Increased Use of Second-Line Therapies Has Not Improved Survival in Metastatic Urothelial Cancer

Sumanta K. Pal, MD

Survival, measured as either disease-specific survival or relative conditional survival, has not improved for patients with metastatic urothelial carcinoma despite increasing use of second-line therapies with no formal indication in this setting.

Recently, the Retrospective International Study of Cancers of the Urothelium estimated that nearly half of patients with metastatic urothelial cancer receive second-line treatment even though no agents have been approved for this indication, said Sumanta K. Pal, MD, who presented an analysis of survival trends in de novo metastatic urothelial cancer at the 2014 Genitourinary Cancers Symposium.

“We’re not changing the natural history of the disease with these [second-line] treatments, and this poses a huge economic burden,” he said.

Some of the agents being used in the second-line setting are paclitaxel, docetaxel, and pemetrexed, he said, each of which has demonstrated only modest activity as second-line therapy in phase II studies.

In the analysis, Pal and colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to compare disease-specific survival and relative conditional survival over two eras (1994-2000 vs 2001-2009) in patients with metastatic urothelial cancer. The year 2000 was chosen as the cut-off given the emergence of multiple phase II datasets published subsequent to this date.

“I wouldn’t expect that second-, third-, and fourth-line therapies may be reflected in improvements in disease-specific survival, but certainly I would suggest that for patients making it out to more distant landmarks—1, 2, and 3 years—we may actually see their survival improve on the basis of these new therapies,” said Pal, assistant professor in the Department of Medical Oncology and Experimental Therapeutics at City of Hope, in Duarte, California. “But that hasn’t been the case.”

From 1994 to 2008, a total of 6495 patients with metastatic urothelial cancer (1802 diagnosed from 1994-2000 and 4693 diagnosed from 2001-2008) were identified within the SEER database. In each cohort, the mean age was 70 years, about three-fourths had poorly differentiated or undifferentiated tumors, and about 80% were characterized as non-Hispanic white.

The median disease-specific survival was 6 months for each cohort. Disease-specific survival at 1, 2, and 3 years post-diagnosis was 28%, 15%, and 11% for the cohort diagnosed during 1994-2000, compared with 29%, 14%, and 10% for those diagnosed from 2001-2008 (P = .7972).

“As we look across conditional survival at a 1-year landmark and a 2-year landmark out to 5 years, we actually don’t see any significant improvement in conditional survival for this disease,” he said.

One-year relative conditional survival rates at 1 to 5 years post-diagnosis were as follows for the 1994-2000 cohort and the 2001-2008 cohort, respectively:

• 45% vs 42% at 1 year
• 72% vs 69% at 2 years
• 79% vs 80% at 3 years
• 86% vs 87% at 4 years
• 95% vs 89% at 5 years

The 2-year relative conditional survival rates post-diagnosis for the 2 cohorts were:

• 35% vs 29% at 1 year
• 55% vs 57% at 2 years
• 67% vs 70% at 3 years
• 81% vs 79% at 4 years
• 91% vs 88% at 5 years

On multivariate analysis, age >65 years was independently associated with shorter disease-specific survival, while use of radiation and surgery was associated with longer disease-specific survival.

“To us in the investigative community, it means we need to look long and hard at further therapies for this disease,” said Pal. “In the setting of phase II clinical trials, usually what we’re seeing is progression-free survival on the order of 3 to 6 months and overall survival on the order of 6 to 10 months, but nothing that falls outside of those expectations at this point. What we’re looking for in bladder cancer at this moment is a very good signal in a phase II study that suggests activity beyond those estimates.”

Pal SK, Vogelzang NJ, Nelson RA, et al. Changes in relative conditional survival in de novo metastatic urothelial carcinoma: a Surveillance, Epidemiology, and End Results database analysis. Presented at: the 10th Annual Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract 314.

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