Choosing Earlier Therapy for Muscle-Invasive Bladder Cancer

One of the most difficult clinical challenges urologists face is the management of superficial bladder cancer. Approximately 70% of patients who present with bladder cancer have tumors confined to the mucosa or submucosa, so-called superficial bladder cancers. These superficial bladder tumors represent a heterogeneous group of cancers with varying degrees of malignant potential. The overall treatment goals for superficial bladder cancer are twofold: 1) reducing tumor recurrence and the subsequent need for additional therapies (ie, cystoscopy, transurethral resection, and intravesical therapy) and the morbidity associated with these treatments, and 2) preventing tumor progression and the subsequent need for more aggressive therapy.

The administration of intravesical chemotherapy and/or immunotherapy is critical in accomplishing these treatment goals following transurethral resection (TUR) for superficial bladder cancer. However, despite the advent of improved intravesical therapies, there remains a group of patients with superficial bladder tumors that is at risk for disease progression, metastases, and even death from the disease. It is exactly this high-risk group of patients with superficial bladder cancer that may not respond to conservative therapy that we must be better able to identify and treat earlier with more aggressive therapy.

Prognosis of Muscle-Invasive Bladder Cancer: Difference between Primary and Progressive Tumours and Implications for Therapy

Schrier BP, Hollander MP, van Rhijn BWG, et al.

Eur Urol. 2004;45:292-296.

This important retrospective study compared and evaluated the clinical outcomes of patients with primary muscle-invasive bladder cancer and patients with progressive muscle-invasive bladder cancer. Patients with primary muscle-invasive bladder cancer were defined as those having no prior history of superficial disease, and patients with progressive muscle-invasive tumors were defined as those who had been treated previously for a history of superficial (non-muscle-invasive) bladder cancer and subsequently developed a muscle-invasive tumor.

A total of 163 patients were included in the study, 89 with primary muscle-invasive bladder tumors and 74 with a history of superficial disease and subsequent progression to muscle invasion. All patients with superficial disease in this study initially received at least 2 courses of intravesical bacillus Calmette-Guérin (BCG) therapy or maintenance BCG therapy. All patients with T2 or T3 disease underwent a cystectomy and an extended lymphadenectomy within 10 weeks of diagnosis. Systemic chemotherapy was offered to patients with T4 tumors and to those with nodal or metastatic disease. The baseline characteristics of the 2 cohorts were relatively similar, with a slightly older age group with progressive muscle invasion.

A significant difference was noted in the disease-specific survival between these 2 groups. The primary group had a significantly improved survival at 3 and 5 years compared to the progressive group; 67% and 55% versus 37% and 28%, respectively (P = .0015). Furthermore, in the subgroup analysis of T2 and T3 disease and node-positive disease, a similar finding was observed favoring patients with primary muscle-invasive tumors. In a multivariate analysis, the risk for disease-specific death in the primary group was about half that seen in the progressive group at all times during the follow-up.

Unfortunately, the authors do not provide pathologic data on the primary bladder tumor (p stage) or the regional lymph node status following cystectomy in these 2 groups of patients. The authors recognize that this retrospective study did not adhere to any standard treatment protocol. Despite these methodological issues, this study highlights the potential differences in the clinical outcomes of those patients who present with muscle-invasive tumors (initially) compared with those who have been treated for superficial bladder cancer and subsequently develop muscle-invasive bladder tumors.

Several important lessons can be gleaned from this study. First, the natural history of superficial bladder cancer is difficult to predict owing to tumor heterogeneity. The risks for tumor recurrence (70%) and tumor progression (15% to 20%) for superficial bladder cancer are related to multiple histopathologic factors, including tumor grade, depth of invasion (stage), multiplicity, tumor size, presence of vascular or lymphatic invasion, and presence of carcinoma in situ. Conventional histopathology (tumor grade and stage) has historically been, and continues to be, the most useful measure to provide some degree of prognostic stratification. Revisions by the World Health Organization/International Society of Urological Pathology Consensus Group of uropathologists have attempted to better delineate risk stratification as determined by conventional histopathology.¹ It has been suggested that actual depth of lamina propria (T1) invasion may be prognostic. In one series, progression was noted in 5% of T1a lesions (superficial lamina propria invasion) and approximately 50% of T1b tumors (deep lamina propria invasion).² Unfortunately, despite these contemporary histopathologic updates and modifications, these measures still fail to evaluate each bladder tumor’s true malignant potential. Such limitations have led to other research efforts to define more precisely a tumor's biological potential on a molecular level.^3,4 Numerous studies have explored the role and interactions of various tumor suppressor genes (eg, p53, Rb), cell cycle regulatory proteins, and substances involved in angiogenesis. Despite recent advances in molecular biology, the application of molecular markers in the treatment and management of superficial bladder cancer is not currently appropriate for clinical practice.

The importance of staging and treating patients with superficial bladder cancer with a properly performed TUR should not be underestimated. Transurethral resection should remove all gross, visible tumor. For proper staging, muscle should be seen on the specimen, particularly for bladder tumors with suspected invasion. Studies have shown the presence of residual tumor at the first follow-up cystoscopy in a significant number of patients with superficial bladder cancer,^5,6 suggesting the first resection is often not complete. Furthermore, it has been shown that in patients with T1 bladder cancers, nearly a quarter of the patients will have residual T1 disease found on re-resection, with 3% upstaged to muscle invasion.⁷ Other authors have also shown that a significant number of patients treated with TUR for superficially invasive tumors had no muscle submitted or identified in the resection.⁸ In a recent pathologic review of superficial bladder cancers treated with endoscopic resection, muscularis propria was missing in more than half of TUR specimens submitted by the urologists.⁹ It seems that if a complete resection is not performed (with inclusion of muscle in the specimen), there may be a significant incidence of understaging, with potential early tumor recurrence and stage progression in these patients.

Treatment of superficial bladder cancer can be difficult. Although we generally rely upon conventional histopathologic factors to direct therapy, they may be inadequate in some patients with superficial disease. A proper resection should remove all gross disease and should include muscle in the specimen to provide the best clinical staging. There is now evidence to suggest that some patients previously treated for a history of superficial bladder cancer, who subsequently develop and are treated aggressively for muscle-invasive bladder cancer, may have a worse prognosis than those who present initially with muscle-invasive bladder cancer and undergo similar treatment. The physician must be astute enough to know when to proceed to more aggressive therapies that may improve survival. We must continue to search for better ways to provide risk-assessment in patients with superficial bladder cancer.