Journal of Surgical Oncology 2014;110:468–475
Impact of Surgical Wait Time on Oncologic Outcomes in Upper Urinary Tract Urothelial Carcinoma JUN NYUNG LEE,1 SE YUN KWON,1 GYU-SEOG CHOI,2 HYUN TAE KIM,1 TAE-HWAN KIM,1* TAE GYUN KWON,1 AND BUP WAN KIM1 1
Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea Department of Surgery, School of Medicine, Kyungpook National University, Daegu, Korea
2
Background and Objectives: To assess the effect of surgical wait time on the oncologic outcomes of patients with upper urinary tract urothelial carcinoma (UTUC), particularly in the ureter. Methods: Using an optimal surgical wait time cutoff value of 30.5 days, we allocated patients to an early group or a late group. Cancer specific survival (CSS) and local/distant recurrence‐free survival (RFS) rates were estimated using the Kaplan–Meier method. Factors influencing CSS and RFS after radical surgery were identified using Cox proportional hazards regression models. Subgroup analysis was performed on ureteral urothelial carcinoma using the same methods. Results: Of the 138 UTUC patients, CSS and RFS were not significantly different between the two groups. However, subgroup analysis of the 80 patients with ureteral urothelial carcinoma showed that CSS and RFS were significantly higher in the early subgroup, and multivariate analysis showed that a surgical wait time of >1 month was an independent prognostic factor of CSS and RFS in ureteral urothelial carcinoma (P ¼ 0.04 and P < 0.001). Conclusions: A surgical wait time of >1 month in ureteral urothelial carcinoma was found to be an independent prognostic factor of disease recurrence and cancer‐specific mortality.
J. Surg. Oncol. 2014;110:468–475. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: ureter; transitional cell carcinoma; nephroureterectomy; delayed surgery; survival
INTRODUCTION
PATIENTS AND METHODS
Upper urinary tract urothelial carcinoma (UTUC) is a rare neoplasm with a prevalence of 5% among all urothelial carcinomas [1]. Furthermore, muscle‐invasive UTUC usually have a dismal prognosis [2,3]. To prevent cancer progression, accurate diagnosis, and aggressive treatment are important for the management of UTUC. However, many factors can cause delays between diagnosis and definite surgery (surgical wait time). These causes include disease‐unrelated factors, such as preoperative medical evaluation, the health care delivery system, surgical schedule limitations, and patients’ psychological factors, and disease‐related factors, such as an attempt at ureteroscopic resection of the tumor and neoadjuvant chemotherapy. However, unlike disease‐related causes, the effect of disease‐unrelated factors on treatment delay can be reduced by efforts to improve them. Generally, surgeons believe that the surgical wait time in UTUC should be as short as possible, due to its invasiveness [4]. If the tumor is located in the ureter, the surgical wait time may be considered more important than if the tumor is located in the renal pelvis, because of anatomical vulnerability. However, some studies have concluded that surgical delays in UTUC are not associated with poor outcomes [5–7]. In previous studies, the main causes of surgical delay included neoadjuvant chemotherapy [5] or the attempt to perform endoscopic procedures associated with the management of the UTUC prior to radical surgery [6,7]. Therefore, the oncologic impact of the surgical wait time caused by disease‐unrelated factors is more important in terms of the appropriate timing for the management of UTUC. We hypothesized that a surgical delay between diagnosis and nephroureterectomy negatively affects oncologic outcomes in UTUC, particularly when the disease is located in ureter, because of its anatomic features. Therefore, we evaluated the oncologic outcomes according to surgical wait time caused by disease‐unrelated factors in patients with UTUC and in patients with ureteral urothelial carcinoma.
Patients
ß 2014 Wiley Periodicals, Inc.
We retrospectively reviewed the charts of 156 consecutive UTUC patients who underwent radical nephroureterectomy at our institution between January 2001 and December 2010. Patients were excluded if they had previous or concurrent muscle‐invasive bladder cancer (seven cases), received neoadjuvant chemotherapy (three cases) or ureteroscopic management (0 cases), or had evidence of synchronous metastasis (four cases). We also excluded four patients whose charts were unavailable for review. After applying these exclusion criteria, 138 patients with UTUC were included in the present study. There were 58 patients with UTUC located in the renal pelvis and 80 patients with UTUC located in the ureter. When cancer occurred in both the renal pelvis and the ureter, the location was classified according to the dominant site. After radical nephroureterectomy, bladder cuff resection was performed using the extravesical approach via a Gibson incision; lymphadenectomy was performed if lymphadenopathy was suspected by preoperative imaging or observed during surgery. The majority of
Grant sponsor: Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea; Grant number: A111345. Conflict of interest: none. *Correspondence to: Tae‐Hwan Kim, 807 Hoguk‐ro Buk‐gu, Daegu 702‐ 210, Korea. Fax: þ82‐53‐200‐3029. E‐mail: [email protected] Received 8 November 2013; Accepted 10 February 2014 DOI 10.1002/jso.23589 Published online 25 July 2014 in Wiley Online Library (wileyonlinelibrary.com).
Surgical Timing of Upper Urinary Tract Urothelial Carcinoma patients with non‐organ confined disease underwent platinum‐based adjuvant chemotherapy. The follow‐up regimen included cystoscopy, urine cytology, chest X‐ ray, and computed tomography (CT) scanning. Cystoscopy and urine cytology were performed at 3, 6, and 12 months postoperatively, then every 6 months until 2 years post‐operation, and yearly thereafter. Image analyses, including chest X‐ray and CT scan were performed at 3, 6, and 12 months post‐operation, then every 6 months from 1 to 5 years, and annually thereafter.
Analyzed Factors and Statistical Analysis Cancer stage was determined using the American Joint Committee on Cancer (AJCC) staging system and histological grade was determined using the 2004 World Health Organization (WHO) classification system. Surgical wait time was defined as the period between diagnosis and nephroureterectomy. Receiver operating characteristic (ROC) curve analysis of cancer‐specific survival (CSS) was used to identify the optimal surgical wait time cutoff point of 30.5 days, which was used to define study groups (Fig. 1). The sensitivity and specificity of this cutoff point were assessed. The Institutional Review Board at our institution approved this study. Based on an optimal surgical wait time cutoff value of 30.5 days, we allocated the 138 patients with UTUC to an early group (1 month). Student’s t‐test and the chi‐square test were used to evaluate associations between variables in the two groups. CSS, local/ distant recurrence‐free survival (RFS), and bladder RFS rates after nephroureterectomy were estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression models were used to assess CSS, local/distant recurrence, and bladder recurrence after nephroureterectomy. The covariables included in the analysis were age, sex, surgical wait time, previous bladder tumor, concurrent bladder tumor, type of surgery, laterality, cuff resection, operative time, size of tumor, presence of carcinoma in situ, multifocal tumor, hydronephrosis, T stage, grade, lymphovascular invasion, N stage, and margin status. In addition, we analyzed 80 patients with ureteral urothelial carcinoma using the same methods. Statistical analysis was performed using SPSS V.18 (SPSS, Inc., Chicago, IL), and statistical significance was accepted for P values 3 months due to psychological factors. Adjuvant chemotherapy was recommended for patients with non‐organ confined disease and was performed for 22 patients (29.33%) in the early group and 21 patients (33.33%) in the late group. Kaplan–Meier analysis showed no statistical intergroup differences for CSS, local/distant metastasis‐free survival, or bladder RFS (Fig. 2). Multivariate Cox proportional hazards analysis revealed that CSS was significantly associated with pathologic stage T3 or greater (P ¼ 0.036), high grade (P ¼ 0.049), lymph node involvement (Nþ) (P < 0.001), and positive surgical margin (P < 0.001; Table II). The factors found to influence local/distant RFS by multivariate analyses were pathologic stage T3 or greater (P ¼ 0.042), lymphovascular invasion (P ¼ 0.011), lymph node involvement (Nþ) (P < 0.001), and a positive surgical margin (P ¼ 0.002; Table II). The presence of hydronephrosis (P ¼ 0.036), and a positive surgical margin (P ¼ 0.003) were related to bladder RFS in multivariate analyses (Table II). For urothelial carcinoma located in the renal pelvis, there were no statistical intergroup differences for CSS or bladder RFS (Fig. 3). However, 5‐year local/distant RFS rates were 66.3% in the early group and 91.6% in the late group (P ¼ 0.028; Fig. 3). Multivariate Cox proportional hazards analysis revealed that CSS was significantly associated with lymphovascular invasion (P ¼ 0.011; Table III). The factors found to influence local/distant RFS and bladder RFS by multivariate analyses were lymphovascular invasion (P ¼ 0.004), lymph node involvement (Nþ) (P ¼ 0.045) and previous bladder cancer (P < 0.001; Table III).
Fig. 1. Receiver‐operating characteristic (ROC) curve for surgical wait time in all upper urinary tract urothelial carcinoma (A) and ureteral urothelial carcinoma (B). Points (black arrows) on the ROC curve represent probability levels generated by logistic regression analysis that was used to select the optimal surgical wait time cutoff point. (A) A predicted probability of two provided a sensitivity of 58.1% and a specificity of 57.0%. (B) A predicted probability of two provided a sensitivity of 78.9% and a specificity of 65.6%. Journal of Surgical Oncology
470
Lee et al.
TABLE I. The Characteristics of Upper Urinary Tract Urothelial Carcinoma Patients in the Early Surgical Wait Time (1 Month) Group Early
Late
P‐value
Patients, n 75 63 Mean age, years 64.29 10.56 66.13 10.40 0.308 Male/female, n 57/18 39/24 0.073 Mean follow‐up duration, months 52.29 33.46 34.22 27.45 0.001 Mean time to surgery, days 16.57 8.48 70.10 105.37 1 month vs. < 1 month Previous bladder tumor, yes vs. no Concomitant bt, yes vs. no Surgery, open vs. LPS Laterality, left vs. right Cuff resection, yes vs. no Operative time, hr Maximal tumor size, cm Concomitant CIS yes/no Multifocal tumor, yes vs. no Hydronephrosis, yes vs. no T stage, non OC vs. OC Grade, high vs. low Lymphovascular invasion, yes vs. no N stage, N(þ) vs. Nx/N0 Positive surgical margin, yes vs. no
0.079 0.729 0.089 0.515 0.746 0.451 0.418 0.667 0.949 0.066 0.592 0.205 0.021 0.001 0.002
Impact of Surgical Wait Time on Oncologic Outcomes in Upper Urinary Tract Urothelial Carcinoma JUN NYUNG LEE,1 SE YUN KWON,1 GYU-SEOG CHOI,2 HYUN TAE KIM,1 TAE-HWAN KIM,1* TAE GYUN KWON,1 AND BUP WAN KIM1 1
Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea Department of Surgery, School of Medicine, Kyungpook National University, Daegu, Korea
2
Background and Objectives: To assess the effect of surgical wait time on the oncologic outcomes of patients with upper urinary tract urothelial carcinoma (UTUC), particularly in the ureter. Methods: Using an optimal surgical wait time cutoff value of 30.5 days, we allocated patients to an early group or a late group. Cancer specific survival (CSS) and local/distant recurrence‐free survival (RFS) rates were estimated using the Kaplan–Meier method. Factors influencing CSS and RFS after radical surgery were identified using Cox proportional hazards regression models. Subgroup analysis was performed on ureteral urothelial carcinoma using the same methods. Results: Of the 138 UTUC patients, CSS and RFS were not significantly different between the two groups. However, subgroup analysis of the 80 patients with ureteral urothelial carcinoma showed that CSS and RFS were significantly higher in the early subgroup, and multivariate analysis showed that a surgical wait time of >1 month was an independent prognostic factor of CSS and RFS in ureteral urothelial carcinoma (P ¼ 0.04 and P < 0.001). Conclusions: A surgical wait time of >1 month in ureteral urothelial carcinoma was found to be an independent prognostic factor of disease recurrence and cancer‐specific mortality.
J. Surg. Oncol. 2014;110:468–475. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: ureter; transitional cell carcinoma; nephroureterectomy; delayed surgery; survival
INTRODUCTION
PATIENTS AND METHODS
Upper urinary tract urothelial carcinoma (UTUC) is a rare neoplasm with a prevalence of 5% among all urothelial carcinomas [1]. Furthermore, muscle‐invasive UTUC usually have a dismal prognosis [2,3]. To prevent cancer progression, accurate diagnosis, and aggressive treatment are important for the management of UTUC. However, many factors can cause delays between diagnosis and definite surgery (surgical wait time). These causes include disease‐unrelated factors, such as preoperative medical evaluation, the health care delivery system, surgical schedule limitations, and patients’ psychological factors, and disease‐related factors, such as an attempt at ureteroscopic resection of the tumor and neoadjuvant chemotherapy. However, unlike disease‐related causes, the effect of disease‐unrelated factors on treatment delay can be reduced by efforts to improve them. Generally, surgeons believe that the surgical wait time in UTUC should be as short as possible, due to its invasiveness [4]. If the tumor is located in the ureter, the surgical wait time may be considered more important than if the tumor is located in the renal pelvis, because of anatomical vulnerability. However, some studies have concluded that surgical delays in UTUC are not associated with poor outcomes [5–7]. In previous studies, the main causes of surgical delay included neoadjuvant chemotherapy [5] or the attempt to perform endoscopic procedures associated with the management of the UTUC prior to radical surgery [6,7]. Therefore, the oncologic impact of the surgical wait time caused by disease‐unrelated factors is more important in terms of the appropriate timing for the management of UTUC. We hypothesized that a surgical delay between diagnosis and nephroureterectomy negatively affects oncologic outcomes in UTUC, particularly when the disease is located in ureter, because of its anatomic features. Therefore, we evaluated the oncologic outcomes according to surgical wait time caused by disease‐unrelated factors in patients with UTUC and in patients with ureteral urothelial carcinoma.
Patients
ß 2014 Wiley Periodicals, Inc.
We retrospectively reviewed the charts of 156 consecutive UTUC patients who underwent radical nephroureterectomy at our institution between January 2001 and December 2010. Patients were excluded if they had previous or concurrent muscle‐invasive bladder cancer (seven cases), received neoadjuvant chemotherapy (three cases) or ureteroscopic management (0 cases), or had evidence of synchronous metastasis (four cases). We also excluded four patients whose charts were unavailable for review. After applying these exclusion criteria, 138 patients with UTUC were included in the present study. There were 58 patients with UTUC located in the renal pelvis and 80 patients with UTUC located in the ureter. When cancer occurred in both the renal pelvis and the ureter, the location was classified according to the dominant site. After radical nephroureterectomy, bladder cuff resection was performed using the extravesical approach via a Gibson incision; lymphadenectomy was performed if lymphadenopathy was suspected by preoperative imaging or observed during surgery. The majority of
Grant sponsor: Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea; Grant number: A111345. Conflict of interest: none. *Correspondence to: Tae‐Hwan Kim, 807 Hoguk‐ro Buk‐gu, Daegu 702‐ 210, Korea. Fax: þ82‐53‐200‐3029. E‐mail: [email protected] Received 8 November 2013; Accepted 10 February 2014 DOI 10.1002/jso.23589 Published online 25 July 2014 in Wiley Online Library (wileyonlinelibrary.com).
Surgical Timing of Upper Urinary Tract Urothelial Carcinoma patients with non‐organ confined disease underwent platinum‐based adjuvant chemotherapy. The follow‐up regimen included cystoscopy, urine cytology, chest X‐ ray, and computed tomography (CT) scanning. Cystoscopy and urine cytology were performed at 3, 6, and 12 months postoperatively, then every 6 months until 2 years post‐operation, and yearly thereafter. Image analyses, including chest X‐ray and CT scan were performed at 3, 6, and 12 months post‐operation, then every 6 months from 1 to 5 years, and annually thereafter.
Analyzed Factors and Statistical Analysis Cancer stage was determined using the American Joint Committee on Cancer (AJCC) staging system and histological grade was determined using the 2004 World Health Organization (WHO) classification system. Surgical wait time was defined as the period between diagnosis and nephroureterectomy. Receiver operating characteristic (ROC) curve analysis of cancer‐specific survival (CSS) was used to identify the optimal surgical wait time cutoff point of 30.5 days, which was used to define study groups (Fig. 1). The sensitivity and specificity of this cutoff point were assessed. The Institutional Review Board at our institution approved this study. Based on an optimal surgical wait time cutoff value of 30.5 days, we allocated the 138 patients with UTUC to an early group (1 month). Student’s t‐test and the chi‐square test were used to evaluate associations between variables in the two groups. CSS, local/ distant recurrence‐free survival (RFS), and bladder RFS rates after nephroureterectomy were estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression models were used to assess CSS, local/distant recurrence, and bladder recurrence after nephroureterectomy. The covariables included in the analysis were age, sex, surgical wait time, previous bladder tumor, concurrent bladder tumor, type of surgery, laterality, cuff resection, operative time, size of tumor, presence of carcinoma in situ, multifocal tumor, hydronephrosis, T stage, grade, lymphovascular invasion, N stage, and margin status. In addition, we analyzed 80 patients with ureteral urothelial carcinoma using the same methods. Statistical analysis was performed using SPSS V.18 (SPSS, Inc., Chicago, IL), and statistical significance was accepted for P values 3 months due to psychological factors. Adjuvant chemotherapy was recommended for patients with non‐organ confined disease and was performed for 22 patients (29.33%) in the early group and 21 patients (33.33%) in the late group. Kaplan–Meier analysis showed no statistical intergroup differences for CSS, local/distant metastasis‐free survival, or bladder RFS (Fig. 2). Multivariate Cox proportional hazards analysis revealed that CSS was significantly associated with pathologic stage T3 or greater (P ¼ 0.036), high grade (P ¼ 0.049), lymph node involvement (Nþ) (P < 0.001), and positive surgical margin (P < 0.001; Table II). The factors found to influence local/distant RFS by multivariate analyses were pathologic stage T3 or greater (P ¼ 0.042), lymphovascular invasion (P ¼ 0.011), lymph node involvement (Nþ) (P < 0.001), and a positive surgical margin (P ¼ 0.002; Table II). The presence of hydronephrosis (P ¼ 0.036), and a positive surgical margin (P ¼ 0.003) were related to bladder RFS in multivariate analyses (Table II). For urothelial carcinoma located in the renal pelvis, there were no statistical intergroup differences for CSS or bladder RFS (Fig. 3). However, 5‐year local/distant RFS rates were 66.3% in the early group and 91.6% in the late group (P ¼ 0.028; Fig. 3). Multivariate Cox proportional hazards analysis revealed that CSS was significantly associated with lymphovascular invasion (P ¼ 0.011; Table III). The factors found to influence local/distant RFS and bladder RFS by multivariate analyses were lymphovascular invasion (P ¼ 0.004), lymph node involvement (Nþ) (P ¼ 0.045) and previous bladder cancer (P < 0.001; Table III).
Fig. 1. Receiver‐operating characteristic (ROC) curve for surgical wait time in all upper urinary tract urothelial carcinoma (A) and ureteral urothelial carcinoma (B). Points (black arrows) on the ROC curve represent probability levels generated by logistic regression analysis that was used to select the optimal surgical wait time cutoff point. (A) A predicted probability of two provided a sensitivity of 58.1% and a specificity of 57.0%. (B) A predicted probability of two provided a sensitivity of 78.9% and a specificity of 65.6%. Journal of Surgical Oncology
470
Lee et al.
TABLE I. The Characteristics of Upper Urinary Tract Urothelial Carcinoma Patients in the Early Surgical Wait Time (1 Month) Group Early
Late
P‐value
Patients, n 75 63 Mean age, years 64.29 10.56 66.13 10.40 0.308 Male/female, n 57/18 39/24 0.073 Mean follow‐up duration, months 52.29 33.46 34.22 27.45 0.001 Mean time to surgery, days 16.57 8.48 70.10 105.37 1 month vs. < 1 month Previous bladder tumor, yes vs. no Concomitant bt, yes vs. no Surgery, open vs. LPS Laterality, left vs. right Cuff resection, yes vs. no Operative time, hr Maximal tumor size, cm Concomitant CIS yes/no Multifocal tumor, yes vs. no Hydronephrosis, yes vs. no T stage, non OC vs. OC Grade, high vs. low Lymphovascular invasion, yes vs. no N stage, N(þ) vs. Nx/N0 Positive surgical margin, yes vs. no
0.079 0.729 0.089 0.515 0.746 0.451 0.418 0.667 0.949 0.066 0.592 0.205 0.021 0.001 0.002
