Abstract
Background/Aim: There are few reports confirming the relationship between the therapeutic effects of adjuvant systemic chemotherapy and intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma. We aimed to evaluate the benefits of adjuvant systemic chemotherapy on intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma. Patients and Methods: We retrospectively reviewed the medical records of 133 patients with pathological T stage ≥3 upper urinary tract urothelial carcinoma or lymph node metastasis who underwent radical nephroureterectomy between January 2010 and September 2020 at our hospital and other satellite hospitals. In total, 60 patients received adjuvant systemic chemotherapy, and 73 did not. The Student’s t-test and chi-square (χ2) test were used to compare between-group differences. The log-rank test was utilized to compare differences in intravesical recurrence between patients with or without adjuvant systemic chemotherapy. Cox proportional hazards regression analysis was performed to identify the predictive factors of intravesical recurrence. Results: The median follow-up period was 25 months. Forty (30.1%) patients presented with intravesical recurrence. The 1-year intravesical recurrence-free survival rates of patients with and without adjuvant systemic chemotherapy were 86.0% and 70.2%, respectively (p=0.046). Multivariate analysis showed that adjuvant systemic chemotherapy was significantly associated with a lower risk of intravesical recurrence (p=0.032). Conclusion: Patients with pathological T stage ≥3 upper urinary tract urothelial carcinoma or lymph node metastasis can have a satisfactory intravesical recurrence-free survival rate with adjuvant systemic chemotherapy.
- Adjuvant systemic chemotherapy
- intravesical recurrence
- radical nephroureterectomy
- upper urinary tract urothelial carcinoma
The incidence rate of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma is approximately 22%-50% (1-4). Wo et al. have shown that patients with intravesical recurrence had a worse prognosis after radical nephroureterectomy than those with primary bladder cancer. Further, they reported that not only advanced T, N, M stage but also a shorter interval between radical nephroureterectomy and bladder recurrence were independent risk factors of overall survival and cancer-specific mortality after radical nephroureterectomy (5). Several studies and systematic reviews have shown that intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma are associated with male sex, previous history of bladder cancer, preoperative chronic kidney disease, positive preoperative urinary cytology, without preoperative bacteriuria, ureteral location, tumor diameter, multifocality, use of diagnostic ureteroscopy, invasive pT stage, tumor necrosis, laparoscopic approach, extravesical bladder cuff removal, and positive surgical margins (4, 6-11). Two prospective randomized clinical trials and systematic reviews based on these trials have shown that a single early intravesical instillation of mitomycin C or pirarubicin after radical nephroureterectomy for upper urinary tract urothelial carcinoma can decrease the risk of intravesical recurrence (2, 6, 12, 13). This strategy has been recommended by the European Association of Urology guidelines (8). However, in clinical practice, the compliance rate to this treatment is low because several urologists avoid the risk of chemotherapy extravasation (1). A phase III prospective randomized trial assessed the benefit of gemcitabine–platinum combination chemotherapy initiated within 90 days after radical nephroureterectomy. Results showed that the disease-free survival of patients with locally advanced upper urinary tract urothelial carcinoma (pT2-4 and/or pathological lymph node positivity) significantly improved (14). Based on these results, this strategy has been recommended for patients with locally advanced upper urinary tract urothelial carcinoma at evidence level 1 based on the European Association of Urology guidelines (8). Therefore, adjuvant systemic chemotherapy is expected to become the standard treatment for many cases after radical nephroureterectomy. However, the efficacy of adjuvant systemic chemotherapy against intravesical recurrence is controversial. Ku et al. has reported that positive surgical margin and the use of adjuvant systemic chemotherapy were independent predictors of intravesical recurrence in patients with invasive upper urinary tract urothelial carcinoma (15). Fradet et al. have shown that age, renal pelvic and ureteral tumor, use of adjuvant systemic chemotherapy, and laparoscopic surgery are risk factors of bladder cancer recurrence (16).
In our previous report, preoperative chronic kidney disease, anemia, and Eastern Cooperative Oncology Group Performance Status score of ≥2 are predictive factors of postoperative cancer-specific survival in patients with upper urinary tract urothelial carcinoma (17). Furthermore, a risk stratification model was developed by including factors such as C-reactive protein level (≥0.5 mg/dl), tumor grade, and lymph node positivity in addition to those stated in our previous report. Results showed that patients with several prognostic factors had a worse cancer-specific survival rate (18). The current study aimed to evaluate the effect of adjuvant systemic chemotherapy on intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma.
Patients and Methods
We retrospectively reviewed the medical records of 154 patients diagnosed with pathological T stage ≥3 upper urinary tract urothelial carcinoma or lymph node metastasis who underwent radical nephroureterectomy between January 2010 and September 2020 at our hospital and other satellite hospitals. To accurately evaluate the effect of adjuvant systemic chemotherapy on intravesical recurrence, we excluded 21 patients who received neoadjuvant systemic chemotherapy prior to radical nephroureterectomy for upper urinary tract urothelial carcinoma or less than two courses of adjuvant systemic chemotherapy. Consequently, 133 patients were included in the analysis. Among them, 60 received adjuvant systemic chemotherapy [adjuvant (+) group], and 73 did not [adjuvant (−) group]. Data on clinicopathological characteristics (such as age, body mass index, sex, presence of diabetes mellitus, smoking history, preoperative chronic kidney disease, preoperative cytology, previous or concomitant bladder cancer, tumor location, clinical TNM stage, tumor grade, tumor variant status, surgical approach, lymph node dissection, adjuvant intravesical instillation of chemotherapy, pathological TNM stage, and adjuvant systemic chemotherapy) were recorded. Smoking history was defined as current or previous smoking, including brief periods of smoking. Tumor stage was evaluated according to the International Union Against Cancer TNM classification. Grade 3 tumors based on the 2004 World Health Organization classification were considered as high grade. The study protocol was approved by the institutional review board of the Tottori University Faculty of Medicine (approval no. 20A164). Intravesical recurrence was defined as the presence of any bladder tumor at the time of cystoscopy after radical nephroureterectomy. Intravesical recurrence-free survival was defined as the period from radical nephroureterectomy to the detection of any bladder tumor on cystoscopy. Adjuvant systemic chemotherapy included at least three courses of gemcitabine/cisplatin and/or gemcitabine/carboplatin regimens based on postoperative renal function. For postoperative follow-up, cystoscopy, urinary cytology, and computed tomography scan were conducted once every 3 months within the first 3 years, then once every 6 months for up to 5 years, and annually after 5 years.
The Student’s t-test and the chi-square (χ2) test were used to compare significant differences in the means and proportions of clinical and perioperative characteristics, respectively. The log-rank test was used to compare differences in terms of intravesical recurrence-free-survival rate between patients with or without adjuvant systemic chemotherapy. Cox proportional hazards regression analysis was performed to identify the predictive factor of intravesical recurrence. All statistical analyses were performed using Easy R (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (19). A p-value of <0.05 was considered statistically significant.
Results
Table I shows the characteristics of all patients (n=133). The adjuvant (−) group had a higher mean age and a significantly higher proportion of patients with diabetes than the adjuvant (+) group. There was no significant difference in terms of body mass index, proportion of female and male participants, smoking history, preoperative chronic kidney disease and cytology, previous history of bladder cancer, concomitant bladder cancer, tumor location, and clinical TNM stage between patients with and without adjuvant systemic chemotherapy. In total, 102 (76.7%) patients underwent laparoscopic radical nephroureterectomy. Only five (3.7%) patients received some type of postoperative intravesical instillation therapy. Approximately 80% of patients underwent lymph node dissection. Further, 13 of 14 patients with a preoperative diagnosis of clinical N+ underwent lymph node dissection. Eleven patients were lymph node-positive upon pathological diagnosis. However, 14 patients who were lymph node-negative upon preoperative diagnosis were actually lymph node-positive. In total, 35 (58%) patients in the adjuvant (+) group and 39 (53%) in the adjuvant (−) systemic group were upstaged to ≥T3. The median follow-up period was 25 months, and 40 (30.1%) patients presented with intravesical recurrence.
Clinicopathological characteristics of patients who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma.
The 1-year intravesical recurrence-free survival rates of patients with and without adjuvant systemic chemotherapy were 86.0% and 70.2%, respectively (p=0.046) (Figure 1). Multivariate analysis showed that adjuvant systemic chemotherapy was significantly associated with a lower risk of intravesical recurrence (hazard ratio=0.49, 95% confidence interval=0.25-0.94, p=0.032) (Table II).
Intravesical recurrence-free survival rate after radical nephroureterectomy in patients with and without adjuvant systemic chemotherapy.
Univariate and multivariate logistic regression analyses of intravesical recurrence with adjuvant systemic chemotherapy in patients receiving radical nephroureterectomy for upper urinary tract urothelial carcinoma.
Discussion
According to some systematic reviews and other studies, the factors correlated with intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma were male sex, previous bladder cancer history, preoperative chronic kidney disease, positive preoperative urinary cytology, ureteral location, tumor diameter, multifocality, use of diagnostic ureteroscopy, invasive pT stage, tumor necrosis, laparoscopic approach, extravesical bladder cuff removal, and positive surgical margins (4, 6-11). A meta-analysis revealed that adjuvant systemic chemotherapy was not a significant predictor of intravesical recurrence (6). However, the rate of adjuvant systemic chemotherapy in the cohort of negative reports on its effect on intravesical recurrence after radical nephroureterectomy was as low as 10% (15). Due to the low rate of adjuvant systemic chemotherapy, its impact on intravesical recurrence may not have been properly assessed. A meta-analysis evaluated the effect of adjuvant systemic chemotherapy on intravesical recurrence after radical nephroureterectomy based on three papers and reported that adjuvant systemic chemotherapy was not a significant predictor of intravesical recurrence (6). Two of the three papers were negative on the efficacy of adjuvant systemic chemotherapy for intravesical recurrence (16, 20). On the other hand, one of the three papers reported the efficacy of adjuvant systemic chemotherapy on intravesical recurrence (15). The rate of adjuvant systemic chemotherapy in the cohort of negative reports for the efficacy of adjuvant systemic chemotherapy on intravesical recurrence after radical nephroureterectomy were 9.9% and 12.1% (16, 20). In contrast, the rate of adjuvant systemic chemotherapy was as high as approximately 30% in the cohort of reports that showed its efficacy on intravesical recurrence following radical nephroureterectomy (15). In the current study, the proportion of patients receiving adjuvant systemic chemotherapy was as high as 45%. Furthermore, the adjuvant (+) group received at least three courses of chemotherapy. This high implementation and completion rate of adjuvant systemic chemotherapy might be correlated with a lower intravesical recurrence rate. In the latest study, adjuvant systemic chemotherapy was associated with better disease-free survival after radical nephroureterectomy for upper urinary tract urothelial carcinoma (14). Therefore, adjuvant systemic chemotherapy is expected to become the standard treatment for many cases after radical nephroureterectomy. Intravesical recurrence necessitates the discontinuation of adjuvant systemic chemotherapy to implement the transurethral resection of the bladder tumor. Controlling intravesical recurrence through adjuvant systemic chemotherapy can have a higher completion rate for patients receiving chemotherapy. Ku et al. showed that several studies which evaluate whether adjuvant systemic chemotherapy is effective for intravesical recurrence have included all pathologic stages. However, in their study, they divided the patients into the superficial (pT1 or less) group and the invasive (pT2 or more) group. Results showed that adjuvant systemic chemotherapy was significantly associated with reduced intravesical recurrence in the invasive group (15). In our present study, most cases were pT3 or higher [131 (98.5%) of 133 patients], which may have been effective in reducing intravesical recurrence in patients receiving adjuvant chemotherapy, as reported in previous reports.
Patients who received neoadjuvant systemic chemotherapy prior to radical nephroureterectomy for upper urinary tract urothelial carcinoma were excluded to accurately evaluate the effect of adjuvant systemic chemotherapy on intravesical recurrence. Previous studies did not show that neoadjuvant systemic chemotherapy can reduce the incidence rate of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma. However, several retrospective studies evaluated the role of neoadjuvant chemotherapy. Results showed that neoadjuvant chemotherapy had a positive effect on pathological downstaging and complete response rates (21, 22). Moreover, resulted in lower disease recurrence and mortality rates than radical nephroureterectomy alone (23, 24). Hence, it may affect the development of intravesical recurrence. Nevertheless, further studies must be performed to assess the impact of neoadjuvant systemic chemotherapy on intravesical recurrence after radical nephroureterectomy.
The current study is valuable because it excluded patients with neoadjuvant systemic chemotherapy and examined the effect of adjuvant systemic chemotherapy alone on intravesical recurrence. According to our present study, targeted patients with pathological T-stage ≥3 or lymph node metastasis who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma and received adjuvant systemic chemotherapy showed significantly lower risk of intravesical recurrence. We believe that these results will be useful in treatment selection for invasive upper urinary tract urothelial carcinoma after radical nephroureterectomy.
The current study has several limitations. First, it was retrospective in nature. Moreover, we did not include all pathologic stages and did not collect data on clinicopathological characteristics such as tumor diameter, multifocality, tumor necrosis, and extravesical bladder cuff removal, which are predictors of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma. Second, the target patients were from 10 different hospitals, and they underwent surgery performed by different surgeons at each hospital. Although the surgical technique was very similar, there may have been slight differences depending on the skills of the surgeon. Specimens were examined by different pathologists in each hospital. Third, the number of target patients was not large, and the observation period was short. Thus, prospective studies on the association between adjuvant systemic chemotherapy and intravesical recurrence after radical nephroureterectomy for upper urinary tract carcinoma must be conducted in the future. In conclusion, patients with pathological T stage ≥3 upper urinary tract urothelial carcinoma or lymph node metastasis can have a satisfactory intravesical recurrence-free survival rate with adjuvant systemic chemotherapy.
Acknowledgements
The Authors would like to thank the doctors of satellite hospitals for their contribution in data collection.
Footnotes
Authors’ Contributions
NY designed and performed the research and collected and analyzed the data and wrote the manuscript. SM designed and performed the research, collected data, and assisted in the preparation of the manuscript. All other Authors contributed to data collection and interpretation, and critically reviewed the manuscript. All Authors approved the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received January 30, 2023.
- Revision received February 11, 2023.
- Accepted February 13, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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