Factors Affecting Recurrence Rates in Superficial Bladder Cancer 1,2

Factors Affecting Recurrence Rates in Superficial Bladder Cancer 1,2 Maria Koch, 3 Gerry B. Hill, 4 and Malcolm S. McPhee 5,6 ABSTRACT -A prospective study of all patients with superficial bladder cancer diagnosed in Northern Alberta (population 1.2 million) from 1977 to 1983 was performed to establish patterns of recurrence. Of the 761 patients with all stages of bladder cancer at diagnosis, 642 were deemed to be free of disease after primary treatment consisting of transurethral resection, fulguration, or laser surgery. Follow-up of these patients showed that approximately two-thirds of first recurrences occur within 18 months of diagnosis and that more of these patients have died of unrelated causes (n = 73) than of bladder cancer (n = 34). Censored disease-free interval comparisons showed that initial recurrences occurred sooner in patients with multifocal rather than unifocal disease and also sooner in females than in males. Known risk factors (occupational exposure to chemicals and cigarette smoking) and suspected risk factors (coffee consump!ion and artificial sweetener use) had no effect on disease-free interval and are not related to tumor multiplicity.-jnci 1986; 76:1025-1029. Cancer of the bladder incidence has been steadily increasing in most industrialized nations of the world, and this disease has been the subject of many epidemiological studies to determine possible risk factors [bibliography in (1)]. The etiologic factors that have been confirmed by several independent studies are cigarette smoking (2-4) but not pipes, cigars, or smokeless tobacco (5), and certain occupational exposures (6). Other potential risk factors under study include ionizing radiation, biological factors (chromosomal abnormalities, blood group effect), diet (vitamin A and C deficiency, artificial sweeteners, coffee), and infections [both bacterial and by Schistosoma haematobium (1, 7)]. At the time of diagnosis, a large proportion of cases of bladder cancer are of low grade and early stage. Although they are considered to have been totally excised after primary treatment, the recurrence rate is high. The prognostic factors described as being significant to predict recurrences are the presence of multiple tumors (8-10), depth of invasion (8), high tumor grade (9), and short disease-free interval after initial treatment (10). It has been postulated that a discontinuation of smoking may decrease recurrence rates in head and neck cancer (11) and increase survival in patients with lung cancer (12), but discontinuation has no effect on bladder cancer recurrences (13). The purpose of this study is to determine the recurrence pattern in those bladder cancer patients who were deemed to be free of disease after primary treatment and to assess the possible effect of some of the "life-style" risk factors on heir disease-free interval. MATERIALS AND METHODS The Alberta Cancer Registry is population based and receives notification of all new cancer cases in the province. There were 761 patients diagnosed with carcinoma of the bladder from 1977 to 1983 in Northern Alberta (population 1.2 million). Of these, 642 patients were considered to be free of disease after primary treatment and were followed at regular intervals. The routine follow-up is done at 3-month intervals for the first 2 years, at 6-month intervals for the next 3 yeats, and yearly thereafter. Each follow-up includes a cystoscopy performed by a urologist. The cystoscopy reports, as well as all pathology reports whenever a specimen is taken, are forwarded to, be included in the patient's chart at the Cross Cancer Institute. Patients who do not comply with this schedule have been considered lost to follow-up for the purpose of this study. Every time a histologically proved recurrence was diagnosed, its date was recorded as well as the treatment and its outcome. A total number of 474 patients were eligible for this study, inasmuch as 61 had been lost to follow-up and 107 patients were deceased. Of the deceased patients, 34 had died of bladder cancer, 67 died of other causes without any evidence of bladder cancer recurrence, and in the remaining 6 the bladder cancer status was unknown. Permission to contact the patients was obtained from the attending urologists for all except 25 of the 474 eligible patients, and all remaining 449 patients were sent a questionnaire that included questions on past and present risk factor exposures, such as employment history, smoking habits before and after the diagnosis of bladder cancer, coffee consumption, artificial sweetener, and soft drink use. There were 334 responders (74%). Of the nonresponders, 69 refused, 35 had not continued their regular follow-up schedule, and II had died. At the time of t!leir 1 Received May 28, 1985; revised December 4, 1985; accepted January 3, 1986. 2 The Alberta Cancer Board's Research Assessment Committee reo viewed and approved the project for ethical considerations as well as providing the required funding. 3 Department of Epidemiology and Preventive Oncology, Alberta Cancer Board, Cross Cancer Institute, 11560 University Ave., Edmon ton, AB, Canada T6G lz2. 4 Department of Epidemiology and Preventive Oncology, Alberta Board, 6th Floor, 9707-110 St., Edmonton, AB, Canada T5K 2L9. 5 Department of Surgery, Alberta Cancer Board, Cross Cancer Institute. 6We are grateful to all the urologists practicing in Northern Alberta for their cooperation, as well as to Mr. John Hanson, Ms. Betty Irvine, Ms. Herta Gaedke, and Ms. Diane Wilson for data collection and analysis. 1025

1026 Koch, Hill, and McPhee 2 patients with a first recurrence 119 15.6% O remained free of disease disease progressed n free of disease w but recurred TEXT-FIGURE I.-Results of treatment in all 761 patients with carcinoma of the bladder. death, 7 of these patients were free of demonstrable bladder cancer recurrence. The general disease evolution of all 642 patients that were free of disease after primary treatment (text-fig. 1) shows that 362 (56%) remained free of disease and 2 recurred. After treatment of this first recurrence, 232 were free of disease, and of these 138 later presented with a second recurrence. Of these, 123 were free of disease after treatment, but 70 went on to have a third recurrence. As for the 334 responders, 197 (59%) remained free of disease for the duration of the study, had one recurrence, 35 had two recurrences, and 22 more than two recurrences. Crude disease-free interval was calculated in those patients diagnosed between 1977 and 1979 (n = 311) so that the length of follow-up would be at least 4 years (median 59 mo, range 48-85). Table 1 shows a comparison between the responders and the nonresponders with respect to several prognostic factors showing that the responder group is similar to nonresponders with respect to sex and age distribution, proportion of unifocal versus multifocal tumors, and stage. Comparisons of censored disease-free interval were done with the use of the life-table method (14). Regression analyses were performed with the use of the propor- tiona I hazards model of Cox (15) to assess the importance of life-style habits including smoking, coffee and artificial sweetener consumption, and exposure to workplace chemicals as related to disease-free interval, controlling for stage, tumor centricity, age, and sex. RESULTS Crude disease-free interval of 311 patients diagnosed from 1977 to 1979, including both responders and nonresponders, is shown in table 2. Nearly two-thirds of first recurrences occurred in the 18 months following primary treatment, with the largest number becoming evident in the first 6 months. After 18 months, the rate becomes steady with one to two percent of disease-free patients recurring in any 6-month interval. For the disease-free interval comparisons, all 642 eligible patients were considered, including responders and nonresponders. Of the prognostic factors tested, only tumor multiplicity and sex proved to be significant (text-figs. 2, 3). Age or stage (comparison between Ta, Tl, and T2) did not affect disease-free interval. The relationship between these proven unfavorable prognostic factors (tumor multiplicity and patient's sex) and the life-style habits of the 334 patients that answered the questionnaire is summarized in table 3. Analysis by chi square shows that they are unrelated. Further analysis was done considering lifetime consumption of cigarettes and years of use, also with negative results. For instance, the proportion of heavy TABLE I.-Comparison of 334 responders with 308 nonresponders with respect to several prognostic factors Factor Responders N onresponders No. % No. % Sex Male 237 71 245 Female 97 29 63 Age, yr 0-49 51 15 47 15 50-69 159 48 141 46 70 124 37 1 39 of diagnosis 1977 42 13 73 24 1978 44 13 55 18 1979 42 13 55 18 19 75 23 34 11 1981 71 21 45 15 1982 60 18 46 15 Tumor type Unifocal 222 66 193 63 Multifocal 106 32 68 22 Unknown 6 2 47 15 Stage Ta 7 2 11 4 T1 269 81 215 69 T2 41 12 37 12 Unknown 17 5 45 15 No. of recurrences 0 197 59 192 62 1 24 45 15 2 35 11 31 10 >2 22 7 40 13

Recurrence Rates in Bladder Cancer 1027 TABLE 2.-Rate of first recurrences occurring in 811 patients diagnosed during 1977-79 who were free of disease after primary treatment a Time after No. of patients Deceased No. of Recurrences, Total % diagnosis, mo disease-free recurrences recurrences, % 0-6 311 0 24 7.7 32.8 7-12 287 0 16 5.6 21.9 13-18 271 2 8 3.0 11.0 19-24 261 1 3 1.1 4.1 25-30 257 1 5 1.9 6.8 31-36 251 1 3 1.2 4.1 37-42 247 3 4 1.6 5.5 43-48 240 1 5 2.0 6.8 >48 234 2 5 2.1 6.8 Total 11b 73 23.5.0 a As of December 31, 1983. b Includes 7 patients that died of unrelated causes, free of disease, and 4 that died of unknown causes. smokers who present with multicentric tumors is similar to that of nonsmokers. There are considerable differences in life-style factors between males and females: A higher proportion of males smoke and have been exposed to chemicals in their work. The fact that women, although less exposed to these factors, still have a poorer prognosis confirms the lack of effect of these factors on disease-free interval. When the proportional hazards model of Cox was applied to data obtained on the 334 responders (table 4), it showed that the only significant risk factors are sex (P =.012) and tumor centricity (P<0005). Stage has no significant effect, probably due to the fact that all patients had superficial lesions, and only those free of demonstrable disease after primary treatment were included in the study. The charts of all 308 nonresponders were reviewed to determine smoking habits. Information was available in 175 cases (57%). Of the 175, 24 had never smoked, which is a similar proportion of nonsmokers to that found in the responders (14 vs. 17%). This seems to indicate that for smoking habits, the responder group is similar to the nonresponders (text-fig. 4). '" L1... 60 C. 40 Cl li'-i! 0 - All Patients.( n ' 642) ----- Unicentre Tumor (n' 388) 1 _... 00_... 00, Multifocal Tumor (n' 164) p<o.ooi 2 3 4 5 6 7 TEXT FIGURE 2.-Censored disease-free interval for all patients with superficial bladdt;r cancer and according to tumor centricity. DISCUSSION Superficial cancer of the bladder seems to be an acceptable model to observe the influence of possible "risk factors" on the natural history of the disease. Treatment in most cases is limited to local resection. The low case fatality rate combined with a high recurrence rate allows for long follow-up of patients and accurate documentation of the factors affecting recurrences and survival. Heney et ai., as members of the National Bladder Cancer Collaborative Group A (16), have confirmed that the "tumor" factors associated with shorter disease-free intervals included stage, grade, multiplicity, level of invasion, and positive urinary cytology. Among other factors affecting recurrence rates in bladder cancer, continued exposure to carcinogens has been implicated (17) but without supporting evidence. In a similar study looking at recurrence rates after head and neck cancer (11), results show that in this type of tumor, smoking is a risk factor and also influences recurrences. Smokers show a fourfold increase, and exsmokers show a twofold increase of recurrence rates as compared to nonsmokers. The data presented suggests <1> 60 <1> o o 40 a-e "-... '-- -------- Males (n'482) 1 p'002 Females (n' 160) J ----------::::!--- OJ-----_r--_r--_r--_r--_+-- 2 3 4 5 6 7 TEXT FIGURE 3.-Censored disease free interval by sex.

1028 Koch, Hill, and McPhee TABLE 3.-Relationship between unfavorable prognostic factors and life-style habits of patients Factors Unifocal, n=222 Multifocal, n=106 Male, n=237 Female, n=97 Smoking Nonsmokers 36 21 38 Ex-smokers 105 45 128 7 Smokers 81 40 89 52 Coffee consumption None 21 15 27 11 Moderate a 96 45 98 45 High a 76 36 82 32 Unknown 29 10 30 9 Artificial sweeteners Nonusers 178 84 188 75 Users 39 21 41 Unknown Exposure to chemicals 5 1 8 2 in work place Yes 74 43 109 9 Uncertain 48 55 17 No 43 73 71 a Moderate = <60,000 cups lifetime consumption. High = >60,000 cups lifetime consumption. that cigarette smoking is both a cancer initiator and a promoter, implying that the recurrences found were "new" cancers (11). Another mechanism of lower recurrence rates in nonsmokers has been proposed to explain the prolongation of survival in patients with carcinoma of the lung that stop smoking. It is apparently related to the deleterious effect that cigarette smoking has on the patients' immune system (12). In bladder cancer, one of the best predictors of recurrences is multicentricity of the primary tumor (8-10). The intrinsic mechanism of multifocal lesions is unknown (18), but several hypotheses have been forwarded. It may be caused by the continuous action of a carcinogenic agent (19) or by dissemination from a single focus (). We have failed to demonstrate an association between tumor multiplicity and some risk factors, such as smoking and coffee consumption, as well as between those same risk factors and disease-free interval. This indicates that these factors are more likely to be tumor "initiators" than promoters. Multicentricity could be due to either local disease spread or mucosal transformation caused by a carcinogen, with a long delay between the injury and the appearance of a visible lesion in the bladder. TABLE 4.-Regression modeljor predicting disease-free survival by sex, stage, tumor centricity, age, smoking status, coffee and artificial sweetener consumption, and exposure to chemicals Variable Multicentricity Sex Coffee consumption Artificial sweeteners Chemical exposure Age Smoking Stage P-value.000.012.150.163.267.400.400.935 u.. 13 Cl a-'1 - All Responders (n' 334 )... Non Smokers (n' 58 ).---- Ex Smokers (n' 132 ).--. Smokers (n' 144 ) 60...':>..,. '- 40 0... _-. '---'-==.: ------- ------- --------- 2 3 4 5 6 TEXT-FIGURE 4.-Censored disease-free interval according to smoking history in the patients who answered the questionnaire. REFERENCES (l) HILL GB. Epidemiologic considerations. In: Javadpour N. ed. Bladder cancer: International perspectives in urology. Vol 12. Baltimore Williams & Wilkins, 1984:5-36. (2) VENEIS P, FREA B, UBERTI E, et al. Bladder cancer and cigarette smoking in males: A case control study. Tumori 1983; 69:17-22. (3) MORRISON AS, BURING JE, VERHOEK WG, et al. An international study of smoking and bladder cancer. J Uro11984; 131:650-654. (4) MILLER AB. The etiology of bladder cancer from the epidemiological viewpoint. Cancer Res 1977; 37:2939-2942. (5) HARTGE P, HOOVER R, KANTOR A. Bladder cancer risk and pipes, cigars, and smokeless tobacco. Cancer 1985; 55:901-906. (6) SCHOENBERG JB, STEMHAGEN A, MOGIELNICKI AP, et al. Casecontrol study of bladder cancer in New Jersey. I. Occupational exposures in white males. JNCI 1984; 72:973-981. (7) BOICE JD, LAND CEo Ionizing radiation. In: Schottenfeld D, Fraumeni JF Jr. Cancer epidemiology and prevention. Philadelphia: Saunders, 1982. (8) HENEY NM, NOCKS BN. DALY 11. et al. Ta and Tl bladder 7 jnci, VOL. 76, NO.6, JUNE 1986

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