André P. Fay, MD
Dana-Farber Cancer Institute/Lank Center for Genitourinary Oncology
Urothelial carcinoma is the most common histologic subtype of bladder cancer and accounts for 90% of all cases.1
In the United Sates, more than 72,000 new cases of bladder cancer and about 15,000 deaths were estimated in 2013.2
In patients with muscle invasive bladder cancers (MIBC), pathologic stage and nodal status are the most important prognostic factors for progression and overall survival (OS).3
Radical cystectomy alone is associated with a 5-year survival rate of 80% for organ-confined disease without lymph node metastasis.4
However, patients with extravesical disease and patients with lymph node involvement have a 5-year survival rate of approximately 40-50% and 15-35%, respectively.5
Contemporary management of patients with MIBC consists of a multimodality treatment including surgery, cytotoxic systemic chemotherapy, and, for selected patients, chemoradiation with the objective of bladder preservation. While chemotherapy is part of the standard of care in the neoadjuvant setting, studies show it is infrequently used, and while some of the benefits of cytotoxic therapy alternatively may be attained via adjuvant treatment, the effectiveness of that strategy is still under investigation.
Here, we review the data supporting the standard use of neoadjuvant and adjuvant chemotherapy for patients with MIBC.6
Neoadjuvant Treatment Demonstrates Mild Benefit Neoadjuvant chemotherapy (NC) allows the in vivo assessment of the response in the primary tumor, indicating whether the individual’s tumor is responsive to a specific chemotherapy regimen. In addition, the magnitude of the chemotherapy response correlates with long-term remission or survival.7
There can be some drawbacks to neoadjuvant chemotherapy use in this population. For patients without major responses to NC, the delay of definitive therapy may potentially increase the risk of disease progression. Furthermore, pre-surgical staging is not always correctly evaluated before radical cystectomy, and some low-risk patients may unnecessarily receive chemotherapy.3
However, several clinical trials have demonstrated that there is a role for NC in eligible patients with MIBC.
The Nordic I trial randomized 311 patients with cT1G3-T4NxM0 disease to two cycles of cisplatin and doxorubicin versus no chemotherapy. All patients received radiation therapy before radical cystectomy. There was no significant difference in OS and cancer-specific survival (CSS). However, the subgroup of patients who presented with pT3-T4 disease and received NC had a 15% absolute survival benefit.8
The Nordic Cystectomy-2 trial enrolled 309 patients who were randomized to receive three cycles of neoadjuvant cisplatin and methotrexate or surgery alone. No statistically significant differences in OS were found between the two groups (53% vs 46%)9
While these two studies were underpowered and used what would now be considered suboptimal chemotherapy, a combined analysis of these two trials revealed a trend for better OS favoring NC (OS: 56% vs 48%; P
A large prospective trial (EORTC-MRC) evaluated 976 patients with cT2 grade 3-T4N0 MIBC. Patients were randomized to receive three cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) or no therapy before local definitive therapy.11
In this trial, local therapy was radiotherapy in 42% of patients, radical cystectomy in 50%, and a combination of surgery and radiotherapy in 8%. Updated long-term follow-up of these patients showed a statistically significant benefit in OS (36% vs 30%; HR: 0.84; P
Following NC, pathologic complete response (pCR) was observed in 32.5% compared with 12.3% with surgery alone.
Southwest Oncology Group (SWOG) 8710 was a prospective randomized controlled trial of 317 patients with cT2-T4aN0M0 MIBC to compare three cycles of MVAC chemotherapy (methotrexate,vinblastine, doxorubicin, and cisplatin) preceding radical cystectomy against cystectomy alone.13
The pCR rate with MVAC was 38% compared with 12% with surgery alone. Although NC did not provide a statistically significant benefit in OS (57% vs 43%; P
= 0.06), the original planned analysis was defined with one-sided P
< 0.05, and this goal was achieved. In addition, NC did not increase surgeryrelated complications, and median OS was poor for patients with residual muscle-invasive disease or lymph node-positive disease: 3.4 and 2.4 years, respectively.14