Li et al1 analyzed Surveillance, Epidemiology, and End Results–Medicare data to contemporaneously compare overall survival and disease-specific survival of patients treated with nontargeted immunotherapy (interleukin 2 and interferon alfa) vs patients treated with targeted therapies for metastatic stage IV clear cell renal cell carcinoma (RCC) in the early targeted therapy era (2000-2011). The importance of this study is perhaps best communicated by eFigure 1 in the Supplement: 79% of patients with metastatic RCC (7795 of 9826) were excluded from analysis because they received no treatment during the 10-year period analyzed by the authors. Older patients and those with worse performance status (according to the Eastern Oncology Cooperative Group criteria) tend to be underrepresented in oncological randomized clinical trials (RCTs). For example, in a recent trial of targeted RCC treatment, only 38% of patients were older than 65 years.2
Although the role of cytoreductive nephrectomy in metastatic disease has been questioned in the era of targeted therapy,3 78% of patients underwent nephrectomy in a recent RCT.2 In the community setting, during the time when cytoreductive nephrectomy was thought to be beneficial, only 35% of patients in that study of a Medicare population underwent nephrectomy.
The study by Li et al1 confirms the relevance of data from RCTs to older and sicker patients. Patients who are older and sicker than patients typically enrolled in RCTs, when treated with targeted therapy, experienced longer overall survival compared with those treated with nontargeted therapies (8.7 months vs 7.2 months), confirming the applicability of findings from RCTs to this population. Nonetheless, median survival in the older population appears to be much shorter with either targeted or nontargeted immunotherapy treatment than that reported in contemporary RCTs. This discrepancy may be associated with competing causes of mortality in older patients and with poorer baseline health-related quality of life (HRQoL), an independent predictor of overall survival.4
Multidisciplinary tumor board discussions often devolve into debates between purists and pragmatists. Purists focus on a strict reading of inclusion and exclusion criteria of RCTs in choosing therapeutic options. With many patients falling outside the inclusion criteria for RCTs, pragmatists advocate a heuristic approach: using clinical experience and knowledge about disease biology and extrapolating data from RCTs to infer an optimal approach to patients who need treatment.5 Pragmatic trials have been suggested as an alternative to bridge the disconnect between carefully staged RCTs and clinical practice.6
What happens when you give targeted therapy for RCC to all comers, outside the carefully guarded façade of a clinical trial? Pragmatic clinical trials would certainly provide useful information. In the absence of carefully planned prospective pragmatic clinical trials, population-level retrospective studies, like the one by Li et al,1 can provide useful information, with the usual limitations associated with a retrospective analysis, including selection bias and confounding bias among others.
Survival benefit is not the only relevant criterion that needs to be considered when making treatment choices. Palliation, as measured by improved HRQoL, is an important consideration.
The limitations of applicability of RCTs to real-life clinical scenarios are unlikely to abate. Clinicians often find themselves trying to make the best possible recommendations for the sickest patients and for older patients who often have multiple comorbidities. Fortunately, there are several clues that can help.
An abundance of evidence demonstrates that the HRQoL measures tend to be strongly associated with objective response rates and the survival benefit of a particular treatment. Both baseline HRQoL and changes in HRQoL measures in response to treatment are associated with overall survival.4
There is no association between HRQoL improvement and isolated progression-free survival improvement in the absence of improvement of overall survival.7 On the other hand, treatments that improve overall survival also improve the HRQoL, and the degree of survival improvement is associated with the HRQoL improvement.4
Newer approaches to targeted therapy have shown significant improvement in overall survival and HRQoL outcomes compared with early-era targeted therapy examined in the study by Li et al.1 More-aggressive therapy, when significantly more effective, can improve HRQoL, a somewhat counterintuitive finding. In a recent study, despite treatment-related adverse events leading to discontinuation in 22% of patients in the nivolumab plus ipilimumab group vs 12% in the sunitinib group, the nivolumab plus ipilimumab group was shown to have a significantly improved overall survival at 18 months (75% vs 60%).2 In another study, the authors stated, “Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.”4
The sickest patients pose the greatest challenge because of the concern that they are very dissimilar to patients enrolled in RCTs. There is a legitimate worry that offering treatment to patients who are older or sicker than those enrolled in RCTs will worsen their HRQoL and survival. However, both direct and indirect evidence suggest that many of these patients are likely to benefit from the most effective treatment available, in terms of survival, palliation, and HRQoL.
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. 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 metastatic RCC who received no treatment would benefit from treatment.
In the meantime, the clinician is left with a greater understanding of outcomes of targeted therapy in older adults that can be incorporated into heuristic models to help in the treatment decisions. Early diagnosis and early start of therapy before HRQoL deterioration, which can occur quickly in patients with RCC, are likely to have a beneficial effect for older patients with more comorbidities.
Published: June 14, 2019. doi:10.1001/jamanetworkopen.2019.5815
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Shteynshlyuger A. JAMA Network Open.
Corresponding Author: Alex Shteynshlyuger, MD, New York Urology Specialists, 33 W 46th St, Fifth Floor, New York, NY 10036 (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
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