Introduction

Bladder cancer (BC) is the 11^th most commonly diagnosed cancer worldwide¹. Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 75% of the cases. Despite advanced treatment methods, the recurrence and progression rates of NMIBC are still high (70-75% and 10%, respectively)². To reduce the risk of recurrence and progression, re-staging transurethral resection (Re-TUR) of high risk bladder tumor and application of intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) to that tumor are recommended by uro-oncology guidelines¹,³.

European Association of Urology (EAU) guidelines recommend that Re-TUR should be performed within 2-6 weeks after initial TUR¹,⁴. Nevertheless, these recommendations are based on low levels of evidence⁴. To the best of our knowledge, there are no prospective studies in the literature addressing that issue. Therefore in this prospective, randomized controlled study, we aimed to investigate the significance of time to re-TUR on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer.

Materials and methods

This study was performed between August 2016 and December 2020 after obtaining the approval of local ethics committee (0651-5479). Clinical Trials Registration ID of the present study is NCT04768894. Patients diagnosed with primary high risk non-muscle-invasive bladder cancer at our clinic as well as the patients who were referred to our clinic with the same diagnosis were included to the study. All patients gave their written informed consent. The patients were randomly separated into three groups according to Re-TUR timing with the random number table envelope method. The names of the groups were written on small papers with the same size, they were folded, put in an envelope, and drawn by the doctors. In Groups 1, 2, and 3, the time interval between initial and re-TUR were 14-28 days, 29-42 days, and 43-56 days, respectively. Separate analysis was also performed for patients who had Re-TUR at ≤ 42 and > 42 days. All patients received six weekly instillations of BCG therapy, and at least 1 year of maintenance BCG therapy (3 weekly instillations administered at 3, 6, and 12 months).

Patients with a tumor pathology other than transitional cell carcinoma, incomplete resection at initial TUR, who cannot complete 1 year of maintenance BCG treatment, did not attend their regular cystoscopic control or wanted to leave from the study voluntarily and finally, with a diagnosis of muscle-invasive cancer on Re-TUR were excluded from the study. Inclusion criteria were having a high grade Ta or T1 transitional cell carcinoma with or without carcinoma in situ (CIS) after a complete initial TUR of bladder carcinoma, and receiving 6 weekly induction BCG therapy with at least 1 year maintenance.

Re-TUR contained resection of all visible tumor, deep resection of previously resected areas and adequate sampling of muscle layers. Cystoscopic control was performed according to EAU guideline recommendations for high-risk non-muscle-invasive bladder cancer⁵,⁶. Progression was defined as an increase in the pathological stage (Ta-T1 or T1-T2).

Demographic data of the patients such as age, gender, and parameters related to bladder cancer such as tumor grade, T stage, concomitant CIS, number of tumors, main tumor size, application of early single dose chemotherapy, recurrence, and progression were noted. Primary end point of the current study was recurrence and progression free survival rates. Pathologic investigations were made by single expert uropathologist at our hospital.

Results

A total of 109 patients with primary high risk non-muscle-invasive bladder cancer were randomly divided into three groups. Twenty patients were excluded because of loss to follow-up. Five patients with incomplete resection at initial TUR, ten patients who could not complete 1 year of maintenance BCG treatment, and three patients with a diagnosis of muscle-invasive cancer on re-TUR were excluded from the study. Twenty patients in Group 1 (14-28 days), 22 patients in Group 2 (29-42 days), and 29 patients in Group 3 (43-56 days) completed the study (Fig. 1).

Figure 1 Flow charts. 

The mean age of the study population was 64.5 ± 8.7 years and the mean follow-up was 20 ± 8.9 months. Of our patients 58 (81.7%) male and 13 (18.3%) were female. All tumors in this study were high grade. Stage Ta and T1 tumors were present in 14 (19.7%) and 57 (80.3%) patients, respectively. Concomitant CIS was present in 7 (9.9%) patients. Residual tumors were detected in 9 of 71 (12.6%) patients. No T2 tumor was detected in any patient after the re-TUR. There were no differences between the groups in age, sex, T stage, concomitant CIS, largest tumor diameter, tumor numbers, and instillation of immediate post-operative intravesical chemotherapy (Table 1). In the follow-up period, 4 (5.6%) patients underwent radical cystectomy. One patient had been administered radiation therapy with chemotherapy.

Recurrence-free survival rates of the patients were 80 %, 63.6%, and 69% in Groups 1, 2, and 3, respectively, at a mean follow-up of 20 months (p = 0.56). When we performed a separate analysis by dividing patients into two groups based on the interval between initial and Re-TUR (≤ 42 days and > 42 days), we did not also detect statistically different RFS rates (71.4% and 69%, respectively, p = 0.85) (Figs. 2 and 3). The progression rate in group > 42 days was similar to that of group ≤ 42 days (2.4% and 10.3% p = 0.20, respectively) (Table 2).

Figure 2 Recurrence-free survival rates of the three groups at a mean follow-up of 20 months (14-28 days, 29-42 days, and 43-56 days). 

Figure 3 Recurrence-free survival rates of the two groups at a mean follow-up of 20 months (≤ 42 and > 42 days). 

The progression was observed in 0, 1 (4.5%), 3 (10%) patients in groups 1, 2, and 3, respectively, at a mean follow-up of 20 months (p = 0.36). PFS was found as 100%, 95.5%, and 89.7% in Groups 1, 2, and 3 at a mean follow-up of 20 months (Fig. 4) (p = 0.36). According to the cox regression analysis, only number of tumors was found to be a prognostic factor on RFS rates (Table 3).

Figure 4 Progression-free survival rates of the three groups at a mean follow-up of 20 months. 

Discussion

A complete resection is vital to achieve a good prognosis in non-muscle invasive bladder cancer⁷,⁸. The goal of TUR of bladder cancer in NMIBC is to achieve the correct diagnosis and completely remove all visible lesions and it is an essential procedure in the management of NMIBC. The absence of muscularis propria in the specimen is associated with a significantly higher risk of residual tumor, early recurrence, and tumor understaging⁹. The significant risk of residual disease after initial TURB of NMIBC has been demonstrated⁸,¹⁰. Especially high-grade T1 bladder cancer has a high recurrence and progression rate.

A Re-TUR of bladder cancer can increase RFS, improve outcomes after BCG treatment and provide prognostic information¹¹-¹⁴. Therefore, a Re-TUR is recommended in patients with high risk NMIBC. Although Re-TUR is mostly recommended within 2-6 weeks after initial TUR in the recent EAU guideline, review of the literature regarding the timing of a Re-TUR arises a large range from an immediate second TUR to 3 months after the initial TUR¹⁴,¹⁵. This recommendation to perform Re-TUR 2-6 weeks after initial TUR is based on a retrospective study recently performed by Baltaci et al.⁴

To the best of our knowledge, the present study is the first prospective, randomized, and controlled study evaluating the time lapse from initial TUR to Re-TUR and its association with RFS rates and progression rates. Our results revealed that the RFS rates of the Groups 1, 2, and 3 were 80%, 63.6%, and 69%, respectively, at a mean follow-up of 20 months (p = 0.56). These rates were not statistically significant. Similarly, PFS was found as 100%, 95.5%, and 89.7% in Groups 1, 2, and 3 at a mean follow-up of 20 months, respectively, and these results were also not statistically significant. When we divide the patients into two groups, we found that the progression rate in group > 42 days was also similar to that of group ≤ 42 days. To the best of our knowledge, there are three retrospective studies evaluating the role of time from initial TUR to Re-TUR⁴,¹⁶,¹⁷. Two of them are multicentric studies. Calo et al. investigated the timing from initial TUR to Re-TUR in patients with high grade NMIBC. The authors divided the patients into three groups (A, B, and C) based on time to Re-TUR in their study. In Group A, B, and C, Re-TUR times are determined as within 6 weeks, > 6-12 weeks, and > 12-18 weeks, respectively. They found that recurrence rate was 38.3%, 24.8%, and 28.3% in Groups A, B, and C, respectively. Kaplan–Meier plots showed that such differences were not statistically significant (p = 0.1). They also found that progression rates between the groups were also not statistically significant. The authors thought that biological tumor characteristics might be more relevant than the “traditional” clinical and pathological characteristics in predicting the oncological outcomes. Similarly, we could not detect any significant effect of time from initial TUR to Re-TUR on PFS and RFS rates. In the present study, residual tumor was detected in 9 of 71 (12.6%) patients after the Re-TUR. This finding is lower than the results of previous studies, as residual cancer can be found in 20-78% of cases on a Re-TUR³,¹²,¹⁸. Therefore, this may be one reason why we could not find any effect of time from initial TUR to Re-TUR on RFS and PFS rates in the current study.

Baltaci et al. showed that second TUR performed 14-42 days after initial resection yielded longer RFS and PFS rates compared to a second TUR performed after 43-90 days⁴. Specifially, the 3-year RFS rates were 73.6% versus 46.2% (p < 0.001) and the 3-year PFS rates were 89.1% versus 79.1% (p = 0.006) for those having a second TUR 14-42 days and 43-90 days after initial TUR, respectively. This study is a valuable study, but because of it is multi-centric, it is a disadvantage that the second TURs were performed by different surgeons and the pathology results were evaluated by different pathologists, which might have caused interobserver differences. At present, interobserver differences are common in reporting tumor grade and stage.

Another recently published study by Krajewski et al. demonstrated that a second TUR performed within 6 weeks was associated to better RFS, PFS and CSS rates¹⁷. There was a great heterogeneity in BCG treatment in this study as it included patients who received al least 7 BCG instillations. Studies have confirmed that BCG after TURB is superior to TURB alone or TURB plus chemotherapy for preventing the recurrence of NMIBC. Studies have also demonstrated that BCG therapy delays and potentially lowers the risk of tumor progression¹⁹-²². For this reason, it is important for such study that patients must receive BCG treatment for a similar time and similar dose to avoid bias.

The relatively low number of patients and the short follow-up period are the main limitations of the present study. However, to the best of our knowledge, this is the first prospective, randomized, and controlled study evaluating the time lapse from initial TUR to Re-TUR and its association with RFS rates and progression rates in a single tertiary center.

Conclusions

Our prospective study demonstrated that time lapse from initial TUR to Re-TUR did not significantly affect RFS and PFS rates. Further prospective randomized larger sample studies are needed to confirm these findings.