INTRODUCTION
Upper tract urothelial carcinomas (UTUCs) ac- count for 5%-10% of all urothelial cancers. With its rising incidence, it is the fifth most frequently diagnosed noncutaneous cancer in the US.1,2 UTUCs can be located in the whole urinary tracts, but upper urinary tract urothelial carcinoma is a relatively rare entity.3-5 UTUCs, on an average, have the highest incidence rate at 65 years of age, and a few recent studies have shown their prevalence in the United States amongst those aged 70 years and older. The cause of UTUCs is unclear. However, according to previous studies, smoking, job-related factors, abuse of painkillers, Chinese herbs nephropathy, and lithiasis were reported to be associated with the incidence of UTUCs.6
Radical nephroureterectomy (NUx) with bladder cuff excision is a standard treatment method for UTUCs7 and is performed using various pro- cedures such as robotic surgery, laparoscopic surgery, hand-assisted laparoscopic surgery, or open NUx. The biggest problem in UTUCs is recurrence after surgery. Recurrences in the retroperitoneum, contralateral urinary tract, and bladder are common. Of these types of recurrences, intravesical recurrence (IVR) is the most common. A recent study reported that relapses occurred in about 22%-47% of UTUC patients.8,9
There are many studies on factors that influence bladder recurrence rate. The multifocality of UTUCs, the presence of Carcinoma in situ (CIS), and laparoscopic surgery have been suggested as representative risk factors.10 In a few studies, factors influencing the incidence of muscle invasive bladder cancer after NUx were investigated. These studies identified bladder cancer history prior to NUx, pathologic T stage at the first transurethral resection of the bladder (TURB), presence of CIS, and previous intravesical therapy as important factors in the muscle invasive bladder cancer (MIBC)-occurrence group.11,12 Radical cystectomy is recognized as the most common and effective treatment when MIBC is confirmed.13 Cystectomy with recurred MIBC or a recurrent bladder tumor has a high risk of surgery and adversely affects the patients’ quality of life (QoL) and life span.14
However, since there are very few studies con- ducted so far and the analysis is limited, a more detailed study is needed based on the data accumulated over a long period of time. Therefore, in this paper, we tried to identify the factors that predict the implementation of radical cystectomy according to IVR, in patients who underwent NUx.
MATERIALS AND METHODS
1. Patient Population
This retrospective study was approved by the Institutional Review Board of Seoul Asan Medical Center (S2020-2618-0001). We retrospectively screened the medical records of patients who un- derwent NUx at Seoul Asan Medical Center, from January 2011 to December 2019. A total of 646 patients underwent surgery during this period.
Patients included in this study were (1) those whose primary origin was ureter cancer, (2) those who underwent NUx for UTUC, (3) those who were followed up within 3 months, and (4) medical records are required for the study. The exclusion criteria were as follows: (1) metastatic cancer, (2) NUx performed for ureter cancer that occurred in patients who underwent radial cystectomy, and (3) cases with insufficient clinical data or loss of follow-up.
2. Diagnosis and Pathologic Evaluations
All patients underwent computed tomography (CT) and cystoscopy before surgery. Preoperative ureteroscopy was not performed as a routine, but was recommended based on CT and urine cytology results. Nine surgeons performed all the surgeries and the surgical methods were open and laparoscopic NUx with open-bladder cuff excision; there was no difference between the surgeons in any of the surgical methods.
The pathological examination of all specimens after surgery was performed using the same procedure. Tumors were classified according to the American Joint Committee on Cancer- Union Internationale Contre le Cancer TNM classification, 8th edition15 and the 1998 World Health Organization/International Society of Urologic Pathology consensus classification grade.16 Multiplicity and location were reported by a pathologist.
3. Follow-up Protocols
For the first 2 years after surgery, the patients were followed up every 3 months, via cystoscopy, urine cytology, CT, and chest radiography. When no evidence of recurrence was observed, follow- up was performed at 6-month intervals over 2 years, followed by annual examinations. IVR was defined whenever a lesion was observed by follow-up cystoscopy and confirmed by biopsy or cytology, as well as by radiological examination. Most of the patients with confirmed bladder recurrence received TURB.
4. Statistical Analyses
Quantitative data are expressed as median (range) or mean (standard deviation) and categorical variables were expressed as absolute values (percentage). Univariate and multivariate Cox regression analyses were performed for the analysis of risk factors leading to radical cystectomy in patients undergoing NUx. Correlations between outcomes and the assessed variables were ex- pressed as hazard ratios (HRs) with 95% confiden- ce intervals (CIs).
All statistical analyses were performed using IBM SPSS Statistics ver. 25.0 (IBM Co., Armonk, NY, USA).
RESULTS
The clinical and pathological characteristics are summarized in Table 1. A total of 646 patients were evaluated and all patients underwent NUx for UTUCs. Their median age was 70 years (interquartile range [IQR], 62-71 years), and the median follow-up period was 45.1 months (IQR, 18-66 months) with 459 males (71.1%) and 187 females (29.4%).
Table 1.
Clinical characteristics of the study patients
Among the subjects, 114 (17.6%) had a previous history of bladder cancer before NUx. A total of 418 patients (64.7%) underwent laparoscopic surgery including hand-assisted laparoscopic surgery, and the other 228 (35.3%) underwent open NUx. Upon the analysis of the specimens of the subjects after surgery, the T stage was T3 or higher in 241 patients (37.3%), and node metastasis was identified in a total of 55 patients. Distal ureter tumors were observed in 190 patients (29.4%), and 164 patients (25.4%), and multiplicity was confirmed in 192 patients (29.7%). A total of 49 patients (7.6%) underwent neoadjuvant CTx, and 99 (15.3%) underwent adjuvant CTx. Further, 11 patients underwent radical cystectomy by bladder recurrence after NUx (1.7%).
To eliminate the effects of previous bladder cancer, we performed a subgroup analysis on patients without previous history of bladder cancer. A total of 532 patients (82.4%) had no previous bladder cancer history. Their median age was 68 years (IQR, 61-75.8 years) with 373 males (70.1%) and 159 females (29.9%), and the median follow- up period was 43.7 months (range, 18-63 months). Of these, 177 patients (33.3%) underwent open surgery, and 355 patients (66.7%) underwent laparoscopic surgery including hand-assisted laparoscopic surgery. The T stage of 201 patients (37.8%) was above T3, and node metastasis was confirmed in a total of 46 patients (8.5%). CIS was confirmed in 217 patients (40.8%) and high-grade tumors in 437 patients (82.1%). lymphovascular invasion (LVI) was observed in 132 patients (24.8%), and multiplicity was observed in 147 patients (27.6%). A total of 135 patients (25.4%) had distal ureter involvement, 40 patients (7.5%) underwent neoadjuvant CTx, and 74 patients (13.9%) under- went adjuvant CTx after NUx. Cystectomy accor- ding to bladder recurrence was confirmed in a total of 6 patients (1.1%) (Table 1).
A risk factor analysis for radical cystectomy after NUx was performed. The factors identified as independent predictors in the multivariable logistic regression analysis were LVI (HR, 4.728; 95% CI, 1.463-15.570; p=0.011), previous TURB history (HR, 3.825; 95% CI, 1.164-12.571; p=0.027), and IVR within 6 months (HR, 3.733; 95% CI, 1.091-12.778; p=0.036) (Table 2).
Table 2.
Multivariate Cox proportional hazard regression analysis of risk factors for radical cystectomy after NUx
Univariate analysis revealed that a distal tumor location is a risk factor for performing radical cystectomy after NUx inpatients without previous bladder cancer history. When the tumor is locat- ed distally (HR, 6.229; 95% CI, 1.140-34.029; p=0.035), an IVR within 6 months (HR, 10.799; 95% CI, 1.977-58-996; p=0.006) was confirmed. Multivariate analysis performed with these factors revealed bladder recurrence within 6 months (HR, 8.608; 95% CI, 1.545-47.976; p=0.014) as a risk factor (Table 3).
Table 3.
Multivariate Cox proportional hazard regression analysis of risk factors for radical cystectomy after NUx in patients with no previous bladder cancer history
We reported 11 patients who underwent radical cystectomy after NUx. Of these, 4 patients had a previous bladder cancer history, and 7 patients had tumor involvement in the distal ureter. Their first IVR occurred at a median of 8.2 months (IQR, 2-24 months); cystectomy was performed due to IVR at a median of 27 months (IQR, 7-69 months). The median follow-up period was 43.7 months (IQR, 22-79 months). The pathology after NUx and the basis for cystectomy are shown in Table 4.
Table 4.
Analysis of patients who underwent radial cystectomy after NUx
Table 5 presents the characteristics of 81 pa- tients who developed IVR within 6 months. The average age of the patients was 68.28 years (IQR, 66-70 years), and the gender was 61 males (74.4%) and 21 females (25.6%). The T stage was T3 or higher in 24 patients (29.6%), and node metastasis was confirmed in 2 patients, corresponding to 2.4%. Thirty-three patients (40.2%) included distal ureter tumor. A total of 5 patients (6.1%) underwent radical cystectomy during the follow-up period. The median follow-up period was 49.2 months (range, 42.01-56.55 months). As a result of analysis using the Kaplan-Meier method, the group with IVR confirmed within 6 months showed a higher probability of performing cystectomy than the other group (p=0.024. log-lank test, Fig. 1).
Table 5.
Characteristics of patients with bladder recurrence within 6 months after NUx
DISCUSSION
The high bladder recurrence rate of UTUCs worsens patients’ QoL17-19 after NUx and increases the economic burden.20,21 In addition, patients need to receive TURB repeatedly, exposing them to the possibility of operation-related risk and complications caused by surgery. The progression to MIBC should be scrutinized further as it directly relates to the patient's survival.22,23 Since the implementation of NUx, some studies have been conducted on the factors that affect IVR. However, a clear cause was not identified and the results were variable.
Seisen et al.24 performed a meta-analysis based on a total of 18 previous studies. In this paper, IVR-specific predictors were identified in terms of patient-, tumor-, and treatment-related factors. Among the patient-specific predictors, male sex, previous bladder cancer history, and preoperative chronic kidney disease showed significant results, and preoperative urinary cytology, tumor location, tumor multifocality, pathologic T (pT) stage, and tumor necrosis were confirmed as tumor-specific predictors. Finally, management laparoscopic surgery, an extravesical approach, and a positive surgical margin were found to have significant results as specific predictors.24
In the meta-analysis by Azémar et al.,25 it was difficult to classify the tumor site as a risk factor for IVR, and it was confirmed that IVR was higher in males, but the limitations of not considering other patient characteristic factors were explained. Previous bladder tumor history was suggested to have an effect. Recently, Shigeta et al.11 in a study conducted in Japan, confirmed the factors affecting IVR after the implementation of NUx and attempted to identify the risk factors leading to MIBC progression after IVR. In this study, tumor location, the pT stage, and tumor multifocality were identified as risk factors. As factors predicting the likelihood of progression to MIBC after IVR, the bladder recurred tumor was pT1, concomitant CIS was confirmed, and intravesical therapy was not performed.
In this study, the previously suggested predictors corroborated with data from our center, and the time of first occurrence of IVR was set as a new predictor, through the analysis of the risk of radical cystectomy implementation after NUx during the follow-up period.
For this study, factors affecting radical cystecto- my implementation were identified in all patients who underwent NUx for UTUCs. The multivariate analysis revealed that with NUx and regular follow-up, bladder recurrence within 6 months (HR, 10.014; 95% CI, 1.827-54.896; p=0.008), LVI (HR, 4.728; 95% CI, 1.436-15.570; p=0.011), and previous TURB history (HR, 3.825; 95% CI, 1.164-12.571; p=0.027) were factors predicting radical cystectomy after NUx.
We performed a subgroup analysis on patients with no bladder cancer history and tried to identify predictors through a multivariate analysis, which identified IVR occurring within 6 months (HR, 8.608; 95% CI, 1.545-47.976; p=0.014) as a significant predictor. The univariate analysis indicated tumor location in the distal ureter (HR, 6.229; 95% CI, 1.140-34.029; p=0.035) as a predictor, but it was difficult to obtain meaningful results for the same in the case of the multivariate analysis (HR, 4.638; 95% CI, 0.831-25.889; p=0.080).
As this was a retrospective study and used data from a single center, the possibility of there being a selection bias in the subject selection process could not be excluded and because of the lack of international implications for the benefit of lymph node dissection in UTUC, this study was excluded from the risk factor.26
Previous studies aimed to determine the cause of IVR, but most of the preceding studies did not specify the follow-up period or did not analyze the time of occurrence.
Despite these limitations of the study and the small number of patients who underwent radical cystectomy, this study is meaningful in that it is the first one to confirm IVR occurring within the first 6 months of follow-up as a predictor of radical cystectomy implementation.
CONCLUSIONS
A confirmed LVI or an IVR occurrence within 6 months of NUx is a risk factor that can predict radical cystectomy implementation. For patients without previous bladder cancer history, early bladder cancer recurrence within 6 months is a predictor of radical cystectomy implementation. Characterizing the importance of distal ureter involvement in UTUCs requires follow-up studies in a larger patient population.
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