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Abstract

Background:

The evidence supporting personalized surveillance strategies for upper-tract urothelial carcinoma (UTUC) remains limited. This study seeks to explore how smoking habits influence the oncological outcomes of UTUC

Methods:

Data on disease characteristics from UTUC patients were gathered prospectively. Recurrence-free survival was the primary outcome measured. Patients were stratified based on smoking status for Kaplan–Meier and multivariable Cox regression analyses.

Results:

A total of 1952 patients were involved, including 684 (35%) patients who never smoked, 572 (29%) that were ex-smokers, and 696 (36%) that were current smokers. For female patients, most of them were nonsmokers (n = 328). Current smokers were significantly younger and had higher American Society of Anesthesiologist (ASA) scores and Charlson Comorbidity Index. A total of 19.9% (n = 236) of patients developed tumor recurrence. Kaplan–Meier analyses showed that smoking status was associated with a greater likelihood of urothelial carcinoma recurrence (p = 0.011) and intravesical recurrence (p = 0.021). The multivariable Cox regression analysis identified the smoking status as an independent risk factor for urothelial carcinoma recurrence (p = 0.046). When compared with former smokers, current smokers showed a higher urothelial carcinoma recurrence (p = 0.016) and intravesical recurrence (p = 0.006).

Conclusion:

Smoking at the time of diagnosis was significantly associated with an increased risk of tumor recurrence in the bladder but not significantly in the upper urinary tract. This study confirms that cumulative smoking exposure accelerates the risk of tumor recurrence and underlines the importance of smoking cessation.

Trial registration:

NCT02281188.

Plain language summary

The influence of smoking status for patients with UTUC

Based on the CROES-UTUC registry, we confirmed that both previous non-urothelial and urothelial cancers could accelerate the risk of tumour recurrence and, more personalized follow-up plans and active treatment strategies should be considered for UTUC patients.

Keywords

oncological outcomes recurrence smoking upper tract urothelial carcinoma

Introduction

Upper-tract urothelial carcinoma (UTUC), a less common yet medically important form of urothelial carcinomas, constitutes around 5%–10% of all urothelial malignancies.¹ Primarily impacting the renal pelvis and ureter, this condition poses distinctive diagnostic and management challenges owing to its anatomical position and unique biological characteristics.²

Various environmental factors have been linked to the onset of UTUC. However, apart from smoking and aristolochic acid, there is scant evidence supporting the causal role of these factors.^3,4 It is crucial for UTUC patients to be particularly vigilant about smoking due to its established association not just with cancer outcomes but also with overall health deterioration.^5,6 Numerous studies highlight tobacco exposure as a significant risk factor for UTUC development, tumor recurrence, and mortality. Smoking is also recognized as a common risk factor for exacerbating life-threatening comorbidities like cardiovascular diseases and other major malignancies.^7,8 Recent research emphasizes the substantial impact of smoking on UTUC-related deaths.⁹ Moreover, smoking may enhance the risk of genetic mutation, especially for individuals carrying variants in NAT2 and GSMT1, which could increase the risk of tumor occurrence.¹⁰

The Clinical Research Office of the Endourology Society Urothelial Carcinomas of the Upper Tract (CROES-UTUC) registry, initiated in 2014, represents one of the largest real-world prospective global datasets focusing on UTUC management.¹¹ With the clinical outcome of patients with UTUC, we investigated the influence of cigarette exposure. Our hypothesis speculates that individuals who were current smokers at diagnosis would exhibit a decreased recurrence-free survival (RFS) compared to former smokers or those who had never smoked. These findings aim to offer critical insights into how smoking habits influence UTUC patient outcomes.

Materials and methods

The CROES-UTUC registry is a global, observational, multicenter cohort study dedicated to investigating the care of patients with suspected UTUC.¹¹ Since its establishment in November 2014, the registry has garnered participation from 101 centers across 29 countries. Adhering to the guidelines set forth by the Agency for Healthcare Research and Quality, the registry aims to serve scientific, clinical, and health policy purposes.¹² This study is registered on clinicaltrials.gov [ClinicalTrials.gov identifier: NCT02281188], and its protocol has been previously published.¹¹ The reporting of this study confirms to the Strengthening the Reporting of Observation Studies in Epidemiology (STROBE) statement (Supplemental Material).¹³

Patient selection

The study encompassed consecutive patients aged 18 years and older with suspected UTUC undergoing various diagnostic or therapeutic surgical procedures, including radical nephroureterectomy, segmental resection, and ureteroscopy (URS). Patients with previous bladder cancer or other malignancies were not excluded. The criteria were deliberately inclusive to furnish comprehensive real-world insights into the management and results of individuals with suspected UTUC.

Data collection

All relevant information were collected and stored using an online Data Management System, including baseline characteristics and clinical information.¹⁴ The Data Management System, a web-based platform, was situated and maintained at the CROES Office. Upon diagnosis, all urological patients were requested to document their medical histories.

Smoking exposure

At the point of diagnosis, all urology patients were required to provide details on their smoking habits. This included their smoking status (current, ex-, or nonsmoker) and the number of pack-years smoked for ex- and current smokers (<20 vs ⩾20 pack-years),¹⁵ which was collected for analysis. Current smokers were those who reported smoking at diagnosis or within 1 year of histological diagnosis, while ex-smokers were individuals who had quit smoking at least a year before diagnosis.

Follow-up regimen

The primary outcome of this study was RFS. When distant metastases, local failure in the bladder, upper tract, or regional nodes occurred, it could be defined as disease recurrence. The follow-up duration was measured from the diagnosis date to the occurrence of the first recurrence. Patients without any recurrence were considered censored at their last follow-up date if they were still alive.

Statistical analysis

Descriptive statistics were computed for demographic, disease, and smoking traits. Chi-squared test was employed to analyze the relationship between categorical variables. Kaplan–Meier (K-M) analysis, log-rank test, and multivariable Cox regression analysis were also used to analyze oncological outcomes. Complete case analysis was performed in case of any missing data on the variables of interest. A p-value <0.05 was considered statistically significant. We conducted statistical analyses via software SPSS version 26 (IBM Corporation, Armonk, New York) and R studio (RStudio Team, Boston, Massachusetts).

Results

Overview

This study enrolled a total of 1952 individuals with UTUC (Figure 1), including 578 female and 1370 male (3 missing). Table 1 outlined the clinicopathological features of this patient cohort. Approximately 67% of patients had an ASA grading of I–II, and 35.6% had a CCI of ⩾2. Among all patients, 757 patients had pTa/Tis/T1 disease, while 737 patients had T2–4 tumor. A total of 59.2% of patients were diagnosed with G2–4 tumor.

Figure 1.

Flowchart describing the selection of patients with upper-tract urothelial carcinoma.

Table 1.

Baseline characteristics between the two groups for all patients.

Characteristics of patients	Overall, no. (%)(n = 1952)	Nonsmoker, no. (%)(n = 684)	Ex-smoker, no. (%)(n = 572)	Current smoker, no. (%)(n = 696)	p-Value
Age					<0.001***
Mean (SD)	71.3 (10.7)	73.3 (10.2)	72.4 (9.4)	67.4 (11.7)
Median [Min, Max]	72.0 [35.0, 94.0]	75.0 [40.0, 94.0]	73.0 [35.0, 91.0]	68.0 [39.0, 93.0]
Missing	542 (27.8)	215 (31.4)	162 (28.3)	165 (23.7)
Gender					<0.001***
Female	578 (29.6)	328 (48.0)	138 (24.1)	112 (16.1)
Male	1370 (70.2)	355 (51.9)	432 (75.5)	584 (83.9)
Missing	3 (0.2)	1 (0.1)	2 (0.4)	0
Race					<0.001***
White	1447 (74.1)	460 (67.3)	441 (77.1)	546 (78.4)
Asian	322 (16.5)	171 (25.0)	78 (13.6)	73 (10.5)
Black	22 (1.1)	5 (0.7)	12 (2.1)	5 (0.7)
Hispanic	79 (4.0)	25 (3.7)	20 (3.5)	34 (4.9)
Others	26 (1.3)	5 (0.7)	4 (0.7)	17 (2.5)
Missing	56 (3.0)	18 (2.6)	17 (3.0)	21 (3.0)
ASA grading					0.001**
I–II	1215 (62.2)	462 (67.5)	359 (62.8)	394 (56.6)
III–V	695 (35.6)	210 (30.7)	197 (34.4)	288 (41.4)
Missing	42 (2.2)	12 (1.8)	16 (2.8)	14 (2.0)
CCI					<0.001***
0–1	733 (37.6)	274 (40.1)	214 (37.4)	245 (35.2)
⩾2	696 (35.6)	199 (29.1)	198 (34.6)	299 (43.0)
Missing	523 (26.8)	211 (30.8)	160 (28.0)	152 (21.8)
Preoperative eGFR (ml/min)					0.001**
Mean (SD)	64.6 (23.3)	63.0 (23.3)	67.7 (24.3)	63.7 (22.2)
pT stage					<0.001***
Ta/Tis/T1	757 (38.8)	213 (31.2)	257 (44.9)	287 (41.2)
T2–4	737 (37.7)	297 (43.4)	184 (32.2)	256 (36.8)
Missing	458 (23.5)	174 (25.4)	131 (22.9)	153 (22.0)
Tumor grade					<0.001***
G1	292 (15.0)	63 (9.2)	122 (21.3)	107 (15.4)
G2	397 (20.3)	133 (19.4)	137 (24.0)	127 (18.2)
G3	759 (38.9)	290 (42.4)	174 (30.4)	295 (42.4)
GX	21 (1.1)	7 (1.0)	7 (1.2)	7 (1.0)
Missing	483 (24.7)	191 (27.9)	132 (23.1)	160 (23.0)
Lymph node status					0.449
Negative (pN0)	96 (4.9)	25 (3.7)	29 (5.1)	42 (6.0)
No dissection performed (pNx)	1356 (69.5)	471 (68.9)	399 (69.8)	486 (69.8)
Positive (pN+)	53 (2.7)	19 (2.8)	29 (5.1)	19 (2.7)
Missing	447 (22.9)	169 (24.7)	129 (22.6)	149 (21.4)
RNU performed					0.750
Yes	1278 (65.5)	446 (65.2)	367 (64.2)	465 (66.8)
No	172 (8.8)	57 (8.3)	51 (8.9)	64 (9.2)
Missing	502 (25.7)	181 (26.5)	154 (26.9)	167 (24.0)

ASA, American Society of Anesthesiologists; CCI, Charlson Comorbidity Index; RNU, radical nephroureterectomy; eGFR, estimated Glomerular Filtration Rate.

p < 0.01. ***p < 0.001.

Association of smoking features with clinicopathological characteristics

Among the patients, 684 (35%) had never smoked, 572 (29%) were ex-smokers, and 696 (36%) were current smokers. Among ex-smokers and current smokers, there is a significant male predominance, with 432 males compared to 138 females in the ex-smoker group and 584 males compared to 112 females in the current smoker group. Moreover, more than half of smokers had smoked for 20 pack-years or more. Current smokers, when compared to nonsmokers and former smokers, were notably younger and presented with higher ASA scores and CCI, all statistically significant (p < 0.05).

Association of smoking features with survival outcomes

Patients were monitored for a median period of 6.8 months (ranging from 0 to 89.3 months), with 469 individuals having follow-up data exceeding 12 months. A total of 765 participants (39.2%) were lost to follow-up during the observation period, and 111 patients passed away. Disease recurrence was observed in 12.1% of patients (n = 236), with 17 of these cases resulting in mortality due to UTUC.

The Kaplan–Meier analysis revealed a significant association between smoking status and RFS of urothelial carcinomas (UCs) (p = 0.011, Figure 2(a)). Specifically focusing on intravesical recurrence (IVR) or upper-tract recurrence, the data indicated that individuals with a history of smoking were more prone to developing IVR (p = 0.021, Figure 2(b)), while no notable difference was observed concerning upper-tract recurrence (p = 0.215, Figure 2(c)). In the multivariable Cox regression analyses, smoking status exhibited an association with the risk of UCs recurrence (p = 0.046, Table 2) after accounting for traditional prognostic factors. Additionally, an advanced pT stage was linked to reduced RFS (p = 0.005, Table 2). However, when analyzing bladder or upper-tract recurrence separately, smoking status did not demonstrate statistical significance.

Figure 2.

(a) Kaplan–Meier analysis estimates of recurrence-free survival (urothelial carcinoma) stratified by smoking status. (b) Kaplan–Meier analysis estimates of recurrence-free survival (intravesical recurrence) stratified by smoking status. (c) Kaplan–Meier analysis estimates of recurrence-free survival (upper tract recurrence) stratified by smoking status.

Table 2.

Multivariable Cox regression analyses on recurrence-free survival of urothelial carcinoma, intravesical recurrence, and upper-tract recurrence.

Variable	Urothelial carcinoma
Variable	HR (95% CI)	p Value
Smoke
No	Reference
Yes	1.433 (1.006–2.042)	0.046*
Gender
Female	Reference
Male	0.77 (0.551–1.076)	0.126
ASA grading
I–II	Reference
III–V	1.164 (0.860–1.576)	0.326
pT stage
Ta/Tis/T1	Reference
T2–4	1.667 (1.162–2.390)	0.005**
Tumor grade
G1–2	Reference
G3	1.18 (0.835–1.668)	0.348
Intravesical recurrence
Smoke
No	Reference
Yes	1.305 (0.851–2.002)	0.223
Gender
Female	Reference
Male	0.805 (0.531–1.223)	0.31
ASA grading
I–II	Reference
III–V	1.093 (0.749–1.594)	0.645
pT stage
Ta/Tis/T1	Reference
T2–4	1.705 (1.102–2.637)	0.017*
Tumor grade
G1–2	Reference
G3	0.955 (0.626–1.457)	0.831
Upper tract recurrence
Smoke
No	Reference	0.195
Yes	1.396 (0.843–2.311)
Gender
Female	Reference
Male	0.735 (0.457–1.183)	0.205
ASA grading
I–II	Reference
III–V	1.105 (0.712–1.716)	0.655
pT stage
Ta/Tis/T1	Reference
T2–4	1.756 (1.032–2.988)	0.038*
Tumor grade
G1–2	Reference
G3	1.773 (1.059–2.971)	0.030*

ASA, American Society of Anesthesiologists; CI, confidence interval; HR, hazard ratio.

p < 0.05. **p < 0.01. ***p < 0.001.

Further exploring the impact of cigarette smoking, Kaplan–Meier analyses were conducted across the three smoking categories. Both current and ex-smokers exhibited a heightened risk of UCs recurrence (p = 0.016, Figure 3(a)) and IVR (p = 0.006, Figure 3(b)), and no significant influence of upper-tract recurrence (p = 0.41, Figure 3(c)). Notably, current smokers displayed a worse disease recurrence profile compared to former smokers. Following adjustment for traditional prognostic factors in a multivariable Cox regression analysis, current smokers demonstrated an escalated risk of UCs recurrence (p = 0.031, Table 3) and IVR (p = 0.087, Table 3). Interestingly, pack-years did not exhibit a significant association with disease recurrence (data not shown).

Figure 3.

(a) Recurrence-free survival between ex-smoker, current smoker, and nonsmoker of urothelial carcinoma. Recurrence-free survival of (b) intravesical recurrence and (c) upper-tract recurrence for all patients.

Table 3.

Multivariable Cox regression analyses on recurrence-free survival of urothelial carcinoma, intravesical recurrence and upper-tract recurrence.

Variable	Urothelial carcinoma		Intravesical recurrence		Upper-tract recurrence
Variable	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p Value
Smoking status
Nonsmoker	Reference		Reference		Reference
Ex-smoker	1.326 (0.885–1.989)	0.172	1.080 (0.649–1.800)	0.767	1.481 (0.847–2.587)	0.168
Current smoker	1.529 (1.039–2.249)	0.031*	1.497 (0.943–2.375)	0.087	1.316 (0.749–2.312)	0.340
Gender
Female	Reference		Reference		Reference
Male	0.763 (0.545–1.068)	0.115	0.791 (0.521–1.203)	0.273	0.739 (0.459–1.190)	0.213
ASA grading
I–II	Reference		Reference		Reference	0.645
III–V	1.159 (0.856–1.570)	0.339	1.083 (0.742–1.580)	0.679	1.109 (0.714–1.722)
pT stage
Ta/Tis/T1	Reference		Reference		Reference	0.036*
T2–4	1.657 (1.155–2.377)	0.006**	1.684 (1.088–2.606)	0.019*	1.765 (1.037–3.005)
Tumor grade
G1–2	Reference		Reference		Reference
G3	1.200 (0.847–1.701)	0.304	0.989 (0.646–1.512)	0.958	1.750 (1.042–2.940)	0.034*

ASA, American Society of Anaesthesiologists; CI, confidence interval; HR, hazard ratio.

p < 0.05. **p < 0.01. ***p < 0.001.

Discussion

This extensive study, one of the largest examining the influence of tobacco smoking on oncological outcomes in UTUC patients, uncovered a notable association between smoking at diagnosis and heightened tumor recurrence risk, particularly within the bladder. In alignment with prior research,^16
–18 our findings underscore that cumulative smoking history heightens the likelihood of UC tumor recurrence, emphasizing the critical role of smoking cessation in improving outcomes.

Among the 1952 UTUC patients, 70.2% of patients were male, with a median (range) age at diagnosis of 72.0 (35.0–94.0) years, and 57.7% of smokers have a long-term smoking history. Compared with nonsmokers and former smokers, current smokers were significantly younger and had higher ASA scores. The Kaplan–Meier analysis showed that cigarette smoking would negatively affect the RFS of UTUC patients, especially for IVR. Compared with ex-smokers, current smokers would have a higher risk of developing IVR. In other words, cigarette smoking may influence the tumor recurrence occurring in the bladder. After adjusting for traditional prognostic factors in a multivariable Cox regression analysis, smoking status did not show statistically significant association with recurrence. However, it still showed a trend that smoking could influence oncological outcomes and smoking cessation may benefit UTUC patients.

Cigarette smoking is an established risk factor for UTUC local and distant recurrence.^4,19 Michael et al. reported that smoking is associated with advanced oncological outcomes among 864 UTUC patients who underwent RNU.¹⁷ Keisuke et al. also found that smoking can increase the risk of UTUC-related death compared with death from other diseases.⁹ Similarly, a retrospective study also showed that smoking status was associated with IVR, and long-term smoking cessation could mitigate this influence.²⁰ However, there is little knowledge regarding the difference in impact of smoking exposure on IVR or upper-tract recurrence. Improving our understanding of these links could provide valuable insights into the development of UTUC and potentially enhance outcomes by promoting changes in smoking habits.

In line with earlier studies, we confirmed the impact of tobacco smoking and identified that IVR would be easier influenced by cigarette smoking. As we know, aromatic amines are well-known carcinogens, and tobacco contains many types of them, such as β-naphthylamine and polycyclic aromatic hydrocarbons. Because bladder is the organ for urine storage, it would be more likely to be influenced by the carcinogens concentrated in the urine.²¹ These days, researchers are trying to draw the genomic landscape of urothelial carcinoma using next-generation sequencing methods. Francois et al. sequenced 195 UTUC samples and concluded that the mutation in FGFR3, KDM6A, CCND1, and TP53 was associated with the risk of IVR.²² Meanwhile, there is evidence that nicotine could upregulate FGFR3.²³ It is plausible that smoking may contribute to an elevated risk of FGFR3 mutation, which is linked to IVR. However, further investigation is warranted to explore this potential relationship more thoroughly. In addition, Muramaki et al. reported that patients exhibiting positive E-cadherin expression experienced significantly better RFS within and outside bladder compared with those with reduced E-cadherin expression.^21,24 Nagathihalli et al. also found that E-cadherin down-regulation correlated with the number of pack-years in those with lung cancer.²⁵ Regarding the impact of long-term tobacco exposure, Stella et al. concluded that current smokers have greater ERCC2-signature mutations than former smokers, which is associated with tumor progression.²⁶ This implies that cigarette smoking, especially long-term exposure, might enhance the risk of carcinogens exposure and cause some molecular changes, thus leading to intravesical recurrence in patients with UTUC. Therefore, our results may contribute to establishing an appropriate follow-up protocol and improving the protocol of postoperation chemotherapy, especially the single instillation of chemotherapy.²⁷

As a nonrandomized clinical trial, this study has a risk of introducing bias in an ad hoc analysis. In addition, variations in clinical practices among participating centers could lead to result interpretation challenges. Without a standardized follow-up protocol, many follow-up data were lost, which may influence the accuracy of results. Meanwhile, the follow-up period is not long enough, which may be the reason for the failure of K-M analyses about the effects of pack-years. Furthermore, the brevity of the follow-up period poses a risk of insufficient observation, which may lead to the potential inaccuracy of conclusion. This implies that additional follow-up data are required for a more comprehensive analysis.

Conclusion

Based on the CROES-UTUC registry, our results support the hypothesis that long-term cigarette smokers are at an increased risk of tumor recurrence. For this reason, the use of smoking cessation programs for UTUC patients and the urologist’s role as a smoking cessation advocate should be top priorities in disease management. Except that, the study identified the significant association between smoking status and IVR. This is a novelty and suggests that urologists pay more attention on IVR for lifetime smokers with UTUC, thus improving the follow-up plan.

Supplemental Material

sj-pdf-1-tau-10.1177_17562872251352049 – Supplemental material for Impact of smoking status at diagnosis on oncological outcomes of upper-tract urothelial carcinoma

Supplemental material, sj-pdf-1-tau-10.1177_17562872251352049 for Impact of smoking status at diagnosis on oncological outcomes of upper-tract urothelial carcinoma by Hongda Zhao, Kang Liu, Alfonso Crisci, Ed te Slaa, Tomonori Habuchi, Murat Akand, Chi Fai Ng, Pilar Laguna, Jeremy Yuen-Chun Teoh and Jean de la Rosette in Therapeutic Advances in Urology

Footnotes

Acknowledgements

We would like to thank Mrs Sonja van Rees – Vellinga (Executive Director CROES) for her collaboration and support.

Declarations

ORCID iDs

Hongda Zhao

Jean de la Rosette

Supplemental material

Supplemental material for this article is available online.

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