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Strategies for managing older patients with renal cell carcinoma and comorbidities
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More than half of patients diagnosed with renal cell carcinoma are at least 65 years old, and the median age at diagnosis is 64. Although increased life expectancies in general and prolonged survival times as a result of targeted therapies deserve optimism, elderly patients with renal cell carcinoma also bring unique clinical challenges. Beyond medical factors, social, psychological and financial elements also influence treatment practicalities and outcomes.
Because prospective research specific to this subpopulation is nonexistent, guidelines are scarce, and recommendations may be outpaced by recent research. On top of these factors, more than 80% of elderly patients have at least one comorbidity.3 Two out of three have gastrointestinal disorders, diabetes, hypertension or cardiovascular disease. Comorbidities are therefore the rule rather than the exception. Throw in the fog of polypharmacy, and the best path for elderly patients becomes increasingly unclear.
To navigate clinical decisions and achieve best outcomes for elderly patients, it is necessary to develop a framework that encompasses age, stage, life expectancy, comorbidities, pharmacology and patient willingness.
Assessments
The term “elderly” typically applies to patients 65 years of age or older, although some studies use 70 or 75 years as a threshold. Regardless of these discrepancies, chronological age offers a limited view of patient status. Physiological age is more useful, as this takes into account factors such as organ function and comorbidities.
In addition to physiological factors, psychological, social and practical elements often influence the treatment of elderly patients, making assessments more complex and perhaps more necessary than in other subpopulations.
Despite this lack of guidance, the following assessments are worthy of consideration:
WHO performance status
WHO performance status applies to patients of all ages. It is a fundamental starting point when quantifying well-being, activity level and quality of life.
Charlson Comorbidity Index
This scoring system includes 19 factors that influence mortality. Findings from the index can be weighed against treatment efficacy and risk for adverse events. Multiple studies have demonstrated a high predictive value for the Charlson Comorbidity Index in various treatment scenarios. Comorbidities are especially relevant when considering the risk for renal failure with surgery and possible drug interactions.
Comprehensive geriatric assessment
Comprehensive geriatric assessment (CGA) is an in-depth patient assessment that includes functional, social and psychological status. Broader elements such as a living situation, financial status, ethical values and motivation are also considered. Results can help determine whether elderly patients should be treated like young patients and considered “fit,” or if they fall into the categories of “vulnerable” or “frail.”
Although this kind of assessment may be time-consuming and require the efforts of a multidisciplinary team, it offers a pragmatic approach to elderly patient care. After all, the latest and greatest therapies are useless in the face of a patient’s inability or unwillingness to undergo treatment. If strict adherence to the CGA is not possible because of limited resources, then self-directed questionnaires and abridged versions of the CGA are still helpful.
The Lee and Carey prognostic indices
To best individualize care for elderly patients, prognosis should be heavily weighted. For this purpose, the Lee prognostic index for 4-year mortality and the Carey prognostic index for 2-year mortality can help guide decision-making. Although both assessments use demographic and functional factors, only the Lee prognostic index includes comorbidities.
Localized disease
The 2018 National Comprehensive Cancer Network guidelines recommend active surveillance for elderly patients with localized renal tumors. Localized kidney cancer does not greatly increase the risk for death in elderly patients, as comorbidities tend to have a bigger impact. If necessary, minimally invasive techniques such as radiofrequency ablation or cryoablation can be performed.
This guidance is supported by two retrospective studies conducted in 2010 and 2012. Each analysis showed that active treatment of localized renal tumors in elderly patients did not lead to increased survival, and radical nephrectomy in particular actually decreased survival.
The study from 2010 followed 537 patients who were 75 years of age or older. Patients had localized renal tumors less than or equal to 7 cm in diameter (stage T1). The researchers concluded that survival times were not significantly improved by selected management strategy — surveillance, nephrectomy or nephron-sparing interventions. Overall survival was significantly correlated with comorbidity (P < .0001) and age (P = .0004), but not management selection (P = .3).
Radical nephrectomy actually appeared to decrease survival. After this procedure, 86% of patients had renal dysfunction, which is a known risk factor for cardiovascular disease.
Decreased survival after radical nephrectomy was further supported by a second study conducted in 2012, which analyzed 7,138 patients with early-stage kidney cancer. A significantly lower risk for death was found in patients who had partial vs. radical nephrectomy (HR = 0.54; 95% CI, 0.34-0.85).
The first study found that elderly patients with small, localized renal tumors were more likely to succumb to cardiovascular disease than cancer, which is in line with expectations for older people in general. The second study found that only 1.9% of patients treated with partial nephrectomy died from kidney cancer. These findings suggest that comorbidities play a much greater role in survival than renal tumors themselves.
The authors of the 2010 study concluded, “Current research indicates that localized renal tumors are over treated, and our data suggest that active surveillance is a reasonable strategy and is greatly underused in the elderly population.”
Advanced disease
Surgery
The 2018 NCCN guidelines recommend surgical intervention, when possible, for patients with advanced disease before systemic treatment. On the other hand, the guidelines also acknowledge that elderly patients may not be good surgical candidates.
In the past, cytoreductive nephrectomy has been recommended for patients before systemic therapy; however, this guidance has not been adequately studied with more recent targeted therapies. Comorbidities reduce the benefit of cytoreductive nephrectomy, and older patients are at greater risk for postoperative complications and in-hospital mortality. Even with similar performance status, one study found that perioperative mortality was far more likely in patients 75 years of age or older compared with younger patients (21% vs. 1.1%).
Although studies that incorporate newer targeted therapies are still pending, enough research exists to suggest that nephrectomy should only be performed in elderly patients who exhibit highly favorable characteristics. As discussed with localized disease, the risk of cardiovascular disease makes nephrectomy a poor choice for most elderly patients with metastatic renal cell carcinoma.
Targeted therapies
Targeted therapies have significantly improved metastatic renal cell carcinoma survival over the past decade, but data are lacking for elderly populations. Although the median age of diagnosis for renal cell carcinoma is 64 years, less than 30% of patients in clinical trials for targeted therapies are 65 years of age or older. This imbalance is likely due to comorbidities and polypharmacy that exclude participation.
A recent meta-analysis of elderly patients showed that first-line therapies were less effective in elderly patients compared with younger patients. Overall, efficacy research is lacking, and toxicity profiles are incomplete. As comorbidities and low performance status are common in this subpopulation, toxicities are a major factor when choosing between targeted therapies.
Although some retrospective analyses have shown similar tolerability across age groups, it should be noted that most older patients included in clinical trials also have above average performance status. If prospective studies were conducted with typical elderly patients, the outcomes may not be so favorable.
First-line targeted therapies for elderly patients with predominantly clear cell renal cell carcinoma
Sorafenib
Although no longer recommended as a first-line therapy in the 2018 NCCN guidelines, sorafenib (Nexavar, Bayer) usage in elderly patients has more available data than newer targeted therapies. In a retrospective study of 4,684 patients, those who were 65 years of age or older did not experience a higher rate of adverse events compared with younger patients. Comorbidities did not increase adverse event risk either. However, the researchers of this study noted that patients older than 75 were treated for shorter time periods and sometimes had dose reductions. Only 8% of elderly patients received sorafenib for more than a year.
Sunitinib
In one study, 1,059 patients who received sunitinib (Sutent, Pfizer) were analyzed by age. Patients 70 years of age or older were compared with patients who were younger than 70. Efficacy was similar between groups, although certain adverse events were more common in older patients, such as fatigue (69% vs. 60%), cough (29% vs. 20%), peripheral edema (27% vs. 17%), anemia (25% vs. 18%), decreased appetite (29% vs. 13%) and thrombocytopenia (25% vs. 16%).
Another retrospective study evaluated real-world sunitinib use in elderly patients. Among those treated, 80.9% had cardiovascular risk factors and an average of 1.9 comorbidities. Using the CGA, seven patients were frail, 14 were vulnerable and 13 were fit. CGA category did not correlate with likelihood of adverse events. Median progression free survival was 13.6 months, which is consistent with clinical trials. Unfortunately, the small population involved in this study limits its reliability.
Pazopanib
Pazopanib (Votrient, Novartis) appears to have similar efficacy compared with sunitinib in elderly patients. Some studies suggest that sunitinib may be slightly more effective, but this could be offset by a patient preference for pazopanib, which results in less fatigue and offers a better quality of life. These factors may be particularly important if patient willingness is low. When considering pazopanib, clinicians should be on the lookout for hepatotoxicity, which may occur because of drug interactions. Liver function should be assessed before and during therapy.
Bevacizumab plus interferon-alfa
Data are sparse for the efficacy or safety of the combination of bevacizumab (Avastin, Genentech) and interferon-alfa in elderly patients. Of note, interferon therapy is known for psychological adverse events. Depression and/or mood disturbances may be nonstarters for elderly patients, particularly those with dementia or psychosocial issues.
Temsirolimus
Temsirolimus (Torisel, Pfizer) is typically indicated as a first-line agent in patients with poor prognostic features, but this may not hold true for elderly patients. One retrospective analysis showed that younger patients benefited more from this therapy than older patients. Patients 65 years of age or older showed no significant difference in overall survival when treated with temsirolimus compared with interferon-alfa (8.6 vs. 8.3 months). However, the same group of elderly patients experienced less adverse events with temsirolimus therapy.
Axitinib
No analyses are available that address the efficacy or safety of axitinib (Inlyta, Pfizer) in an elderly subpopulation.
Cabozantinib
Although no findings specifically address the efficacy or safety of cabozantinib (Cabometyx/Cometriq, Exelixis) in elderly patients, toxicity concerns warrant caution. Common adverse events are diarrhea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), palmar-plantar erythrodysesthesia syndrome (42%), hypertension (37%), vomiting (32%) and weight loss (31%).
Quick reference for first-line therapies in elderly patients
| First-line Therapy* | Considerations for Elderly |
|---|---|
| Sorafenib | Most data, well tolerated |
| Sunitinib | Possibly higher risk of adverse events |
| Pazopanib | Preferred by patients, but drug interactions may lead to liver toxicity |
| Bevacizumab plus interferon alpha | Possible psychological disturbances |
| Temsirolimus | Decreased efficacy in elderly patients |
| Axitinib | No subgroup data |
| Cabozantinib | No subgroup data and toxicity concerns |
Considering the findings summarized above and in the Table, sorafenib offers the most evidence for usage in elderly patients, but 2018 NCCN guidelines no longer recommend it in first-line therapy.
Between sunitinib and pazopanib, the latter may be a better choice for elderly patients. Despite a possible decrease in efficacy, the improved adverse event profile of pazopanib could win the day, especially in light of comorbidities or patient unwillingness.
The remaining therapeutics may have unfavorable efficacy and/or tolerability in elderly patients, along with a scarcity of data.
Unfortunately, this final note sets the tone for treating metastatic renal cell carcinoma in elderly patients. Pertinent research is scarce and prospective studies are nonexistent. More data are needed to establish firmer guidelines. What is known should be considered within a framework that includes the many factors that guide elderly care.
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