasion of subepithelial connective tissue; T2 tumor invasion of superficialmu& (mer half); T3a: tumor invasion of deep muscle (outer half); T3b mor invasion of perivesical fat, microscopicallyor macroscopically;T4a:tumor invasionof the prostate, uterus, or vagina; T4b tumor invasion of the pelvic or abdominal wall; NO: no regional lymph node metastasis; NI-N3metastisii of one or more lvmoh nodes;MO no distant metastasis; M1:distant metastasis. and 1%had their carcinomas diagnosed at reporting hospitals but were treated at another location. Treatment of all cases was analyzed by stage (anatomic extent of disease). Cases were staged using the American Joint Committee on Cancer (AJCC) staging ~ y s t e m W. ~hen possible, pathologic staging (pAJCC) was used, supplemented by clinical staging (CAJCC) when pathologic stage was not known. Stage groupings have been combined into summary categories to minimize the number of cases under analysis that did not have AJCC stage designation. The TNM staging system is used by many investigators and predominates in the literature on bladder carcinoma. Table 1 summarizes the TNM staging system." Treatment management strategiesfor bladder carcinoma include combinations of surgery, radiation, and chemotherapy. Surgery has been defined as any cancer-directed surgical procedure. Radiation includes beam radiation, radioactive implants, radioisotopes, or any combination thereof. Chemotherapy includes the use of single or multiple agents. Surgicalprocedures have been defined in the following manner. Transurethral resection of the bladder TTUR) was identified as one procedure. The`headingof cystectomy included all procedures ranging from partial cystectomies (with or without lymph node dissection) to radical cystectomy. The category "other" combined surgery of regional sites and surgery not otherwise specified. The designation "none" was used when surgery was recorded as being noncancer directed. Income level was inferred for each case based on the average family income of the zip code of the patient's residence. RESULTS Patient Characteristics When patients diagnosed with bladder carcinoma in 1993were compared with those diagnosed in 1988,no Bladder CarcinomalFleshneret al. 1507 significant differences in age, sex, race/ethnicity, or income level were noted. Generally speaking, bladder carcinoma is a disease of older, non-Hispanic white men from a middle income level background. In 1993, patients who were 60 years of age or older comprised 82.3% of all reported cases. Approximately 73.5% of reported diagnosed patients were male, 92.1%of reported patients were non-Hispanic white, and 78.1% of patients were from a middle income level. The geographic distribution of cases remained the same between the two study years, with the exception of the Pacific states, in which the proportion of reported cases dropped from 20.3% in 1988 to 14.1% in 1993, which was due to problems encountered in gathering data from institutions in California. In 1988, 91.7%of patients were treated at teaching or community hospitals; by 1993, this proportion had fallen to 84.4%.Concomitant with the decrease in the proportion of patients treated at teaching or community hospitals was an increase from 5.8%in 1988 to 13.5%in 1993 in the frequency of patients with bladder carcinoma treated at nonapproved hospitals. The proportion of bladder carcinoma patients being treated at hospitals with large cancer patient case loads (500 or more per year) remained constant between the 2 study years; in 1993, 73.2% of reported bladder carcinoma ' patients were treated at these hospitals. Disease Characteristics The histology of bladder carcinoma remained unchanged between the study periods. Transitional cell carcinoma (TCC), which includes papillary and epidermoid carcinomas, was the most prevalent histologic type. TCC was reported in 93.4%and 94%of the cases in 1988 and 1993, respectively. The anatomic subsite of bladder tumors did not change appreciably between the two study years. The greatest proportion of tumor locations were not otherwise specified (NOS) in both years. The three most frequently reported subsites in 1993 were bladder NOS, the lateral wall, and overlapping lesions. AJCC Stage Grouping It is extremely important that all patients be properly staged to evaluate the effect upon therapy outcome. (Table 2) shows the frequency distribution of all reported cases by stage at diagnosis in 1988 and 1993. Elsewhere, because stage of disease and treatment modality are so closely associated, cases of unknown stage have been excluded from our analysis because reporting these results does not contribute to our understanding of changing patterns of treatment or outcome results. In 1988, 36.8%of reported bladder carcinoma pa- tients were diagnosed with an unknown stage; this percentage dropped dramatically by 1993 when only 13.4% of patients were reported with an unknown stage (Table 2). Controlling for cases of unknown stage, analysis indicates a 5.8%increase in the proportion of reported Stage 0 and Stage I cases and slightly more than a 1.6%increase in the proportion of Stage 11,111,and IV cases between 1988 and 1993, suggesting improving documentation practice between the two study periods. The relationship between stage and patient age indicates that the frequency of superficial disease (Stage 0) diminishes with advancing chronology. In 1993,53.4%of patients younger than age 40 were diagnosed with Stage 0 cancer, whereas only 32.8%of patients 80 years of age and older presented with superficial disease. The elevated risk of invasive disease with advancing age was associated with increases in Stage I1 and Stage I11 disease. Only 8.5%of patients younger than age 40 presented with Stage I1 bladder carcinomas, whereas 18.6%of patients 80 years of age or older were diagnosed with Stage I1 disease. The pattern is similar for Stage 111, increasing from 3.5%among the youngest patients to 8.7%in the oldest group of patients. The distribution of cases presenting with metastatic disease (Stage rv)did not appear to be related to age. Although only one-third as many women as men developed bladder carcinoma, they were slightly more likely to be diagnosed with advanced stage disease (Stages 11, 111, and rv) than men (33.1% and 27.7%, respectively). There was little difference in stage distribution between non-Hispanic whites and Hispanics with the exception of higher frequencies of Stage IV presenta- tion among Hispanics. The most noticeable differences between ethnic groups existed between African Americans and non-Hispanic whites or Hispanics. Only 54.2% of African Americans presented with superficial (Stage 0) or early (Stage I) disease, whereas 71.6% of non-Hispanic whites and 70% of Hispanics were diagnosed at these earlier stages. The likelihood of African Americans being diagnosed with invasive or metastatic bladder carcinoma was markedly higher than that of non-Hispanic whites, and slightly higher than Hispanics for metastatic disease. The small number of cases reported for the Asian American and Native American populations make comparative statements difficult. The relationship between income level and stage at diagnosis indicated that increasing income favorably impacts on clinical stage. This is evident among patients diagnosed with either superficial or metastatic disease. Individuals from a low income back- 1508 CANCER October 1,1996 / Volume 78 / Number 7 TABLE 2 Percentage of Bladder Carcinoma Cases by AJCC Stage at Diagnosis Study year 0 AJCC stage I I1 111 1988 13.3 28.6 8.3 6.7 1993 32.5 28.9 12.5 6.6 N 6.2 6.1 unlrnown 36.8 13.4 capes 18,171 22,675 ground were almost twice as likely as individuals from a high income background to be diagnosed with Stage IV bladder carcinoma (10.3%vs. 5.4%).This contrasts with the likelihood of diagnosis with superficial disease in which 39.6%of high income patients and 31.3% of low income patients presented with Stage 0 bladder carcinoma. Although the likelihood of patients in the medium income stratum presenting at any particular stage was between the low and high stratum, there was a tendency for them to be closer to those in the high stratus rather than the low. National Cancer Institute (NCI)-designated centers tended to treat fewer early stage patients and more advanced stage patients when compared with other facilities. Of those patients treated at NCI-designated cancer centers, only 6.5%presented with Stage 0 dis- ease whereas 21.1% were diagnosed with Stage IV bladder carcinoma. In contrast, 36.2%of reported patients, on average, were treated at other types of hospitals (teaching hospitals, community-comprehensive, community, other approved, and nonapproved) and presented with Stage 0 bladder cancer, whereas only 8.6% had been diagnosed with metastatic disease. NCI-designated centers also treated a higher proportion of patients with Stage 111disease. These data suggest that resources available at NCI-designated centers are targeted toward the treatment of advanced stage disease. However, in spite of the fact that 67.2% of bladder carcinoma patients treated at NCI-designated centers had been diagnosed elsewhere, there is no evidence that proportionately more of these referred patients suffered from late or metastatic disease when compared with patients referred for treatment to other types of cancer treatment centers. The percentages of patients who were diagnosed with Stage 0 or Stage I disease by histologic subtype are as follows: TCC, 73.3%;adenocarcinoma, 32.1%; squamous cell carcinoma (SCC), 13.8%;and others, 36.1%. These data suggest that nontransitional subtype patients are more likely to present with advanced disease than patients with TCC. Treatment Management Between the 2 study periods, the use of surgery without adjuvant treatment increased from 70.9%in 1988 to 79.6%in 1993. Surgery alone was the predominant treatment of choice across all age, sex, and ethnic categories. Treatment by surgery alone is sensitive to the stage of diagnosis. As stage at diagnosis increases, the reliance on surgical monotherapy decreases; 91.6%of patients with Stage 0 disease were treated with surgery alone whereas only 35.4% of patients with Stage IV disease received this type of treatment management (Table 3). NCI-designated centers tended to use slightly less surgicalmonotherapy (73.5%)than other types of cancer treatment centers. This can be explained by the fact that late stage bladder carcinoma, which NCI centers tend to treat more of, is less likely to be treated by surgery done than earlier stage disease. Between the 2 study periods, the proportionate use of surgery with radiotherapy decreased slightly from 5.4%to 3.2%,in 1988 and 1993, respectively (Table 3). Adjuvant radiotherapy tended to be used with greater frequency in elderlypatients, particularlythose 80 years of age and older. Women were slightly more likely to receive a combination of surgery and radiation therapy than men. With respect to ethnic categories, African Americans were more than twice as likely to be treated with a combination of surgery and radiotherapy than were patients of non-Hispanic white or Hispanic backgrounds. Low income patients were more likely to receive adjunctive radiotherapy than either middle and high income patients. These demographic groups tended to be diagnosed with'more advanced stage disease and were thus more likely to be treated with a combination of surgery and radiation. The treatment combination of surgery and radiation is linked to stage at diagnosis and, in contrast to treatment by surgery alone, was used with greater frequency as stage at diagnosis increased. Few patients who presented with superficial or early stage disease were treated with a combination of surgery and radiotherapy (Stage 0, 0.2%; Stage I, 1%). Patients with later stage (Stage I1 and 111) and metastatic (Stage IV)disease were much more likely to receive adjuvant radiotherapy (9.6%,9.9%,and 10.4%,respectively) (Table 3). Between reporting periods, the use of surgery in Bladder Carcinoma/Fleshner et al. 1509 TABLE 3 Percentage of Bladder Carcinoma Cases by Treatment Management and AJCC Stage of Diagnosisa Study Year Surgery Surgery& radiation Treatment management Surgery& surgery radiation & chemotherapy chemotherapy Other None 1988 1993 AJCC stageb 0 I I1 I11 N 70.9 81 91.6 88.6 70.6 58.2 35.4 5.4 3.3 0.2 1 9.6 9.9 10.4 11.2 6.9 3.2 5 8.3 15.6 23.1 1.8 2.1 0 0.2 5.1 7.6 9.1 2.7 8 1.8 4.9 0.3 4.6 0.5 4.8 2.5 4 4.1 4.6 12.5 9.6 AJCC:American Joint Committee on Cancer. a Cases with unknown stage are excluded. '1993data only. Cases 11,490 19,636 7366 6545 2844 1493 1388 combination with chemotherapy decreased from Surgical Treatment 11.2%in 1988 to 6.9%in 1993.Adjuvant chemotherapy Bladder carcinomais treated with a multidisciplinaryap- tended to be used with slightly less frequency among proach, and has been discussed above. However, as the older patients; this was particularly the case for indi- prior discussion made clear, surgeryaloneis the predom- viduals 80 years of age or older. Factors of sex, income, inant treatment modality for bladder carcinoma.In 1993, and ethnicity did not appear to be associated with nearly 80% of bladder carcinoma patients were treated differentialtreatment of chemotherapy in conjunction with surgery alone. The two most frequently utilized sur- with surgical procedures. NCI-designated cancer cen- gical procedures performed for patients with bladder car- ters tended to use adjuvant chemotherapy more fre- cinoma were TUR and cystectomy. In 1993, 81.2%of all quently; 14.2% of patients treated at these facilities patients treated by surgery alone underwent TUR and received cytotoxic agents. In contrast, on average, 12.1%of surgical patients underwent a cystectomy. other facilities combined surgery and chemotherapy The association of stage at diagnosis and disease treatment for 5.8%of patients. histology clearly affect the choice of surgical proce- The use of surgery and chemotherapy together dure. Table 4 shows that in 1993 the frequency with was also linked to the clinical stage at diagnosis. Few which TUR was performed decreased for patients di- patients with early stage disease received chemother- agnosed with TCC as stage increased. Patients with apy in tandem with surgery (Stage 0, 3.2%; Stage I, TCC presenting with superficialdisease and minimally 5%).Patients who presented with Stage 11, 111, or IV invasive disease (Stages0 and I) were primarily treated disease were likely to have received this treatment by TUR (94.4%and 92.4%,respectively). TCC patients combination (8.3%, 15.6%, and 23.1%, respectively) who presented with muscle invasive disease or meta- (Table 3). static disease (StagesI11 and IVI were surgicallytreated The use of all three treatment modalities together with TUR only (40.9% and 44.7%, respectively). The was unchanged between 1988 and 1993, and was com- pattern of decreasing use of TUR for patients with parably infrequent as a choice of treatment manage- more advanced stage disease also occurred in patients ment. In 1993, only 2%of reported bladder carcinoma with adenocarcinoma and SCC. Patients were treated with a combination of all three In contrast, the use of cystectomy as the means modalities. Surgery with adjuvant radiation and che- of surgical treatment was rare for patients with TCC motherapy was used with increasing likelihood as the who had been diagnosed with either Stage 0 or Stage clinical stage at diagnosis progressed. Among patients I disease. A cystectomy was more frequently used for Who presented with superficial or early stage disease, patients with more advanced stages of adenocaxci- % the use of a combination of all three treatment modal- noma, SCC, and TCC. Among patients diagnosed with m,i ities was very infrequent. In later stages (Stages11, 111, Stage I11 disease, 80% of patients with adenocarcipatients were more likely to receive surgery in noma, 62.2% of patients with SCC, and 51.1%of pa- with radiotherapy and chemotherapy. tients with TCC underwent a cystectomy (Table 4). 1510 CANCER October 1,1996 / Volume 78 / Number 7 TABLE 4 Percentage of Bladder CarcinomaCases,Surgical Procedureby AJCC Stage and Histology' 0 Adenocarcinoma 92.9 SCC 75 25 TCC 94.4 1.4 Otherlunspecibed 80.2 3.4 I Adenocarcinoma 79.2 17 SCC 53.1 34.4 TCC 92.4 3.6 Otherlunspecified 72.7 12.7 II Adenocarcinoma 52.9 41.2 SCC 40.4 51.4 TCC 63.8 31.4 Otherlunspecified 59.6 28.3 m Adenocarcinoma 17.5 80 SCC 32 62.1 TCC 40.9 51.1 Otherlunspecified 38.2 49.4 Iv Adenocarcinoma 37 32.6 SCC 42.7 41.5 TCC 44.7 35.9 Otherlunsuedfied 36.3 22.1 7.1 100 14 100 12 0.3 3.9 100 7163 0.9 15.5 100 116 3.8 100 53 3.1 9.4 100 32 0.3 3.7 100 6330 1.8 12.7 100 55 2 3.9 100 51 1.8 6.4 100 109 0.6 4.3 100 2532 2 10.1 100 99 2.5 100 40 5.8 100 103 1.6 6 100 1225 3.4 9 100 89 10.9 19.6 100 46 1.2 14.6 100 a2 4.8 14.6 100 1066 2.7 38.9 100 113 AICC AmencanIoint Committeeon Cancec TUR:tmxmdml resection of the bladder; SCC squamouscellcarcinoma;TCC transitional d carcinoma. '1993 data onlv. The type of surgical intervention varied among the types of cancer treatment centers. NCI-designated centers were almost half as likely to perform TUR but were more than two to three times as likely to perform cystectomiesthan other classifications of cancer treatment centers. NCI-designated centers also performed substantially more surgical procedures that were neither TUR nor cystectomythan any other type of cancer treatment center. Cystectomy and other non-TUR surgical procedures are typically reserved for late stage and metastatic bladder carcinoma. As reported earlier in this article,NCI-designated centers were more likely to treat patients diagnosed with late stage disease, many of whom had been referred for treatment from other medical institutions. Survival The relative survival rates for each stage of bladder carcinoma are presented in Figure 1. Survival rates were negatively impacted by advancing stage at diagnosis; for patients diagnosed with Stage 0, I, 11, 111, and N disease, the 5-year relative survival rates were 90.2%, 86.6%, 65.1%, 47.9%, and 23.2%, respectively. Table 5 shows the 5-year relative survival rates broken down by sex, ethnicity, treatment modality, and the type of surgery performed. Regardless of the stage of diagnosis, survival rates for women were not as good as those for men. Similarly,survival rates among Afri- can Americans compared poorly with those of either non-Hispanic whites or Hispanics. Patients receiving radiation as part of a treatment modality had lower survival rates. DISCUSSION These data are in agreement with the well accepted epidemiologyand history of bladder carcinoma. Most bladder carcinoma patients in the U.S. develop TCC. The majority of TCC patients (70-80%) present with superficial disease and are usually managed conservatively with TUR. In some cases, TCC can progress to muscle invasion or present de novo as invasive carcinomas. Once muscle invasion occurs, the 'threat to life increases. Consequently, more aggressive interventions (cystectomy, chemotherapy, and radiotherapy) are employed. Non-TCC are less common and often are associated with chronic inflammati~nP.~atients tend to present with more advanced stage and are less often managed by conservative means. An increasing number of institutions have been participating in the NCDB data collection process in recent years and may account for some of the changes observed in this study. However, many of the demographic variables, such as sex, ethnicity, income, tumor location, and histology, remain largelyunchanged over the two reporting periods. Conversely,the chang- .,.. b Cumuiative S U M 100 90 80 70 60 50 -*w,"40 30 . ............ .............. .. .......... ~ .... .. . 20 0 .. .. 1 100 97.5 100 06.4 100 87.3 100 74.5 2 86.2 93.3 77.4 59.8 Bladder Carcinoma/Fleshner et ai. 1511 ..................... . . . . . ~ ~ . ~. ~.. .~~ ~ ................................. " v 3 93.9 90.9 70.9 53.6 492.2 06.8 68.1 49.9 590.2 86.6 65.1 47.9 FIGURE 1. Five-year cumulative relative survival rates by AJCC stage at diagnosis. TABLE 5-YearRelative Survival Rates (W),Bladder Carcinoma by AJCCStage of Diagnosisand Selected Patient and Treatment Characteristics' AJCC Btage 0I II rn Iv cases Sex Male 94.7 87.8 68.3 48 26.8 18,525 Female 90.7 84.7 59.3 47.7 15.4 6672 Ethnidty" Non-Hispanic white 94.4 87.3 66.5 48.5 25.7 17,462 Hispanic African American 95.6 82.1 70.3 51.8 29.9 569 81.4 79.4 48.9 42.6 18.3 w Treatment surgery 94.9 89.1 71.3 54.7 34.5 17,698 Surgery & radiation 58 56.5 46.1 40.2 16.6 1791 Surgery & chemotherapy 91.3 89 70.4 54.8 24.4 2784 Surgery, radiation, chemotherapy 71.4 52.8 39.3 32.5 22 407 Other 68.7 45.3 38.8 23 9.9 742 None 92.2 78 67.5 34.7 7 I770 surgery TUR Cystectomy Other None 94.7 88.6 64.3 45.6 26.1 18,960 80.5 79.1 72.2 54 28.1 3261 94.3 90.3 70.1 47.5 22.4 852 87.5 67.1 50.5 29.3 9.7 1060 AICC: AmericanJoint Committee on Cancer; TIIR:transurethral resection of the bladder. 'Cases diagnosed between 1985 and 1998.Survivaldata on treatmentlsqeryare presented only to provide a record of outcomeqeriencewhensuchtreatments were used. Patientswerenot randomizedinto sqery/trearment groups, nor weretheynecessarilycomparablewith regard to allprognosticfactors.Casesdiagnosed between 1985 and 1988. A s i Americans and Native Americansare not included in this table because there were too few cases in each EIOUD to calculatemeanin& results. I' j~ I :I ing distribution of stage at diagnosis is likely related to improved reporting techniques in 1993. Although the data reported here are consistent Nth established findings on bladder carcinoma,some Potentially important trends warrant discussion. A n interesting trend is that individuals appeared to have been diagnosed with bladder carcinoma at a later age in 1993 than in 1988. This contrasts with other neoplasms, such as prostate carcinoma, in which the introduction of new diagnostic methods has shifted the 1512 CANCER October 1, 1996 / Volume 78 / Number 7 diagnosis trends to younger individuals."A hypothe- NCI-designated centers for patients with invasive tu- sized rationale for this shift may be related to dimin- mors. ishing smoking rates coupled with the high incidence Changes in the use of multimodal therapy have of smoking cessation in bladder carcinoma patients been noted. In particular, the use of adjuvant chemo- prior to the time of diagnosi~.'~F"u~rther studies are therapy appears to be decreasing. The likely explma. necessary to formally test this hypothesis. tion for this phenomenon rests with the initial enthusi- Regarding the influence of demographic features asm for methotrexate, vinblastine, doxorubicin, and on stage, the most disturbing finding relates to the cisplatin (M-VAC)combination therapy. Early reports higher incidence of advanced stage disease among Af- suggested that durable complete remissions were at- rican Americans. Only 54.2%of African Americans pre- tainable in 50% of patients who were diagnosed with sented with superficial disease compared with 71.6% metastatic disease." Recently however, diminished of non-Hispanic whites. Several theories have been evidence of M-VAC efficacy along with increased evi- put forward to explain racial differences in disease pre- dence of treatment-related toxicity have tempered the sentation: access to care, cultural beliefs leading to enthusiasm for cytotoxic chemotherapy in patients symptom denial, and biologic difference^.'^ with bladder carcinoma.21'22The toxicity of M-VAC Stageprocession in bladder carcinoma is generally likely explains the disproportionate use of chemother- not regarded as a definitive event. Most cases of super- apy in NCI-designated treatment centers as well as the ficial disease (AJCC Stage0 or I) remain superficialand less frequent use of these agents in elderly patients. pose little threat to patient m~rtality.'O~nly 20-30% The data in Table 5 illustrate some important de- of superficial disease progresses to muscle invasion. mographic risk factors associated with survival in pa- 1 In contrast, most cases of muscle invasive disease tients with bladder carcinoma. Patients receiving ra- I ! present de n0v0.~Therefore, it is unlikely that access diotherapy generally did worse than nonradiated pa- ! to care or cultural differences entirely explain the tients. The likely explanation for this finding relates to findings presented in these data. African Americans, the use of radiotherapy in patients with poor perfor- I through differential exposure to uroepithelial carcino- mance status and bladder carcinomas associated with I gens or preexisting genotypic differences in suscepti- poor pathologic features (higher grade and tentacular I bility, may possess an altered bladder carcinoma biol- pattern of muscle invasion).23 In addition, women tend ogy. Indirect evidence supports this view. Bums and to fare worse, stage for stage, than men. The reasons Swanson have demonstrated that African Americans for this finding are less clear and deserve further inves- were more susceptible to cigarette smoke-induced tigation. I bladder carcinoma than whiteAmericans."Significant The survival data in Figure 1 display the strong differences in the levels of glutathione transferase MU effect of stage at diagnosis on relative survival rates I 1-1, a carcinogen metabolizing enzyme associated for bladder carcinoma. Patients diagnosed with Stage I with bladder carcinoma, have been demonstrated to 0 disease have a 92.6% 5-year survival rate; Patients 4 exist between ethnic groups." Data from individuals with Stage I disease also appear to have a low 5-year i with lung carcinoma have also demonstrated ethnic mortality rate. Although mortality may not be high, differences in p53 tumor suppressor gene polymor- 40-60% of patients will experience at least 1 recurrent phisms.18Mutations in p53 are associated with bladder tumor? Recent data from Holmang et al., who report carcinoma progres~ion,'a~nd it is conceivable that 20-year follow-up data, suggest that approximately certain alleles are more prone to carcinogen-induced 30% of patients with Stage I disease ultimately die mutation.'8 from bladder ~arcinoma.'I~f these data are valid, more Another difference noted in these data relates to effort must be placed on definingbiologic and life style the proportion of African American patients who re- risk factors related to disease progression. ceived no therapy (10.9%),compared with non-His- Patients with muscle invasive disease (AJCC Stage panic white patients (5.4%).This difference may be 11) have potentially curable disease with a 5-year sur- related to differences in stage at diagnosis and access vival rate of 64.5%. Surgery remains the most viable to care. option for these patients. Although morbidity of sur- Surgical intervention is the major type of therapy gery is diminishingwith the increased use of continent used to treat patients with bladder carcinoma. As ex- urinary diversion, more effort should be made toward pected, TUR predominates over cystectomy (used determining molecular risk factorsfor distant metasta- principally for patients with TCC and early stage dis- ses. Detection of circulating tumor cells or other mo- ease). TUR was performed proportionately less often lecular alterations should be explored with the objec- at NCI-designated centers than other types of surgery. tive of eliminating unnecessary surgical intervention In contrast, cystectomy was performed primarily at for patients expected to die with metastatic disease. I .. . $or patients with Stage IV disease, effective systemic therapy is required. Alternative cytotoxic agents, biologic response modifiers, or gene therapy strategies are necessary to improve prognosis. CONCLUSIONS This NCDB report demonstrates some important changes in the epidemiology of bladder carcinoma, most specificallya shift toward diagnosisof the disease in later age. Bladder carcinoma among African Americans may have a different disease phenotype, although differences in access to care may also explain these discrepancies. The early enthusiasm for cytotoxic chemotherapy appears to be waning, although effective systemictherapies are still needed. These findingsprovide fruitful avenues to guide further epidemiologic and basic research. REFERENCES 1. Cancer Facts and Figures: 1996. Atlanta: American Cancer Society, 1995. 2. Burch JD, Rohan TE, Howe GE. Risk of bladder cancer by source and type of tobacco exposure: a case-control study. IntJ Cancer 1989;44622. 3. Catalona W. Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED, editors. Urology. 6th edition. Philadelphia: W.B. Saunders, 1992:OO-00. 4. Pederson-Bjergaard J, Ersboll J, Hansen V. 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