The present retrospective study aimed to examine the outcomes of stage II–IV upper-tract urothelial carcinoma (UTUC) and determine whether adjuvant chemotherapy is a beneficial treatment for patients with locally advanced UTUC (specifically, stage III–IV). The analysis included 126 patients with muscle-invasive UTUC who were treated between June 2003 and June 2012. All patients underwent laparoscopic or open nephroureterectomy and bladder cuff excision. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS) were assessed. Outcomes were compared between groups of patients with stage II (high-stage localized) disease, stage III–IV (high-stage locally advanced) disease treated with chemotherapy, and stage III–IV disease not treated with chemotherapy. Among patients with high-stage locally advanced UTUC (stage III–IV), those who received adjuvant chemotherapy had significantly better rates of OS (67.1 vs. 33.7%; P=0.004), DFS (70.2 vs. 46.0%; P=0.030) and DMFS (86.3 vs. 65.2%; P=0.048) at 5-years compared with those who did not undergo adjuvant chemotherapy. However, there was no significant difference between the 5-year LRFS rates in these two groups (78.2 vs. 62.5%; P=0.525). Importantly, the survival curve of patients with high-stage UTUC who received adjuvant chemotherapy was similar to that of patients with low-stage UTUC who underwent surgery only. Multivariate analysis revealed that adjuvant chemotherapy was an independent risk factor for OS [without adjuvant chemotherapy vs. with adjuvant chemotherapy: Hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.129–0.654; P=0.003] and DFS (without adjuvant chemotherapy vs. with adjuvant chemotherapy: HR, 0.381; 95% CI, 0.168–0.865; P=0.021). In conclusion, adjuvant chemotherapy may improve the outcome for patients with high-stage locally advanced UTUC.
Urothelial carcinoma (UC) is the ninth most common type of tumor globally (
Nephroureterectomy is the gold standard in the initial management of invasive localized UTUC (
UC is a chemosensitive tumor (
The objective of the present study was to observe the outcome of high-stage UTUC and determine whether adjuvant chemotherapy is beneficial for patients with high-stage UTUC.
The present study was approved by the Research Ethics Committee of China Medical University and Hospital (IRB approval no. CMUH103-REC1-094; Taichung, Taiwan). Personal records and data were retrospectively collected and analyzed anonymously. A tertiary referral center (China Medical University Hospital, Taichung, Taiwan) database was used, and included 139 patients who underwent nephroureterectomy between June 2003 and December 2012 for pathological stage II to IV UTUC at the China Medical University Hospital. Patients with concomitant UBUC (n=5); patients with incomplete data (n=2); patients with a follow-up duration of <3 months (n=4); or patients receiving neoadjuvant chemotherapy (n=2) were excluded. Finally, the study population comprised 126 patients with UTUC of pathological stage II [pT2, node (N)0/X, metastasis (M)0], stage III (pT3, N0/X, M0) and stage IV (T4, N0/X, M0; or T1-4, N1-3, M0).
The present retrospective study analyzed age at surgery, sex, tumor location, adjuvant chemotherapy status and regimen, estimated glomerular filtration rate (eGFR), tumor pathology (grade and lymphovascular invasion), tumor recurrence and cause of mortality. All patients underwent open or laparoscopic nephroureterectomy with bladder cuff excision and achieved free pathological margins. Lymph node dissection was performed if preoperative computerized tomography (CT) of the abdomen and pelvis revealed lymph node enlargement or if palpable lymph nodes were identified during surgery. Extended lymphadenectomy was not routinely performed due to potential complications, including lymphocele development, vascular injury and bowel injury. Regional lymph node recurrence was defined according to a previous study by Kondo
Tumor stage was determined according to the American Joint Committee on Cancer TNM classification (
Patients were followed up by physical examination, blood tests and cystoscopy postoperatively every 3 months for the first 3 years after surgery, every 6 months for the subsequent 2 years, and then annually for up to 10 years. Abdominal CT or magnetic resonance imaging were performed every 6 months to evaluate tumor recurrence, lymph node metastasis and distant metastasis.
Patients with a stage I tumor were defined as low-stage while those with stage II–IV were defined as high-stage. In the high-stage group, patients with pathological stage II tumors were categorized as the localized UTUC group, and patients with T3, T4 and/or node-positive non-distant metastatic UTUC were categorized as the locally advanced UTUC group.
The endpoints assessed were overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS).
Local recurrence was established by urine cytology, cystoscopy, retrograde ureteropyeloscopy or biopsy, and/or CT or magnetic resonance imaging scans of the abdomen and pelvis. Distant metastasis was diagnosed on the basis of physical examination and imaging methods. OS was defined as the time from treatment until mortality; the follow-up of the patients that survived was censored at the latest date of follow-up (date of mortality). DFS was defined as the time from treatment until the earliest occurrence of recurrence or mortality from any cause. For analysis of LRFS and DMFS, the latencies were recorded (time from date of treatment) to the first detection of locoregional recurrence or distant metastasis, respectively.
χ2 or Fisher's exact tests were used to assess differences between groups. All survival data were analyzed using the Kaplan-Meier method with a log-rank test to compare the disease free survival and overall survival rate. Multivariate analysis was carried out using a Cox proportional hazards regression model. P<0.05 was considered to indicate a statistically significant difference. Statistical analysis was performed using SPSS statistical software (version 22.0; IBM Corp., Armonk, NY, USA).
The median follow-up period was 23.6 months (range, 3.1–120.9 months). Clinicopathological characteristics are listed in
In the localized group, the 5-year OS, DFS, LRFS and DMFS were 70.7, 82.2, 82.0 and 97.3%, respectively; whereas, in the locally advanced group with and without chemotherapy, these rates were 49.5, 56.8, 71.1 and 75.2%, respectively. Overall, in the locally advanced group, 29 patients (33.3%) succumbed to UTUC, and 5 patients (5.7%) succumbed to other causes. Furthermore, 19 patients with locally advanced UTUC presented with distant metastasis at diagnosis of disease recurrence and 17 presented with locoregional recurrence. By contrast, in the localized UTUC group, 4 patients (10.5%) succumbed to UTUC and 4 (10.5%) succumbed to other causes; 1 patient presented with distant metastasis at diagnosis of disease recurrence; and 5 patients presented with locoregional recurrence.
Lymph node metastasis was detected in 5 patients, and all of these patients received adjuvant chemotherapy. The mean age was 60.6 years. Of the 5 patients, 3 (60%) survived for >5 years and 1 patient (20%) developed distant metastasis. No patients suffered from local recurrence. These patients were included in the locally advanced with chemotherapy group to expand the case number.
Univariate log-rank analysis was performed for OS. Age, pathological stage and lymphovascular invasion were identified as significant prognostic factors for OS, while there were no significant differences in terms of sex, tumor location, tumor grade or renal function (eGFR) (
Adjuvant chemotherapy was not administered to the localized group. Of the locally advanced group, 38 (43.2%) received adjuvant chemotherapy. These patients were scheduled to receive >4 courses of carboplatin-based chemotherapy, including the carboplatin, methotrexate and vinblastine (CarMV) regimen (13 patients), and the gemcitabine and carboplatin (GCar) regimen (25 patients). The median interval between surgery and the beginning of systemic therapy was 1.2 months (range, 0.7–2.3 months).
Patients treated with the CarMV regimen received methotrexate (30 mg/m2), vinblastine (3 mg/m2), and carboplatin [area under the plasma drug concentration-time curve (AUC)=5] intravenously on day 1, and methotrexate (30 mg/m2) and vinblastine (3 mg/m2) intravenously on days 15 and 22. Cycles were repeated every 4 weeks.
The GCar regimen was administered in a 4-week cycle, with gemcitabine (1,000 mg/m2) administered intravenously on days 1, 8, and 15, and carboplatin (AUC=5) administered intravenously on day 1. The majority of patients received >4 cycles of chemotherapy (median, 5 cycles; range, 2–6 cycles), with the exception of 1 patient who received 2 cycles, and 3 patients who received 3 cycles of chemotherapy.
In the locally advanced UTUC group, there were no significant differences in clinicopathological characteristics between patients who received and those who did not receive adjuvant chemotherapy, except that an eGFR of <60 ml/min was more prevalent among patients who did not receive adjuvant chemotherapy (
Of the 50 patients who did not receive adjuvant chemotherapy, 14 (28%) developed distant metastasis, and 10 (20%) developed locoregional recurrence. On the other hand, of the 38 patients administered with adjuvant chemotherapy, 5 (13.2%) developed distant metastasis and 7 (18.4%) developed locoregional recurrence.
Kaplan-Meier curve analysis revealed that, in locally advanced patients, those who received adjuvant chemotherapy had significantly better 5-year OS (67.1 vs. 33.7%, P=0.004;
Log-rank analysis was performed for OS and DFS. Administration of adjuvant chemotherapy (without vs. with) was a significant independent risk factor for OS [hazard ratio (HR), 0.291; 95% CI, 0.129–0.654; P=0.003] and DFS (HR, 0.381; 95% CI, 0.168–0.865; P=0.021). Additionally, tumor stage (III vs. IV) was an independent predictor of OS and DFS, while lymphovascular invasion (absent vs. present) predicted OS only (HR, 2.248; 95% CI, 1.124–4.497; P=0.022) (
In the present study, 65.9% of the patients with UTUC were female. Although the majority of UTUC cases occur in men, the high prevalence of UTUC in Taiwan is notably impacted by the high use of
A carboplatin-based regimen was selected for adjuvant chemotherapy, as carboplatin had been demonstrated to provide an equivalent effect and improved tolerability compared with cisplatin in numerous other types of cancer (
Owing to the relatively low frequency of UTUC, thus far, no randomized trial has been conducted to evaluate the impact of chemotherapy on patients with UTUC. However, a number of retrospective studies have been published (
In 2009, Hellenthal
In contrast to the studies of adjuvant chemotherapy by Vassilakopoulou
In the present study, distant metastasis in patients with locally advanced UTUC was the most probable cause of mortality. The implementation of adjuvant chemotherapy significantly improved DMFS but not LRFS rates, resulting in improved OS rates in patients with locally advanced UTUC. Similar results were observed in the study by Vassilakopoulou
There were a number of limitations to the present study. First, this was a retrospective study, and therefore it was not possible to determine the rationale behind administering or not administering chemotherapy to these patients. Second, the sample size was relatively small, and the treatments were not uniform. Third, a number of patient demographics, including performance status and comorbidities, were not recorded in the present study, and thus there may have been a selection bias in the study cohort. Therefore, the results of the present study should be considered as hypothesis-forming.
In summary, survival rates were higher in patients with localized UTUC compared with locally advanced patients who did not receive adjuvant chemotherapy. The present study supports the hypothesis that adjuvant chemotherapy may improve outcomes in patients with locally advanced UTUC. Further large-scale, prospective, randomized studies are required in order to verify the results of the present study and determine the precise effectiveness of adjuvant chemotherapy in patients with UTUC.
Kaplan-Meier plot of overall survival estimation for patients with localized UTUC, and locally advanced UTUC with and without C/T. UTUC, upper-tract urothelial carcinoma; C/T, chemotherapy.
Kaplan-Meier plot of disease-free survival estimation for patients with localized UTUC, and locally advanced UTUC with and without C/T. UTUC, upper-tract urothelial carcinoma; C/T, chemotherapy.
Kaplan-Meier plot of distant metastasis-free survival estimation for patients with localized UTUC, and locally advanced UTUC with and without C/T. UTUC, upper-tract urothelial carcinoma; C/T, chemotherapy.
Kaplan-Meier plot of locoregional recurrence-free survival estimation for patients with localized UTUC, and locally advanced UTUC with and without C/T. UTUC, upper-tract urothelial carcinoma; C/T, chemotherapy.
Clinicopathological characteristics of patients with high stage (II–IV) upper-tract urothelial carcinoma.
Clinicopathological characteristic | Value |
---|---|
Age (years); median (range) | 70.0 (26–86) |
Sex |
|
Male | 43 (34.1) |
Female | 83 (65.9) |
eGFR (ml/min) |
|
>60 | 30 (23.8) |
<60 | 96 (76.2) |
Pathological stage |
|
II | 38 (30.2) |
III | 73 (57.9) |
IV | 15 (11.9) |
Grade |
|
Low | 35 (27.8) |
High | 91 (72.2) |
Lymphovascular invasion |
|
No | 80 (63.5) |
Yes | 46 (36.5) |
Perineural permeation |
|
No | 104 (82.5) |
Yes | 22 (17.5) |
Location |
|
Ureter | 52 (41.3) |
Renal pelvis | 74 (58.7) |
Lymph node metastasis |
|
Negative | 121 (96.0) |
Positive | 5 (4.0) |
Data are presented as number of patients (%). eGFR, estimated glomerular filtration rate.
Univariate analysis of overall survival in patients with high stage (II–IV) upper-tract urothelial carcinoma.
Variable | 5-year overall survival rate (%) | P-value |
---|---|---|
Age (years) | 0.018 | |
>70 | 39.9 | |
<70 | 70.8 | |
Sex | 0.900 | |
Male | 38.9 | |
Female | 60.5 | |
Location | 0.681 | |
Renal pelvis | 56.9 | |
Ureter | 53.3 | |
Grade | 0.231 | |
Low | 59.0 | |
High | 52.7 | |
Lymphovascular invasion | 0.002 | |
With | 42.4 | |
Without | 61.3 | |
Stage | <0.001 | |
II | 70.7 | |
III | 56.7 | |
IV | 16.0 | |
eGFR (ml/min) | 0.303 | |
<60 | 51.0 | |
>60 | 63.1 |
eGFR, estimated glomerular filtration rate.
Characteristics of patients in the locally advanced group stratified by adjuvant chemotherapy.
Clinicopathological characteristics | Adjuvant chemotherapy | No adjuvant chemotherapy | P-value |
---|---|---|---|
Age (years), mean | 63.57 | 68.86 | 0.735 |
Sex |
|||
Male | 17 | 13 | 0.107 |
Female | 21 | 37 | |
eGFR (ml/min) |
|||
>60 | 15 | 8 | 0.025 |
<60 | 23 | 42 | |
Pathological stage |
|||
III | 30 | 43 | 0.558 |
IV | 8 | 7 | |
Grade |
|||
Low | 8 | 13 | 0.774 |
High | 30 | 37 | |
Lymphovascular invasion |
|||
No | 21 | 27 | 1.000 |
Yes | 17 | 23 | |
Perineural permeation |
|||
No | 30 | 38 | 0.944 |
Yes | 8 | 12 | |
Location |
|||
Ureter | 13 | 15 | 0.850 |
Renal pelvis | 25 | 35 |
Data are presented as the number of patients. eGFR, estimated glomerular filtration rate.
Multivariate analysis for overall survival and disease-free survival in patients in the locally advanced group.
Overall survival | Disease-free survival | |||
---|---|---|---|---|
Clinicopathological characteristic | HR (95% CI) | P-value | HR (95% CI) | P-value |
Adjuvant chemotherapy: Without vs. with | 0.291 (0.129–0.654) | 0.003 | 0.381 (0.168–0.865) | 0.021 |
Age: <70 vs. >70 years | 2.042 (0.987–4.224) | 0.054 | 1.750 (0.841–3.645) | 0.135 |
Stage: III vs. IV | 4.286 (2.006–9.159) | <0.001 | 3.928 (1.755–8.794) | 0.001 |
Lymphovascular invasion: Without vs. with | 2.248 (1.124–4.497) | 0.022 | 1.235 (0.603–2.530) | 0.564 |
eGFR: <60 vs. >60 ml/min | 1.072 (0.464–2.473) | 0.871 | 0.816 (0.346–1.928) | 0.644 |
eGFR, estimated glomerular filtration rate; HR, hazard ratio; CI, confidence interval.
Outcomes of adjuvant chemotherapy for patients with locally advanced UTUC.
Number of patients | ||||||
---|---|---|---|---|---|---|
First author, year | With adjuvant chemotherapy | Without adjuvant chemotherapy | UTUC stage | Chemotherapy regimen (%) | Survival outcomes (with vs. without chemotherapy) | (Refs.) |
Vassilakopoulou |
140 | 487 | T3N0, T4N0 and/or N+ and/or M+ | Cisplatin-based (52.8%); carboplatin-based (39.4%) | HR (95% CI) for cancer-specific survival: 4.63 (0.16–128.69) | ( |
Hellenthal |
121 | 421 | T3N0M0, T4N0M0 and/or N+ | Cisplatin-based (89%); methotrexate + vinblastine + doxorubicin + cisplatin (59%) | HR (95% CI) for OS: 1.06 (0.80–1.40) | ( |
Kwak |
32 | 11 | T2N0M0 and T3N0M0 | Cisplatin-based | 5-year OS rate: 78.1 vs. 36.4% | ( |
Soga |
24 | 22 | T2N0M0 and T3N0M0 | Methotrexate + vinblastine + doxorubicin + cisplatin | 5-year OS rate: 95.8 vs. 86.5% | ( |
Chang |
38 | 50 | T3N0, T4N0 and/or N+ | Gemcitabine + carboplatin; or carboplatin + methotrexate + vinblastine | 5-year OS rate: 67.1 vs. 33.7% | – |
UTUC, upper-tract urothelial carcinoma; T, tumor; N, node; M, metastasis; HR, hazard ratio; CI, confidence interval; OS, overall survival.