Results of a phase three study evaluating second-line chemotherapy with gemcitabine/paclitaxel for metastatic bladder cancer failed to answer its primary question of whether maintenance treatment is superior to a temporary six-cycle regimen because maintenance treatment was usually not possible. However specific subgroups of patients who may be more likely to benefit from this combination regimen after failing first-line chemotherapy.
Chicago-Results of a phase III study evaluating second-line chemotherapy with gemcitabine/paclitaxel (G/P [Gemzar/Abraxane, Onxol, Taxol]) for metastatic bladder cancer failed to answer its primary question of whether maintenance treatment is superior to a temporary six-cycle regimen because maintenance treatment was usually not possible. However, an analysis of response predictors identified specific subgroups of patients who may be more likely to benefit from this combination regimen after failing first-line chemotherapy, German investigators reported.
"However, for individuals who do not fulfill these criteria, our practical and clinical recommendation would be to provide best supportive care."
"The trial was designed based on the publication by C. Sternberg [Cancer 2001; 92:2993-8] that showed a 19-month progression-free survival in patients who received maintenance treatment with gemcitabine and paclitaxel, including growth factor support. Therefore, our study was designed to have 90% power for detecting at least a 9.1-month difference in disease-specific survival in favor of the maintenance arm," Dr. Albers noted.
Few received full intervention
However, the average patient in both arms received very few cycles. In both groups, only about two-thirds of patients received the allocated intervention. About 20% of patients in both groups either died before cycle 2 or refused treatment because of side effects. Only about one-third of patients in the temporary group received all six cycles, and in the maintenance group, only one-fourth of patients received six cycles and only 14% received more than six. The mean number of cycles administered was 4.3 in the maintenance arm and 3.5 in patients randomized to temporary treatment.
Findings from an analysis based on an according-to-protocol population was consistent with the results from the phase II trial in showing that the overall response rate to second-line G/P was about 50% as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. However, results of the primary efficacy analysis of disease-specific survival also confirmed that favorable tumor response does not necessarily translate into prolonged survival. Median disease-specific survival was relatively short and not significantly different between the temporary and maintenance groups (9.5 months vs. 8.1 months). There was also no difference between patients who received the temporary or maintenance regimen in the secondary efficacy analysis of median progression-free survival (5.7 vs. 3.5 months).
Who may benefit?
The data were also analyzed to identify factors predicting response to treatment. The results showed that patients with metastases to the lymph nodes only and those with a complete or partial response to first-line treatment exceeding 18 months were most likely to benefit from G/P. Compared with patients who had distant and lymph node metastases, those with only lymph node involvement had a significantly longer progression-free survival (7.0 vs. 2.8 months) and disease-specific survival (13.6 vs. 6.3 months). Every month of response to first-line treatment was associated with an approximate 2.5% reduction in the risk of progression after second-line treatment.
Dr. Albers noted that about 20% of the patients in the study lived more than 2 years, and included within that subgroup were four long-term survivors who now have lived more than 4 years.
"These patients also mostly had lymph node metastases with no distant metastases, but many also received additional surgery after a major response to second-line treatment," Dr. Albers noted.
The study was supported by grants from Lilly Oncology and Bristol Myers Squibb.