- Email: [email protected]
Differences in Tumor Characteristics and Prognosis in Newly Diagnosed Ta, T1 Urothelial Carcinoma of Bladder According to Patient Age
Oncology Differences in Tumor Characteristics and Prognosis in Newly Diagnosed Ta, T1 Urothelial Carcinoma of Bladder According to Patient Age Kang Su Cho, Tae-Kon Hwang, Bup Wan Kim, Duck Ki Yoon, Sung-Goo Chang, Se Joong Kim, Jong Yeon Park, Jun Cheon, Gyung Tak Sung, and Sung Joon Hong, for the Korean Urological Oncology Society OBJECTIVES METHODS
RESULTS
CONCLUSIONS
To evaluate the differences in tumor characteristics and prognosis according to age at presentation in patients with newly diagnosed Stage Ta, T1 urothelial carcinoma of the bladder. From 1998 to 2002, 1587 patients with newly diagnosed nonmuscle-invasive bladder cancer treated with transurethral resection were enrolled in this study. The median age was 63 years (range 21-98), and the median follow-up duration was 44 months (range 12-97). The study cohort was subdivided into 3 age groups: age ⬍60 years (group 1, n ⫽ 614), age ⱖ60 but ⬍70 years (group 2, n ⫽ 566), and age ⱖ70 years (group 3, n ⫽ 398). Comparing the clinical and pathologic characteristics, the tumor size (2trend ⫽ 4.01, P ⫽ .045), multiplicity (2trend ⫽ 14.50, P ⬍ .001), T category (2trend ⫽ 17.11, P ⬍ .001), and tumor grade (2trend ⫽ 31.36, P ⬍ .001) tended to increase in the older age groups. The presence of carcinoma in situ and squamous differentiation, however, did not differ among the age groups (P ⬎ .05). The 5-year recurrence-free probability was 63.6%, 52.1%, and 43.9% for groups 1, 2, and 3, respectively (P ⬍ .001). The 5-year progression-free probability was 95.7%, 91.1%, and 84.2% for groups 1, 2, and 3, respectively (P ⬍ .001). Stage Ta, T1 bladder urothelial carcinoma in the younger patients tended to be smaller, have fewer lesions, be less invasive, and have a more favorable tumor grade at the initial presentation. Furthermore, younger patients appeared to have a more favorable prognosis than older patients. UROLOGY 73: 828 – 832, 2009. © 2009 Elsevier Inc.
U
rinary bladder cancer ranks ninth in worldwide cancer incidence and is more frequent in men than in women.1 Although bladder cancer can occur at any age, it is generally a disease of middle-age and elderly people. The mortality from bladder cancer is greater in the elderly population, but data are lacking to explain these facts.2 It has been debated whether younger patients have a better prognosis than their older counterparts. Several studies have shown that the natural history of bladder cancer at a younger age resembles that of bladder cancer in older patients.3-6 Other studies have demonstrated
that younger patients tend to have lower disease recurrence and progression rates, as well as better survival, compared with older patients.7-12 It is also unclear whether a better prognosis in younger patients is a result of a lower stage and grade at presentation, or whether it is a result of the indolent nature of the tumors in younger patients. In this study, we evaluated the differences in tumor characteristics and prognosis according to age at presentation in patients with newly diagnosed Stage Ta, T1 urothelial carcinoma (UC) of the bladder.
MATERIAL AND METHODS This study was sponsored by the Korean Urological Oncology Society. A part of this study was presented as a podium presentation at the American Urological Association Annual Meeting, Orlando, Florida, 2008, and as a poster presentation at the Annual Congress of the European Association of Urology, Milan, Italy, 2008. From the Department of Urology and Urological Science Institute, Yonsei University College of Medicine; Catholic University of Korea; Korea University; Kyung Hee University; University of Ulsan, Seoul, Korea; Kyungpook National University, Daegu, Korea; Ajou University, Suwon, Korea; and Donga University, Busan, Korea Reprint requests: Sung Joon Hong, M.D., Ph.D., Department of Urology and Urological Science Institute, Yonsei University College of Medicine, 134 Shinchondong, Seodaemun-gu, Seoul, Korea. E-mail: [email protected] Submitted: August 28, 2008, accepted (with revisions): October 20, 2008
828
© 2009 Elsevier Inc. All Rights Reserved
Database This study used a nationwide nonmuscle-invasive bladder cancer database maintained by the Korean Urological Oncology Society. From 1998 to 2002, the clinical and pathologic data of 3060 patients with newly diagnosed nonmuscle-invasive bladder cancer were retrospectively collected from 38 training hospitals. All patients had been treated with transurethral resection and diagnosed with Stage Ta or T1 UC of the bladder according to the 2002 American Joint Committee on Cancer TNM staging system. The clinical and pathologic data, includ0090-4295/09/$34.00 doi:10.1016/j.urology.2008.10.038
Table 1. Patient characteristics Characteristic Sex Male Female Age (y) ⬍60 ⱖ60, ⬍70 ⱖ70 Tumor size (cm) ⬍3 ⱖ3 Multiplicity Single Multiple T stage Ta T1 Tumor grade 1 2 3 CIS No Yes Squamous differentiation No Yes Intravesical therapy No Yes BCG Mitomycin C Epirubicin Other Total
Patients (n) 1329 (84.2) 249 (15.8) 614 (38.9) 566 (35.9) 398 (25.2) 1130 (71.6) 448 (28.4) 874 (55.4) 704 (44.6) 568 (36.0) 1010 (64.0) 354 (22.4) 918 (58.2) 306 (19.4) 1510 (95.7) 68 (4.3) 1499 (95.0) 79 (5.0) 496 (31.4) 1082 (68.6) 827 (52.4) 108 (6.8) 135 (8.6) 12 (0.8) 1578 (100)
CIS ⫽ carcinoma in situ; BCG ⫽ bacille Calmette-Guérin. Data in parentheses are percentages.
ing sex, age, tumor size (⬍ 3 or ⱖ3 cm), multiplicity (single or multiple), T category (Stage Ta or T1), tumor grade, presence of concomitant carcinoma in situ or squamous differentiation, and intravesical therapy, were obtained from each hospital and merged. The follow-up data were also obtained, including pathologically proven recurrence and progression. Disease progression was defined as muscularis propria invasion of UC. The interval to recurrence or progression was defined as the period between the date of the initial diagnosis and the date of recurrence or progression. Living patients or those who had died before recurrence or progression were censored at the date of the last available follow-up cystoscopy.
Study Population In this study, patients with concomitant UC of the upper urinary tract, a history of UC, including of the lower and upper urinary tract, primary carcinoma in situ, or non-UC histologic features were excluded. The study population was also limited to those with tumors graded using the World Health Organization system; however, no central histologic review was performed. Ultimately, a total of 1587 patients were eligible for this study. The median age was 63 years (range 21-98), and the median follow-up duration was 44 months (range 12-97). The patient characteristics are summarized in Table 1. The study population was subdivided into 3 age groups: ⬍60 years (group UROLOGY 73 (4), 2009
1, n ⫽ 614), ⱖ60 but ⬍70 years (group 2, n ⫽ 566), and ⱖ70 years (group 3, n ⫽ 398). The patients were also classified according to an individual risk score using the European Organization for Research and Treatment of Cancer risk tables for Stage Ta, T1 bladder cancer.13
Statistical Analysis We investigated the correlations between patient age and the clinical or pathologic features. These correlations were validated by 2 tests and linear-by-linear association. The recurrence-free and progression-free survival curves were estimated using the Kaplan-Meier method, and a log-rank test was performed to validate the differences among the 3 age groups. The Statistical Package for Social Sciences for Windows, version 12.0 (SPSS, Chicago, IL), was used for statistical analysis. Two-sided P ⬍ .05 was considered significant.
RESULTS Comparisons of Clinical and Pathologic Characteristics According to Age A 2 test of linear trend showed that tumor size (2trend ⫽ 4.01, P ⫽ .045), multiplicity (2trend ⫽ 14.50, P ⬍ .001), T category (2trend ⫽ 17.11, P ⬍ .001), and tumor grade (2trend ⫽ 31.36, P ⬍ .001) tended to increase in older age groups. The presence of carcinoma in situ and squamous differentiation, however, did not differ among the age groups (P ⬎ .05; Table 2). Differences in Recurrence-Free and Progression-Free Probabilities Among Age Groups Recurrence developed in 605 patients (38.3%) and progression in 110 patients (7.0%). The 5-year recurrence-free probability was 63.6%, 52.1%, and 43.9% in groups 1, 2, and 3, respectively (P ⬍ .001; Fig. 1). The 5-year progression-free probability was 95.7%, 91.1%, and 84.2% in groups 1, 2, and 3, respectively (P ⬍ .001; Fig. 1). The individual risk score was calculated using the European Organization for Research and Treatment of Cancer risk tables13 (see Appendix, available online at www.goldjournal.net), and the study population was classified as listed in Table 3. For disease recurrence, age had a significant influence on recurrence-free survival in patients with a recurrence score of 1-9 (P ⬍ .05). No difference was found in recurrence-free survival among the age groups for recurrence scores of 10-17 (P ⬎ .05). Older age groups had a significantly poorer prognosis for patients with a progression score of 0, 2-6, and 7-13 (P ⬍ .05). No difference was found in progression-free survival according to age for progression scores of 14-23 (P ⬎ .05; Table 3).
COMMENT During the past few decades, urologists have been interested in the presentation and natural history of bladder UC in young adults, and previous studies have provided conflicting results. Some investigators have suggested that bladder tumors in young patients behave less aggressively and more favorably.7-10 Other studies have indi829
Table 2. Comparisons of clinical and pathologic characteristics
Variable Tumor size (cm) ⬍3 ⱖ3 Multiplicity Single Multiple T stage Ta T1 Tumor grade 1 2 3 CIS No Yes Squamous differentiation No Yes Intravesical therapy No Yes
⬍60 y
Patients (n) 60-69 y
⬎70 y
457 (74.4) 157 (25.6)
399 (70.5) 167 (29.5)
274 (68.8) 124 (31.2)
374 (60.9) 240 (39.1)
305 (53.9) 261 (46.1)
195 (49.0) 203 (51.0)
251 (40.9) 363 (59.1)
206 (36.4) 360 (63.6)
111 (27.9) 287 (72.1)
170 (27.7) 355 (57.8) 89 (14.5)
129 (22.8) 314 (55.5) 123 (21.7)
55 (13.8) 249 (62.6) 94 (23.6)
587 (95.6) 27 (4.4)
540 (95.4) 26 (4.6)
383 (96.2) 15 (3.8)
581 (94.6) 33 (5.4)
537 (94.9) 29 (5.1)
381 (95.7) 17 (4.3)
220 (35.8) 394 (64.2)
156 (27.6) 410 (72.4)
120 (30.2) 278 (69.8)
2trend, Ptrend 4.014, .045 14.508, ⬍.001 17.110, ⬍.001 31.362, ⬍.001
0.179, .672 0.575, .448 4.865, .027
CIS ⫽ carcinoma in situ. Data in parentheses are percentages.
Figure 1. (A) Recurrence-free and (B) progression-free survival curves according to age group. P values determined using log-rank test.
cated no difference when stratified by age. The investigators of these studies have maintained that younger patients appear to have a more favorable prognosis, because these patients often present with nonmuscle-invasive, low-grade tumors. They have argued that the disease progression risk is the same in younger and older patients, grade-for-grade.3-6 All these studies focused largely on 830
patients ⬍30 or 40 years of age, thus the study populations were too small to draw convincing conclusions. Our results have shown differences in tumor characteristics and prognosis in patients with newly diagnosed Stage Ta, T1 UC of the bladder according to age at presentation using a large database. In the present study, the tumors in younger patients tended to be less aggresUROLOGY 73 (4), 2009
Table 3. Recurrence-free and progression-free survival rates among age groups after considering individual risk scores Risk Score* Recurrence 1-4 (n ⫽ 715) 5-9 (n ⫽ 805) 10-17 (n ⫽ 58) Progression 0 (n ⫽ 261) 2-6 (n ⫽ 547) 7-13 (n ⫽ 694) 14-23 (n ⫽ 76)
Age Group
Patients (n)
5-y EFS Rate (%)
P Value
1 2 3 1 2 3 1 2 3
315 251 149 286 287 232 13 28 17
72.9 59.3 52.2 53.5 48.1 37.2 76.1 54.0 52.9
.0034
1 2 3 1 2 3 1 2 3 1 2 3
127 92 42 231 186 130 234 255 205 22 33 21
100 100 94.1 98.9 95.4 86.7 93.5 86.3 79.5 74.1 82.7 77.9
.0142 .3559
.0093 .0001 .0038 .8012
EFS ⫽ event-free survival. * Determined using European Organization for Research and Treatment of Cancer risk tables for Stage Ta, T1 bladder cancer.13
sive in terms of clinical and pathologic features, and younger patients appeared to have a more favorable prognosis than older patients. Although no difference was found in recurrence-free and progression-free survival among the age groups in the high-risk groups (recurrence score 10-17, progression score 14-23), it might be that the number of patients in these groups was too small to allow for valid statistical analyses. However, age was an independent prognostic factor for disease recurrence and disease progression even using a multivariate Cox proportional hazards model in our data set (data not shown). Several recent studies have had findings compatible with our observations. Shi et al.11 also showed that elderly patients are more likely to present with poorly differentiated bladder cancer and that the recurrence-free survival rate decreased with increasing age. However, no difference was found in T category distribution or progression-free survival among the age groups in their study. Another study by the Club Urológico Español de Tratamiento Oncológico revealed that age was 1 of the independent predictors of progression on multivariate Cox analysis.12 In addition, Shariat et al.14 suggested nomograms to predict recurrence and progression in patients with nonmuscle-invasive bladder cancer. These nomograms also included age as an important determinant, as well as urinary nuclear matrix protein 22, sex, and cytologic findings.14 The differences in clinical and pathologic features such as multiplicity, tumor size, T category, and prognosis can UROLOGY 73 (4), 2009
be explained by patient and medical provider social influences. For example, the diagnosis might be delayed and less-aggressive therapy offered to, and selected by, elderly patients.2 Nonetheless, a high proportion of high-grade tumors in elderly patients cannot be explained with these reasons; thus, it is unclear whether older patients have a poorer prognosis, even after considering the individual risk scores. Biologic reasons such as impaired host defenses in the elderly might be partly responsible. It could also be explained by the tumor response to intravesical bacille Calmette-Guérin therapy. Several studies have reported that aging appeared to be associated with a decreased response to intravesical immunotherapy and was particularly apparent in patients ⬎80 years.15,16 In addition, accumulated genetic and molecular aberrations in older patients might contribute to their poorer prognosis. Cigarette smoking and specific occupational exposures are the main known causes of bladder cancer. A metaanalysis reported that current cigarette smokers have a bladder cancer risk of 2.57 compared with nonsmokers.17 In particular, a positive dose-response relationship was found with both the number of cigarettes smoked daily and the number of years of smoking.1 This dose-response relationship could provide some insight into our observations. Exposure to carcinogens is related to accumulating genetic and molecular aberrations in normal-looking epithelium and bladder tumors. However, our database does not contain any information on smoking history or patient environmental exposure; thus, we could not perform those analyses. Active tobacco smoking is now the most commonly studied factor regarding prognosis. A recent systematic review concluded that cigarette smoking might be a weak factor influencing prognosis, but the results were inconclusive.18 Some researchers have investigated the molecular and genetic differences among age groups; however, data are lacking with which to evaluate our hypothesis. Linn et al.19 studied genetic alterations in bladder cancer samples from patients ⬍30 years and reported frequent p53 gene overexpression. The tumors analyzed were uniformly of low grade and low stage, and no noted correlation was found between the immunohistochemical findings and clinical endpoints. Iori et al.20 identified a frequency of chromosomal alterations (ie, aneusomy of chromsomes 7 and 17) in young patients that was greater than in old patients. Because these alterations are typical of more aggressive tumors, it is not compatible with the favorable clinical outcomes of young patients, such as was shown in that study. Nonetheless, additional investigation of normal and tumor epithelium from a large cohort of young and old patients with bladder cancer is needed to support our hypotheses. Our study had several weaknesses, including the general limitations of a retrospective design. An important limitation was that a central review of the pathologic slides was not performed. The limitation with the 1973 831
World Health Organization system is the high intraobserver variability and the tendency for many pathologists to disproportionately classify tumors as grade 2. Thus, interobserver differences in tumor grade and stage could not be excluded. In our database, the number of tumors was dichotomized as single or multiple, but the tumor numbers were subdivided into 3 groups (single, 2-7, and ⱖ8) in the original European Organization for Research and Treatment of Cancer risk tables. Therefore, we assigned the same recurrence score to all tumors ⱖ2. In addition, we focused on patients with newly diagnosed bladder cancer; therefore, a risk category for the previous recurrence rate was not included. For these reasons, the number of patients with a high-risk score was relatively small.
CONCLUSIONS Our results have shown that Stage Ta, T1 bladder UC in younger patients tends to be smaller, fewer in number, less invasive, and more favorable in tumor grade at initial presentation; thus, younger patients appear to have a more favorable prognosis than do older patients. Biologic reasons, such as impaired host defenses in the elderly, might be partly responsible. In addition, accumulated genetic and molecular aberrations in older patients might contribute to their poorer prognosis compared with younger patients. Additional investigation is needed to support these hypotheses. Acknowledgment. To the other Korean Urological Oncology Society members and the 38 hospitals and urologists who participated in this multicenter study. References 1. Murta-Nascimento C, Schmitz-Drager BJ, Zeegers MP, et al. Epidemiology of urinary bladder cancer: from tumor development to patient’s death. World J Urol. 2007;25:285-295. 2. Messing EM. Urothelial tumors of the bladder. In: Wein AJ, Kavoussi LR, Novick AC, et al., eds. Campbell-Walsh Urology, vol. 2, 9th ed. Philadelphia: Elsevier Saunders; 2007:2407-2446. 3. Kurz KR. Pitts WR, and Vaughan ED Jr. The natural history of patients less than 40 years old with bladder tumors. J Urol. 1987; 137:395-397.
832
4. Kutarski PW, Padwell A. Transitional cell carcinoma of the bladder in young adults. Br J Urol. 1993;72:749-755. 5. Wan J, Grossman HB. Bladder carcinoma in patients age 40 years or younger. Cancer. 1989;64:178-181. 6. Yossepowitch O, Dalbagni G. Transitional cell carcinoma of the bladder in young adults: presentation, natural history and outcome. J Urol. 2002;168:61-66. 7. Benson RC Jr, Tomera KM, Kelalis PP. Transitional cell carcinoma of the bladder in children and adolescents. J Urol. 1983;130:54-55. 8. Fitzpatrick JM, Reda M. Bladder carcinoma in patients 40 years old or less. J Urol. 1986;135:53-54. 9. Madgar I, Goldwasser B, Nativ O, et al. Long-term follow up of patients less than 30 years old with transitional cell carcinoma of bladder. J Urol. 1988;139:933-934. 10. Witjes JA, Debruyne FM. Bladder carcinoma in patients less than 40 years of age. Urol Int. 1989;44:81-83. 11. Shi B, Zhang K, Zhang J, et al. Relationship between patient age and superficial transitional cell carcinoma characteristics. Urology. 2008;71:1186-1190. 12. Fernandez-Gomez J, Solsona E, Unda M, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials. Eur Urol. 2008;53:992-1001. 13. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466467. 14. Shariat SF, Zippe C, Ludecke G, et al. Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder. J Urol. 2005;173:1518-1525. 15. Joudi FN, Smith BJ, O’Donnell MA, et al. The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy. J Urol. 2006;175:1634-1640. 16. Heiner JG, Terris MK. Effect of advanced age on the development of complications from intravesical bacillus Calmette-Guérin therapy. Urol Oncol. 2008;26:137-140. 17. Zeegers MP, Tan FE, Dorant E, et al. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000;89:630-639. 18. Aveyard P, Adab P, Cheng KK, et al. Does smoking status influence the prognosis of bladder cancer? A systematic review. BJU Int. 2002;90:228-239. 19. Linn JF, Sesterhenn I, Mostofi FK, et al. The molecular characteristics of bladder cancer in young patients. J Urol. 1998;159:14931496. 20. Iori F, De Dominicis C, Liberti M, et al. Superficial bladder tumors in patients under 40 years of age: clinical, prognostic and cytogenetic aspects. Urol Int. 2001;67:224-227.
UROLOGY 73 (4), 2009
Appendix. Weights used to calculate recurrence and progression scores* Factor Tumors Single Multiple† Tumor size (cm) ⬍3 ⱖ3 Previous recurrence rate‡ Primary ⱕ1/y ⬎1/y T stage Ta T1 Carcinoma in situ No Yes Tumor grade 1 2 3
Recurrence
Progression
0 3
0 3
0 3
0 3
0 2 4
0 2 2
0 1
0 4
0 1
0 6
0 1 2
0 0 5
EORTC ⫽ European Organization for Research and Treatment of Cancer. * Determined using EORTC risk tables for Stage Ta, T1 bladder cancer,13 partly modified. † In original EORTC risk tables, tumor numbers were subdivided into 3 groups (single, 2-7, and ⱖ8); however, number of tumors was dichotomized as single or multiple in our database. ‡ Patients with history of urothelial carcinoma were not enrolled in present study.
UROLOGY 73 (4), 2009
832.e1
RESULTS
CONCLUSIONS
To evaluate the differences in tumor characteristics and prognosis according to age at presentation in patients with newly diagnosed Stage Ta, T1 urothelial carcinoma of the bladder. From 1998 to 2002, 1587 patients with newly diagnosed nonmuscle-invasive bladder cancer treated with transurethral resection were enrolled in this study. The median age was 63 years (range 21-98), and the median follow-up duration was 44 months (range 12-97). The study cohort was subdivided into 3 age groups: age ⬍60 years (group 1, n ⫽ 614), age ⱖ60 but ⬍70 years (group 2, n ⫽ 566), and age ⱖ70 years (group 3, n ⫽ 398). Comparing the clinical and pathologic characteristics, the tumor size (2trend ⫽ 4.01, P ⫽ .045), multiplicity (2trend ⫽ 14.50, P ⬍ .001), T category (2trend ⫽ 17.11, P ⬍ .001), and tumor grade (2trend ⫽ 31.36, P ⬍ .001) tended to increase in the older age groups. The presence of carcinoma in situ and squamous differentiation, however, did not differ among the age groups (P ⬎ .05). The 5-year recurrence-free probability was 63.6%, 52.1%, and 43.9% for groups 1, 2, and 3, respectively (P ⬍ .001). The 5-year progression-free probability was 95.7%, 91.1%, and 84.2% for groups 1, 2, and 3, respectively (P ⬍ .001). Stage Ta, T1 bladder urothelial carcinoma in the younger patients tended to be smaller, have fewer lesions, be less invasive, and have a more favorable tumor grade at the initial presentation. Furthermore, younger patients appeared to have a more favorable prognosis than older patients. UROLOGY 73: 828 – 832, 2009. © 2009 Elsevier Inc.
U
rinary bladder cancer ranks ninth in worldwide cancer incidence and is more frequent in men than in women.1 Although bladder cancer can occur at any age, it is generally a disease of middle-age and elderly people. The mortality from bladder cancer is greater in the elderly population, but data are lacking to explain these facts.2 It has been debated whether younger patients have a better prognosis than their older counterparts. Several studies have shown that the natural history of bladder cancer at a younger age resembles that of bladder cancer in older patients.3-6 Other studies have demonstrated
that younger patients tend to have lower disease recurrence and progression rates, as well as better survival, compared with older patients.7-12 It is also unclear whether a better prognosis in younger patients is a result of a lower stage and grade at presentation, or whether it is a result of the indolent nature of the tumors in younger patients. In this study, we evaluated the differences in tumor characteristics and prognosis according to age at presentation in patients with newly diagnosed Stage Ta, T1 urothelial carcinoma (UC) of the bladder.
MATERIAL AND METHODS This study was sponsored by the Korean Urological Oncology Society. A part of this study was presented as a podium presentation at the American Urological Association Annual Meeting, Orlando, Florida, 2008, and as a poster presentation at the Annual Congress of the European Association of Urology, Milan, Italy, 2008. From the Department of Urology and Urological Science Institute, Yonsei University College of Medicine; Catholic University of Korea; Korea University; Kyung Hee University; University of Ulsan, Seoul, Korea; Kyungpook National University, Daegu, Korea; Ajou University, Suwon, Korea; and Donga University, Busan, Korea Reprint requests: Sung Joon Hong, M.D., Ph.D., Department of Urology and Urological Science Institute, Yonsei University College of Medicine, 134 Shinchondong, Seodaemun-gu, Seoul, Korea. E-mail: [email protected] Submitted: August 28, 2008, accepted (with revisions): October 20, 2008
828
© 2009 Elsevier Inc. All Rights Reserved
Database This study used a nationwide nonmuscle-invasive bladder cancer database maintained by the Korean Urological Oncology Society. From 1998 to 2002, the clinical and pathologic data of 3060 patients with newly diagnosed nonmuscle-invasive bladder cancer were retrospectively collected from 38 training hospitals. All patients had been treated with transurethral resection and diagnosed with Stage Ta or T1 UC of the bladder according to the 2002 American Joint Committee on Cancer TNM staging system. The clinical and pathologic data, includ0090-4295/09/$34.00 doi:10.1016/j.urology.2008.10.038
Table 1. Patient characteristics Characteristic Sex Male Female Age (y) ⬍60 ⱖ60, ⬍70 ⱖ70 Tumor size (cm) ⬍3 ⱖ3 Multiplicity Single Multiple T stage Ta T1 Tumor grade 1 2 3 CIS No Yes Squamous differentiation No Yes Intravesical therapy No Yes BCG Mitomycin C Epirubicin Other Total
Patients (n) 1329 (84.2) 249 (15.8) 614 (38.9) 566 (35.9) 398 (25.2) 1130 (71.6) 448 (28.4) 874 (55.4) 704 (44.6) 568 (36.0) 1010 (64.0) 354 (22.4) 918 (58.2) 306 (19.4) 1510 (95.7) 68 (4.3) 1499 (95.0) 79 (5.0) 496 (31.4) 1082 (68.6) 827 (52.4) 108 (6.8) 135 (8.6) 12 (0.8) 1578 (100)
CIS ⫽ carcinoma in situ; BCG ⫽ bacille Calmette-Guérin. Data in parentheses are percentages.
ing sex, age, tumor size (⬍ 3 or ⱖ3 cm), multiplicity (single or multiple), T category (Stage Ta or T1), tumor grade, presence of concomitant carcinoma in situ or squamous differentiation, and intravesical therapy, were obtained from each hospital and merged. The follow-up data were also obtained, including pathologically proven recurrence and progression. Disease progression was defined as muscularis propria invasion of UC. The interval to recurrence or progression was defined as the period between the date of the initial diagnosis and the date of recurrence or progression. Living patients or those who had died before recurrence or progression were censored at the date of the last available follow-up cystoscopy.
Study Population In this study, patients with concomitant UC of the upper urinary tract, a history of UC, including of the lower and upper urinary tract, primary carcinoma in situ, or non-UC histologic features were excluded. The study population was also limited to those with tumors graded using the World Health Organization system; however, no central histologic review was performed. Ultimately, a total of 1587 patients were eligible for this study. The median age was 63 years (range 21-98), and the median follow-up duration was 44 months (range 12-97). The patient characteristics are summarized in Table 1. The study population was subdivided into 3 age groups: ⬍60 years (group UROLOGY 73 (4), 2009
1, n ⫽ 614), ⱖ60 but ⬍70 years (group 2, n ⫽ 566), and ⱖ70 years (group 3, n ⫽ 398). The patients were also classified according to an individual risk score using the European Organization for Research and Treatment of Cancer risk tables for Stage Ta, T1 bladder cancer.13
Statistical Analysis We investigated the correlations between patient age and the clinical or pathologic features. These correlations were validated by 2 tests and linear-by-linear association. The recurrence-free and progression-free survival curves were estimated using the Kaplan-Meier method, and a log-rank test was performed to validate the differences among the 3 age groups. The Statistical Package for Social Sciences for Windows, version 12.0 (SPSS, Chicago, IL), was used for statistical analysis. Two-sided P ⬍ .05 was considered significant.
RESULTS Comparisons of Clinical and Pathologic Characteristics According to Age A 2 test of linear trend showed that tumor size (2trend ⫽ 4.01, P ⫽ .045), multiplicity (2trend ⫽ 14.50, P ⬍ .001), T category (2trend ⫽ 17.11, P ⬍ .001), and tumor grade (2trend ⫽ 31.36, P ⬍ .001) tended to increase in older age groups. The presence of carcinoma in situ and squamous differentiation, however, did not differ among the age groups (P ⬎ .05; Table 2). Differences in Recurrence-Free and Progression-Free Probabilities Among Age Groups Recurrence developed in 605 patients (38.3%) and progression in 110 patients (7.0%). The 5-year recurrence-free probability was 63.6%, 52.1%, and 43.9% in groups 1, 2, and 3, respectively (P ⬍ .001; Fig. 1). The 5-year progression-free probability was 95.7%, 91.1%, and 84.2% in groups 1, 2, and 3, respectively (P ⬍ .001; Fig. 1). The individual risk score was calculated using the European Organization for Research and Treatment of Cancer risk tables13 (see Appendix, available online at www.goldjournal.net), and the study population was classified as listed in Table 3. For disease recurrence, age had a significant influence on recurrence-free survival in patients with a recurrence score of 1-9 (P ⬍ .05). No difference was found in recurrence-free survival among the age groups for recurrence scores of 10-17 (P ⬎ .05). Older age groups had a significantly poorer prognosis for patients with a progression score of 0, 2-6, and 7-13 (P ⬍ .05). No difference was found in progression-free survival according to age for progression scores of 14-23 (P ⬎ .05; Table 3).
COMMENT During the past few decades, urologists have been interested in the presentation and natural history of bladder UC in young adults, and previous studies have provided conflicting results. Some investigators have suggested that bladder tumors in young patients behave less aggressively and more favorably.7-10 Other studies have indi829
Table 2. Comparisons of clinical and pathologic characteristics
Variable Tumor size (cm) ⬍3 ⱖ3 Multiplicity Single Multiple T stage Ta T1 Tumor grade 1 2 3 CIS No Yes Squamous differentiation No Yes Intravesical therapy No Yes
⬍60 y
Patients (n) 60-69 y
⬎70 y
457 (74.4) 157 (25.6)
399 (70.5) 167 (29.5)
274 (68.8) 124 (31.2)
374 (60.9) 240 (39.1)
305 (53.9) 261 (46.1)
195 (49.0) 203 (51.0)
251 (40.9) 363 (59.1)
206 (36.4) 360 (63.6)
111 (27.9) 287 (72.1)
170 (27.7) 355 (57.8) 89 (14.5)
129 (22.8) 314 (55.5) 123 (21.7)
55 (13.8) 249 (62.6) 94 (23.6)
587 (95.6) 27 (4.4)
540 (95.4) 26 (4.6)
383 (96.2) 15 (3.8)
581 (94.6) 33 (5.4)
537 (94.9) 29 (5.1)
381 (95.7) 17 (4.3)
220 (35.8) 394 (64.2)
156 (27.6) 410 (72.4)
120 (30.2) 278 (69.8)
2trend, Ptrend 4.014, .045 14.508, ⬍.001 17.110, ⬍.001 31.362, ⬍.001
0.179, .672 0.575, .448 4.865, .027
CIS ⫽ carcinoma in situ. Data in parentheses are percentages.
Figure 1. (A) Recurrence-free and (B) progression-free survival curves according to age group. P values determined using log-rank test.
cated no difference when stratified by age. The investigators of these studies have maintained that younger patients appear to have a more favorable prognosis, because these patients often present with nonmuscle-invasive, low-grade tumors. They have argued that the disease progression risk is the same in younger and older patients, grade-for-grade.3-6 All these studies focused largely on 830
patients ⬍30 or 40 years of age, thus the study populations were too small to draw convincing conclusions. Our results have shown differences in tumor characteristics and prognosis in patients with newly diagnosed Stage Ta, T1 UC of the bladder according to age at presentation using a large database. In the present study, the tumors in younger patients tended to be less aggresUROLOGY 73 (4), 2009
Table 3. Recurrence-free and progression-free survival rates among age groups after considering individual risk scores Risk Score* Recurrence 1-4 (n ⫽ 715) 5-9 (n ⫽ 805) 10-17 (n ⫽ 58) Progression 0 (n ⫽ 261) 2-6 (n ⫽ 547) 7-13 (n ⫽ 694) 14-23 (n ⫽ 76)
Age Group
Patients (n)
5-y EFS Rate (%)
P Value
1 2 3 1 2 3 1 2 3
315 251 149 286 287 232 13 28 17
72.9 59.3 52.2 53.5 48.1 37.2 76.1 54.0 52.9
.0034
1 2 3 1 2 3 1 2 3 1 2 3
127 92 42 231 186 130 234 255 205 22 33 21
100 100 94.1 98.9 95.4 86.7 93.5 86.3 79.5 74.1 82.7 77.9
.0142 .3559
.0093 .0001 .0038 .8012
EFS ⫽ event-free survival. * Determined using European Organization for Research and Treatment of Cancer risk tables for Stage Ta, T1 bladder cancer.13
sive in terms of clinical and pathologic features, and younger patients appeared to have a more favorable prognosis than older patients. Although no difference was found in recurrence-free and progression-free survival among the age groups in the high-risk groups (recurrence score 10-17, progression score 14-23), it might be that the number of patients in these groups was too small to allow for valid statistical analyses. However, age was an independent prognostic factor for disease recurrence and disease progression even using a multivariate Cox proportional hazards model in our data set (data not shown). Several recent studies have had findings compatible with our observations. Shi et al.11 also showed that elderly patients are more likely to present with poorly differentiated bladder cancer and that the recurrence-free survival rate decreased with increasing age. However, no difference was found in T category distribution or progression-free survival among the age groups in their study. Another study by the Club Urológico Español de Tratamiento Oncológico revealed that age was 1 of the independent predictors of progression on multivariate Cox analysis.12 In addition, Shariat et al.14 suggested nomograms to predict recurrence and progression in patients with nonmuscle-invasive bladder cancer. These nomograms also included age as an important determinant, as well as urinary nuclear matrix protein 22, sex, and cytologic findings.14 The differences in clinical and pathologic features such as multiplicity, tumor size, T category, and prognosis can UROLOGY 73 (4), 2009
be explained by patient and medical provider social influences. For example, the diagnosis might be delayed and less-aggressive therapy offered to, and selected by, elderly patients.2 Nonetheless, a high proportion of high-grade tumors in elderly patients cannot be explained with these reasons; thus, it is unclear whether older patients have a poorer prognosis, even after considering the individual risk scores. Biologic reasons such as impaired host defenses in the elderly might be partly responsible. It could also be explained by the tumor response to intravesical bacille Calmette-Guérin therapy. Several studies have reported that aging appeared to be associated with a decreased response to intravesical immunotherapy and was particularly apparent in patients ⬎80 years.15,16 In addition, accumulated genetic and molecular aberrations in older patients might contribute to their poorer prognosis. Cigarette smoking and specific occupational exposures are the main known causes of bladder cancer. A metaanalysis reported that current cigarette smokers have a bladder cancer risk of 2.57 compared with nonsmokers.17 In particular, a positive dose-response relationship was found with both the number of cigarettes smoked daily and the number of years of smoking.1 This dose-response relationship could provide some insight into our observations. Exposure to carcinogens is related to accumulating genetic and molecular aberrations in normal-looking epithelium and bladder tumors. However, our database does not contain any information on smoking history or patient environmental exposure; thus, we could not perform those analyses. Active tobacco smoking is now the most commonly studied factor regarding prognosis. A recent systematic review concluded that cigarette smoking might be a weak factor influencing prognosis, but the results were inconclusive.18 Some researchers have investigated the molecular and genetic differences among age groups; however, data are lacking with which to evaluate our hypothesis. Linn et al.19 studied genetic alterations in bladder cancer samples from patients ⬍30 years and reported frequent p53 gene overexpression. The tumors analyzed were uniformly of low grade and low stage, and no noted correlation was found between the immunohistochemical findings and clinical endpoints. Iori et al.20 identified a frequency of chromosomal alterations (ie, aneusomy of chromsomes 7 and 17) in young patients that was greater than in old patients. Because these alterations are typical of more aggressive tumors, it is not compatible with the favorable clinical outcomes of young patients, such as was shown in that study. Nonetheless, additional investigation of normal and tumor epithelium from a large cohort of young and old patients with bladder cancer is needed to support our hypotheses. Our study had several weaknesses, including the general limitations of a retrospective design. An important limitation was that a central review of the pathologic slides was not performed. The limitation with the 1973 831
World Health Organization system is the high intraobserver variability and the tendency for many pathologists to disproportionately classify tumors as grade 2. Thus, interobserver differences in tumor grade and stage could not be excluded. In our database, the number of tumors was dichotomized as single or multiple, but the tumor numbers were subdivided into 3 groups (single, 2-7, and ⱖ8) in the original European Organization for Research and Treatment of Cancer risk tables. Therefore, we assigned the same recurrence score to all tumors ⱖ2. In addition, we focused on patients with newly diagnosed bladder cancer; therefore, a risk category for the previous recurrence rate was not included. For these reasons, the number of patients with a high-risk score was relatively small.
CONCLUSIONS Our results have shown that Stage Ta, T1 bladder UC in younger patients tends to be smaller, fewer in number, less invasive, and more favorable in tumor grade at initial presentation; thus, younger patients appear to have a more favorable prognosis than do older patients. Biologic reasons, such as impaired host defenses in the elderly, might be partly responsible. In addition, accumulated genetic and molecular aberrations in older patients might contribute to their poorer prognosis compared with younger patients. Additional investigation is needed to support these hypotheses. Acknowledgment. To the other Korean Urological Oncology Society members and the 38 hospitals and urologists who participated in this multicenter study. References 1. Murta-Nascimento C, Schmitz-Drager BJ, Zeegers MP, et al. Epidemiology of urinary bladder cancer: from tumor development to patient’s death. World J Urol. 2007;25:285-295. 2. Messing EM. Urothelial tumors of the bladder. In: Wein AJ, Kavoussi LR, Novick AC, et al., eds. Campbell-Walsh Urology, vol. 2, 9th ed. Philadelphia: Elsevier Saunders; 2007:2407-2446. 3. Kurz KR. Pitts WR, and Vaughan ED Jr. The natural history of patients less than 40 years old with bladder tumors. J Urol. 1987; 137:395-397.
832
4. Kutarski PW, Padwell A. Transitional cell carcinoma of the bladder in young adults. Br J Urol. 1993;72:749-755. 5. Wan J, Grossman HB. Bladder carcinoma in patients age 40 years or younger. Cancer. 1989;64:178-181. 6. Yossepowitch O, Dalbagni G. Transitional cell carcinoma of the bladder in young adults: presentation, natural history and outcome. J Urol. 2002;168:61-66. 7. Benson RC Jr, Tomera KM, Kelalis PP. Transitional cell carcinoma of the bladder in children and adolescents. J Urol. 1983;130:54-55. 8. Fitzpatrick JM, Reda M. Bladder carcinoma in patients 40 years old or less. J Urol. 1986;135:53-54. 9. Madgar I, Goldwasser B, Nativ O, et al. Long-term follow up of patients less than 30 years old with transitional cell carcinoma of bladder. J Urol. 1988;139:933-934. 10. Witjes JA, Debruyne FM. Bladder carcinoma in patients less than 40 years of age. Urol Int. 1989;44:81-83. 11. Shi B, Zhang K, Zhang J, et al. Relationship between patient age and superficial transitional cell carcinoma characteristics. Urology. 2008;71:1186-1190. 12. Fernandez-Gomez J, Solsona E, Unda M, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials. Eur Urol. 2008;53:992-1001. 13. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466467. 14. Shariat SF, Zippe C, Ludecke G, et al. Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder. J Urol. 2005;173:1518-1525. 15. Joudi FN, Smith BJ, O’Donnell MA, et al. The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy. J Urol. 2006;175:1634-1640. 16. Heiner JG, Terris MK. Effect of advanced age on the development of complications from intravesical bacillus Calmette-Guérin therapy. Urol Oncol. 2008;26:137-140. 17. Zeegers MP, Tan FE, Dorant E, et al. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000;89:630-639. 18. Aveyard P, Adab P, Cheng KK, et al. Does smoking status influence the prognosis of bladder cancer? A systematic review. BJU Int. 2002;90:228-239. 19. Linn JF, Sesterhenn I, Mostofi FK, et al. The molecular characteristics of bladder cancer in young patients. J Urol. 1998;159:14931496. 20. Iori F, De Dominicis C, Liberti M, et al. Superficial bladder tumors in patients under 40 years of age: clinical, prognostic and cytogenetic aspects. Urol Int. 2001;67:224-227.
UROLOGY 73 (4), 2009
Appendix. Weights used to calculate recurrence and progression scores* Factor Tumors Single Multiple† Tumor size (cm) ⬍3 ⱖ3 Previous recurrence rate‡ Primary ⱕ1/y ⬎1/y T stage Ta T1 Carcinoma in situ No Yes Tumor grade 1 2 3
Recurrence
Progression
0 3
0 3
0 3
0 3
0 2 4
0 2 2
0 1
0 4
0 1
0 6
0 1 2
0 0 5
EORTC ⫽ European Organization for Research and Treatment of Cancer. * Determined using EORTC risk tables for Stage Ta, T1 bladder cancer,13 partly modified. † In original EORTC risk tables, tumor numbers were subdivided into 3 groups (single, 2-7, and ⱖ8); however, number of tumors was dichotomized as single or multiple in our database. ‡ Patients with history of urothelial carcinoma were not enrolled in present study.
UROLOGY 73 (4), 2009
832.e1