|Year : 2020 | Volume
| Issue : 6 | Page : 258-266
Conservative management of upper tract urothelial carcinoma with endoscopic thulium laser ablation: A retrospective study with subgroup analyses
Yu-Che Hsieh1, Steven K Huang1, Chia-Cheng Su1, Jhih-Cheng Wang1, I-Jung Feng2, Allen W Chiu3, Chien-Liang Liu1
1 Division of Urology, Department of Surgery, (Division is under Department in hospital), Chi Mei Medical Center, Tainan City, Taiwan
2 Department of Medical Research, Chi Mei Medical Center, Tainan City, Taiwan
3 Department of Urology, Mackay Memorial Hospital; Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
|Date of Submission||27-Apr-2020|
|Date of Decision||27-Aug-2020|
|Date of Acceptance||16-Oct-2020|
|Date of Web Publication||26-Dec-2020|
Division of Urology, Department of Surgery (Division is under Department in hospital), Chi Mei Medical Center, No. 901, Zhonghua Road, Yongkang District, Tainan City
Source of Support: None, Conflict of Interest: None
Purpose: The gold standard treatment for upper tract urothelial carcinoma (UTUC) is radical nephroureterectomy. The combination of ureterorenoscopy and laser ablation has recently become more accepted. This study aims at investigating the risk factors of tumor recurrence associated with the thulium laser ablation of UTUC and reporting its clinical outcomes with subgroup analyses. Materials and Methods: Patients who underwent endoscopic thulium laser ablation of UTUC as the primary treatment from June 2012 to November 2018 were reviewed retrospectively. Sixty-eight patients were enrolled, of whom 34 had complete data for analysis after applying the exclusion criteria. Bivariate analysis was performed to compare patients with and without recurrence. Multivariable Cox regression models were applied. Kaplan–Meier survival estimates were presented, and three tumor characteristics were used for subgroup analyses. Results: Fifteen patients (44%) had local tumor recurrence. Four patients (12%) had cancer-specific death. In bivariate analysis, statistical significance was noted for age, tumor grade, and tumor size (P = 0.018, 0.047, and 0.014, respectively). In multivariate analysis, statistical significance was noted for age and tumor size (P = 0.017 and 0.042, respectively). In the Kaplan–Meier estimates for subgroup analysis, statistical significance was noted only in the tumor size and tumor grade group (P = 0.0275). The study limitations included the retrospective design and small sample size. Conclusion: Tumor size and tumor grade are influential recurrence factors. The tumor stage did not show statistical significance in recurrence analysis. In subgroup analyses, tumor size was more influential than tumor grade with respect to the prognosis of local recurrence.
Keywords: Conservative treatment, kidney sparing surgery, laser therapy, thulium, upper tract urothelial carcinoma
|How to cite this article:|
Hsieh YC, Huang SK, Su CC, Wang JC, Feng IJ, Chiu AW, Liu CL. Conservative management of upper tract urothelial carcinoma with endoscopic thulium laser ablation: A retrospective study with subgroup analyses. Urol Sci 2020;31:258-66
|How to cite this URL:|
Hsieh YC, Huang SK, Su CC, Wang JC, Feng IJ, Chiu AW, Liu CL. Conservative management of upper tract urothelial carcinoma with endoscopic thulium laser ablation: A retrospective study with subgroup analyses. Urol Sci [serial online] 2020 [cited 2021 Jan 21];31:258-66. Available from: https://www.e-urol-sci.com/text.asp?2020/31/6/258/305096
| Introduction|| |
Upper tract urothelial carcinoma (UTUCs) are rare malignancies responsible for 5%–10% of all urothelial carcinomas (UCs). However, an increased prevalence was noted in areas with high arsenic pollution and in areas with Chinese herb-consuming residents, like southwestern and northeastern Taiwan, where the inhabitants are at a high risk of developing lung cancer, bladder cancer, and black foot disease. Residents of such areas have consumed arsenic-contaminated water from wells for > 40 years, and the odds ratio of bladder cancer is 4.10. This group of patients has unique characteristics; such as (1) a disproportionally high incidence rate of UTUC (20%–25%) relative to all other UCs due to arsenic exposure;, (2) ureteral UCs being twice as common as renal pelvic UCs; and (3) a male-to-female ratio of 1:2, in contrast to the male predominance seen in other regions of the world.,,
The incidence of UTUCs in Western countries is 2.0/100,000 persons, accounting for only 5%–10% of UCs. Renal pelvic UCs are approximately twice as common as ureteral UCs. However, the incidence of UTUCs in Taiwan is 5.56/100,000 persons in men and 7.37/100,000 persons in women. Owing to its high prevalence in southwestern Taiwan, where our hospital is located, we manage more patients with UTUCs than hospitals in other regions. Compared to urinary bladder UCs, UTUCs tend to have a worse prognosis as a multifocal disease with a high recurrence rate. The 5-year urinary bladder recurrence rate is 28%, and the 5-year mortality rate is 23%.
Conventionally, the gold standard treatment for UTUCs is radical nephroureterectomy (RNU) with bladder-cuff excision. Because of continuous advances in the imaging and endoscopic armamentarium, the role of kidney-sparing surgery (KSS) has recently become more essential. According to the latest European Association of Urology (EAU) guidelines, well-selected patients with UTUCs are suitable candidates for KSS. In low-risk patients (unifocal disease, tumor size < 2 cm, low-grade cytology, low-grade ureterorenoscopy [URS] biopsy, and no invasive aspect on computed tomography urography [CTU]), a similar cancer-specific survival was noted between the KSS and RNU groups.
The advanced development of flexible URS has allowed checking the collecting system in detail. URS treatment for UTUCs using electrodes has shifted to laser ablation with holmium laser or thulium laser., Laser ablation has been thoroughly investigated over the last decade. Compared to traditional electrode resection, laser ablation has the advantage of providing a continuous wave for a sharply defined resection and fulguration of the tumor bed with excellent hemostasis. Thulium laser ablation has resulted in better recurrence-free survival, less bleeding, and less mucosal perforation than holmium laser ablation.
This study aims at investigating the risk factors of tumor recurrence associated with the thulium laser ablation of UTUC and whether KSS can have similar outcomes in patients with potentially more aggressive UTUCs from arsenic-polluted areas.
| Subjects and Methods|| |
Patients who underwent endoscopic thulium laser ablation of UTUC as the primary treatment from June 2012 to November 2018 were reviewed retrospectively. All UTUCs were diagnosed using URS biopsy. The indications for laser ablation of UTUC were: (1) a low-risk tumor as defined by the EAU guidelines, (2) existence in a solitary kidney, (3) chronic kidney disease stage ≥3, (4) bilateral UTUCs, and (5) medical comorbidities advanced enough to be life-limiting or to cause additional risks with RNU [Appendix Figure 1].
Sixty-eight patients underwent laser ablation of UTUC, of whom 34 patients were excluded because of having a (1) follow-up duration of <6 months, (2) history of urinary bladder UC, and (3) concomitant diagnosis of UTUC and bladder UC at the first visit. All patients underwent a diagnostic evaluation, including intravenous pyelography, urine cytology, retrograde pyelography, CTU/magnetic resonance imaging (MRI), cystoscopy, and URS. For most patients, tumor biopsy and urine cytology were initially obtained. After a discussion with the patient, the thulium laser ablation was performed. Flexible URS would be performed if the tumor was located in the renal pelvis. The lesions were vaporized with a thulium laser (“Quanta” Cyber TM 200-W thulium laser system made in Italy). The power setting was 10–15 W for vaporization and 5 W for hemostasis to obtain proper vapo-coagulation effect with minimal tissue injuries. For renal pelvic UCs, flexible URS was used with optical fiber 200 μm. The power setting of the laser was 10 W initially and increased to 15 W according to the tumor size (<2 cm: 10 W, >2 cm: 15 W). For ureteral UCs, semi-rigid URS was used with 365-μm optical fiber. The power setting was 10 W initially and also increased to 15 W if the tumor was large.
Three months after the first endoscopic thulium laser ablation, another URS was performed. A routine biopsy of the previous ablation site was performed to determine the recurrence status, which could be followed by a second thulium laser ablation of the previous tumor site. The second laser ablation procedure would not be performed if no suspicious lesion was found. However, if the biopsy of second-look URS showed recurrence, then a third endoscopic thulium laser ablation would be performed. The patients were followed up using a stringent surveillance protocol, including urine cytology, cystoscopy, and URS after 3 months. If no evidence of recurrence was found, urine cytology, cystoscopy, URS/retrograde pyelography would be scheduled every 3 months. However, CTU/MRI would be scheduled every 6 months for the first 2 years and yearly thereafter for 5 years [Appendix Figure 2]. Recurrence was defined as ipsilateral UTUCs determined with ureteroscopic biopsy. Disease progression was defined as radiological or pathological upstaging.
Continuous and categorical data of the clinical characteristics of patients and tumors were separately presented as counts with percentages and medians with ranges [Tables 1]a and [Tables 1]b. Bivariate analysis was performed to compare patients with and without recurrence, and the results were examined using the Wilcoxon rank-sum test for continuous data and the Chi-square test or Fisher's exact test for categorical data [Table 2]. Multivariable Cox regression models adjusted for age, biopsy stage, tumor grade, and tumor size were further applied for identifying the association between the clinical characteristics of patients and the risk factors of recurrence [Table 3]. Survival estimates were calculated using the Kaplan–Meier method [Table 4]. Kaplan–Meier survival plots were further presented for each group, and the comparison of survival curves was tested using a log-rank test. We combined two of three tumor characteristics (tumor stage, size, and grade) for subgroup analyses. In this study, the difference was considered significant if the P < 0.05.
|Table 2: Demographic and clinical characteristics of patients with and without recurrence (bivariate analysis)|
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|Table 3: Analyses of risk factors of tumor recurrence by multivariable Cox regression model|
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| Results|| |
Thirty-four patients met the inclusion criteria. The patients' age ranged from 36 to 89 years (median 71 years). A female predominance (24 of 34, 71%) was noted [Table 1]a, and 15 patients (44%) had local tumor recurrence during the follow-up. Seven patients (21%) had a recurrence in the urinary bladder. Two patients (6%) had lymph node or distal metastasis: one patient had lung metastasis and eventually died at 9 months of follow-up, whereas the other patient had para-aortic lymph node metastasis and bone metastasis and eventually died at 28 months of follow-up. Four patients (12%) had cancer-specific death during the follow-up, and another two patients died of obstructive uropathy with urosepsis. A 69-year-old patient underwent laser ablation once before the treatment was shifted to RNU because of persistent hematuria, and the final pathology was T2N0. Five patients (15%) had ureteral stricture as a postoperative complication.
In bivariate analysis, statistical significance was noted for age, tumor grade, and tumor size, with P values of 0.018, 0.047, and 0.014, respectively [Table 2]. In multivariate analysis, statistical significance was noted for age and tumor size, with P = 0.017 and 0.042, respectively. However, non-significance was noted in tumor grade, with a P = 0.286 [Table 3].
The incidence of UTUCs was more than two-fold higher in women than in men, and the male-to-female hazard ratio of UTUC recurrence was 2.090 (95% confidence interval [CI] 0.704–6.201) [Table 3].
We treated UTUC of the renal pelvis using flexible URS, whereas ureteral UTUCs were treated using semi-rigid URS. No significance was noted between these two groups.
In both bivariate and multivariate analyses, the tumor stage showed no significant difference. Only two patients had Tis stage, and no recurrence was found in these patients. Most patients (n = 20) had small tumors (<2 cm), and the recurrence rate after laser ablation was 25%. Both bivariate and multivariate analyses found a statistically significant difference. The hazard ratio of large tumors (>2 cm) to small tumors was 3.225 (95% CI 1.041–9.988).
Five patients received intra-ureteral (or intra-pelvic) chemotherapy with mitomycin or epirubicin. The recurrence rate of patients with or without intraureteral chemotherapy was not statistically significantly different.
We used Kaplan–Meier estimates for survival rate analysis [Table 4]. Because the mean duration of follow-up was 25 months, we compared 2 years of local recurrence-free survival, bladder recurrence-free survival, metastasis-free survival, and cancer-specific survival. As for the 2-year local recurrence-free survival, the use of flexible URS for laser ablation of UTUC was not inferior to the use of semi-rigid URS (P = 0.972, log-rank test).
High-grade UTUCs had a higher tendency of recurrence than low-grade tumors and had a statistically significant difference with a P = 0.0477 [Figure 1]a. The biopsy stage had no significant difference according to the log-rank test [Figure 1]b. Large tumors (>2 cm) had a higher tendency of recurrence than small tumors (<2 cm), which showed a statistically significant difference with a P = 0.0066 [Figure 1]c.
We combined two of three tumor characteristics (tumor stage, size, and grade) for subgroup analyses. In the tumor grade and tumor size group, a statistically significant difference was noted with a P = 0.0275 [Figure 2]a. In the tumor size and biopsy stage group, statistical significance was almost reached, as noted by the P = 0.0518 [Figure 2]b. In the tumor grade and biopsy stage group, no significant difference was noted [Figure 2]c.
|Figure 2(a-c): Kaplan–Meier plot: Recurrence-free survival rate (subgroup analyses)|
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| Discussion|| |
The EAU guidelines have confirmed the effectiveness of a minimally invasive and conservative kidney-sparing approach for low-risk UTUCs as an alternative treatment to RNU. As the EAU and National Comprehensive Cancer Network (NCCN) guidelines suggest, URS as a treatment for UTUC should be performed in patients with low-grade tumors; however, KSS was also imperatively indicated for highly selected patients with UTUC in a solitary kidney, impaired renal function, and bilateral UTUCs.,
In a systematic review by Seisen et al., only patients with low-grade and noninvasive UTUCs showed a similar survival rate between URS and RNU. However, in the current study, only tumor grade and tumor size had a statistical significance. The biopsy stage was not statistically significant. This difference may imply that both tumor size and tumor grade are more influential factors than biopsy stage with respect to local recurrence-free survival. This suggests that the biopsy stage with URS may not reflect the actual tumor stage properly because biopsy cannot precisely evaluate the depth of tumor invasion. However, the present study found that the tumor size may be indicative of the grade of tumor invasion.
Owing to the high prevalence of UTUCs in southwestern Taiwan, many patients cannot be classified into the low-risk group. The review by Fiuk and Schwartz extended the indication for KSS to patients with (1) UTUC in a solitary kidney; (2) renal insufficiency, which poses the risk of needing hemodialysis if any further renal insult occurs; (3) bilateral UTUCs; (4) comorbidities advanced enough to be life-limiting or to incur additional risks with RNU; and (5) low-risk tumors with a stringent follow-up. Therefore, patients with imperative indications were selected, and the results after laser ablation of UTUCs were analyzed.
In the current study, a female predominance was noted. It has been speculated that female patients are highly exposed to arsenic steam from boiling water during cooking. Likewise, some other reports revealed this phenomenon, explaining that as most postpartum women take special nourishments involving Chinese herbal medicines daily for at least 1 month in Taiwan, they have a higher risk of exposure to aristolochic acid, which is a well-known cause of UTUCs., However, our statistical data showed that men had a higher tendency of recurrence with near statistical significance. Similarly, Huang et al. reported that more women than men were diagnosed at the early pT-stages (Ta/Tis/T1) in southwestern Taiwan. The present study found that age had a statistically significant difference in multivariate analysis; however, Chromecki et al. suggested that age was not an independent predictor of the outcomes of UTUCs.
Two major laser systems are available for the ablation of UTUTC: thulium and holmium laser systems. In many reports, the thulium laser system showed higher effectiveness and precision with fewer complications than the holmium laser system.,, Thulium laser provides a continuous wave, which allows precise incisions and excellent coagulation, avoiding temperature increases that could damage tissues. With a higher power setting (10–15 W), it provides faster vaporization of lesions and allows maintaining a proper coagulation function, which reduces the time of the procedure and prevents kidney injury. In contrast, holmium laser demonstrated similar efficacy to thulium laser; however, it causes a discontinuous “tear-like” damage to tissues, resulting in ureteral transluminal microperforations or macroperforations.
Flexible URS was used, combined with the thulium laser system, for treating renal pelvic UTUCs. The statistical results showed no significant difference between renal pelvic tumors (treated with flexible URS) and ureteral tumors (treated with rigid URS), which may be due to current technological advances that allow approaching all parts of the renal collecting system.
In the NCCN guidelines, treatment of low-grade UC of the renal pelvis with endoscopic resection is recommended to be followed with postsurgical intra-pelvic chemotherapy or bacillus Calmette-Guerin therapy. In the current study, a small number of patients (n = 5) received intraureteral (intrapelvic) chemotherapy. The outcome of local recurrence was not statistically significantly different between patients with and without chemotherapy instillation. Because of the high risk of acute pyelonephritis after intra-ureteral (intra-pelvic) chemotherapy, the therapy was stopped after administering it to some patients. Repeated acute pyelonephritis may cause permanent deterioration of renal function. However, the protocol of intra-ureteral (intra-pelvic) chemotherapy has been modified, and the large-scale application of this protocol is now implemented at our hospital. A further research paper will be reported on this issue.
The recurrence rate of bilateral UTUCs was lower than that of unilateral UTUCs in the present study (only five patients had bilateral disease). Similarly, the statistical analysis showed no significantly higher rate of recurrence in patients with bilateral disease. The five patients with bilateral UTUCs had a small tumor size and earlier tumor stage (Ta and Tis) and had a lower rate of recurrence.
Two of three tumor characteristics (tumor stage, size, and grade) were combined for subgroup analyses. In the tumor grade and tumor size group, statistical significance was noted with a P = 0.0275 [Figure 2]a. Small tumors (<2 cm with low/high grade) still had a lower local recurrence than large tumors (>2 cm with low/high grade) [Figure 2]a. The subgroup analysis of the tumor size and biopsy stage group also showed the same pattern: small tumors (<2 cm with Tis/Ta/T1) had a lower local recurrence than large tumors (>2 cm with Tis/Ta/T1) [Figure 2]b. However, no statistical significance was noted in the subgroup analysis of the tumor grade and biopsy stage group [Figure 2]c. These results imply that tumor size was more influential than tumor grade and biopsy stage with respect to local recurrence.
In multivariate analysis [Table 3], no difference in recurrence was observed in terms of tumor grade; however, the recurrence-free survival estimate [Table 4] revealed that high-grade tumors were associated with a higher risk of recurrence. Such inconsistent results are due to the fact that low-grade tumors comprise a smaller group (n = 9), whereas high-grade tumors comprise a bigger group with more confounding factors.
Even with considerable experience in treating UTUCs through endoscopic management, the risks of both understaging and undergrading remain. A previous study reported that up to 25% of UTUC lesions and almost 50% of carcinoma in situ lesions were missed.
The limitations of the current study included the (1) small number of patients (n = 34); (2) short follow-up duration (mean 25 months); (3) small number of patients having received intra-ureter/intra-pelvic chemotherapy (n = 5); and (4) retrospective, single-center study design.
The study included a small number of patients because 34 patients were excluded for having a (1) short follow-up duration (<6 months), (2) history of urinary bladder UC, and (3) concomitant diagnosis of UTUC and bladder UC at the first visit.
To our knowledge, this is the first study of this kind to be reported from areas with a high incidence of UTUC like southwestern and northeastern Taiwan, the Balkan area, and other regions with Chinese herb-consuming residents.
| Conclusions|| |
UTUC is a multifocal disease with a high recurrence rate. Tumor size and tumor grade are influential recurrence factors after KSS. However, the biopsy stage did not provide an accurate prediction for recurrence analysis and survival estimation. In the subgroup analysis, tumor size was a more influential factor than tumor grade with respect to local recurrence.
The author wishes to acknowledge to Dr. Tseng for guidance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]