SAN FRANCISCO—Approximately one-third of patients diagnosed with locally advanced urothelial cancer have tumors with mixed histology. Yet there are few data to guide treatment of these patients. Now a reanalysis of randomized Phase III trial data suggests that patients whose tumors have squamous cell or adenocarcinoma elements derive at least as much benefit from platinum-based neoadjuvant chemotherapy as those individuals whose tumors are pure urothelial cancers, researchers reported here at the 2010 Genitourinary Symposium.
To evaluate the impact of mixed histology on the likelihood of response, Edward M. Messing, MD, Chairman and the Winfield W. Scott Chair in Urology at the University of Rochester (NY) School of Medicine and Dentistry, and colleagues performed a secondary analysis of data from the Southwest Oncology Group trial S8710, which compared three cycles of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus cystectomy with cystectomy alone. The previously reported primary results of the trial showed that neoadjuvant therapy improved overall survival in patients with locally-advanced cancer.
For the new analysis, the researchers examined the impact of MVAC neoadjuvant chemotherapy on survival and downstaging in 59 patients with mixed histology tumors and 236 patients whose tumors had a pure urothelial histology.
Only one patient (4%) with mixed histology who went straight to surgery was downstaged to pT0 compared with 11 (34%) of the patients with mixed histology who received neoadjuvant chemotherapy prior to surgery.
By comparison, 17 (14%) of the patients with pure histology who were treated with surgery alone were downstaged, as were 33 (29%) with pure histology who received neoadjuvant chemotherapy and surgery.
The increased likelihood of downstaging with the addition of neoadjuvant chemotherapy was statistically significant in both patient groups.
“Another way of looking at those numbers is that the advantages were almost twice as great for the mixed histology group in terms of downstaging after neoadjuvant chemotherapy compared with pure urothelial cancer,” Dr. Messing said.
A similar advantage was also seen in terms of overall survival. Patients with clinical T2 stage mixed histology tumors who underwent MVAC plus cystectomy had a 73% probability of being alive at five years, compared with a 54% probability with cystectomy alone.
By comparison, patients with T2 pure urothelial tumors had a 64% probability of five-year survival with MVAC plus cystectomy and a 61% probability with surgery alone. In the patients with cT3-4a mixed histology disease, the five-year survival rate was 58% with MVAC plus cystectomy compared with 34% in the cystectomy alone group.
The five-year survival probabilities were 46% for patients with stage cT3-4a pure histology in the chemotherapy-plus-surgery group and 42% for cystectomy alone.
Looking at these numbers a little differently, Dr. Messing noted that patients with mixed histology tumors who went straight to surgery did worse than patients with pure urothelial cancers, regardless of disease stage. The addition of MVAC, however, flipped that prognosis such that patients with mixed histology tumors did better than those with pure histology tumors, regardless of stage.
Overall, 56% Reduction in Risk of Death By Adding Neoadjuvant Chemo
Overall, there was a 56% reduction in risk of death with the addition of neoadjuvant chemotherapy for patients with mixed histology tumors, which was statistically significant. By contrast, there was no statistically significant improvement in overall survival in patients with pure histology tumors with the addition of neoadjuvant treatment.
“This is a pretty impressive hazard ratio,” Dr. Messing said, pointing to the improvement in survival associated with neoadjuvant chemotherapy for patients with mixed histology. “If you have pure urothelial cancer, there was almost no difference. Virtually all of the benefit achieved by MVAC in this fairly large study was achieved because of the mixed histology tumors and their response.”
Limitations, but Still Important
Dr. Messing noted that the number of patients with mixed histology tumors was relatively small in the trial and that the analysis was retrospective. Despite those limitations, however, he thinks the data can guide practice. “Urothelial cancers with squamous or adenocarcinoma components do respond to MVAC and probably other platinum based combination chemotherapy regimens.
“And at least in my practice, and I think in several others who have known the data, we have used this as an indication to go into neoadjuvant chemotherapy, in part because the patients do so poorly with mixed histology tumors if you don't,” Dr. Messing concluded.
Naomi B. Haas, MD, Associate Professor of Medicine and Director of the Prostate Program at the University of Pennsylvania Abramson Cancer Center, who chaired the session, said the findings were a surprise.
“It is counterintuitive,” she said. “We generally are of the belief that transitional cell cancer benefits from platinum based therapy and that these mixed histology tumors, at least in advanced disease, don't do very well with these regimens. And here is a study saying, perhaps, that if you try to treat these patients earlier on, they may actually do better.”
Unlike Dr. Messing though, she thinks it is too early to let the data guide her practice. But the findings do “open people's eyes and shows us that this is something we should address and look at prospectively.”
‘Progress in Multidisciplinary Management’
This year's Genitourinary Cancers Symposium had the subtitle of Progress in Multidisciplinary Management and was co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.