Европейские эпидемиологические онкологические исследования сообщают о 2%-ом инциденте почечно-клеточной карциномы (RCC), частота которой занимает 14-ая место среди всех типов опухолей . Это заболевание, как правило, диагностируется у пожилых пациентов. Из них > 60% случаев наблюдаются у пациентов старше 60 лет [2,3] и > 20% у больных 75 лет и старше . На момент вынесения диагноза приблизительный средний возраст составляет 63 года [2,3], медиана — 65 лет , и только 3-7% пациентов имеют возраст моложе 40 лет . Таким образом преклонный возраст пациентов — основной фактор риска .
Лечение пожилых пациентов требует специфического лечения, поскольку они могут иметь слабое здоровье, оцениваемое по общему состоянию больного (performance status, PS), или сопутствующие патологии, которые влекут большие адверзивные реакции (АР) относительно молодых пациентов . Пожилые пациенты обычно имеют худший прогноз, вероятно, вследствие позднего диагноза. Фактически величина 5-летней полной выживаемости (overall survival, OS) и выживаемости без прогрессирования (PFS) составляет 81% и 91% для молодых пациентов (40 лет) и 71% (PFS) и 78% (OS) для пожилых пациентов (> 40 лет) .
Метастатическую RCС и RCС поздних стадий исторически рассматривают как орфанную болезнь, резистентную к радиотерапии и обычным противоопухолевым агентам с единственным возможным положительным результатом, ассоциированным с иммунотерапией с цитокинами . В последние несколько лет, однако, развитие новых молекулярных таргентных агентов обеспечило новые и эффективные инструменты, которые могут задержать время прогрессирования и вероятно продлить выживаемость . Начинаясь в 2005, американские и европейские контрольные органы одобрили серию ингибиторов ангиогенеза: четыре ингибитора тирозинкиназ (TKIs — сорафениб, сунитиниб, пазопаниб и акситиниб); одно моноклональное антитело (бевацизумаб) и две механистических мишени рапамицина (mTORs — темсиролимус и эверолимус).
Клиническое развитие этих агентов протекало в популяциях молодых пациентов, возраст которых не соответствовал наблюдаемому в ежедневной клинической практике (ТАБЛИЦА 1). Согласно некоторым авторам, это расхождение является следствием исключения из клинических исследований пожилых пациентов, которые показывают сопутствующую патологию наряду с худшим PS и меньшей толерантностью к лечению. Поскольку величина коморбидности отрицательно коррелирует с выживаемостью пациентов , результаты этих исследований вероятно вели к неправильной интерпретации [10,11]. Некоторые авторы утверждают, что в дополнение к сопутствующим заболеваниям включение пожилых пациентов в клинические исследования часто ограничено страхом высокий токсических реакций и/или исключением из терапии, поскольку перцепция токсичности выше в этой возрастной группе [12,13].
Fable Zustovich and Giacomo Novara. Advanced kidney cancer: treating the elderly. Expert Rev. Anticancer Ther. 13(12), 1389–1398 (2013)
European epidemiologic oncology data reported a 2% incidence of renal cell carcinoma (RCC) whose frequency ranks as 14th among all tumor types . It is a disease chiefly diagnosed in elderly patients. Evidence indicates that >60% of cases occur in patients older than 60 years [2,3] and >20% in those 75 years and older . The estimated mean age at diagnosis is 63 years [2,3], the median is 65 years  and only 3-7% of patients are younger than 40 years at diagnosis . Thus advanced patient age is the main risk factor .
The treatment of elderly patients require particular care because they can be in poor health as evaluated by their performance status (PS) or affected by comorbidities that lead them to a greater exposure to adverse events (AEs) compared with younger patients . Older patients generally show the worse prognosis probably due to advanced diagnosis. In fact the 5-years overall survival (OS) and progression free survival (PFS) rates are reported to 81% and 91%, for younger patients ( 40 years) compared with 71% (PFS) and 78% (OS) in older patients (>40 years) .
Advanced/metastatic RCC was historically considered as an orphan disease resistant to radiation therapy and to conventional antineoplastic agents, with the only possible positive outcome associated with immunotherapy with cytokines . In the last few years, however, the development of new molecular-targeted agents have provided new and efficacious tools that can delay the time to progression and probably prolong survival . Beginning in 2005, the American and European regulatory authorities approved a series of angiogenesis inhibitors: four tyrosine kinase inhibitors (TKIs), sorafenib, sunitinib, pazopanib and axitinib; one monoclonal antibody, bevacizumab and two mechanistic targets of rapamycin (mTORs), temsirolimus and everolimus.
The clinical development of these agents was carried out in younger patient populations whose age did not correspond to the reality observed in everyday clinical practice, as shown in the median ages of patients enrolled in the Phase III studies of the agents that have been approved so far (TABLE 1). According to some authors, this discrepancy is due to the exclusion of elderly patients from clinical developmental studies who exhibit comorbidities coupled with a poorer PS and less tolerance for treatment. Because the number of comorbidities negatively correlates with patient survival , the outcomes of these studies most likely led to incorrect interpretations [10,11]. Some authors claim that, in addition to comorbidities, the enrollment of elderly patients in clinical studies is often limited by the fear of increased toxic events and/or dropout from therapy because the perception of toxicity is higher in this patient population [12,13].
Table 1. Comparison between percentage of incidence of RCC in elderly in real world and percentage of elderly enrolled in clinical trials.
The exclusion from clinical trials of the elderly patients whose frequent clinical practise gives rise to an unlikely gap, with physicians facing a challenging dilemma about the choice of the most suitable treatment . This review analyzes and evaluates all the sources presently available for the treatment of elderly patients with RCC, considering both the surgical and medical approach.
For years, the standard treatment for RCC with metastasis at initial diagnosis was cytoreductive nephrectomy (CN). Such a traditional approach was based on the findings of two randomized controlled trials (RCTs) performed in the immunotherapy era that demonstrated CN, was associated with a small but statistically significant survival advantage compared with immunotherapy alone. Flanigan et al., demonstrated that the median survival of patients randomized to surgery followed by interferon (IFN) was 11.1 months versus 8.1 months for those receiving IFNa-2b alone . Mickisch et al. found a 10-month survival difference (17 vs 7 months; hazard ratio [HR]: 0.54; 85% CI: 0.31–0.94) in a similar European RCT . The two RCTs were subsequently meta-analyzed by Flanigan et al., reporting a 5.8-month survival difference in favor of patients receiving CN (13.6 vs 7.8; p = 0.0002) . In addition to survival, CN offered the advantage of treating local symptoms related to the presence of the primary tumor (e.g., gross hematuria and pain) that are relatively common in such patients and otherwise difficult to handle.
However, CN is not devoid of complications (26.5% in a recent population-based study) including cardiovascular (4%), pulmonary (6%), gastrointestinal complications (5%) and urinary complications (2%). Moreover, a significant in-hospital mortality rate is also reported (2.4%) .
Such risks are significantly higher in elderly patients. Overall complication and perioperative mortality rates may approach 28% and 5%, respectively . Elderly patients were also shown to be at a higher risk of dying related to complications following CN . Consequently, indications for CN in elderly comorbid patients might be more critical. Options to reduce morbidity and mortality of CN might be the adoption of nephron-sparing surgery, whenever oncologically and technically feasible, in order to reduce the risk of postoperative acute renal failure. Few surgical series and population-based studies demonstrated indeed that such approach does not undermine cancer-control [21,22].
Similarly, whenever technically feasible, adoption of minimally-invasive techniques such as laparoscopic or robotic surgery may decrease postoperative complications . Finally, patients comorbidity is a strong predictor of perioperative complications and mortality, with Charlson comorbidity index being significantly associated with both kind of events [24,19].
The classic paradigm of upfront CN is still unchanged in the targeted therapies era, due to the lack of large Phase III RCTs evaluating the role of upfront targeted therapies in metastatic RCC in comparison with immediate CN. The currently available evidence is limited and does not allow definitive conclusions. In a retrospective study comparing two heterogeneous cohorts of patients receiving CN or treated with targeted therapies only, CN was associated with significantly longer OS (adjusted HR: 0.68; 95% CI: 0.46–0.99; p = 0.04). However, such advantages failed to be demonstrated in a Memorial Sloan-Kettering Cancer Center (MSKCC) poor risk group as well as in patients with a Karnofsky PS <80% which may suggest that poor risk or elderly frail patients may not experience a significant benefit from CN .
Powles et al., evaluated the role of presurgical targeted therapies in a meta-analysis of two small Phase II RCTs including 66 patients. They demonstrated that upfront sunitinib before CN achieved a PR rate of the primary tumor in only 6% of the cases, with median reduction of only 12% . Presurgical TKIs were not associated with a significantly higher risk of surgical complications . However, disease progression during presurgical medical treatment was shown to be a highly unfavorable prognostic factor, which may allow a hypothesis that CN should be avoided in those patients progressing during presurgical therapies .
Conversely, Richey et al. evaluated a series of 188 patients treated only with targeted therapies without receiving CN, demonstrating a median OS of about 10.4 months, with a patient having four or more risk factors (e.g., elevated baseline lactate dehydrogenase and corrected calcium, PS of two or higher, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites and lymphopenia) experiencing survival as short as 5.5 months . Similarly, a high lactate dehydrogenase level and low albumin level were shown to be associated with poor OS following CN , making those patients candidates for other experimental therapeutic options.
In conclusion, pending the results of the ongoing Phase III RCTs, CN is still regarded the standard of care in metastatic RCC. Elderly patients who are fit for surgery and whose tumors are surgically resectable, should be advised that surgery is the preferred first step in a multimodal approach that would certainly also include targeted therapies. In patients unwilling or unfit for surgery or those cases where cancers are deemed unresectable, upfront targeted therapies may be a valuable option. However, local PR rate is usually very low and can hardly have any impact on surgical strategy (e.g., making resectable and unresectable cancer). Several prognostic factors are available to identify patients with poor outcomes (e.g., MSKCC poor risk, those progressing during targeted therapies, poor PS, high lactate dehydrogenase level and low albumin level), and they should be used to counsel elderly patients who may have a higher risk of severe complications and perioperative deaths following CN.
For many years immunotherapy, based on the administration of IFNa-2a and IL-2, was the cornerstone of the systemic treatment of RCC. However, studies undertaken with immunotherapy in elderly patients not only showed lower response rates and shorter survival but also significantly higher rates of grade 3 and 4 toxicities . The most prevalent hypothesis suggests that patients with a PS >1 often display immune system impairments. Immunotherapy is thus not recommended for patients with a low PS , and it is only considered a valid option for patients with limited disease and a good PS .
At the present time, the treatment of metastatic RCC is essentially based on the use of the so-called small molecule drugs, characterized by low molecular weight, able to interfere with the intracellular active site of receptors (mostly tyrosine kinase receptors). These drugs, as well as the monoclonal antibody bevacizumab, hamper the activation of signal transduction leading to angiogenesis or block the intracellular paths regulating cell growth and proliferation . All these new agents, approved by regulatory authorities, clearly prolong PFS and in some cases OS also .
Sorafenib was the first TKI approved for the treatment of metastatic RCC by the American health authorities in 2005 with the broad indication of ‘renal cell carcinoma’. The European authorities subsequently approved sorafenib in 2006 for advanced RCC patients refractory to cytokines or those considered not amenable to this therapy.
The efficacy and safety of the drug in elderly patients was evaluated in retrospective analyses coming from a registration RCT (Renal Cancer Global Evaluation Trial [TARGET]), two expanded access studies, a Phase IV study and single analyses of clinical practice.
Inclusion criteria of the TARGET study did not exclude the enrollment of elderly patients. The mean age of the whole population was 58 years, and the age of elderly patients was up to 86 years . A published not preplanned subanalysis revealed that, among the 903 patients, 115 (70 assigned to sorafenib and 45 assigned to placebo arm) were 70 years and older vs 787 patients (381 assigned to sorafenib and 407 to placebo) were younger than 70 years . The age-group analysis highlighted that in all cases PFS was almost twofold for patients treated with sorafenib as compared with placebo . A trend of PFS increase was observed in the elderly (26.3 weeks vs 23.9 weeks). Similarly, the OR rate (CR plus partial remission [PR]) was always in favor of elderly patients (15.7% vs 8.7%) . Equal clinical benefit (CR plus PR plus stable disease [SD]) and self-reported health status deterioration were observed in both groups of patients treated with sorafenib. Finally, no significant differences of incidence and seriousness of AEs, which were expected and medically manageable, were observed between younger and elderly patients . In patients 70 years and older, the main AEs consisted of skin alterations, fatigue and anorexia, reported as grades 1 and 2 and medically manageable . Approximately 79% of the elderly patients tolerated sorafenib treatment with a mean duration of 25 weeks.
Results of an unpublished analysis performed on 267 patients (23.3%) aged 70 years and older enrolled in the European expanded access study (EU-ARCCS) showed a prolonged trend in PFS in patients older than 70 years (8.2 months in elderly patients vs 6.4 months in younger ones) . A published analysis undertaken with 736 patients, 70 years and older enrolled in the North American expanded access trial study (AARCCS), which also included patients with non-clear cell histology and more than one metastatic site, showed no differences between elderly and younger patients in the incidence of drug-related AEs, treatment duration, dose reductions and treatment discontinuation . Remarkably, no substantial differences of drug-related grade 3 or higher cardiotoxicity were observed between the second groups (7% in the elderly and 5% in the younger patients). The clinical benefit was similar in both groups of patients, as well as PFS and OS .
An unpublished analysis concerning a Phase IV worldwide study (the Prospective European Doxazosin and Combination Therapy [PREDICT] trial), carried out in 2311 patients including 532 patients aged 70 years and older, showed similar PFS (6.1 months in the elderly and 7.3 months in the younger patients) .
A recent published pooled analysis of the most important trials with sorafenib including 4684 patients treated with sorafenib as a single agent stratified patients in several age groups: <55 years (1126; 24%), 55–65 years (1579; 34%), 65–75 years (1382; 30%) and >75 years (559; 12%) . The large sample size allowed mimicking everyday clinical practice, especially the presence of comorbidities (hypertension, cardiac disorders, anemia, diabetes mellitus and hypercholesterolemia). With the exception of patients 75 years and older in whom treatment duration was 30% shorter, in all the other age groups no difference was observed. The incidence and the prevalence of drug-related AEs of any grade appeared almost constant in all groups or slightly decreased with age. Similarly, no differences were observed as to the most common specific drug-related AEs; only in the subgroup of patients 75 years and older did fatigue and rash exceed 2% .
Among single small-size experiences coming from everyday clinical practice, an aspect worth mentioning is the use of particular levels of patient classification leading to decision-making treatment from unpublished experiences. The use of the ECG comprehensive geriatric assessment stratifying elderly patients as ‘fit,’ ‘unfit’ and ‘frail’ allowed treatment with sorafenib in unfit patients . Similarly, the cumulative Illness Rating Scale for Geriatrics (CIRS-G), which stratifies patients with scores from 0-4 according to comorbidity impact (arrhythmias, hypertension, chronic bronchitis, diabetes mellitus and neurologic diseases), showed that only patients with grades 3 and 4 CIRS-G required dose reductions during the treatment .
Similarly, a second unpublished experience with 57 patients older than 75 years treated with different target agents reported 8.6 and 10.3 months of PFS in patients treated with sorafenib in firstand second-line therapy, respectively. No drug-related toxic deaths were observed in the study .
Sunitinib is a TKI approved in 2006 by European and American health authorities for the treatment of metastatic RCC. The first evidence about the efficacy and safety of the drug in elderly patients came from the analysis of the expanded access program (EAP) trial, which accrued 1418 patients aged 65 years and older. The OR rate, median of PFS and OS were comparable with the whole population. This outcome was also particularly observed in elderly patients with non-clear cell histology. The most common AEs were fatigue and thrombocytopenia .
More evidence comes from an unpublished retrospective analysis undertaken with 57 patients aged 75 years and older treated in five French centers with sunitinib, sorafenib and bevacizumab. Following first-line therapy, patients in the sunitinib arm achieved a PFS of 8.8 months without toxic drug-related deaths . These provisional observations were confirmed in a larger unpublished pooled analysis including 1059 patients enrolled in five clinical trials and undergoing different lines of treatment . A total of 202 patients were 70 years and older (19%); 857 patients (81%) were younger than 70 years. Median PFS and OS were similar in the second groups, with a favorable trend for the elderly (9.0 vs 10.9 months and 23.3 vs 23.7 months, respectively). Concerning safety, some drugrelated AEs were more common in the elderly: fatigue, loss of appetite/weight, cough, peripheral edema, anemia and thrombocytopenia. On the contrary, the hand-foot-skin reaction was more common in younger patients .
A further unpublished analysis included 154 patients aged 70 years and older treated with sunitinib, not consecutively enrolled in the first-line setting of clinical practice . A total of 106 patients (68.8%) began with the standard schedule (50 mg for 4 weeks ‘on’ and 2 weeks ‘off’) . The reduced starting doses were 37.5 mg/d for 4 weeks ‘on’ and 2 weeks ‘off’ (32 patients), 25 mg/d for 4 weeks ‘on’ and 2 weeks ‘off’ (12 patients) and 37.5 mg continuous once-daily dosing (q.i.d.) (four patients). During the therapy, the patients received a median of four cycles of sunitinib .
Considering only patients starting with the standard dose, the analysis revealed a greater increase of grades 3 and 4 AEs (65 vs 42%), dose reductions (64 vs 40%) and dose discontinuation due to drug-related AEs (23 vs 21%) in comparison with patients starting with dose and schedule adjustment. Median PFS was 10.6 months; median OS was 20.1 months . Although a previous Phase II study had not revealed any benefit in efficacy or safety for different schedules of sunitinib suggesting that adherence to 50 mg dose with intermittent schedule (4 weeks on and 2 weeks off) should remain the treatment goal for patients with advanced RCC , the authors of the retrospective study reported that an adapted schedule seems not to influence the efficacy of sunitinib .
A recent study collected consecutive data from 68 patients enrolled in the real-world setting of 6 Italian centers . Analysis with the Comprehensive Geriatric Assessment (CGA) revealed 41% ‘fit’, 41% ‘vulnerable’ and 18% ‘frail’ patients. Sixty patients (88.2%) presented concomitant diseases .
The mean number of cycles performed in the analysis was 7.6. Dose reductions were required in 47 patients (69.2%) due to frailty or toxicity. Among patients starting the full dose, 17.6% required dose reduction immediately during the first cycle; 60.3% had a treatment interruption because of disease progression or toxicity after a median number of four cycles. After starting with a dose reduction, the reescalation to full dose was possible in only one patient . Clinical benefit was observed in 69% of patients, with a median time to progression of 13.6 months; OS was 17.8 months and 18.3 months in the firstand second-line, respectively. According to the authors, the high rate of dose reductions and discontinuation resulted in low-level toxicities. Fatigue, mucositis, and hypertension were the nonhematologic AEs observed in the analysis. A cardiotoxicity rate of 13.3% was reported, consisting of one case of grade 4 acute myocardial infarction, one grade 3 congestive heart failure and grades 1 and 2 asymptomatic decrease of left ventricular ejection fraction or arrhythmias .
The data gathered indicate that sunitinib therapy is technically feasible in elderly patients. However, due to the high toxicity profile of the drug, patients should be carefully monitored and physicians should be ready to recommend a quick reduction/discontinuation of dosing in the case of early signs of toxicity.
Everolimus is an oral mTOR inhibitor approved in 2010 by the American and European regulatory agencies for the treatment of patients who have relapsed after one or more treatment lines with VEGF/VEGF receptor inhibitors. Data concerning the use of everolimus in elderly patients were extensively reported in second published papers. In an unplanned subgroup analysis of the randomized registration study vs placebo (RECORD-1) study , the safety and the efficacy of everolimus was evaluated in a group of 153 patients 65 years and older (36.8% of the whole study population), of whom 112 were treated with everolimus and 41 with placebo; and in 73 patients 70 years and older (17.5% of the population), of whom 53 were treated with everolimus and 20 with placebo . In contrast to other studies, the benefit in terms of PFS was assessed comparing the two groups of elderly patients vs the whole population of the study instead of the group of younger patients. Everolimus significantly delayed PFS compared with placebo both in patients 65 years and older (5.4 vs 2.2 months) and in those 70 years and older (5.1 vs 1.9 months) . The rate of responses turned out rather low in all the groups of patients analyzed, and no statistically significant difference in terms of OS was observed. The safety profile of the second subgroups of elderly patients was similar to that of the general population, although some AEs (peripheral edema, cough, rash and diarrhea) were reported more frequently in elderly patients [42,43].
Additional data about the use of everolimus in elderly patients come from the EAP study in which 592 patients 65 years and older (43.3% of the whole population accrued) were treated . Differently from younger patients where 62.6% of them were treated for more than 6 months, only in 37.4% of elderly patients was it possible to administer everolimus for more than 6 months .
The most frequent AEs due to everolimus reported in elderly patients enrolled in the RECORD-1 study consisted of stomatitis, cough, infection, asthenia, rash, peripheral edema and diarrhea . Similar to what was already observed with other mTOR inhibitors, this study showed that everolimus induces nonbacterial pneumonia and metabolic alterations (hyperglycemia, diabetes and hypercholesterolemia) . Even if these inconveniences did not turn out to be significant in the subgroup analysis, it must be borne in mind that they particularly have an impact on elderly patients, especially in the presence of coexisting or preexisting comorbidities. Therefore, additional information on the safety of everolimus coming from elderly patients accrued in the EAP study becomes essential to better characterize this agent.
The combination of bevacizumab plus IFN was only approved by the European regulatory authorities in 2009 for the first-line treatment of RCC; the American one extended this approval to RCC globally, independently of the line of treatment. Data concerning the use of this combination are available only for an unpublished per-protocol subgroup analysis of a study comparing bevacizumab plus IFN versus placebo (AVOREN study) carried out with 239 patients. In the comparison between younger patients (younger than 65 years) versus elderly patients (older than 65 years), the latter represented 37% of the whole population enrolled in the study .
The analysis showed that the combination of bevacizumab plus IFN provided an advantage of PFS with a benefit in terms of HR of 0.77 in elderly patients versus 0.54 in younger patients. On the whole, the combination was equally tolerated in both groups.
Among the AEs of all the grades observed, the incidence of fatigue and asthenia was twofold in elderly patients compared with younger ones. Concerning grade 3 and higher AEs, a slight not statistically significant increase in elderly patients as compared with younger patients was observed (66 vs 58%) .
Another confirmatory Phase III study was carried out in the US accrued patients with a median age of 61 years and no one older than 70 years. Up to now no data are available concerning patients 65 years and older .
Recent Phase II data showed that bevacizumab with a low dose of IFN (3 MIU instead of 9 MIU) is equally effective if compared to data from AVOREN study as historic control . Bevacizumab itself is generally well tolerated also among elderly patients and IFN is generally responsible of all toxicity observed in this subset with the exception of hypertension and risk of congestive heart failure, thus, bevacizumab with low doses of IFN or in monotherapy if IFN is not tolerated could be considered for elderly patients without severe cardiac comorbidity.
The mTOR inhibitor temsirolimus received approval from the European authorities in 2006 for the treatment of patients with a poor prognosis according to the modified MSKCC risk criteria. The 3-arm registration pivotal study showed superiority in terms of OS in the group of patients treated with temsirolimus alone as compared with the other groups (combination temsirolimus plus IFN and IFN alone) .
A preplanned subgroup analysis of this study showed that, among patients of the temsirolimus-alone arm, the benefit in terms of HR of OS was higher in the group of 287 patients younger than 65 years in comparison with 129 patients aged 65 years and older [50,51].
The same age-group comparison between temsirolimus and IFN showed a trend in favor of OS in the group of patients younger than 65 years treated with temsirolimus alone (12 vs 6.9 months); no difference between the two experimental arms in patients 65 years and older was observed (8.6 vs 8.3 months) [50,51].
Data of the toxicity profile, available only as an abstract, favored temsirolimus for both age groups. In regard to grade 3 and 4 AEs, temsirolimus was related to lower rates of asthenia, nausea, fever and neutropenia. Conversely, a higher frequency of grades 3 and 4 dyspnea and hyperglycemia were observed with temsirolimus. In all, age seems to have little impact on the incidence of grades 3 and 4 AEs induced by temsirolimus .
Box 1. Recommendations for elderly patients of NCCN guidelines and International Society of Geriatric Oncology.
SIOG findings & recommendations
- Hypertension, cardiovascular disease, diabetes and gastrointestinal disorders are frequent in elderly patients.
- Toxicity profiles of the individual targeted agents and implications for specific comorbid conditions should be considered.
NCCN guidelines: senior adult oncology: treatment of RCC
- Sorafenib and sunitinib
- “Similar efficacy in younger and older patients”
- “Some adverse events, including fatigue, occur with increased frequency”
- “Similar efficacy in older and younger adults”
- “Older adults are at increased risk for AEs (most commonly stomatitis, anemia and infection)”
- “Frequency of grade 3/4 AEs is low”
- “IFN is not recommended for first-line treatment”
NCCN Guidelines. Senior Adult Oncology v.2.2012.
IFN: Interferon; RCC: Renal cell carcinoma; SIOG: International society of geriatric oncology.
Data taken from 
The oral TKI pazopanib was approved in 2009 in EU for firstline treatment-naive patients and for second-line patients who have relapsed after cytokines. On the contrary, the American authorities approved the drug for the treatment of RCC regardless of the number and type of previous therapies. Data concerning the use of pazopanib in elderly patients have not yet been published. However, they are described in detail in the file submitted to the US FDA where information in terms of both efficacy and safety relevant to the registration study that accrued 196 patients 65 years and older and 34 patients older than 75 years are reported [101,102].
The most common AEs observed in the whole patient population were diarrhea, fatigue and hair discoloration. However, the major concern derived from the use of this agent was in the induction of grade 3 liver toxicity occurring in about 12% of patients with a 0.05% mortality rate . Therefore, even if fatal events appear very uncommon, patients older than 60 years, frequently showing transaminase elevations at baseline, could be at higher risk compared with younger ones. Another additional risk factor due to the comorbidities frequently occurring in elderly patients derives from the simultaneous administration of drugs metabolized by the liver. In this regard, warnings recommending careful use and strict monitoring of liver function of patients simultaneously taking statins are outlined in the Summary of Product Characteristics .
Clinical trials with pazopanib for the treatment of RCC involved 196 subjects (33%) 65 years and older and 34 subjects (6%) older than 75 years. No overall differences in safety or effectiveness of pazopanib were observed between these subjects and younger patients [52,53]. Even if only 6% of patients included in the trials with pazopanib were older than 75 years, no differences in safety and effectiveness were observed in comparison with younger ones [52,53]. Recently, two further studies with pazopanib have been presented during oncology meetings but, presently, are unpublished. The patient preference Phase II study (PISCES) compared pazopanib with sunitinib and revealed 70% of patients preferring pazopanib . A second Phase III study (COMPARZ) demonstrated that pazopanib was non-inferior to sunitinib in the front-line therapy . Unfortunately no full information is available for elderly patients enrolled in these studies
The multikinase inhibitor axitinib was recently introduced with the indication for second-line of therapy only after previous failure with sunitinib or cytokines. To date, little data are available regarding the use of axitinib in elderly patients. A Phase II study enrolled 62 patients with a median age of 60 years with a range between 35 and 70 years . No information is available for the efficacy and tolerability of the drug in patients older than 65 years. In addition, the pivotal Phase III trial enrolled patients with a median age of 61 years and age ranges between 20 and 81 years. A subgroup analysis showed no differences in patients 65 years and older. No information has been reported concerning the safety profile .
The definition of elderly patients today is not related as much to chronological age but increasingly to individual physiology reflecting the general status of the person (biologic age) . The current geriatric perspectives weigh biologic age in relation to physical structure, motor skills, mental health, functional performance, independence activities of daily living and comorbidities . Therefore, an approach to patients based on geriatric grading rather than solely age, as reported in some of the papers considered in this review, is preferable [4,60].
At the present time, available studies favor the activity and safety of sorafenib, sunitinib, everolimus, bevacizumab, temsirolimus and pazopanib in patients 65 years and older. In particular, data of safety are available for sunitinib, sorafenib and everolimus in patients 70 years and older; only sorafenib presents robust safety data for patients 75 years and older.
The main limitation of data so far evaluated lies in the absence of head-to-head studies conducted on the six current available therapies aimed at estimating safety and efficacy in elderly patients with metastatic RCC. Keeping this in mind, the evidence taken into consideration seems to indicate a different benefit in terms of PFS and response rate in elderly patients treated with different targeted agents [11,41]. In particular, a greater benefit seems to be related to the use of sorafenib in elderly patients, a lower benefit could be related to temsirolimus, and no differences seem to be associated with sunitinib [11,41].
Table 2. Decision-making algorithm based on patient with concomitant disease evaluated at baseline.
Data regarding safety profile do not seem to indicate important differences for sorafenib, everolimus, bevacizumab and temsirolimus between elderly and younger patients; data referring to sunitinib seem to indicate a greater incidence of some toxicity in elderly patients .
The great number of therapies presently available for metastatic RCC allows evaluating a different approach to the elderly patient that does not focus exclusively on evidence-based medicine but instead on individual patient characteristics.
The correct therapy could be applied integrating the individual patient preference with two critical issues for the elderly patient: comorbidities evaluated at baseline and the risk of pharmacologic interactions with the problems related to a polytherapy regimen.
Literature data reported that in an oncologic population of patients 75 years and older, the most common comorbidities observed were cardiovascular and metabolic [10,61]. Generally, the result of the presence of these comorbidities is a reduced PS and, consequently, safety profile for oncologic therapies. This happens mainly for those therapies inducing toxic side effects that overlap patient comorbidities. Consequently, reductions, interruptions or discontinuations could be required with the risk of diminishing the efficacy of treatment.
As reported in the current geriatric guidelines (BOX 1), a winning strategy could be to choose the therapy with a toxicity profile able to minimize the interaction with baseline toxicity; for example, a TKI could be the best drug for patients with metabolic alterations or infections at baseline, whereas mTOR inhibitors could be the first choice for patients with important cardiovascular comorbidity.
An additional critical point includes the evaluation of the concomitant use of drugs for preexisting diseases. Some authors reported that elderly oncologic patients before the diagnosis were already taking a mean number of six drugs to manage their comorbidities .
Table 3. Patients at risk of drug interactions: the decision making process adopted in our institution includes molecules with a lower pharmacokinetic half-life in order to turn off the safety-event induced by the interaction.
A polytherapy regimen could increase the risk of pharmacologic interaction between drugs, commonly assumed to control comorbidities and antitumor therapy. Our experience is that a drug with a short elimination half-life, administered according to a twice-daily regimen, could facilitate a rapid switch-off of the AEs related to pharmacologic interaction (TABLE 3).
The addition of an anticancer drug to patients already receiving polytherapy may negatively affect not only drug interactions but also the possibility of even taking the drug. In fact, patients with impaired cognitive status may find difficult to get further oral therapy, especially if characterized by intermittent regimens . In this regard, continuous oral dosing or, when possible, intravenous therapies administered during hospitalization might be more appropriate.
The analysis of elderly patients presenting hypertension at baseline requires a separate discussion. Antitumor therapies consisting of TKIs with an intermittent schedule of administration based on the alternation of therapy and suspension requires continuous dosage adjustment of the antihypertensive drug. In fact, the dosage of antihypertensives will increase during the period of TKI administration and will decrease during TKI suspension. This could cause confusion in an elderly patient in the absence of familial support. Therefore, we believe that a TKI therapy with a continuous schedule is preferable for such patients .
Taking into account data from clinical studies, retrospective analyses, and an approach focused on patients, we report the decision-making algorithm currently adopted in the author’s institution (TABLE 2).
In near future, the therapeutic armamentarium of medical oncologist and urologist will be enriched with additional new targeted therapies and probably with immune modulatory acting molecules. While this undoubtedly represents a major advance in metastatic RCC management, to our knowledge, no head-to-head study is planned to compare the different molecules, with the goal to evaluate the efficacy and safety in elderly patients. Faced with this scenario, we believe that, in the next 5 years, the clinical experience acquired with drugs with a wellestablished safety and efficacy profile is likely to remain a landmark in the treatment of metastatic RCC in this setting of patients.
Financial & competing interests disclosure
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Editorial assistance for this manuscript was provided by Dragonfly Editorial funded by Bayer Healthcare.
- Currently available data suggest that elderly patients may tolerate the same treatment of younger patients, even if dose adjustments are required.
- Not all the therapies could be administered to all elderly patients.
- The algorithm proposed in (TABLE 2) takes into account data coming from the literature and an approach focused on patients.
- Our experience suggests a careful monitoring of elderly patients treated with targeted agents, especially in the early phase of treatment.
- Ferlay J, Autier P, Boniol M, Heanue M et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann. Oncol. 18, 581–592 (2007).
- Lynch CF WM, Davila JA, PLatz CE. Cancer of the kidney and renal pelvis.
- Nese N, Paner GP, Mallin K, Ritchey J et al. Renal cell carcinoma: assessment of key pathologic prognostic parameters and patient characteristics in 47,909 cases using the National Cancer Data Base. Ann. Diag. Pathol. 13, 1–8 (2009).
- Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9, 179–186 (1969).
- Denzinger S, Otto W, Burger M et al. Sporadic renal cell carcinoma in young and elderly patients: are there different clinicopathological features and disease specific survival rates? World J. Surg. Oncol. 5, 16 (2007).
- Mc Laughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects of renal cell carcinoma. Semin. Oncol. 33(5), 527–533 (2006).
- Dutcher JP, Tannir N, Bellmunt J et al. Experience with sorafenib and the elderly patient. Med. Oncol. 27, 1359–1370 (2010).
- Hutson TE, Bukowski RM, Cowey CL, Sequential use of targeted agents in the treatment of renal cell carcinoma. Crit. Rev. Oncol. Hematol. 77, 48–62 (2011).
- Berger DA, Megwalu, II, Vlahiotis A et al. Impact of comorbidity on overall survival in patients surgically treated for renal cell carcinoma. Urology 72, 359–363 (2008).
- Bellmunt J, Negrier S, Escudier B et al. The medical treatment of metastatic renal cell cancer in the elderly: position paper of a SIOG Taskforce. Crit. Rev. Oncol. Hematol. 69, 64–72 (2009).
- Eisen T, Oudard S, Szczylik C et al. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J. Natl Cancer Inst. 100, 1454–1463 (2008).
- Kornblith AB, Kemeny M, Peterson BL et al. Survey of oncologists’ perceptions of barriers to accrual of older patients with breast carcinoma to clinical trials. Cancer 95, 989–996 (2002).
- Yee KW, Pater JL, Pho L, Zee B, Siu LL. Enrollment of older patients in cancer treatment trials in Canada: why is age a barrier? J. Clin. Oncol. 21, 1618–1623.
- Shuch B, La Rochelle JC, Wu J et al. Performance status and cytoreductive nephrectomy: redefining management in patients with poor performance. Cancer 113, 1324–1331 (2008).
- Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N. Engl. J. Med. 345, 1655–1659 (2001).
- Mickisch GH, Garin A, van Poppel H et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 358, 966–970 (2001).
- Flanigan RC, Mickisch G, Sylvester R et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J. Urol. 171, 1071–1076 (2004).
- Abdollah F, Sun M, Thuret R et al. Mortality and morbidity after cytoreductive nephrectomy for metastatic renal cell carcinoma: a population-based study. Ann. Surg. Oncol. 18, 2988–2996 (2011).
- Sun M, Abdollah F, Schmitges J et al. Cytoreductive nephrectomy in the elderly: a population-based cohort from the USA. BJU Inter. 109, 1807–1812 (2012).
- Sun M, Bianchi M, Karakiewicz PI et al. Reply to georgios papadopoulos, georgios stathouros, and konstantinos doumas’ letter to the editor re: Maxine Sun, Marco Bianchi, Jens Hansen et al. Chronic Kidney Disease After Nephrectomy in Patients with Small Renal Masses: A Retrospective Observational Analysis. 62, 696–703. Urol. 63(5), e65–e66 (2013).
- Capitanio U, Zini L, Perrotte P et al. Cytoreductive partial nephrectomy does not undermine cancer control in metastatic renal cell carcinoma: a population-based study. Urology 1090–1095 (2008).
- Krambeck AE, Leibovich BC, Lohse et al. The role of nephron sparing surgery for metastatic (pM1) renal cell carcinoma. J. Urol. 1990–1995 (2006).
- Guzzo TJ, Allaf ME, Pierorazio PM et al. Perioperative outcomes of elderly patients undergoing laparoscopic renal procedures. Urology 572–576 (2009).
- Trinh QD, Bianchi M, Hansen J et al. In-hospital mortality and failure to rescue after cytoreductive nephrectomy. Eur. Urol. 1107–1114 (2013).
- Choueiri TK, Schutz FA, Hevelone ND et al. Thermal ablation vs surgery for localized kidney cancer: a Surveillance, Epidemiology, and End Results (SEER) database analysis. Urology 78, 93–98 (2011).
- Powles T, Kayani I, Blank C et al. The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer. Ann. Oncol. 22, 1041–1047 (2011).
- Chapin BF, Delacroix SE Jr, Culp SH et al. Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma. Eur. Urol. 60, 964–971 (2011).
- Richey SL, Culp SH, Jonasch E et al. Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive nephrectomy. Ann. Oncol. 22, 1048–1053 (2011).
- Margulis V, Shariat SF, Rapoport Y et al. Development of accurate models for individualized prediction of survival after cytoreductive nephrectomy for metastatic renal cell carcinoma. Eur. Urol. 63(5), 947–952 (2012).
- De la Rosette JCS, van Poppel H. Old and Fragile Patients. In: Renal Cell Cancer. Springer, London, UK (2008).
- Porta CBS, Beck J, Procopio G et al. Efficacy and safety of sorafenib in elderly patients, results from a large open label, non comparative phase III study in european patients with advanced RCC (EU-ARCCS). Ann. Oncol. 19, 596P (2008).
- Stadler WM, Figlin RA, McDermott DF et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer 116, 1272–1280 (2010).
- JaЁger D KE, Zemanova M, Leonhartsberger N et al. PREDICT (Patient Characteristics in Renal Cell Carcinoma and Daily Practice Treatment with Sorafenib) global non-interventional study: final report. Eur. J. Cancer 48 (2011).
- Procopio G, Bellmunt J, Dutcher J et al. Sorafenib tolerability in elderly patients with advanced renal cell carcinoma: results from a large pooled analysis. Brit. J. Cancer 108, 311–318 (2013).
- Simonelli C FL, Giancalone A, Lleshi A et al. Sorafenib in elderly cancer patients with renal cell carcinoma: a single-institution experience. Presented at 2008 Genitourinary Cancers Symposium (abst 382).
- Gernone A PA, Pagliarulo V. Comorbidity and sorafenib (SOR) therapy in elderly patients with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 29(Suppl. 7), Abstract 398 (2011).
- Billemont B, Massard C, Negrier S et al. Antiangiogenic treatment in elderly patients (>75 years) with metastatic renal cell carcinoma (mRCC): experience from the French Renal Group. Presented at: 2010 Genitourinary Cancers Symposium. Abstract 364 (2010).
- Gore ME, Szczylik C, Porta C et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 10, 757–763 (2009).
- Hutson TB, R, Rini BI, Gore ME et al. A pooled analysis of the efficacy and safety of sunitinib in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 29 (2011).
- Ugo De Giorgi KR, Giovanni Lo Re et al. Sunitinib as first-line therapy in elderly patients (age 70 and older) with metastatic renal cell cancer. J. Clin. Oncol. 30 (2012).
- Brunello A, Basso U, Sacco C et al. Safety and activity of sunitinib in elderly patients (>=70 years) with metastatic renal cell carcinoma: a multicenter study. Ann. Oncol. 2012.
- Porta C, Calvo E, Climent MA et al. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial. Eur. Urol. 61, 826–833 (2012).
- Danesi R, Boni JP, Ravaud A. Oral and intravenously administered mTOR inhibitors for metastatic renal cell carcinoma: pharmacokinetic considerations and clinical implications. Cancer Treat. Rev. 39(7), 784–792 (2013).
- Grunwald V, Karakiewicz PI, Bavbek SE et al. An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. Eur. J. Cancer 48, 324–332 (2012).
- van den Eertwegh AJ, Karakiewicz P, Bavbek S et al. Safety of everolimus by treatment duration in patients with advanced renal cell cancer in an expanded access program. Urology 81, 143–149 (2013).
- Motzer RJ, Escudier B, Oudard S et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116, 4256–4265 (2010).
- Bajetta E RA, Bracarda S, Neґgrier S et al. Efficacy and safety of first-line bevacizumab (BEV) plus interferon-2a (IFN) in patients (pts) >65 years with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 26 (2008).
- Rini BI, Halabi S, Rosenberg JE et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J. Clin. 28, 2137–2143 (2010).
- Melichar B, Bracarda S, Matveev V et al. A multinational phase II trial of bevacizumab with low-dose interferon-2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN. Ann. Oncol. (2009) (Epub ahead of print).
- Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. New Engl. J. Med. 356, 2271–2281 (2007).
- Dutcher J SC, Tannir N, Escudier B. Correlation of survival with tumor histology, age and prognostic-risk group for previously untreated patients with advanced renal cell carcinoma receiving temsirolimus or interferon alpha. J. Clin. Oncol. 25 (2007).
- Escudier B. Patient preference between pazopanib and sunitinib: Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. 2012 ASCO Annual Meeting. Abstract CRA4502. 2012.
- Motzer RJ, Hutson TE, Reeves J. Randomized open-label phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): Results of the COMPARZ trial. 2012 ESMO Congress. Abstract LBA8, 2012
- Calvo E, Maroto P, del Muro XG et al. Update from the Spanish Oncology Genitourinary Group on the treatment of advanced renal cell carcinoma: focus on special populations. Cancer Metastasis Rev. 29(Suppl. 1), 11–20 (2010).
- Bukowski RM. Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma. Cancer Manag. Res. 3, 273–285 (2011).
- Rini BI, Wilding G, Hudes G et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J. Clin. 27, 4462–4468 (2009).
- Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378, 1931–1939 (2011).
- Aapro MS. The frail are not always elderly. J. Clin. Oncol. 23, 2121–2122 (2005).
- Passage KJ, McCarthy NJ. Critical review of the management of early-stage breast cancer in elderly women. Int. Med. J. 37, 181–189 (2007).
- Katz S, Akpom CA. A measure of primary sociobiological functions. Inter. J. Health Ser. 6, 493–508.
- Coebergh JW, Janssen-Heijnen ML, Post PN et al. Serious co-morbidity among unselected cancer patients newly diagnosed in the southeastern part of The Netherlands in 1993-1996. J. Clin. Epidemiol. 52, 1131–1136 (1999).
- Extermann M. Interaction between comorbidity and cancer. Cancer Control 14, 13–22 (2007).
- Bellmunt J, Fishman M, Eisen T et al. Expert opinion on the use of first-line sorafenib in selected metastatic renal cell carcinoma patients. Expert Rev. Anticancer Ther. 10, 825 (2010).
- Motzer RJ, Hutson TE, Olsen MR et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J. Clin. Oncol. 30(12), 1371–1377 (2012).
- Eisen T, Oudard S, Szczylik C et al. Clinical benefit of sorafenib in the elderly with advanced renal cell carcinoma: Subgroup analysis of The Approaches in Renal Cancer Global Evaluation Trial (TARGETs). 2007 European Association of Urology Annual Abstract 964 (2007).
- Eisen T, Oudard S, Szczylik C et al. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J. Natl Cancer Inst. 100, 1454–1463 (2008).
- Bukowski RM, Stadler WM, Figlin RA et al. Safety and efficacy of sorafenib in elderly patients (pts) ‡65 years: a subset analysis from the Advanced renal cell carcinoma sorafenib (ARCCS) expanded access program in North America. J. Clin. Oncol. 26(15), Abstract 5045 (2008).
- Sternberg CN, Davis ID Mardiak J et al. Pazopanib in Locally Advanced or Metastatic Renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061–1068 (2010).
- Rini B, Escudier B, Tomczak P et al. Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): Results of phase III AXIS trial. 2011 ASCO Meeting. Abstract 4503 (2007).
- Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370, 2103–2111 (2007).
- Rini BI, Halabi S, Rosenberg JE et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J. Clin. Oncol. 26, 5422–5428 (2008).
- Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).
- Osanto S, Hutson TE, Calvo E et al. Efficacy and safety of everolimus in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 28(15), Abstracts 4608 (2010).
- Bellmunt J, Neґgrier S, Escudier B et al. The medical treatment of metastatic renal cell cancer in the elderly: position paper of a SIOG Taskforce. Crit. Rev. Oncol. Hematol. 69(1), 64–72 (2009).
101 FDA: SPC-Pazopanib. Summary of Product Characteristics for Pazopanib. (2012) FDA Pazopanib (label). www.accessdata.fda.gov/drugsatfda_docs/ label/2012/022465s-010S-012lbl.pdf.
102 Pazopanib. FDA prescribing information. www.accessdata.fda.gov/drugsatfda_docs/ label/2009/022465lbl.
103 Howlader N, Noone AM, Krapcho M et al. SEER Cancer Statistics Review (1975-2008). National Cancer Institute, Bethesda, MD, USA. http://seer.cancer.gov/csr/1975_2008/