Lamm describes a success story in oncology that he helped create, namely, the favorable therapeutic effect of intravesical bacillus Calmette-Guérin (BCG) against carcinoma in situ (CIS) of the bladder. Virtually every study conducted over the past decade reports complete responses in 70% or more patients treated with BCG, which are often durable for years . Such results have been documented empirically in prospective controlled trials without complete understanding of the mechanism of action of BCG or the optimal dose and treatment regimen. More importantly, not only may BCG eradicate CIS but also it may delay or prevent tumor progression and improve patient survival . Conversely, patients failing to respond to an adequate trial of BCG therapy are at increased risk for disease progression and death from bladder cancer. We now realize that the natural history of CIS in the bladder has been significantly altered by intravesical BCG.
Prognosis Via p53
Current research focuses on bladder preservation and improving survival. This requires identifying patients upfront who are at high or low risk for subsequent disease progression. As one example, p53 mutations within in situ tumor cells appear to be an independent marker of tumor invasion . Of 18 patients with CIS whose tumors expressed "normal" p53, 3 progressed within 5 years, compared with 13 of 15 patients overexpressing p53 in their tumor specimens. Furthermore, recent data show that p53 pattern cannot predict who will or will not respond to BCG, but among BCG failures, p53 mutation expression in recurrent tumors portends rapid local tumor invasion, metastasis, and reduced survival .
Thus, combining conventional tumor characteristics with a validated tumor marker or markers predictive of underlying biologic behavior of a particular tumor diathesis may lead to better and more rational care of individual patients. For example, early cystectomy may be contemplated to improve survival in patients with p53-positive tumors who fail to respond to BCG, whereas for nonresponding patients with p53-negative tumors, alternative conservative measures designed to preserve the bladder can be tested. It is also conceivable that patients with initially p53-negative tumors who respond to BCG do not need repeated treatments, maintenance therapy, or frequent invasive follow-up cystoscopy and transurethral resection or biopsy of abnormal bladder mucosa. Such issues can now be addressed, hopefully for patient benefit, because of the favorable effect BCG has on the clinical course of CIS within the bladder.
Lastly, while BCG has helped segregate patients into risk groups for tumor invasion within the bladder, it has consequently exposed the panurothelial nature of transitional-cell CIS. Among 86 patients followed for 15 years after BCG therapy, 17% have developed tumors in the upper urinary tracts and another 13% have tumors involving the urethral mucosa . Extravesical sites of disease were detected often after 5 years and, in some cases, after 10 years. Half of the tumors were invasive, presumably arising from undetected areas of urothelial CIS, and have resulted in a number of cancer deaths.
This finding suggests that in designing future therapeutic strategies, a combination of intense therapy directed to the bladder early in the course of tumor evolution coupled with systemic chemoprevention designed to protect the urothelium as a whole will be required. The aims are to maintain an intact urinary tract for as long as possible and to prevent silent tumor invasion progressing to metastasis. Lamm mentions several chemoprevention agents under study, namely, bropirmine and megadose vitamins. Another class of prophylactic agents not discussed in his article, retinoids (specifically, fenretinide, or 4-HPR) also is being investigated. We look forward to the results of such trials with anticipation. In the meantime, local BCG therapy will remain the standard for CIS of the bladder, especially among patients with diffuse disease who are at particular risk for early tumor invasion