Takashige Abe md phd, Department of Urology, Hokkaido University Graduate School of Medicine, North-15, West-7, North Ward, Sapporo 060-8638, Japan. Email: email@example.com
Objectives: To evaluate the prognostic role of different clinico-pathological parameters in node-positive patients treated by radical cystectomy.
Methods: A retrospective multi-institutional study of 435 patients who underwent radical cystectomy between 1990 and 2005 was carried out. Of them, pathological lymph node (LN) metastases were found in 83 patients. Sixty of these 83 patients, whose clinical information and follow-up data were available, were included in the analysis. Twenty-five patients had undergone adjuvant chemotherapy, whereas 35 had not. A Cox proportional hazards model was used to determine the impact of the following clinico-pathological parameters on patient survival: number of resected LNs, number of positive LNs, LN density (defined as the ratio of the number of positive LNs divided by the total number of resected LNs) and adjuvant chemotherapy.
Results: Median follow-up for surviving patients was 41 months (range 4–138) after surgery. The median survival time for all patients was 22 months (95% confidence interval, 15–42 months). At multivariate analysis, LN density of 25% or less, adjuvant chemotherapy and pure urothelial carcinoma were independently significant predictors of survival.
Conclusions: Lymph node density predicts survival in patients with node-positive bladder cancer.
Radical cystectomy has been the standard treatment of high grade, invasive bladder cancer and it has been well accepted that pelvic lymph node (LN) dissection is an important component of radical cystectomy. Adequate regional LNs resection and subsequent pathologic evaluation facilitates postoperative risk stratification because the presence of LN metastasis is the most powerful prognostic factor.
Recent studies have demonstrated that the number of LNs as well as that of positive nodes has a significant impact on disease-specific survival in node-positive patients.1–4 In addition, several studies from individual academic institutions have showed that the new concept of lymph node density (LND), a ratio of the number of positive LNs divided by the total number of LNs resected could better stratify patients with node-positive bladder cancer than the number of positive LNs.4–8 In the present study, we collected clinical data from one academic institution and four community hospitals and re-evaluated the prognostic significance of LN-related parameters in node-positive patients and in the context of adjuvant chemotherapy.
A retrospective multi-institutional study of 435 patients who underwent radical cystectomy for refractory superficial or muscle-invasive bladder cancer between 1990 and 2005 was carried out (Hokkaido University Hospital [n = 122], Hospital A [n = 148], Hospital B [n = 59], Hospital C [n = 55] and Hospital D [n = 51]). Of these patients, 83 (19%) had nodal metastasis. Exclusion criteria in the present study were patients with neoadjuvant chemotherapy (n = 3), either previous or synchronous upper urinary tract cancer (n = 4), distant metastasis (n = 1), pure non-urothelial carcinoma (n = 2) or missing data (n = 11). Additional two patients were excluded because they underwent unilateral endopelvic lymphadenectomy. Finally, a total of 60 patients were included in the present study.
All patients underwent a standard surgical procedure, including bilateral endopelvic lymphadenectomy with radical cystectomy and urinary diversion. The extent of staging LN dissection was limited below the bifurcation of common iliac vessels in almost all of the patients, whereas a few patients underwent lymphadenectomy above the iliac bifurcation. Whether adjuvant chemotherapy was given or not depended on a consent decision between the surgeon and patient. In the present study, patients were considered as having received adjuvant chemotherapy if at least two courses of chemotherapeutic agents had been given.
All tumors were graded according to the World Health Organization (WHO) grading for urothelial carcinoma and staged according to TNM classification (TNM 1997) by different pathologists. The number and size of LNs were palpated and determined visually by pathologists. The LNs detected were embedded for histopathological evaluation. Survival time was analyzed from the date of surgery. After surgery, patients were followed with routine blood tests, a chest X-ray or chest CT scan and CT scan of the abdomen and pelvis every 3–6 months for the first 2–3 years and every 6–12 months thereafter. Bone scans were carried out if symptoms were present. The endpoints of univariate and multivariate analyses were overall survival. Survival curves were estimated by Kaplan–Meier methods and survival distributions were compared by log-rank test. The characteristics entered in the analyses were gender, age, histology, pathological tumor stage, tumor grade, pathological node status (pN), the number of LNs resected, that of positive nodes, LND, lymphovascular invasion and adjuvant chemotherapy. Age, the number of LNs resected and that of positive nodes were analyzed as categorical variables based on the median values. As for LND, we selected 20% and 25% as the cutoff point with reference to the previous reports.4–8 Multivariate analyses were carried out for variables that were identified as significant on univariate analyses, using a Cox proportional hazards model. All calculations were carried out on commercially available software (Statview 5.0, SAS Institute, Cary, NC, USA). P-values <0.05 were considered significant.
Table 1 lists the clinical characteristics of the patient population. Median patient age was 68 years. Median follow-up of surviving patients was 41.0 months (range 4–138). Of 60 patients, 25 received adjuvant chemotherapy. Two to four cycles of conventional cisplatin-based regimens were given to the majority of patients, as shown in Table 1. The median number of LNs removed was 12.0 (range 1–80; mean ± SD 13.4 ± 11.2) and it varied among the institutions (Hokkaido University Hospital – median of 15 nodes [range 4–80; mean ± SD 19.2 ± 15.9], Hospital A – median of 11 [range 1–23; mean ± SD 11.7 ± 7.3], Hospital B – median of 9.5 [range 5–9; mean ± SD 9.5 ± 6.4], Hospital C – median of 9 [range 6–19; mean ± SD 11.1 ± 5.1] and Hospital D – median of 7 [range 3–12; mean ± SD 7.1 ± 2.7]). The median number of positive nodes was 2 (range 1–12) and the median percentage of LND was 23.1% (range 1.25–100%), respectively.
Table 1. Characteristics of patients with lymph node metastases after radical cystectomy
n = 60
LNs, lymph nodes.
Median age (range)
Pure urothelial carcinoma
No. pathological tumor stage
No. tumor grade
No. pathological node stage
No. LNs resected (range)
Median 12.0 (1–80)
No. positive nodes
Median 2.0 (1–12)
Lymph node density (%)
Median 23.1 (1.25–100)
Adjuvant chemotherapy regimens used in the current series
Two to four cycles of MVAC (methotrexate, vinblastine, adriamycin, cisplatin)
Two or three cycles of MEC (methotrexate, etoposide, cisplatin)
Two cycles of paclitaxel+carboplatin
Two cycles of 5-fluorouracil+cisplatin
Figure 1 represents the Kaplan–Meier estimates of overall survival for all patients. The median survival time for all patients was 22 months (95% confidence interval, 15–42 months). Eleven factors were subjected to univariate analyses for prognostic significance (Table 2). Histology, the number of positive LNs, LND and adjuvant chemotherapy were significant factors for overall survival. To determine what was an independent prognostic factor, a multivariate analysis was carried out. Pure urothelial carcinoma, LND of 25% or less and adjuvant chemotherapy were independently significant predictors of prolonged survival (Table 3). When we selected 20% as a cutoff point of LND, the P-value became larger (P = 0.0366) although these three characteristics were independently significant for prolonged survival (data not shown).
Table 2. Results of univariate analysis
Median survival, month (95% CI)
CI, confidence interval; LNs, lymph nodes.
38 (17 not reached)
Pure urothelial carcinoma
35 (8 not reached)
Pathological node status
38 (18 not reached)
No. LNs resected
42 (17 not reached)
No. positive nodes
35 (18 not reached)
Lymph node density
51 (22 not reached)
56 (21 not reached)
35 (8 not reached)
Table 3. Results of multivariate analysis
Hazard ratio (95% CI)
CI, confidence interval.
Pure urothelial carcinoma
No. positive nodes
Lymph node density
Figure 2a shows the Kaplan–Meier survival curve by LND of 25%. Overall survival at 5 years for the patients with LND ≤ 25% was 39.6%, whereas that for the patients with LND > 25% was 10.3%. Figure 2b shows the Kaplan–Meier survival curve by adjuvant chemotherapy. Overall survival at 5 years for the patients receiving adjuvant chemotherapy was 52.4%, whereas that for the patients not receiving chemotherapy was 9.9%. To clarify the patients group for whom adjuvant chemotherapy would be most beneficial, we sub-classified the patients with regard to LND or the number of positive nodes. The effect of adjuvant chemotherapy was most apparent in patients with one to two positive nodes. In this group, patients receiving adjuvant chemotherapy had a 5-year overall survival rate of 75%, while the patients not receiving adjuvant chemotherapy had that of 16.3% (P = 0.0042).
The present multi-institutional study supports the relevance of LND as a prognostic parameter and also suggests the benefit of adjuvant chemotherapy in patients with node-positive disease following radical cystectomy.
The relationship of survival with the number of LNs resected or positive LNs has been the subject of several reports. For example, Leissner showed in a univariate analysis that bladder cancer patients with ≥16 LNs removed had a significantly superior tumor-specific survival rate and disease-free interval than those with ≤15 LNs removed.9 Herr et al. also showed that the number of LNs removed had an impact on local recurrence and survival for LN-positive as well as LN-negative patients, and suggested that at least nine LNs be excised.1 In addition, recent reports emphasized the importance of extended lymphadenectomy, with the cephalad extent that includes the common iliac lymph nodes, as well as removal of those in the presacral area.10,11 Although the appropriate level of proximal LNs dissection at radical cystectomy has not been determined, Steven et al. reported that 64 (19%) of 336 patients had LN metastases of whom 22 (34.4%) had LN involvement above the bifurcation of the common iliac vessels outside the template of the standard LN dissection. In addition, they reported that the overall 5-year survival rates were similar in patients with LN involvement above the bifurcation of the common iliac vessels (37%) compared with the entire population with LN metastasis (41%) and to those with lymphatic metastases in the true pelvis below the bifurcation of the common iliac vessels (42%), carrying out extended LN dissection from an area bounded proximally 1–2 cm above the bifurcation of the aorta.12 As for the number of positive nodes, many studies have shown that this parameter affects survival. In the present study, neither the number of positive nodes nor the total number of LNs resected was associated with overall survival on multivariate analysis, although the number of positive nodes was significant on univariate analysis. However, when these two factors were conjoined and represented as LND, there was a significant association with overall-survival on multivariate analysis. Overall survival at 5 years for patients with LND ≤ 25% was 39.6%, whereas that for patients with LND > 25% was 10.3% (P = 0.0012), consistent with the findings reported from M. D. Anderson Cancer Center that patients with LND ≤ 25% had a 5-year overall survival rate of 37.4% compared with 18.7% in those with LND > 25%.7 Although the usefulness of LND was supported in several studies including our results,4–8 Herr pointed out some caveats before routine clinical use of LND.13 For example, he indicated the lack of a universal standard template for nodal dissection at the time of cystectomy and the need of prospective validation of LND. It would also be necessary to determine the most predictive cutoff-point. In the present study, 25% was better to stratify the patients than 20% on multivariate analysis. Because LND is an attractive prognostic parameter, prospective validation using multi-institutional patient datasets is warranted.
Although the available trials provide insufficient evidence to support the routine use of adjuvant chemotherapy,14,15 several retrospective studies have shown a benefit of adjuvant chemotherapy in patients with node-positive disease.4,7,16–20 Our series also supported a benefit of adjuvant chemotherapy in patients with node-positive disease, although our observation was biased due to a lack of prospective criteria for adjuvant chemotherapy. In the present study, we found that the effect of chemotherapy was most apparent in patients with one to two positive nodes, which was similar to the observation by Stockle et al.17 A possible explanation is that chemotherapy could eradicate residual cancer cells in the setting of minimal tumor burden. However, Park et al. reported the contradictory result that the effect of chemotherapy was limited to those with pN2.18 Regarding this observation, Park et al. commented that in node-positive patients with minimal nodal disease burden (N1) surgery would be sufficient to eradicate the tumor burden, resulting in the absence of a survival benefit of adjuvant chemotherapy. At present, three large cooperative phase 3 studies are ongoing. Two of these compare surgery plus adjuvant chemotherapy versus chemotherapy at the time of disease recurrence (Italian Multicentric Study and European Organization for Research and Treatment of Cancer/Southwest Oncologic Group); the other study (Spanish Oncologic Genito-Urinary Group) compares surgery plus adjuvant chemotherapy versus surgery alone. The results from these studies could clarify the exact role of adjuvant chemotherapy and facilitate the identification of patients who can benefit from this approach.21
Finally, we found that patients with pure urothelial carcinoma had a better survival benefit than mixed pathology in a multivariate model. Although it is known that high-grade urothelial carcinoma is often associated with a squamous cell carcinoma component or adenocarcinoma component, we could not find any report consistent with our observation.
Limitation of this study includes its retrospective design, small patient population and absence of data on patient performance status. In addition, the surgeons and pathologists were different at every institution. However, even with these limitations our findings show that LND is a useful prognostic parameter for node-positive patients.
Our study supported the significant influence of LND on survival in patients with node-positive bladder cancer.