Abstract
Background: Although laparoscopic radical nephroureterectomy is the standard treatment for localized upper urinary tract urothelial carcinoma, open radical nephroureterectomy has been reported to have a different rate of intravesical recurrence. Patients and Methods: Intravesical recurrence-free, progression-free, and overall survival rates among patients undergoing open and laparoscopic radical nephroureterectomy from 2002 to 2013 were analyzed. Results: Although no single factor predicted intravesical recurrence-free survival, a past history of bladder cancer or grade 3 was related to poorer intravesical recurrence-free survival rate in patients treated with laparoscopic radical nephroureterectomy. Moreover, the novel proposed risk classification based on our data clearly showed better progression-free survival and overall survival, as well as intravesical recurrence-free survival, in patients treated with laparoscopic radical nephroureterectomy. Conclusion: The findings reported here may help urologists predict oncological outcomes and to plan follow-up schedules after laparoscopic radical nephroureterectomy.
Although radical nephroureterectomy (RNU) may result in overtreatment of patients with low-stage and low-grade tumors (1), open RNU (O-RNU) with bladder cuff removal has been suggested as a standard treatment for localized and noninvasive upper urinary tract urothelial carcinoma (UUTUC). After the development of laparoscopic RNU (L-RNU), including retroscopic procedures, perioperative outcomes such as wound size, duration of hospital stay, dose of analgesic, and total blood loss have improved compared to those in O-RNU (2, 3). Therefore, L-RNU has replaced O-RNU as the standard treatment for localized UUTUC. On the other hand, although oncological outcomes in L-RNU were reported to be similar to those in O-RNU (4), the incidence rates of intravesical recurrence (IVR) were reported to be different (5). The present study was performed to examine whether there are differences in oncological outcomes, especially IVR-free survival, between O-RNU and L-RNU in patients classified according to oncological factors such as stage and grade.
Patients and Methods
Study population. All studies were performed retrospectively at the Kanazawa University using the charts of patients hospitalized at the Department of Urology between March 2002 and January 2013. Among the patients with suspected UUTUC who underwent L-RNU and O-RNU, only those with pathologically-proven UUTUC were included in the analysis.
Definition of past history of bladder cancer (BCa) and survival. Both previous history of BCa and concomitant BCa with UUTUC were included in the past history of BCa. IVR-free survival was defined as the duration from the date of RNU to the date of recurrence in the bladder. One patient who underwent cystectomy at the same time as O-RNU was excluded from the analysis of IVR-free survival. PFS was defined as the duration from the date of RNU to the date of local recurrence or the date of the emergence of metastasis. However, IVR was excluded. OS was defined as the duration from the date of RNU to the date of death.
TNM classification and grade. The Seventh Edition of the TNM Classification of Malignant Tumors (Union for International Cancer Control) was used for TNM staging. A three-grade system (G1, G2, and G3) was used instead of the new two-grade system (high and low) published by WHO in 2004 because the three-grade system was available for all enrolled patients from 2002 to 2013, while the two-grade system was not available for patients treated before 2004 (6, 7).
Patient background.
Statistical analysis. Statistical analyses were performed using commercially available software (Prism, San Diego, California, USA). Comparisons between two groups were performed by unpaired two-sided t-test, Fisher's exact test, and Chi-square test for trends. OS, PFS, and IVR-free survival were estimated using the Kaplan–Meier method. In all analyses, p less than 0.05 indicated statistical significance.
Results
Patient background. L-RNU and O-RNU were performed in 48 and 22 cases, respectively. Out of the 48 cases treated with L-RNU, one was for a metastatic lesion of hepatocellular carcinoma and one was for a benign tumor. Out of the 22 cases treated with O-RNU, two were for benign tumors and one was for renal cell carcinoma. These five patients were excluded from analyses in this study. Patient background data are shown in Table I. Although there were no significant differences between L-RNU and O-RNU with regard to age, sex, tumor location, past history of BCa, or cN stage, cT stage in O-RNU was significantly higher than that in L-RNU. With regard to cT stage, although oncological outcomes of ≤T1 and ≥T2 tumors are known to be different (8-10), borderline distinction was made between T2 and T3 as it is very difficult to distinguish between T1 and T2 with radiological diagnostic modalities, such as computed tomography and magnetic resonance imaging, before surgery. The rate of high c stage indicating any of ≥cT3, ≥cN1, or cM1 in O-RNU was also significantly higher than that in L-RNU.
Surgical results.
Surgical results. Perisurgical and oncological results in L-RNU and O-RNU were compared (Table II). Although there were no differences between L-RNU and O-RNU with regard to median operation time, median volume of bleeding, incidence of transfusion, maximum size, pT stage, pN stage in patients undergoing lymph node dissection (LND), and grade, the rate of LND performed in O-RNU was significantly higher than that in L-RNU. The rate of LND performed in high c stage patients in O-RNU was also significantly higher than that in L-RNU.
Simple comparison of OS, PFS, and IVR-free survival between L-RNU and O-RNU. As previous studies indicated that oncological outcomes of L-RNU and O-RNU were almost equivalent (4), OS and PFS in this study cohort were also examined; consistent with previous reports, the results indicated that there were no differences between L-RNU and O-RNU groups. It was reported that IVR-free survival in L-RNU was shorter than that in O-RNU (5), however, we found no difference in our study cohort (Figure 1).
Simple comparison of overall survival (A), progression-free survival (B), and intravesical recurrence-free survival (C) between patients treated with L-RNU and O-RNU.
Overall survival (OS), progression-free survival (PFS), and intravesical recurrence (IVR)-free survival in patients diagnosed with ≥pT2 and ≤pT1 disease. OS in the overall patient group (A), L-RNU patients (B) and O-RNU patients (C). PFS in the overall patient group (D), L-RNU patients (E) and O-RNU patients (F). IVR-free survival in the overall patient group (G), L-RNU patients (H) and O-RNU patients (I).
Comparison of OS, PFS, and IVR-free survival among groups divided according to different factors. OS, PFS, and IVR-free survival in patients who diagnosed as ≥pT2 and ≤pT1 were analyzed (Figure 2). There was no significant difference in OS between ≥pT2 and ≤pT1 patients in the overall, L-RNU, and O-RNU groups (Figure 2A-C). There was a significant difference between PFS of ≥pT2 and ≤pT1 patients in the group of patients overall and L-RNU, and O-RNU groups (p=0.0001, 0.0135, and 0.0004, respectively) (Figure 2D-F). In addition, there were no significant differences in IVR-free survival between ≥pT2 and ≤pT1 patients in the overall, L-RNU, and O-RNU groups (Figure 2G-I).
OS, PFS, and IVR-free survival in patients diagnosed with G3 and G1-2 disease were also analyzed (Figure 3). There were significant differences in OS of G3 and G1-2 patients in the overall, L-RNU, and O-RNU groups (p=0.0010, 0.0031, and 0.0253, respectively, Figure 3A-C). There were no significant differences in PFS of patients with G3 and G1-2 disease in the overall and L-RNU groups (Figure 3D and E); however, there was a significant difference between PFS in those with G3 and G1-2 disease in the O-RNU group (p=0.0038) (Figure 3F). In addition, there was no significant difference between IVR-free survival of those with G3 and G1-2 disease in the overall, L-RNU, and O-RNU groups (Figure 3G-I).
Overall survival (OS), progression-free survival (PFS), and intravesical recurrence (IVR)-free survival in patients diagnosed with G3 and G1-2 disease. OS in the overall patient group (A), L-RNU patients (B) and O-RNU patients (C). PFS in the overall patient group (D), L-RNU patients (E) and O-RNU patients (F). IVR-free survival in the overall patient group (G), L-RNU patients (H) and O-RNU patients (I).
As T-stage and grade could not predict IVR-free survival, past history of BCa was examined to determine whether it could be used as a predictive factor; however, there were no significant differences in IVR-free survival between those with and those without past history of BCa in any of the groups (Figure 4A-C). Next we examined whether a combination of these oncological factors predicts IVR-free survival. When high-risk IVR was defined as having a past history of BCa or G3 and low-risk IVR was defined as risk other than high risk, there was no difference in IVR-free survival between high-risk and low-risk IVR patients in the overall cohort (Figure 4D). However, there was a significant difference for patients in the L-RNU group (p=0.0381, Figure 4E and F). Moreover, while IVR did not predict for PFS (Figure 4G), a high risk of IVR predicted worse PFS and OS in the L-RNU group (p=0.0379 and p=0.0151, respectively) (Figure 4H and I).
Discussion
L-RNU was first reported in 1991 and has become the standard therapy for localized UUTUC due to its lower invasiveness and better perioperative outcomes than O-RNU (2, 3, 11). Therefore, application of O-RNU for UUTUC has changed towards being indicated for more advanced cases for complete resection of cancerous lesions. Our data indicated that O-RNU was performed in more advanced cases with high cT stage and high c stage. However, the distribution of pT in the O-RNU group was similar to that in the L-RNU group, but the rate of LND in O-RNU was significantly higher than that in L-RNU. These surgical results may have contributed to the similar OS, PFS, and IVR-free survival in both L-RNU and O-RNU. PFS in ≥pT2 and in ≤pT1 for all was also significantly different. With regard to grade, OS of patients with G3 compared with G1-2 disease in all groups was significantly different. These results were consistent with previous reports (12-14) and suggest that both pT stage and grade are important factors for survival. However, our results indicated that IVR-free survival cannot be predicted even using pT stage and grade, which clearly predicted PFS and OS in this Japanese cohort. Predicting the possibility of IVR-free survival is very important for patients and clinicians because a very high incidence (21%-54%) of IVR after RNU was reported (14-22). It has also been reported that IVR lesions sometimes develop to muscle-invasive BCa and impacts prognosis (23). To prevent delay in identifying IVR, it is very important to have an appropriate timeline of examinations, including urinary analysis, cystoscopy, urine cytology, computed tomography, and magnetic resonance imaging. In addition, patients should also pay attention to their symptoms, bearing in mind their own probability of IVR. This was why we examined the risk of IVR in this study.
Intravesical recurrence (IVR)-free survival in the overall patient group (A), L-RNU patients (B), and O-RNU patients (C) according to past history of bladder cancer, and high and low risk of IVR (D-F, respectively). G: Progression-free survival in the overall patient group according to IVR. PFS (H) and overall survival (I) in L-RNU patients by IVR risk.
Previous studies identified a wide variety of risk factors for IVR, including multifocality (16, 17, 22-24), pT stage (17), renal function (14), gender (14, 18, 20), prominent papillary configuration (18), concomitant carcinoma in situ (15, 23), tumor size (15), necrosis, surgical margin, adjuvant chemotherapy (19), tumor site (20), and immunosuppression status (24). Interestingly, the most recent large-scale study indicated that L-RNU itself was also an independent risk factor for IVR (23). Therefore, we aimed to determine the risk factors for IVR in L-RNU, identifying grade and history of BCa as components of IVR risk because the Kaplan–Meier curves of IVR-free survival by these factors were opposite in L-RNU and O-RNU (Figure 3H and I, and Figure 4B and C). Moreover, both grade and history of BCa were also reported as independent risk factors of IVR (5, 18, 21, 23). We showed that the high-risk IVR group had significantly worse IVR-free survival than the low-risk group. Surprisingly, although both grade and pT were not factors of PFS and OS (Figure 2B and E, and Figure 3B and E), the high-risk IVR group showed significantly worse PFS and OS in L-RNU (Figure 4H and I). Consequently, this risk classification was able to predict IVR-free survival, PFS, and OS in L-RNU for UUTUC.
This study had some limitations. Firstly this was a retrospective study with a small sample size, and all patients were Japanese. Accumulation of evidence is needed because the incidence rate of UUTUC is relatively rare. Large prospective studies including patients of different ethnicities are needed to validate our results. In summary, novel risk classification based on our data were able to predict IVR-free survival, PFS, and OS in L-RNU for UUTUC and thus may help urologists to predict PFS and OS as well as IVR and to plan follow-up schedules after L-RNU.
- Received October 1, 2013.
- Revision received November 11, 2013.
- Accepted November 12, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved