SMOKING INCREASED BLADDER TUMOR RECURRENCE RATE IN UPPER TRACT

UROTHELIAL CARCINOMA

吸菸增加上泌尿道泌尿上皮癌之膀胱復發

Tai, Yi-ShengDepartment of Urology, National Taiwan University Hospital

Background & Purpose

Cigarette smoking increases bladder recurrence in bladder UC patients.

Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer. Eur Urol. 2011

Stopping smoking decreases bladder recurrence in bladder UC patients. Stopping smoking might reduce tumour recurrence in nonmuscle-invasive bladder

cancer. BJU Int. 2007

Whether smoking also plays an important role on bladder recurrence in UUC patients?

Materials and Methods

Patient population: Consecutive UUC patients from 2000~2011 All received nephroureterectomies

Exclusion criteria Arsenic endemic residency Previous chemothrapy and radiotherapy for

any reason Insufficient tissue samples for etiology

identification

Materials and Methods

Etiology identification Questionnaire: cigarette smoking and herbs

Renal cortex: aristolactam-DNA adduct (aristolochic acid exposure)

Tumor: TP53 gene sequencing (signature mutation for aristolochic acid-induced UC)

Materials and Methods

Outcome measurement Bladder recurrence: only tumor recurrence 3

months after nephroureterectomy

Tumor recurrence within 3 months was considered as synchronous bladder cancer

excluded from the analysis

Patient demographics

Patient charcteristics No. of patients (%)Patient number 159Median age 66.4 (22-90)Sex

Female 72 (45.3)Male 89 (54.7)

Ever smoking 34 (21.7)Heavy smokers* 27 (17.2)Herbs usage 28 (17.8)AL-DNA adduct 95 (61.3)TP53 mutation, all 84 (55.6)TP53 signature mutation, AA related

49 (31.6)

ESRD 24 (15.5)DM 38 (24.2)Hypetension 66 (42.0)Grade

High 108 (69.2)Low 48 (30.8)

StageTa-1NoMo 74 (48.4)T2-4NoMo 69 (45.1)

nodal or metastatic 10 (6.5)Multiple tumor location 49 (30.8)

Heavy smoker * : greater than 20 pack-year of smoking

Patient demographics stratified by smoking

Heavy smokerNon-heavy

smoker*p value

Median age 66 (45-83) 67 (22-91) 0.483Sex

Female 0 72 (55)Male 27 (100) 58 (45) <0.001

Herbs usage 1 (4) 27 (21) 0.035AL-DNA adduct 14 (52) 81 (64) 0.227All TP53 mutation, 9 (35) 74 (60) 0.017TP53 signature mutation 2 (8) 47 (37) 0.004ESRD 3 (11) 21 (17) 0.471DM 8 (30) 30 (23) 0.469Hypertension 13 (48) 53 (41) 0.48Grade

Low 10 (37) 38 (30)High 17 (63) 89 (70) 0.468

StageTa-1NoMo 13 (48) 61 (49)T2-4NoMo 13 (48) 54 (44)

nodal or metastatic 1 (4) 9 (7) 0.486Multiple tumor location 12 (44) 37 (28) 0.103

Bladder tumor recurrence

Non-heavy smoker

Heavy smoker

Log-rank p=0.034

Bladder tumor recurrence stratified by etiologies

AA-UUC: signature p53 mutation and AL-DNA adduct

Prognostic factors for bladder tumor recurrenceUnivariate Multivariate

Factors HR p value HR p valueMedian age 0.99 0.246 ▬ ▬Sex

Female 1 ▬ ▬ ▬Male 1.56 0.163 ▬ ▬

Ever smoking 1.66 0.151Heavy smokers* 2.24 0.034 3.63 0.002Herbs usage 2.01 0.037 1.52 0.328AL-DNA adduct 0.97 0.924TP53 mutation, all 2.27 0.027 3.11 0.004TP53 signature mutation

0.98 0.954 ▬ ▬

ESRD 1.64 0.209 ▬ ▬DM 2.36 0.008 3.13 0.001Hypetension 1.48 0.205Grade

Low 0.9 0.731 ▬ ▬High 0.9 0.731 ▬ ▬

StageTa-1NoMo 1 ▬ ▬ ▬T2-4NoMo 1.42 0.26 ▬ ▬

Multiple tumor location 2.93 0.001 2.61 0.019

Discussion

Cigarette smoking and bladder cancer

Cigarette smoking and UTUC

Smoking and bladder tumor recurrence in UUC

Cigarette smoking and bladder cancer

Current cigarette smokers have an approximately threefold higher risk of urinary tract cancer than nonsmokers. Cancer. 2000 Aug 1;89(3):630-9.

Ex- and current smoking result in significantly shorter recurrence-free survival than non-smoking

Eur Urol 60 (2011) (713 - 720)

Chen et al. - Benefit of smoking cessation on bladder cancer

recurrence. - Continued smokers have a 2.2-time increased risk

than cessation BJU Int. 2007 Aug;100(2):281-6

Cigarette smoking and UTUC

Cigarette smoking : risk factor for the development of UTUC

- 3.1-fold higher risk in smokers

- 7.2-fold higher risk in long-term smokers

CANCER RESEARCH 52, 254-257. January 15, 1992

Associated with advanced disease stages, disease recurrence, and cancer-specific mortality in patients treated with RNU for UTUC. Eur Urol. 2012 Jun 22.

Smoking cessation >10 yr seems to mitigate

some detrimental effects. Eur Urol. 2012 Jun 22.

Smoking and bladder tumor recurrence in UUC

Few published studies focued on the smoking as prognostic factors for bladder cancer recurrence after nephroureterectomy.

Terakawa et al. Pathologic stage and tumor multifocality as

independent predictors for recurrent bladder

Urology. 2008 Jan;71(1):123-7

Simsir et al. smokers had higher cancer-specific

mortality and bladder recurrence rates. not provide a multivariable analysis

Int Urol Nephrol. 2011 Dec;43(4):1039-45

Smoking and bladder recurrence in UUC: this study

Heavy smoking, TP53 mutation, DM and multiple tumor location are independent factors on bladder tumor recurrence after NUx

Aristolochic acid-related UUC: insignificant

Heavy smoking inversely associated with TP53 mutation.

Conclusions

Heavy smokers UUC patients, > 20 pack-years, had more bladder tumor recurrence than non-smokers

and aristolochic acid-related UUC patients

Heavy smoking is an independent factor predicting bladder recurrence in UUC patients and inversely associated with TP53 mutation.

ThanksForYourAttention

A series of studies has demonstrated a significant association between the number of cigarettes smoked per day and p53 nuclear overexpression Cancer Epidemiol Biomarkers Prev. 1994 Jan-Feb;3(1):19-24 as well as between the p53 point mutations and the number of years of smoking in bladder cancer. Carcinogenesis. 2000 Jan;21(1):101-6.

p53 mutation is associated with high-stage disease and p53 overexpression was correlated with advanced tumor stage and grade , and was forwarded as a significant negative predictor of survival . Int J Cancer 53 : 365-370 , J Natl Cancer Inst 85 : 53-58 , Science 252 : 706-709, Cancer, 82 (1998), pp. 715–723

More recently, p53 nuclear accumulation in bladder carcinomas cells was found to correlate with the mitotic index and vascular invasion.  J. Urol., 162 (1999), pp. 1496–1501

The detection of nuclear p53 was a independent predictor significantly associated with an increased risk of recurrence of bladder cancer  and with decreased overall survival. N Engl J Med. 1994 Nov 10;331(19):1259-64.

Rey et al. were the first to investigate the prognostic role of proteins involved in cell-cycle regulation in 83 patients with UTUC [100].

The authors showed that the overexpression of p53 was significantly associated with tumor aggressiveness and patient survival, even after adjustment for several patient and disease characteristics.

More recently, the impact of p53 on survival was investigated by a Japanese single-center study (n = 66) and a European single-center study (n = 53) [101,102].

According to these studies, while p53 was a predictor of survival in univariable analyses, it did not emerge as an independent prognostic factor after adjustment for other clinical and pathologic characteristics.

TP53 mutation (rate and pattern) in UUC patients(overall)