Everything old is new again! Neoadjuvant chemotherapy in the treatment of muscle-invasive bladder cancer.

Abstract

In the last decade, the range of therapeutic options for patients with various malignancies has expanded tremendously, driven primarily by advances in molecular biology and genomic medicine. However, treatments for patients with bladder cancer have changed little in the past two decades. The regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) was first described in 1985, and its use in the neoadjuvant setting was first reported in 1988. Almost 30 years later, two prospective trials conducted in the United States have studied modified MVAC regimens in the neoadjuvant setting for patients with muscle-invasive bladder cancer (MIBC). Everything old is new again! MVAC is one of the most active chemotherapy regimens for bladder cancer, and so far, we have nothing better. Both studies use a variation of escalated MVAC plus growth factor support, a regimen first developed by the European Organisation for Treatment and Research of Cancer Genitourinary Group as high-dose MVAC with recombinant human granulocyte macrophage colonystimulating factor in 1993 and then evaluated in a randomized trial with recombinant human granulocyte colony-stimulating factor in 2001. Bladder cancer is the second most common cancer of the genitourinary tract. Worldwide, approximately 386,000 new cases are reported annually, about one in three of which are locally invasive or metastatic at presentation. Radical cystectomy is considered the gold standard of treatment for patients with localized MIBC, although in expert centers, similar outcomes are seen with bladder preservation using chemoradiotherapy protocols. At 5 years, the survival rate after cystectomy is 65% at best (range, 36% to 48%), depending on the presence of extravesical extension (pT3) and lymph node metastases (N1-N3). Neoadjuvant chemotherapy was intended for patients with clinical stage T2-T4aN0M0 muscle-invasive disease who are candidates for definitive surgery or radiation. The rationale for giving chemotherapy before cystectomy or full-dose radiation therapy is to treat micrometastases present at diagnosis, as approximately half of patients diagnosed with deep MIBC (stages T2b–4a) develop metastatic disease within two years. Discrepancies between clinical and pathologic staging is expected with under staging being common. Toxicity and mortality associated with neoadjuvant chemotherapy have been shown to be acceptable. Downstaging of the tumor may provide an indication of the activity of neoadjuvant chemotherapy, especially in patients who have a pathologic complete response (pCR) or who are pT1N0M0 after therapy. Patients with residual disease stage pT2 at radical cystectomy should be considered for clinical trials evaluating non–crossresistant alternative agents. Two large, well-designed, randomized trials using effective cisplatin-based combinations and two meta-analyses support the concept that neoadjuvant chemotherapy for patients with MIBC provides a greater survival benefit than surgery alone. These trials have shifted the treatment paradigm in muscle-invasive disease to favor the use of neoadjuvant chemotherapy. This approach should be considered for patients who are candidates for cisplatin-based combination chemotherapy and radical cystectomy. The use of perioperative chemotherapy was limited until 2003 to 2005, when the two meta-analyses were published. Among 7,161 analyzable patients in the National Cancer Data Base with stage III bladdercancerdiagnosedbetween1998and2003,perioperativechemotherapy was administered to 11.6%; 10.4% received adjuvant chemotherapy, and 1.2% received neoadjuvant chemotherapy. Since 2003, clinical practice guidelines have led to a slight increase in the use of neoadjuvant chemotherapy. Yet despite level-one evidence, neoadjuvant cisplatin-based chemotherapy continues to be underused, although recent reports suggest that its use is increasing. A report from 15 institutions between 2003 and 2008 found that only 34% of patients with MIBC received perioperative chemotherapy, of which 14% was neoadjuvant and only 11% was cisplatin-based. However, after a quality care initiative was implemented with providers from these 15 institutions, use of perioperative chemotherapy increased by 75.6% over baseline to 58% of all patients with cT2-4N0M0 bladder cancer managed by radical cystectomy. Many urologists remain concerned that toxicities from chemotherapy will preclude surgery, but this concern is not supported by recent large-scale analyses. The major impediment to the use of perioperative chemotherapy in patients with bladder cancer is renal impairment. As many as 50% of patients have a glomerular filtration rate of less than 60 mL/min, making them ineligible for cisplatin treatment by many definitions. In addition, approximately one third of patients have comorbidities that may preclude cisplatin-based treatment. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 18 JUNE 2