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Comparison of 2002 TNM nodal status with lymph node density in node-positive patients after radical cystectomy for bladder cancer: Analysis by the number of lymph nodes removed
Urologic Oncology: Seminars and Original Investigations 29 (2011) 199 –204
Original article
Comparison of 2002 TNM nodal status with lymph node density in node-positive patients after radical cystectomy for bladder cancer: Analysis by the number of lymph nodes removed夡 In Gab Jeong, M.D.a, Jinsung Park, M.D.a, Kanghyon Song, M.D.a, Jae Y. Ro, M.D., Ph.D.b, Cheryn Song, M.D., Ph.D.a, Jun Hyuk Hong, M.D., Ph.D.a, Hanjong Ahn, M.D., Ph.D.a, Choung-Soo Kim, M.D., Ph.D.a,* a b
Department of Urology, Asan Medical Center, Seoul, Korea Department of Pathology, Asan Medical Center, Seoul, Korea
Received 14 January 2009; received in revised form 5 April 2009; accepted 7 April 2009
Abstract Objective: Because 2002 TNM pathologic nodal (pN) status was established in patients from whom a relatively small number of lymph nodes had been removed, it is necessary to validate this staging system in current clinical practice, in which the removal of more lymph nodes is recommended during radical cystectomy and pelvic lymphadenectomy. We assessed the ability of lymph node density (LND) and 2002 TNM pathologic nodal (pN) status to predict disease-specific survival (DSS) in node-positive patients after radical cystectomy for bladder cancer, and investigated whether these factors were affected by the number of lymph nodes removed during pelvic lymphadenectomy. Materials and methods: We retrospectively evaluated outcomes in 130 patients with nodal metastases after radical cystectomy performed between 1989 and 2006. Patients were divided into 2 subgroups based on the median number of lymph nodes removed, those with ⬍15 and those with ⱖ15 lymph nodes removed. The effect of several variables on DSS was assessed. Results: The overall 5-year DSS rate was 38.5%. Multivariate analysis showed that in the entire cohort, LND (HR ⫽ 2.28, 1.04 –5.03, P ⫽ 0.041) and the use of adjuvant chemotherapy (HR ⫽ 2.68, 1.42–5.06, P ⫽ 0.002) were significant predictors of DSS. In patients with ⬍15 lymph nodes removed, pN status (HR ⫽ 5.19, 1.24 –21.75, P ⫽ 0.024) and use of adjuvant chemotherapy (HR ⫽ 6.23, 2.32–16.73, P ⬍ 0.001) were independent predictors of DSS. In patients with ⱖ15 lymph nodes removed, however, only LND (HR ⫽ 4.08, 1.10 –15.10, P ⫽ 0.036) was a predictor of DSS. Conclusions: LND was an independent predictor of DSS in node-positive patients. However, when small numbers of lymph nodes were removed, TNM pN status was a better predictor than LND. These findings suggest that abilities of TNM pN status and LND in node-positive patients to predict DSS could be affected by the total number of lymph nodes removed. © 2011 Elsevier Inc. All rights reserved. Keywords: Bladder neoplasm; Lymph nodes; Cystectomy; Prognosis
1. Introduction The standard surgical treatment for patients with highgrade, invasive bladder cancer consists of radical cystectomy with pelvic lymphadenectomy. The pathologic stages of the primary tumor and regional lymph-node status have 夡
The results of this study were presented at the Annual Meeting of the American Urologic Association, Chicago, Illinois, April 25–30, 2009. * Corresponding author. Tel.: ⫹82-2-3010-3031; fax: 82-2-477-8928. E-mail address: [email protected] (C.S. Kim). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.04.006
been shown to be the most accurate predictors of disease recurrence after radical cystectomy [1]. In the 2002 TNM classification system, pathologic nodal (pN) status was quantified according to the number and size of positive regional lymph nodes. Although the prognostic value of nodal burden in this staging system has been validated [2], this system appears to be inadequate for stratifying node-positive patients, in that assessment of large numbers of patients found no differences in survival among groups with different pN status [3,4]. Lymph node density (LND), the ratio of positive to total nodes removed, has
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been shown to be superior to TNM nodal status in predicting disease-specific survival (DSS), suggesting that LND may be better for risk stratification in node-positive patients [5– 8]. pN status in the current TNM classification system was established in patients from whom a relatively small number of lymph nodes had been removed. A large study representing 12% of the population of the United States in 1988 – 1998 found that pelvic lymph nodes were not retrieved from 40% of patients who underwent radical cystectomy, and only 12% of such patients had more than 15 lymph nodes examined [9]. In addition, 50.1% of 1,260 node-positive patients included in the Surveillance, Epidemiology and End Results (SEER) database (1998 –2002) had fewer than 10 lymph nodes removed [10]. Although recently updated European Association of Urology (EAU) guidelines state that lymph node dissection should be an integral part of cystectomy, the extent was not established. In addition, the 2004 EAU guidelines advocated only a limited lymph node dissection [11–13]. Therefore, it is necessary to validate this staging system in current clinical practice, in which the removal of more lymph nodes is recommended during radical cystectomy and pelvic lymphadenectomy. We therefore compared the ability of LND and TNM nodal status to predict DSS after radical cystectomy for bladder cancer. We also assessed whether the prognostic ability of 2002 TNM nodal status and LND was affected by the total number of lymph nodes removed during pelvic lymphadenectomy.
2. Materials and methods From December 1989 to December 2006, a total of 494 patients at our institute underwent radical cystectomy with bilateral pelvic lymphadenectomy for urothelial carcinoma of the bladder. Of these 494 patients, 130 (26.3%) had nodal metastases on histologic examination. The medical records of these patients were reviewed, and information regarding their demographic characteristics and perioperative variables was obtained. The study protocol was approved by the Institutional Review Board of Asan Medical Center, Seoul, Korea. No patient received preoperative radiation or neoadjuvant chemotherapy. All patients underwent preoperative chest X-ray, computerized tomography scan of the abdomen and pelvis, and bone scan for disease staging. None of the patients showed evidence of metastatic disease on physical examination or staging. All operations were performed by 2 senior surgeons (HA and CSK). Urinary diversions, including ileal conduit diversions and orthotopic bladder substitutions, were performed after radical cystectomy. Of the 130 patients, 114 underwent bilateral standard pelvic lymphadenectomy, which included the distal common iliac, external iliac, hypogastric, obturator, and perivesical lymph nodes. The remaining 16 patients underwent extended lymphadenectomy,
including the lymph node regions described, as well as those at the level of the proximal common iliac, distal aorta, and vena cava. The extent of lymph-node dissection was determined by each surgeon. All nodal tissue removed from each anatomic location was submitted as a separate packet, and identified visually and by manual palpation without the use of clearing solution. In our study, all pathology slides were retrospectively reviewed by a single senior pathologist (JYR). Pathologic staging was performed from the cystectomy specimens and reclassified according to the 2002 TNM classification system. In this classification system, pN status is classified as pN1 (metastasis in single regional lymph nodes, ⱕ2 cm in greatest dimension), pN2 (single regional lymph node metastasis 2 cm to 5 cm in size or multiple metastases ⱕ5 cm in greatest dimension), or pN3 (metastasis ⬎ 5 cm in greatest dimension) [14]. Tumor grade, margin status, total number of lymph nodes, number of positive lymph nodes, and the presence of extracapsular extension were also assessed. LND was calculated by dividing the number of positive lymph nodes by the total number of lymph nodes removed. Adjuvant chemotherapy was routinely recommended for all node-positive patients at our institute, except for those who were medically intolerant or who refused this treatment, and it was initiated within 3 months of surgery in all patients. Chemotherapy consisted of 3 to 6 cycles of MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin, n ⫽ 34) or GC (gemcitabine and cisplatin, n ⫽ 54) combination regimens. From 1992 to 2000, only MVAC regimens were used. GC and MVAC regimens have similar survival benefits but the former has a better safety profile and greater tolerability for patients with advanced or metastatic bladder cancer, so only GC regimens were used from 2001 to 2006 [15]. Following radical cystectomy, patients were generally followed up every 3 months during the first year, every 6 months during years 2 to 6, and annually thereafter. Follow-up consisted of history, physical examination, blood chemistry studies, and urine cytology. Patients underwent chest X-rays and computerized tomography scans at 6 and 12 months and annually thereafter. Patients were divided into subgroups of patients with ⬍15 and ⱖ15 lymph nodes removed, based on the median number of lymph nodes removed. The optimal cutoff value for LND to predict DSS was selected by the analysis of ROC curve. The LND of 18% was the cutoff with the best balance between sensitivity and specificity. Clinicopathologic factors were compared between these 2 subgroups, using the 2 test for categorical variables and Student’s t-test for continuous variables. DSS was measured from the date of cystectomy to death from bladder cancer. KaplanMeier survival curves for DSS, generated according to TNM pN status and LND, were compared using the logrank test. Cox proportional hazards regression model was used to estimate the prognostic significance of each variable. All statistical tests were 2-tailed, with P ⬍ 0.05 con-
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sidered significant. All calculations were performed using the Statistical Package for Social Sciences, version 12.0 (SPSS, Chicago, IL).
3. Results Of the 130 patients, 116 were men and 14 were women; the mean age was 61.8 ⫾ 9.9 years (range, 37– 80 years). Follow-up time ranged from 3 to 160 months (median, 22 months), and 88 patients (67.7% of the entire cohort; 66.7% of pN1, and 68.2% of pN2 disease, respectively) received adjuvant chemotherapy. In the entire cohort, pN status was pN1 in 45 patients (34.6%), pN2 in 84 patients (64.6%), and pN3 in 1 patient (0.8%). The median number of total lymph nodes was 15 (range, 1–94), the median number of positive lymph nodes was 3 (range, 1–37), and the median LND was 18% (range, 3%–100%). The median largest size of the positive lymph nodes was 1.2 cm (range, 0.1– 8.0 cm). Table 1 shows the characteristics of patients stratified by the total number of lymph nodes removed. The mean number of removed lymph nodes was 10.0 in patients with ⬍15 lymph nodes removed and 26.6 in patients with ⱖ15 lymph nodes removed. The mean number of positive lymph node was significantly higher in patients with ⱖ15 lymph nodes removed than in patients with ⬍15 lymph nodes removed
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(6.0 vs. 2.6, P ⬍ 0.001). These 2 subgroups, however, did not differ significantly in pN status or mean LND (29.2% vs. 22.3%, P ⫽ 0.076). A total of 70 (53.9%) patients died after a median time of 13 months (range, 3–142 months). The 1-year, 2-year, and 5-year DSS rates were 79.0%, 57.3%, and 38.5%, respectively. Median DSS time did not differ significantly between 2 subgroups (33 months vs. 40 months, P ⫽ 0.827). The univariate and multivariate Cox regression analyses of variables predicting DSS in the entire cohort are summarized in Table 2. Using an 18% cutoff point for LND, the pN status (P ⬍ 0.001), the number of positive lymph nodes (P ⫽ 0.002), LND (P ⬍ 0.001), extracapsular extension (P ⫽ 0.009), and the use of adjuvant chemotherapy (P ⫽ 0.006) were significant predictors of DSS on univariate analysis. Kaplan-Meier curves for DSS according to pN status and LND showed statistically significant differences (Fig. 1). Multivariate analysis showed that LND (HR ⫽ 2.28, 1.04 –5.03, P ⫽ 0.041) and the use of adjuvant chemotherapy (HR ⫽ 2.68, 1.42–5.06, P ⫽ 0.002) were significant predictors of DSS. Table 2 also shows univariate and multivariate Cox regression analyses of variables predicting DSS according to the number of lymph nodes removed. In patients with ⬍15 lymph nodes removed, the pN status (P ⫽ 0.005), the number of positive lymph nodes (P ⫽ 0.001), LND (P ⫽
Table 1 Patient characteristics stratified by the number of lymph nodes removed
No. patients (%) No. sex (%) Male Female Mean age ⫾ SD (median, range) No. grade (%) 2 3 No. soft tissue surgical margin status (%) Positive Negative No. pathological primary tumor status (%) Organ confined Extravesical No. pathological nodal status (%) 1 2 3 Mean positive lymph nodes ⫾ SD (median, range) Mean lymph node removed ⫾ SD (median, range) Mean % LND ⫾ SD (median, range) No. extracapsular extension (%) Yes No Unknown No. adjuvant chemotherapy (%) Yes No Median disease-specific survival (months)
Totals
⬍15 Lymph nodes removed
ⱖ15 Lymph nodes removed
130
65 (50.0)
65 (50.0)
116 (89.2) 14 (10.8) 61.8 ⫾ 9.9 (63, 37–80)
60 (92.3) 5 (7.7) 61.0 ⫾ 9.9 (62, 37–80)
56 (86.2) 9 (13.8) 62.5 ⫾ 9.9 (64, 42–79)
5 (3.9) 125 (96.1)
3 (4.6) 62 (95.4)
2 (3.1) 63 (96.9)
3 (2.3) 127 (97.7)
1 (1.5) 64 (98.5)
2 (3.1) 63 (96.9)
27 (20.8) 103 (79.2)
12 (18.5) 53 (81.5)
15 (23.1) 50 (76.9)
45 (34.6) 84 (64.6) 1 (0.8) 4.3 ⫾ 5.3 (3, 1–37) 18.3 ⫾ 12.4 (15, 1–94) 25.8 ⫾ 22.2 (18, 3–100)
24 (36.9) 41 (63.1) 0 2.6 ⫾ 1.9 (2, 1–8) 10.0 ⫾ 3.4 (11, 1–14) 29.2 ⫾ 22.7 (21.0, 7–100)
21 (32.3) 43 (66.2) 1 (1.5) 6.0 ⫾ 6.9 (3, 1–37) 26.6 ⫾ 12.7 (23, 15–94) 22.3 ⫾ 21.4 (14, 3–82)
39 (30.0) 66 (50.8) 25 (19.2)
18 (27.7) 30 (46.2) 17 (26.1)
21 (32.3) 36 (55.4) 8 (12.3)
88 (67.7) 42 (32.3) 33
46 (70.8) 19 (29.2) 33
42 (64.6) 23 (35.4) 40
P value 0.258
0.381 0.648
0.559
0.517
0.536
⬍0.001 ⬍0.001 0.076 0.945
0.453
0.827
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Table 2 Univariate and multivariate analyses of variables predicting disease-specific survival according to the number of lymph nodes removed Variables
Entire cohort Primary tumor status (T3-4 vs. T1-2) Pathologic N stage (N2-3 vs. N1) No. positive lymph nodes (continuous variable) Lymph node density (⬎18% vs. 0%–18%) Extracapsular extension (yes vs. no) Adjuvant chemotherapy (no vs. yes) Less than 15 lymph nodes removed Primary tumor status (T3-4 vs. T1-2) Pathologic N stage (N2-3 vs. N1) No. positive lymph nodes (continuous variable) Lymph node density (⬎18% vs. 0%–18%) Extracapsular extension (yes vs. no) Adjuvant chemotherapy (no vs. yes) 15 or more lymph nodes removed Primary tumor status (T3-4 vs. T1-2) Pathologic N stage (N2-3 vs. N1) No. positive lymph nodes (continuous variable) Lymph node density (⬎18% vs. 0%–18%) Extracapsular extension (yes vs. no) Adjuvant chemotherapy (no vs. yes)
Univariate
Multivariate
Hazard ratio
95% CI
P value
Hazard ratio
95% CI
0.93 2.89 1.05 2.77 2.06 2.02
0.54–1.61 1.62–5.16 1.02–1.09 1.70–4.52 1.20–3.54 1.23–3.31
0.804 ⬍0.001 0.002 ⬍0.001 0.009 0.006
1.00 1.78 1.03 2.28 1.28 2.68
0.49–2.02 0.71–4.49 0.98–1.08 1.04–5.03 0.69–2.40 1.42–5.06
0.95 3.04 2.67 1.24 1.83 3.41
0.42–2.18 1.41–6.58 1.47–4.85 1.05–1.46 0.82–4.10 1.72–6.76
0.909 0.005 0.001 0.013 0.143 ⬍0.001
1.66 5.19 1.05 0.94 0.66 6.23
0.49–5.63 1.24–21.75 0.71–1.54 0.26–3.39 0.22–1.98 2.32–16.73
0.416 0.024 0.811 0.930 0.456 ⬍0.001
0.88 2.93 1.05 3.20 2.02 1.14
0.42–1.86 1.20–7.13 1.01–1.09 1.58–6.48 0.97–4.21 0.55–2.40
0.741 0.018 0.010 0.001 0.059 0.715
0.77 1.10 1.00 4.08 1.66 1.79
0.31–1.89 0.25–4.80 0.95–1.06 1.10–15.10 0.73–3.78 0.69–4.64
0.566 0.895 0.916 0.036 0.227 0.233
0.013), and the use of adjuvant chemotherapy (P ⬍ 0.001) were significant predictors of DSS on univariate analysis. Multivariate analysis showed that in this subgroup, pN status remained an independent predictor of DSS after controlling for all other variables (HR ⫽ 5.19, 1.24 –21.75, P ⫽ 0.024). In patients with ⱖ15 lymph nodes removed, pN status was not predictive of DSS. However, univariate and multivariate analyses showed that LND was a unique predictor of DSS (HR ⫽ 4.08, 1.10 –15.10, P ⫽ 0.036).
P value 0.995 0.219 0.247 0.041 0.437 0.002
4. Discussion The 5-year DSS rate in our patients, 38.5%, was similar to the 30%–37% 5-year disease-specific or overall survival rates reported in patients with positive nodes following radical cystectomy and pelvic lymphadenectomy [6,8]. Although it is unclear if the removal of more lymph nodes might be associated with a survival advantage in patients with lymph node-
Fig. 1. Kaplan-Meier survival curves for the entire cohort stratified by (A) 2002 TNM classification of pathologic nodal status and (B) lymph node density. (Color version of figure is available online.)
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positive disease, we observed that survival did not differ significantly in node-positive patients with ⬍15 or those with ⱖ15 lymph nodes removed [5– 8,10,16 –18]. In patients with nodal metastases at the time of radical cystectomy with pelvic lymphadenectomy, risk stratification is based on the 2002 TNM classification system. However, the ability of this nodal staging system to predict DSS has been found to vary. For example, significant differences in DSS were observed among pN1, pN2, and pN3 patients, indicating that the TNM lymph node classification system was an independent predictor of death from bladder cancer [2]. Other studies, however, did not find significant differences in recurrence-free survival and DSS rates between pN1 and pN2 subgroups [3,4]. Following the design of the ratio-based lymph node staging system (the ratio of positive to total number of lymph nodes) [5], LND was reported to be a superior indicator of nodal burden because the absolute number of positive lymph nodes is affected by the total number of nodes removed [6]. This concept, which reflects the burden of regional metastasis in relation to the extent and quality of lymph node dissection, is considered to be an attractive and promising predictor. Studies validating the prognostic value of LND have suggested that LND may be superior to TNM nodal status in predicting DSS for patients with lymph node-positive disease after radical cystectomy [5– 8]. However, another study found that although LND had a significant impact on survival in univariate analysis, this significance was not maintained in multivariate analysis [18]. Although there is increasing evidence to support more extended lymphadenectomy in patients undergoing radical cystectomy, many patients undergoing radical cystectomy for bladder cancer are not receiving adequate lymph node dissection owing to time constraints (an extended node dissection requires approximately 60 additional minutes to complete) and the need for advanced surgical skill; therefore, relatively few lymph nodes are removed [19,20]. We therefore hypothesized that TNM pN status and LND may be affected by the total number of lymph nodes removed because in node-positive patients with a small number of lymph nodes removed the greatest diameter of a positive lymph node may be more important than the total number of lymph nodes. In this context, we analyzed the prognostic impact of various pathologic variables, including TNM pN status and LND, on DSS in node-positive patients relative to the number of lymph nodes removed during radical cystectomy with pelvic lymphadenectomy. We found that LND was a predictor of DSS in our entire cohort, although TNM pN status and LND were analyzed jointly in multivariate analysis. These findings were in agreement with those of a previous report in which LND was shown to be superior to TNM pN status in nodepositive bladder cancer [8]. Although the predictive value of TNM pN status remains controversial, we found that this factor did not show prognostic significance [5– 8].
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It is difficult to directly compare our results with those of previous reports, owing to discrepancies that might result from differences in patient characteristics. First, patient distribution by pN status differed among various studies. In our study, only 1 patient had pN3 disease; this finding is similar to that of a previous report [3], but much lower than that of another large study in which 17% of patients had pN3 disease [8]. Second, the median number of lymph nodes removed in our study was 15, compared with 12 to 30 in other studies of node-positive patients following radical cystectomy [3,4,6,8,18]. Finally, there were differences in the proportions of patients who received adjuvant chemotherapy, which may have altered the effect of TNM pN status and LND on survival. In our study, 67.7% of patients received adjuvant chemotherapy, much higher than the 26.6% to 27.9% reported in other studies [3,8]. This was supported by findings showing that adjuvant chemotherapy had beneficial effects only in node-positive patients, especially those with pN2 disease [21]. Therefore, differences in percentages of patients who received adjuvant chemotherapy may lead to discrepancies in the prognostic value of pN status and LND in node-positive patients. We further investigated whether the number of lymph nodes removed affected the prognostic value of pN status and LND. A subgroup analysis showed that TNM pN status was superior to LND in patients from whom ⬍15 lymph nodes had been removed. In patients with ⱖ15 lymph nodes removed, however, only LND was an independent predictor of survival. Thus, TNM pN status may be a more useful predictor in node-positive patients with a small number of lymph nodes removed. The National Cancer Institute’s SEER database showed that only 26.2% of patients who underwent radical cystectomy had more than 16 lymph nodes removed [10]. Therefore, the prognostic value of current TNM pN status will be maintained in most centers in which limited lymph node dissection is routinely performed. However, in patients with a large number of lymph nodes removed during lymphadenectomy, LND may be more helpful in stratifying patients who are candidates for adjuvant treatment in clinical trials. In addition to TNM pN status and LND, primary tumor stage has been shown to be an independent predictor of survival in node-positive patients [2,8,10,18]. We found, however, no survival differences between patients with organ-confined and extravesical diseases. These findings were similar to the results of other studies in which primary tumor stage was not an independent prognostic factor of DSS in node-positive patients [3,4]. Because our data were collected retrospectively, selection criteria for patients undergoing lymphadenectomy of various extents and adjuvant chemotherapy may lead to selection bias. Thus, prospective trials are needed to determine the prognostic significance of LND and TNM pN status in node-positive patients treated with radical cystectomy for bladder cancer according to the number of lymph nodes removed.
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5. Conclusions We have shown here that LND was an independent predictor of DSS in node-positive patients during radical cystectomy for bladder cancer. However, in node-positive patients from whom a small number of lymph nodes had been removed, TNM pN status was superior to LND. Our results suggest that abilities of TNM pN status and LND in node-positive patients to predict DSS could be affected by the total number of lymph nodes removed.
[9]
[10]
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Original article
Comparison of 2002 TNM nodal status with lymph node density in node-positive patients after radical cystectomy for bladder cancer: Analysis by the number of lymph nodes removed夡 In Gab Jeong, M.D.a, Jinsung Park, M.D.a, Kanghyon Song, M.D.a, Jae Y. Ro, M.D., Ph.D.b, Cheryn Song, M.D., Ph.D.a, Jun Hyuk Hong, M.D., Ph.D.a, Hanjong Ahn, M.D., Ph.D.a, Choung-Soo Kim, M.D., Ph.D.a,* a b
Department of Urology, Asan Medical Center, Seoul, Korea Department of Pathology, Asan Medical Center, Seoul, Korea
Received 14 January 2009; received in revised form 5 April 2009; accepted 7 April 2009
Abstract Objective: Because 2002 TNM pathologic nodal (pN) status was established in patients from whom a relatively small number of lymph nodes had been removed, it is necessary to validate this staging system in current clinical practice, in which the removal of more lymph nodes is recommended during radical cystectomy and pelvic lymphadenectomy. We assessed the ability of lymph node density (LND) and 2002 TNM pathologic nodal (pN) status to predict disease-specific survival (DSS) in node-positive patients after radical cystectomy for bladder cancer, and investigated whether these factors were affected by the number of lymph nodes removed during pelvic lymphadenectomy. Materials and methods: We retrospectively evaluated outcomes in 130 patients with nodal metastases after radical cystectomy performed between 1989 and 2006. Patients were divided into 2 subgroups based on the median number of lymph nodes removed, those with ⬍15 and those with ⱖ15 lymph nodes removed. The effect of several variables on DSS was assessed. Results: The overall 5-year DSS rate was 38.5%. Multivariate analysis showed that in the entire cohort, LND (HR ⫽ 2.28, 1.04 –5.03, P ⫽ 0.041) and the use of adjuvant chemotherapy (HR ⫽ 2.68, 1.42–5.06, P ⫽ 0.002) were significant predictors of DSS. In patients with ⬍15 lymph nodes removed, pN status (HR ⫽ 5.19, 1.24 –21.75, P ⫽ 0.024) and use of adjuvant chemotherapy (HR ⫽ 6.23, 2.32–16.73, P ⬍ 0.001) were independent predictors of DSS. In patients with ⱖ15 lymph nodes removed, however, only LND (HR ⫽ 4.08, 1.10 –15.10, P ⫽ 0.036) was a predictor of DSS. Conclusions: LND was an independent predictor of DSS in node-positive patients. However, when small numbers of lymph nodes were removed, TNM pN status was a better predictor than LND. These findings suggest that abilities of TNM pN status and LND in node-positive patients to predict DSS could be affected by the total number of lymph nodes removed. © 2011 Elsevier Inc. All rights reserved. Keywords: Bladder neoplasm; Lymph nodes; Cystectomy; Prognosis
1. Introduction The standard surgical treatment for patients with highgrade, invasive bladder cancer consists of radical cystectomy with pelvic lymphadenectomy. The pathologic stages of the primary tumor and regional lymph-node status have 夡
The results of this study were presented at the Annual Meeting of the American Urologic Association, Chicago, Illinois, April 25–30, 2009. * Corresponding author. Tel.: ⫹82-2-3010-3031; fax: 82-2-477-8928. E-mail address: [email protected] (C.S. Kim). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.04.006
been shown to be the most accurate predictors of disease recurrence after radical cystectomy [1]. In the 2002 TNM classification system, pathologic nodal (pN) status was quantified according to the number and size of positive regional lymph nodes. Although the prognostic value of nodal burden in this staging system has been validated [2], this system appears to be inadequate for stratifying node-positive patients, in that assessment of large numbers of patients found no differences in survival among groups with different pN status [3,4]. Lymph node density (LND), the ratio of positive to total nodes removed, has
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been shown to be superior to TNM nodal status in predicting disease-specific survival (DSS), suggesting that LND may be better for risk stratification in node-positive patients [5– 8]. pN status in the current TNM classification system was established in patients from whom a relatively small number of lymph nodes had been removed. A large study representing 12% of the population of the United States in 1988 – 1998 found that pelvic lymph nodes were not retrieved from 40% of patients who underwent radical cystectomy, and only 12% of such patients had more than 15 lymph nodes examined [9]. In addition, 50.1% of 1,260 node-positive patients included in the Surveillance, Epidemiology and End Results (SEER) database (1998 –2002) had fewer than 10 lymph nodes removed [10]. Although recently updated European Association of Urology (EAU) guidelines state that lymph node dissection should be an integral part of cystectomy, the extent was not established. In addition, the 2004 EAU guidelines advocated only a limited lymph node dissection [11–13]. Therefore, it is necessary to validate this staging system in current clinical practice, in which the removal of more lymph nodes is recommended during radical cystectomy and pelvic lymphadenectomy. We therefore compared the ability of LND and TNM nodal status to predict DSS after radical cystectomy for bladder cancer. We also assessed whether the prognostic ability of 2002 TNM nodal status and LND was affected by the total number of lymph nodes removed during pelvic lymphadenectomy.
2. Materials and methods From December 1989 to December 2006, a total of 494 patients at our institute underwent radical cystectomy with bilateral pelvic lymphadenectomy for urothelial carcinoma of the bladder. Of these 494 patients, 130 (26.3%) had nodal metastases on histologic examination. The medical records of these patients were reviewed, and information regarding their demographic characteristics and perioperative variables was obtained. The study protocol was approved by the Institutional Review Board of Asan Medical Center, Seoul, Korea. No patient received preoperative radiation or neoadjuvant chemotherapy. All patients underwent preoperative chest X-ray, computerized tomography scan of the abdomen and pelvis, and bone scan for disease staging. None of the patients showed evidence of metastatic disease on physical examination or staging. All operations were performed by 2 senior surgeons (HA and CSK). Urinary diversions, including ileal conduit diversions and orthotopic bladder substitutions, were performed after radical cystectomy. Of the 130 patients, 114 underwent bilateral standard pelvic lymphadenectomy, which included the distal common iliac, external iliac, hypogastric, obturator, and perivesical lymph nodes. The remaining 16 patients underwent extended lymphadenectomy,
including the lymph node regions described, as well as those at the level of the proximal common iliac, distal aorta, and vena cava. The extent of lymph-node dissection was determined by each surgeon. All nodal tissue removed from each anatomic location was submitted as a separate packet, and identified visually and by manual palpation without the use of clearing solution. In our study, all pathology slides were retrospectively reviewed by a single senior pathologist (JYR). Pathologic staging was performed from the cystectomy specimens and reclassified according to the 2002 TNM classification system. In this classification system, pN status is classified as pN1 (metastasis in single regional lymph nodes, ⱕ2 cm in greatest dimension), pN2 (single regional lymph node metastasis 2 cm to 5 cm in size or multiple metastases ⱕ5 cm in greatest dimension), or pN3 (metastasis ⬎ 5 cm in greatest dimension) [14]. Tumor grade, margin status, total number of lymph nodes, number of positive lymph nodes, and the presence of extracapsular extension were also assessed. LND was calculated by dividing the number of positive lymph nodes by the total number of lymph nodes removed. Adjuvant chemotherapy was routinely recommended for all node-positive patients at our institute, except for those who were medically intolerant or who refused this treatment, and it was initiated within 3 months of surgery in all patients. Chemotherapy consisted of 3 to 6 cycles of MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin, n ⫽ 34) or GC (gemcitabine and cisplatin, n ⫽ 54) combination regimens. From 1992 to 2000, only MVAC regimens were used. GC and MVAC regimens have similar survival benefits but the former has a better safety profile and greater tolerability for patients with advanced or metastatic bladder cancer, so only GC regimens were used from 2001 to 2006 [15]. Following radical cystectomy, patients were generally followed up every 3 months during the first year, every 6 months during years 2 to 6, and annually thereafter. Follow-up consisted of history, physical examination, blood chemistry studies, and urine cytology. Patients underwent chest X-rays and computerized tomography scans at 6 and 12 months and annually thereafter. Patients were divided into subgroups of patients with ⬍15 and ⱖ15 lymph nodes removed, based on the median number of lymph nodes removed. The optimal cutoff value for LND to predict DSS was selected by the analysis of ROC curve. The LND of 18% was the cutoff with the best balance between sensitivity and specificity. Clinicopathologic factors were compared between these 2 subgroups, using the 2 test for categorical variables and Student’s t-test for continuous variables. DSS was measured from the date of cystectomy to death from bladder cancer. KaplanMeier survival curves for DSS, generated according to TNM pN status and LND, were compared using the logrank test. Cox proportional hazards regression model was used to estimate the prognostic significance of each variable. All statistical tests were 2-tailed, with P ⬍ 0.05 con-
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sidered significant. All calculations were performed using the Statistical Package for Social Sciences, version 12.0 (SPSS, Chicago, IL).
3. Results Of the 130 patients, 116 were men and 14 were women; the mean age was 61.8 ⫾ 9.9 years (range, 37– 80 years). Follow-up time ranged from 3 to 160 months (median, 22 months), and 88 patients (67.7% of the entire cohort; 66.7% of pN1, and 68.2% of pN2 disease, respectively) received adjuvant chemotherapy. In the entire cohort, pN status was pN1 in 45 patients (34.6%), pN2 in 84 patients (64.6%), and pN3 in 1 patient (0.8%). The median number of total lymph nodes was 15 (range, 1–94), the median number of positive lymph nodes was 3 (range, 1–37), and the median LND was 18% (range, 3%–100%). The median largest size of the positive lymph nodes was 1.2 cm (range, 0.1– 8.0 cm). Table 1 shows the characteristics of patients stratified by the total number of lymph nodes removed. The mean number of removed lymph nodes was 10.0 in patients with ⬍15 lymph nodes removed and 26.6 in patients with ⱖ15 lymph nodes removed. The mean number of positive lymph node was significantly higher in patients with ⱖ15 lymph nodes removed than in patients with ⬍15 lymph nodes removed
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(6.0 vs. 2.6, P ⬍ 0.001). These 2 subgroups, however, did not differ significantly in pN status or mean LND (29.2% vs. 22.3%, P ⫽ 0.076). A total of 70 (53.9%) patients died after a median time of 13 months (range, 3–142 months). The 1-year, 2-year, and 5-year DSS rates were 79.0%, 57.3%, and 38.5%, respectively. Median DSS time did not differ significantly between 2 subgroups (33 months vs. 40 months, P ⫽ 0.827). The univariate and multivariate Cox regression analyses of variables predicting DSS in the entire cohort are summarized in Table 2. Using an 18% cutoff point for LND, the pN status (P ⬍ 0.001), the number of positive lymph nodes (P ⫽ 0.002), LND (P ⬍ 0.001), extracapsular extension (P ⫽ 0.009), and the use of adjuvant chemotherapy (P ⫽ 0.006) were significant predictors of DSS on univariate analysis. Kaplan-Meier curves for DSS according to pN status and LND showed statistically significant differences (Fig. 1). Multivariate analysis showed that LND (HR ⫽ 2.28, 1.04 –5.03, P ⫽ 0.041) and the use of adjuvant chemotherapy (HR ⫽ 2.68, 1.42–5.06, P ⫽ 0.002) were significant predictors of DSS. Table 2 also shows univariate and multivariate Cox regression analyses of variables predicting DSS according to the number of lymph nodes removed. In patients with ⬍15 lymph nodes removed, the pN status (P ⫽ 0.005), the number of positive lymph nodes (P ⫽ 0.001), LND (P ⫽
Table 1 Patient characteristics stratified by the number of lymph nodes removed
No. patients (%) No. sex (%) Male Female Mean age ⫾ SD (median, range) No. grade (%) 2 3 No. soft tissue surgical margin status (%) Positive Negative No. pathological primary tumor status (%) Organ confined Extravesical No. pathological nodal status (%) 1 2 3 Mean positive lymph nodes ⫾ SD (median, range) Mean lymph node removed ⫾ SD (median, range) Mean % LND ⫾ SD (median, range) No. extracapsular extension (%) Yes No Unknown No. adjuvant chemotherapy (%) Yes No Median disease-specific survival (months)
Totals
⬍15 Lymph nodes removed
ⱖ15 Lymph nodes removed
130
65 (50.0)
65 (50.0)
116 (89.2) 14 (10.8) 61.8 ⫾ 9.9 (63, 37–80)
60 (92.3) 5 (7.7) 61.0 ⫾ 9.9 (62, 37–80)
56 (86.2) 9 (13.8) 62.5 ⫾ 9.9 (64, 42–79)
5 (3.9) 125 (96.1)
3 (4.6) 62 (95.4)
2 (3.1) 63 (96.9)
3 (2.3) 127 (97.7)
1 (1.5) 64 (98.5)
2 (3.1) 63 (96.9)
27 (20.8) 103 (79.2)
12 (18.5) 53 (81.5)
15 (23.1) 50 (76.9)
45 (34.6) 84 (64.6) 1 (0.8) 4.3 ⫾ 5.3 (3, 1–37) 18.3 ⫾ 12.4 (15, 1–94) 25.8 ⫾ 22.2 (18, 3–100)
24 (36.9) 41 (63.1) 0 2.6 ⫾ 1.9 (2, 1–8) 10.0 ⫾ 3.4 (11, 1–14) 29.2 ⫾ 22.7 (21.0, 7–100)
21 (32.3) 43 (66.2) 1 (1.5) 6.0 ⫾ 6.9 (3, 1–37) 26.6 ⫾ 12.7 (23, 15–94) 22.3 ⫾ 21.4 (14, 3–82)
39 (30.0) 66 (50.8) 25 (19.2)
18 (27.7) 30 (46.2) 17 (26.1)
21 (32.3) 36 (55.4) 8 (12.3)
88 (67.7) 42 (32.3) 33
46 (70.8) 19 (29.2) 33
42 (64.6) 23 (35.4) 40
P value 0.258
0.381 0.648
0.559
0.517
0.536
⬍0.001 ⬍0.001 0.076 0.945
0.453
0.827
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Table 2 Univariate and multivariate analyses of variables predicting disease-specific survival according to the number of lymph nodes removed Variables
Entire cohort Primary tumor status (T3-4 vs. T1-2) Pathologic N stage (N2-3 vs. N1) No. positive lymph nodes (continuous variable) Lymph node density (⬎18% vs. 0%–18%) Extracapsular extension (yes vs. no) Adjuvant chemotherapy (no vs. yes) Less than 15 lymph nodes removed Primary tumor status (T3-4 vs. T1-2) Pathologic N stage (N2-3 vs. N1) No. positive lymph nodes (continuous variable) Lymph node density (⬎18% vs. 0%–18%) Extracapsular extension (yes vs. no) Adjuvant chemotherapy (no vs. yes) 15 or more lymph nodes removed Primary tumor status (T3-4 vs. T1-2) Pathologic N stage (N2-3 vs. N1) No. positive lymph nodes (continuous variable) Lymph node density (⬎18% vs. 0%–18%) Extracapsular extension (yes vs. no) Adjuvant chemotherapy (no vs. yes)
Univariate
Multivariate
Hazard ratio
95% CI
P value
Hazard ratio
95% CI
0.93 2.89 1.05 2.77 2.06 2.02
0.54–1.61 1.62–5.16 1.02–1.09 1.70–4.52 1.20–3.54 1.23–3.31
0.804 ⬍0.001 0.002 ⬍0.001 0.009 0.006
1.00 1.78 1.03 2.28 1.28 2.68
0.49–2.02 0.71–4.49 0.98–1.08 1.04–5.03 0.69–2.40 1.42–5.06
0.95 3.04 2.67 1.24 1.83 3.41
0.42–2.18 1.41–6.58 1.47–4.85 1.05–1.46 0.82–4.10 1.72–6.76
0.909 0.005 0.001 0.013 0.143 ⬍0.001
1.66 5.19 1.05 0.94 0.66 6.23
0.49–5.63 1.24–21.75 0.71–1.54 0.26–3.39 0.22–1.98 2.32–16.73
0.416 0.024 0.811 0.930 0.456 ⬍0.001
0.88 2.93 1.05 3.20 2.02 1.14
0.42–1.86 1.20–7.13 1.01–1.09 1.58–6.48 0.97–4.21 0.55–2.40
0.741 0.018 0.010 0.001 0.059 0.715
0.77 1.10 1.00 4.08 1.66 1.79
0.31–1.89 0.25–4.80 0.95–1.06 1.10–15.10 0.73–3.78 0.69–4.64
0.566 0.895 0.916 0.036 0.227 0.233
0.013), and the use of adjuvant chemotherapy (P ⬍ 0.001) were significant predictors of DSS on univariate analysis. Multivariate analysis showed that in this subgroup, pN status remained an independent predictor of DSS after controlling for all other variables (HR ⫽ 5.19, 1.24 –21.75, P ⫽ 0.024). In patients with ⱖ15 lymph nodes removed, pN status was not predictive of DSS. However, univariate and multivariate analyses showed that LND was a unique predictor of DSS (HR ⫽ 4.08, 1.10 –15.10, P ⫽ 0.036).
P value 0.995 0.219 0.247 0.041 0.437 0.002
4. Discussion The 5-year DSS rate in our patients, 38.5%, was similar to the 30%–37% 5-year disease-specific or overall survival rates reported in patients with positive nodes following radical cystectomy and pelvic lymphadenectomy [6,8]. Although it is unclear if the removal of more lymph nodes might be associated with a survival advantage in patients with lymph node-
Fig. 1. Kaplan-Meier survival curves for the entire cohort stratified by (A) 2002 TNM classification of pathologic nodal status and (B) lymph node density. (Color version of figure is available online.)
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positive disease, we observed that survival did not differ significantly in node-positive patients with ⬍15 or those with ⱖ15 lymph nodes removed [5– 8,10,16 –18]. In patients with nodal metastases at the time of radical cystectomy with pelvic lymphadenectomy, risk stratification is based on the 2002 TNM classification system. However, the ability of this nodal staging system to predict DSS has been found to vary. For example, significant differences in DSS were observed among pN1, pN2, and pN3 patients, indicating that the TNM lymph node classification system was an independent predictor of death from bladder cancer [2]. Other studies, however, did not find significant differences in recurrence-free survival and DSS rates between pN1 and pN2 subgroups [3,4]. Following the design of the ratio-based lymph node staging system (the ratio of positive to total number of lymph nodes) [5], LND was reported to be a superior indicator of nodal burden because the absolute number of positive lymph nodes is affected by the total number of nodes removed [6]. This concept, which reflects the burden of regional metastasis in relation to the extent and quality of lymph node dissection, is considered to be an attractive and promising predictor. Studies validating the prognostic value of LND have suggested that LND may be superior to TNM nodal status in predicting DSS for patients with lymph node-positive disease after radical cystectomy [5– 8]. However, another study found that although LND had a significant impact on survival in univariate analysis, this significance was not maintained in multivariate analysis [18]. Although there is increasing evidence to support more extended lymphadenectomy in patients undergoing radical cystectomy, many patients undergoing radical cystectomy for bladder cancer are not receiving adequate lymph node dissection owing to time constraints (an extended node dissection requires approximately 60 additional minutes to complete) and the need for advanced surgical skill; therefore, relatively few lymph nodes are removed [19,20]. We therefore hypothesized that TNM pN status and LND may be affected by the total number of lymph nodes removed because in node-positive patients with a small number of lymph nodes removed the greatest diameter of a positive lymph node may be more important than the total number of lymph nodes. In this context, we analyzed the prognostic impact of various pathologic variables, including TNM pN status and LND, on DSS in node-positive patients relative to the number of lymph nodes removed during radical cystectomy with pelvic lymphadenectomy. We found that LND was a predictor of DSS in our entire cohort, although TNM pN status and LND were analyzed jointly in multivariate analysis. These findings were in agreement with those of a previous report in which LND was shown to be superior to TNM pN status in nodepositive bladder cancer [8]. Although the predictive value of TNM pN status remains controversial, we found that this factor did not show prognostic significance [5– 8].
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It is difficult to directly compare our results with those of previous reports, owing to discrepancies that might result from differences in patient characteristics. First, patient distribution by pN status differed among various studies. In our study, only 1 patient had pN3 disease; this finding is similar to that of a previous report [3], but much lower than that of another large study in which 17% of patients had pN3 disease [8]. Second, the median number of lymph nodes removed in our study was 15, compared with 12 to 30 in other studies of node-positive patients following radical cystectomy [3,4,6,8,18]. Finally, there were differences in the proportions of patients who received adjuvant chemotherapy, which may have altered the effect of TNM pN status and LND on survival. In our study, 67.7% of patients received adjuvant chemotherapy, much higher than the 26.6% to 27.9% reported in other studies [3,8]. This was supported by findings showing that adjuvant chemotherapy had beneficial effects only in node-positive patients, especially those with pN2 disease [21]. Therefore, differences in percentages of patients who received adjuvant chemotherapy may lead to discrepancies in the prognostic value of pN status and LND in node-positive patients. We further investigated whether the number of lymph nodes removed affected the prognostic value of pN status and LND. A subgroup analysis showed that TNM pN status was superior to LND in patients from whom ⬍15 lymph nodes had been removed. In patients with ⱖ15 lymph nodes removed, however, only LND was an independent predictor of survival. Thus, TNM pN status may be a more useful predictor in node-positive patients with a small number of lymph nodes removed. The National Cancer Institute’s SEER database showed that only 26.2% of patients who underwent radical cystectomy had more than 16 lymph nodes removed [10]. Therefore, the prognostic value of current TNM pN status will be maintained in most centers in which limited lymph node dissection is routinely performed. However, in patients with a large number of lymph nodes removed during lymphadenectomy, LND may be more helpful in stratifying patients who are candidates for adjuvant treatment in clinical trials. In addition to TNM pN status and LND, primary tumor stage has been shown to be an independent predictor of survival in node-positive patients [2,8,10,18]. We found, however, no survival differences between patients with organ-confined and extravesical diseases. These findings were similar to the results of other studies in which primary tumor stage was not an independent prognostic factor of DSS in node-positive patients [3,4]. Because our data were collected retrospectively, selection criteria for patients undergoing lymphadenectomy of various extents and adjuvant chemotherapy may lead to selection bias. Thus, prospective trials are needed to determine the prognostic significance of LND and TNM pN status in node-positive patients treated with radical cystectomy for bladder cancer according to the number of lymph nodes removed.
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5. Conclusions We have shown here that LND was an independent predictor of DSS in node-positive patients during radical cystectomy for bladder cancer. However, in node-positive patients from whom a small number of lymph nodes had been removed, TNM pN status was superior to LND. Our results suggest that abilities of TNM pN status and LND in node-positive patients to predict DSS could be affected by the total number of lymph nodes removed.
[9]
[10]
[11] [12] [13]
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