Older RCC Patients Live Longer With Targeted Therapy

Older patients with metastatic renal cell carcinoma (mRCC) lived longer and were less likely to die of the disease when treated with targeted therapy instead of nontargeted therapy, a retrospective view of more than 1,000 patients showed.

Treatment with targeted therapy led to a 22-23% reduction in the survival hazard and the RCC-specific survival hazard. Significantly more patients treated with targeted therapy remained alive at 1, 2, and 3 years, reported Jalpa A. Doshi, PhD, of the University of Pennsylvania in Philadelphia, and colleagues.

An unadjusted analysis showed no difference in median overall survival (OS), but the difference did achieve statistical significance in an adjusted analysis, as reported online in JAMA Network Open.

“Targeted therapies were associated with modest survival advantages despite a treatment group with more medical complexity, likely reflecting appropriateness for an expanded population of patients,” the authors wrote. “As advances in cancer treatment continue, rigorous methods that account for unobserved confounders will be needed to evaluate their real-world impact on outcomes.”

The data confirm the relevance of findings from randomized controlled trials (RCTs) with respect to older and sicker patients, according to the author of an invited commentary. Even so, the median survival of the older population appeared to be much shorter with targeted or other therapies, as compared with results of contemporary RCTs. The discrepancy could reflect competing causes of mortality in older patients and those with poorer baseline health-related quality of life (HR-QoL), wrote Alex Shteynshlyuger, MD, of New York Urology Specialists in New York City.

Perhaps the most important aspect of the study was in a data supplement, showing that 7,800 of 9,800 patients were excluded from the analysis because they received no treatment for mRCC during the study period of 2000 to 2013, he said. Additionally, the analysis covered the introduction and early clinical practice experience with targeted therapies.

“Newer approaches to targeted therapy have shown significant improvement in overall survival and HR-QoL outcomes compared with the early-era targeted therapy examined in the study,” Shteynshlyuger continued. “More aggressive therapy, when significantly more effective, can improve HR-QoL, a somewhat counterintuitive finding.”

“With further improvement in the efficacy of newer approaches to treatment with targeted therapy for RCC, the balance of who would benefit from treatment is tipping further to the sicker and older patients,” he added. “The question is, where is the tipping point in the risk-benefit analysis? Further prospective studies are needed to determine who among the 79% of patients with mRCC who received no treatment would benefit from treatment.”

Doshi and co-authors reported findings from an analysis of data from the NCI Surveillance, Epidemiology, and End-Results program linked to Medicare records. They queried the datasets for patients with newly diagnosed stage IV clear cell mRCC during 2000 to 2013. The primary objective was to compare OS and RCC-specific survival in patients treated with targeted versus nontargeted agents, primarily interleukin-2 and recombinant interferon-alfa.

The authors noted that few studies compared outcomes with targeted versus older nontargeted therapies for mRCC, although the available data suggested advantages for targeted therapies. Interpretation of the evidence has been complicated by unmeasured confounders and selection bias. To address the issue, investigators examined outcomes by means of instrumental variable analysis, a statistical method that offers an alternative to randomization and addresses confounding by measured and unmeasured variables.

The analysis included 1,015 patients who had a mean age of 71.2. The data showed that 63% of the patients received targeted therapy. Patients treated with targeted therapy were older, had higher comorbidity and disability scores, and were more likely to be on Medicare because of disability.

The primary analysis showed that treatment with targeted therapy was associated with significant reduction in the survival hazard (HR 0.78, 95% CI 0.65-0.94) and RCC-specific mortality (HR 0.77, 95% CI 0.62-0.96). Unadjusted survival curves showed significant differences in favor of targeted therapy for OS and RCC-specific survival. Median OS did not differ significantly between treatment groups (8.7 vs 7.2 months, respectively), nor did median RCC-specific survival (13.2 vs 10.5 months).

Younger and older patients derived similar benefits from targeted therapies, and patients who had undergone nephrectomy had larger reductions in the hazard ratios, although the differences did not achieve statistical significance because of small sample size.

Landmark analyses of OS favored targeted treatment:

• 1-year OS – 44% vs 36%, P=0.01
• 2-year OS – 25% vs 18%, P=0.009
• 3-year OS – 15% vs 10%, P=0.01

Subgroup analyses yielded smaller, nonsignificant differences between the two groups of patients.

The authors said the demographic and clinical characteristics of their real-world patient population suggested that targeted therapies offered new options for patients who might have not received treatment in the past. Acknowledging that their data suggested lower survival with targeted therapies as compared with results of RCTs, the authors said, “our results underscore that survival benefits may vary when treatments are administered to a broader population of patients.”