Meta-Analysis Indicates Value of Neoadjuvant Chemotherapy for Invasive Bladder Cancer
Abstract & Commentary
Synopsis: The value of neoadjuvant chemotherapy for invasive bladder cancer had not been definitively established, possibly because clinical trials have been of insufficient size to demonstrate efficacy. In a well-constructed meta-analysis of 10 completed clinical trials, investigators found a significant, albeit modest, improvement in overall survival for those who were treated with platinum-based combinations. The research highlights the value of meta-analysis for the evaluation of repeated clinical investigations.
Source: Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Lancet. 2003;361:1927-1934.
There continues to be some controversy with regard to the efficacy of neoadjuvant chemotherapy for patients with invasive bladder carcinoma. The question persists despite several reports involving more than 3000 patients. The Advanced Bladder Cancer (ABC) meta-analysis collaboration was undertaken by a group under the direction of the British Medical Research Council (MRC), which funded the collaborative effort of a large number of investigators. They identified 14 randomized trials that used neoadjuvant strategies. However, 4 of the selected trials were eliminated because of confounding variables (n = 3) or inability to retrieve the complete data set (n = 1). Thus, data for 2688 individual patients from 10 available randomized trials were reviewed.
Platinum-based combination chemotherapy showed a significant benefit to overall survival (combined hazard ratio [HR], 0.87 [95% CI, 0.78-0.98; P = .016]); 13% reduction in risk of death; 5% absolute benefit at 5 years; and increased overall survival from 45% to 50%. The effect was observed regardless of the type of local treatment (surgery, radiation, or combined surgery and radiation). The hazard ratio for all trials, including those using single-agent cisplatin, tended to favor neoadjuvant chemotherapy, although this tendency was not significant (P = .084). Thus, although platinum-based combination chemotherapy was beneficial, there was no evidence to support the use of single-agent platinum. The data were interpreted to demonstrate a clear, albeit modest, improvement in survival with the use of platinum-based combination chemotherapy for patients with invasive bladder cancer.
Comment by William B. Ershler, MD
The advanced bladder cancer meta-analysis collaboration has provided definitive evidence for the use of neoadjuvant chemotherapy for invasive bladder cancer. The analysis clears up considerable confusion introduced because of conflicting reports from small studies. The strength of this report lies in the methodology used. Importantly, the ABC investigators obtained primary data from each individual study rather than depending on the summaries of these studies that were published in the literature. They also sought data from completed but unpublished studies, thereby minimizing any bias created by the tendency to publish only positive reports.
Although the findings indicate the value of neoadjuvant combination chemotherapy, the findings must be tempered with the realization that the added benefit in absolute survival at 5 years is only 5%. However, the result for disease-free survival, locoregional disease-free survival, and metastases-free survival lend support to the evidence of survival benefits associated with combination chemotherapy. Nonetheless, the added benefit needs to be countered with the potential for toxicity with combined chemotherapy and its effect on quality of life.
The neoadjuvant strategy has, therefore, once again been demonstrated to be beneficial as it has under certain circumstances with other tumor types, such as lung, breast, and colorectal carcinoma. Although the demonstrated benefit is modest, the treatment strategy appears sound. Now, as more effective chemotherapeutic agents and combinations are developed and shown to be active in the setting of metastatic disease, these approaches may very reasonably be applied to the neoadjuvant setting and compared to platinum-based combinations.
Dr. Ershler is of INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.