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Keywords:

  • bladder cancer;
  • pathologic staging;
  • overall survival;
  • disease-specific survival;
  • recurrence-free survival

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

BACKGROUND:

The radical cystectomy experience at Vanderbilt University Medical Center was scrutinized to determine whether there was a difference in survival between patients with lymph node-negative pathologic T3a versus pathologic T3b urothelial carcinoma of the bladder.

METHODS:

Pathologic and clinical data were reviewed on patients who underwent radical cystectomy for urothelial carcinoma between 1995 and 2005. We excluded patients with nontransitional cell cancer, lymph node disease, or with unknown lymph node status. Of the 790 reviewed patients, 75 patients (9.4%) were diagnosed with pathologic T3 urothelial cancer of the bladder. The impact of pathologic substaging (pT3a vs pT3b) was examined to determine the effect on overall, disease-specific, and recurrence-free survival.

RESULTS:

The mean age was 68.6 years (36 years to 83 years). Median overall follow-up was 25.3 months (1.13 months to 130.17 months). Median follow-up for patients alive at last follow-up was 55.9 months (25.3 months to 130.2 months). Actuarial overall survival at 5 years was 29.5% for pT3a and 29.3% for pT3b (P = .79). Actuarial disease-specific survival at 5 years was 54.1% for pT3a and 42.4% for pT3b (P = .21). Actuarial recurrence-free survival at 5 years was 68.1% for pT3a and 71.9% for pT3b (P = .53).

CONCLUSIONS:

There were no significant differences in overall, disease-specific, or recurrence-free survival when comparing lymph node-negative pT3a versus pT3b urothelial cancer of the bladder following radical cystectomy. Simplification of pathologic staging for urothelial carcinoma of the bladder should be considered at future revisions of the American Joint Committee on Cancer staging system. Cancer 2009. © 2009 American Cancer Society.

Urothelial carcinoma of the bladder is a common cause of morbidity and mortality with an incidence of 68,810 new cases and 14,100 cancer-related deaths in the United States annually.1 Clinical and pathologic staging of the patient often guide treatment options. Patients found to have muscle invasive or high grade nonmuscle invasive bladder cancer are frequently managed with radical cystectomy. The final pathologic specimen is then reviewed and often staged using the American Joint Committee on Cancer (AJCC) staging system.2

The goals of the AJCC staging system are to assist in the selection of primary and adjuvant therapy, estimate prognosis, assist in the evaluation of the results of treatment, facilitate the exchange of information among treatment centers, and to continue investigation of human cancer.2 Thus, the staging system assists urologists in evaluating, treating, and counseling patients with bladder cancer.

The pathologic tumor stage (pT) and lymph node status (pN) are important components of the AJCC staging system. The TNM staging system for bladder cancer was last modified by the AJCC in 1997, separating tumors that have extended beyond the bladder but not into contiguous organs into pT3a (microscopic) or pT3b (macroscopic). Before this revision, extravesical tumor extension was as a whole defined as pT3b.

The correlation of pathologic staging of transitional cell cancer of the bladder to clinical outcomes have been well documented in contemporary cystectomy series with tumor stage being clearly established as one of the most important predictors of cancer-specific and overall survival after radical cystectomy for bladder cancer.3-6 There have been few studies that have directly assessed the pathologic substages of the revised TNM staging system to determine clinical outcomes.7-9 We reviewed our radical cystectomy experience at Vanderbilt University Medical Center (VUMC) to determine whether there was a difference in survival when comparing lymph node-negative pathologic T3a versus T3b urothelial carcinoma of the bladder.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Patients

Informed consent was obtained from all subjects and the review was performed with the approval from the Institutional Review Board at VUMC.

Since February 1995, clinical and pathologic information on patients having undergone cystectomy was entered into an established prospective cystectomy database. A total of 790 patients who underwent radical cystectomy and pelvic lymphadenectomy at VUMC from February 1995 to July 2005 had data available for analysis. The indications for radical cystectomy included invasion of the muscularis propia, prostatic stroma, or high grade Ta or T1 bladder cancer refractory to transurethral resection and intravesical therapy. In all cases, the upper limit of the lymphadenectomy consisted, at a minimum, of a dissection to the level of the bifurcation of the common iliac artery. The maximum upper extent of dissection was at the level of the IMA. The precise limits were highly variable across surgeon and time period and were at the discretion of the operating surgeon. A total of 206 (26%) patients were found to have pT3 urothelial carcinoma at final pathology. Individuals who were excluded from analysis included patients with nontransitional cell bladder cancers, unknown follow-up status, unknown lymph node status, or positive lymph nodes on pathologic examination. We focused our analysis on the remaining 75 patients found to have lymph node-negative pT3a and pT3b transitional cell cancer of the bladder on final pathologic analysis.

Follow-up

Follow-up intervals were determined by the operating surgeon. In general, patients were seen every quarter for the first year, semiannually for the second year, and annually thereafter. A physical examination, urine cytology, and serum chemistry with liver function tests and alkaline phosphatase occurred at each visit or when clinically indicated. Upper tract imaging (computerized tomography, intravenous pyelogram, or renal ultrasound) along with a chest x-ray was performed routinely or when clinically indicated. The median overall follow-up was 25.3 months (1.13 months to 130.17 months). Median follow-up for patients alive at last follow-up was 55.9 months (25.3 months to 130.2 months). In all patients with pT3 disease, the option of adjuvant chemotherapy was discussed and patients were offered consultation with a medical oncologist. The final decision regarding adjuvant chemotherapy usage was left to the discretion of the medical oncologist in discussion with the patient.

Clinical Outcomes

Clinical outcomes were determined from the electronic hospital chart and physician records. Clinical outcomes were measured from the date of cystectomy to the date of first documented clinical recurrence, the date of death, or the last follow-up date if the patient had not experienced a clinical recurrence or death. Recurrences were categorized into local (within the pelvis), distant (metastatic disease outside of the pelvis), or both. The cause of death was determined by chart review, information from our institution's cancer registry, and/or the death certificate in cases in which the patient was deceased. Overall survival, recurrence-free survival, and disease-specific survival was calculated using these data.

Statistical Analysis

The Student t test (for parametric continuous variables) or the Chi-square or Fisher exact test (for nominal variables) was used for all comparisons between the pT3a and pT3b groups. Overall, disease-specific, and recurrence-free survival was estimated using Kaplan-Meier plots. The log rank test was used to compare each pathologic subgroup. Commercially available software (StatView, Cary, NC) was used for all statistical analysis.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Seventy-five patients were found to have lymph node-negative pathologic T3 (pT3a and pT3b) urothelial carcinoma of the bladder. The pT3 group consisted of 46 patients (61.3%) with pT3a and 29 patients (38.7%) with pT3b disease. The 2 groups were comparable to regards to age, race, sex, pathologic grade, and the proportion of patients who received neoadjuvant chemotherapy, preoperative intravesical therapy, and postoperative chemotherapy (Table 1).

Table 1. Clinical and Pathologic Characteristics in 75 Patients Who Underwent Radical Cystectomy With Bilateral Lymphadenectomy for pT3a and pT3b Transitional Cell Cancer of the Bladder
CharacteristicspT3apT3bP
  1. BCG indicates Bacillus Calmotte-Guerin.

ClinicalNo. (%)No. (%) 
 No. of patients46 (61.3)29 (38.7) 
 Sex   
  Male39 (84.8)22 (75.9).33
  Female7 (15.2)7 (24.1) 
 Age, mean68.71 [range, 66 to 81]68.44 [range, 50 to 81].90
 Race   
  Caucasian45 (97.8)26 (89.7).29
  African American0 (0)3 (10.3) 
  Unknown1 (2.2)0 (0) 
 Neoadjuvant systemic chemotherapy administered2 (4.4)2 (6.9).64
 Preoperative BCG administered7 (15.28)2 (6.9).47
 Preoperative mitomycin administered1 (2.2)0 (0).99
Pathologic   
 Final tumor grade   
  Grade 23 (6.5)2 (6.9).99
  Grade 343 (93.5)27 (93.1) 
 Postoperative systemic chemotherapy administered2 (4.5)4 (13.8).21

In the pT3a group, 14 recurrences (4 local, 9 distant, and 1 with both) were noted, whereas 6 recurrences (3 local and 3 distant) were noted in patients with pT3b (Table 2). Actuarial estimated overall, disease specific, and recurrence free survival for all patients with pT3 disease at 5 years was 33.1%, 49.7%, and 68.4%, respectively. Actuarial estimated overall survival at 5 years was 29.5 % for pT3a and 29.3% for pT3b (P = .79, see Fig. 1 and Table 3). Actuarial estimated disease-specific survival at 5 years was 54.1% for pT3a and 42.4% for pT3b (P = .21, see Fig. 2 and Table 3). Actuarial estimated recurrence-free survival at 5 years was 68.1% for pT3a and 71.9% for pT3b (P = .53, see Fig. 3 and Table 3). No significant difference was noted in estimated overall, disease-specific, or recurrence-free survival between pT3a and pT3b.

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Figure 1. Overall survival compares pT3a versus pT3b.

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Figure 2. Disease-specific survival compares pT3a versus pT3b.

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Figure 3. Recurrence-free survival compares pT3a versus pT3b.

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Table 2. Recurrences Noted in the 75 Patients Who Underwent Radical Cystectomy With Bilateral Lymphadenectomy for pT3a and pT3b Transitional Cell Cancer of the Bladder
Type of RecurrencepT3apT3b
Recurrences (total)14 (30.4%)6 (20.7%)
Local recurrences4 (8.6%)3 (10.3%)
Distal recurrences9 (19.6%)3 (10.3%)
Both local and distal recurrence1 (2.2%)0 (0%)
Table 3. Actuarial Estimated Overall, Disease-Specific, and Recurrence-Free Survival at 5 Years in the 75 Patients Who Underwent Radical Cystectomy With Bilateral Lymphadenectomy for pT3a and pT3b Transitional Cell Cancer of the Bladder
SurvivalpT3apT3bP
Overall survival29.5 %29.3%.79
Disease-specific survival54.1%42.4%.21
Recurrence-free survival68.1%71.9%.53

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Our series demonstrates the survival outcomes of a contemporary cohort of patients treated with radical cystectomy and pelvic lymphadenectomy for urothelial cancer of the bladder. We focused our analysis on comparing the outcomes between specific substages of the AJCC staging system, that is, lymph node-negative pathologic T3 (pT3a vs pT3b). Patients with lymph node-negative extravesical disease (microscopic vs macroscopic) were found to have no significant difference in estimated overall, disease-specific, or recurrence-free survival when comparing pT3a with pT3b.

Quek et al demonstrated no difference in the incidence of lymph node involvement or disease recurrence when comparing pT3a and pT3b disease at their institution, also bringing into question the prognostic significance of the AJCC staging for this subset of patients.8, 9 Bastian et al compared patients with pT3a and pT3b disease to patients with pT2 disease. The study revealed that pT3a group had similar recurrence rates and mortality when compared with pT2 disease. There was no significant difference between the pT3 substages when lymph node status and other pathologic variables were accounted for.7

Our findings are consistent with these studies with a group of patients treated similarly. Microscopic or macroscopic extravesical extension of tumor alone does not appear to have significant impact on patient survival; however, this topic has yet to be thoroughly explored as there have been few direct comparisons of these pathologic substages since the revision to the TNM staging in 1997.

Prior studies raised concerns for comparing survival outcomes for patients with pT3 disease who had received systemic chemotherapy, postulating that patients with pT3b cancer would preferentially receive adjuvant or neoadjuvant chemotherapy.7 In our study, the number of patients receiving systemic therapy (neoadjuvant or adjuvant) was small and equally represented between the substages; hence, they were included for review. Quek et al and Dalbagni et al included patients receiving systemic therapy into their reviews, whereas Bastian et al excluded these patients due to a concern for a potential impact on survival.7

Estimation of patient prognosis is one of the main stated goals of the AJCC staging system.2 Future revisions of the American Joint Committee on Cancer staging system may consider simplification of the current pathologic staging system by consolidating pT3a and pT3b into 1 stage, pT3. This potential revision could allow easier comparisons across studies in the literature and also allow us to better counsel our patients in the postoperative setting. It is our hope that this change would assist in better predicting patient prognosis.

The study is limited to a retrospective analysis of data that did depend on a combination of the cancer registry, the electronic medical record, and death certificates. Ten patients who received neoadjuvant and postoperative adjuvant chemotherapy were included in our analysis possibly impacting disease-specific and recurrence-free survival. We excluded patients with positive lymph nodes or unknown lymph node status, possibly creating a selection bias, as our focus was on pathologic staging of the tumor, and lymph node-positive status is addressed separately by the current AJCC staging system. This allowed us to have a more homogenous group of patients to compare, as positive lymph node status has worse prognostic implications.3-6 Although our series is relatively large, the lack of difference may be explained by a lack of power to determine a statistical difference in survival outcomes. In addition, there was not 1 dedicated pathologist or centralized pathology review. The pathologic distinction between microscopic and macroscopic disease was dependent on interpretation by the reviewing pathologist and could represent another factor explaining the lack of variance seen in survival rates.

Despite these limitations, this review represents 1 of only a small number of studies that have directly compared pT3a with pT3b. It is our hope that comparisons of pathologic substages of urothelial carcinoma of the bladder continue to be reviewed and that our findings are confirmed in other cystectomy series.

CONCLUSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

In this series, no significant difference in overall, disease-specific, and recurrence-free survival was determined when comparing lymph node-negative pT3a to pT3b urothelial cancer of the bladder following radical cystectomy. Future revisions of the American Joint Committee on Cancer staging may consider simplification of the pathologic staging system by consolidating these substages.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

The authors made no financial disclosures.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References