About 48% of all patients with bladder cancer undergoing radical cystectomy have a discrepancy between their clinical stage and pathologic stage, according to the largest study to date to examine this issue. Upstaging after surgery is associated with reduced survival, while downstaging after surgery was associated with improved survival only in patients with locally advanced disease. These findings were reported at the 2013 Genitourinary Cancers Symposium, held recently in Orlando.¹

Study Background

“Appropriate clinical staging is vital for preoperative risk stratification and selecting patients for neoadjuvant therapy or alternative therapies such as chemoradiotherapy. It is also important for clinical trial design and for cross-study comparisons. Unfortunately, few studies report outcomes by clinical stage, and several studies show a high rate of clinical-pathologic discrepancy in patients undergoing radical cystectomy for bladder cancer. We sought to investigate this discrepancy and its relationship to survival in bladder cancer patients undergoing radical cystectomy using a large national database,” explained presenting author Phillip Gray, MD, a third-year resident in the Harvard Radiation Oncology Program, Boston, who has been working with collaborators from the American Cancer Society and senior author Jason A. Efstathious, MD, DPhil, from Massachusetts General Hospital.

The study used the National Cancer Data Base to identify 16,953 patients with a new diagnosis of bladder cancer treated with radical cystectomy from 1998 to 2009. The survival analysis was limited to 7,270 of these patients for whom 5-year follow-up data were available.

Patients were typical of the national bladder cancer population undergoing radical cystectomy, Dr. Gray said. About 73% were male, 82% were Caucasian, and median age was 67 years. About 50% were treated at academic centers and 50% in community centers.

Clinical stage at diagnosis was as follows: T1, 16%; T2, 61%; T3, 13%; and T4, 7% (3% were stage Tis/Ta). Radical cystectomy alone was performed in 74%; 22% had adjuvant chemotherapy, and 4%, neoadjuvant chemotherapy.

Discrepancy Rates

Overall, the discrepancy rate was 47.8%; 41.9% were upstaged at surgery, whereas 5.9% were downstaged. Among the 80% of patients with muscle-invasive bladder cancer, only 5% were downstaged to non–muscle-invasive disease at surgery.

Clinical-pathologic discrepancy in nodal stage was less common; 93% of patients were node-negative at diagnosis; 19% of these patients were upstaged at surgery; 11% of clinically node-positive patients were downstaged to node-negative at the time of surgery.

“When comparing initial clinical stage to final pathologic stage, there was a reduction in the number of patients classified as stages I and II, a doubling of those classified as stage III, and a tripling of those falling into stage IV,” Dr. Gray said.

Factors associated with upstaging included female gender, advanced age, high tumor grade, nonurothelial histology, and more extensive lymphadenectomy. Downstaging was less likely to occur in the elderly, in Hispanics, and with squamous or adenocarcinoma histology. Receipt of neoadjuvant chemotherapy was the strongest predictor of downstaging.

Survival Analysis

In the survival analyses, upstaging was significantly associated with increased 5-year mortality for all clinical stages, whereas downstaging was associated with improved survival only in patients with locally advanced disease (clinical stages III and IV).

“In patients with pathologically positive lymph nodes, increasing T stage was still associated with worse survival regardless of the number of lymph nodes removed and examined at the time of surgery,” Dr. Gray said.

In a multivariate analysis using a Cox proportional hazard model, upstaging was associated with 80% excess mortality, whereas downstaging had no significant association with survival for the entire population. More extensive lymphadenectomy was associated with decreased 5-year mortality, as was receipt of care at a National Cancer Institute–designated cancer center. Receipt of neoadjuvant or adjuvant chemotherapy was associated with decreased overall survival; however, for neoadjuvant chemotherapy recipients, Dr. Gray explained, this may have been due to the inclusion of clinically node-positive patients being treated with palliative intent. When these same patients were removed from the analysis, this effect disappeared.

“This study shows that current clinical staging is inadequate, resulting in high rates of clinical-pathologic stage discrepancy. Pathologic upstaging is associated with an increased risk of death for all patients, while pathologic downstaging may only benefit those with more advanced disease,” Dr. Gray told listeners. ■

Disclosure: Drs. Gray and Efstathious reported no potential conflicts of interest.

Reference

1. Gray PJ, Fedewa SA, Shipley WU, et al: Clinical-pathologic stage discrepancy in patients with bladder cancer treated with radical cystectomy. 2013 Genitourinary Cancers Symposium. Abstract 248. Presented February 15, 2013.