For reprint orders, please contact: [email protected]
Future Oncology
Perspective
Patient approach in advanced/metastatic renal cell carcinoma: focus on the elderly population and treatment-related toxicity Elena Verzoni1, Filippo de Braud1, Francesca Fabiani2, Paolo Grassi1, Isabella Testa1 & Giuseppe Procopio*1 Department of Medical Oncology, Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milan, Italy 2 Department of Emergency–Urgency, San Giuseppe General Hospital, Viale G. Boccaccio, Empoli (Florence), Italy *Author for correspondence: Tel.: +39 0223904450 n Fax: +39 0223902149 n [email protected] 1
Recent therapeutic advances have changed the treatment landscape of metastatic renal cell carcinoma. Unfortunately, the seven agents now available are not based on biomarkers that would indicate which one could provide the best benefit for every patient. We have reviewed the available information concerning the impact of each treatment on comorbidities or status that are frequently seen before commencing treatment for the advanced disease: elderly and patients with cardiovascular complications, metabolic and endocrinology disorders, and infections, as well as impaired organ function (kidney, liver and heart). Additional new drugs will be launched, but no predictive biomarkers are available. Head-to-head studies to evaluate the safety of the different drugs are rare. In this quite complex scenario, we believe that a decision-making approach focused on the patient may represent a suitable strategy.
Until recently, immunotherapy was the only treatment available for metastatic renal cell carcinoma (mRCC). Following the introduction in the oncology therapeutic setting of the new-targeted agents, the oral active multikinase inhibitors (tyrosine kinase inhibitors; TKIs) sorafenib and sunitinib have represented a breaking point and a fundamental step forward in the treatment of mRCC. Paradoxically, we now have plenty of choice thanks to the longawaited availability of seven new therapeutic approaches [1] that have dramatically changed the possibility of treating this disease. Following approval by the US FDA and EMA in 2006 of sorafenib and sunitinib, which were the first two TKIs used for the treatment of mRCC, other different and important agents, such as mTOR inhibitors temsirolimus and everolimus, the monoclonal VEGF antibody bevacizumab, and, more recently, the two TKIs pazopanib and axitinib, have widened the therapeutic armamentarium [2–8]. Unfortunately, often these targeted therapies are not curative for mRCC patients. Despite considerable delayed tumor progression, complete and long-lasting responses are observed in less than 1% of cases [9]. Analyses of different 10.2217/FON.13.150 © 2013 Future Medicine Ltd
studies have shown that no targeted agent seems to be superior to another in terms of overall survival in a first-line setting [10,11]. In this situation, it is likely that a strategy based on the administration of the most suitable agent for a patient, with the aim of assuring the best compliance, could offer a good quality of life while improving efficacy. To reach this goal, the patient must be considered as the center of the decision-making process, rather than planning a sequential strategy for all patients. Of note, a large proportion of mRCC patients are elderly and often present with a number of comorbidities; therefore, we believe that special recommendations on how to best manage elderly patients in clinical practice are required. In our opinion, a strategy that is not only based on guidelines and algorithms but that also highlights the clinical evaluation of the patient may be considered in the decision-making process. We have analyzed data from literature and matched them with the experience gained at our institution in daily clinical practice. We took into consideration information concerning age and comorbidities of the patients, and the toxicity profile of every agent. Future Oncol. (2013) 9(11), 1599–1607
Keywords elderly patient n metastatic renal cell carcinoma n sorafenib n sunitinib n targeted therapy n toxicity n
part of
ISSN 1479-6694
1599
Perspective
Verzoni, de Braud, Fabiani, Grassi, Testa & Procopio
Evidence acquisition
Data collection was based on a search of the PubMed and Medline databases for articles published up to 31 December 2012. Electronic early-release publications were also included. Only articles published in English were considered. The search method included terms used to describe the following topics: elderly patients, cardiac complications, hypertension, thromboembolism, infections, and liver and kidney function alterations. Papers were restricted to the treatment of mRCC with the following drugs: sunitinib, sorafenib, temsirolimus, bevacizumab plus interferon, everolimus and pazopanib. Elderly population
Elderly patients represent a consistent number of the cases of mRCC observed in clinical practice. They include patients who are 65 years of age or older and constitute 20–30% of the entire mRCC population. Despite this, elderly patients have been generally under-represented in Phase III clinical trials, which usually include a selected population of patients with a good performance status (0–1), no concomitant diseases and a median age of approximately 60 years. Therefore, the results collected in those trials are not immediately applicable to elderly patients. To our knowledge, so far no prospective clinical trials including this patient population have been designed. However, the safety profile plays a critical role when treating the elderly. In contrast to younger patients, even mild toxicities may represent obstacles to the therapy, especially when they develop at the same time. Table 1 summarizes the efficacy and all-grade safety data available regarding the use of new targeted agents in elderly patients. The experience acquired with sorafenib is the largest in clinical practice. The first published evidence concerns a post hoc analysis of a Phase III trial comparing 787 patients >70 years of age with 115 patients ≥70 years. A similar overall clinical benefit independent of age was identified in these two subgroups treated with sorafenib, and adverse events (AEs) were predictable and manageable regardless of age [3]. A second analysis of data from the American EAP trial, which evaluated 736 mRCC patients 70 years or older, with different histologies, ethnic groups and lines of treatment, did not show any statistically significant differences in terms of safety and progression-free survival. The frequency of treatment discontinuations, dose reductions, drug-related AEs and cardiotoxic events was similar in the two groups [12]. The 1600
Future Oncol. (2013) 9(11)
most frequent grade 3–4 AEs were rash/desquamation (5% in both groups), hand–foot skin reaction (8% in patients ≥70 years vs 10% in those
Future Oncology
Perspective
Patient approach in advanced/metastatic renal cell carcinoma: focus on the elderly population and treatment-related toxicity Elena Verzoni1, Filippo de Braud1, Francesca Fabiani2, Paolo Grassi1, Isabella Testa1 & Giuseppe Procopio*1 Department of Medical Oncology, Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milan, Italy 2 Department of Emergency–Urgency, San Giuseppe General Hospital, Viale G. Boccaccio, Empoli (Florence), Italy *Author for correspondence: Tel.: +39 0223904450 n Fax: +39 0223902149 n [email protected] 1
Recent therapeutic advances have changed the treatment landscape of metastatic renal cell carcinoma. Unfortunately, the seven agents now available are not based on biomarkers that would indicate which one could provide the best benefit for every patient. We have reviewed the available information concerning the impact of each treatment on comorbidities or status that are frequently seen before commencing treatment for the advanced disease: elderly and patients with cardiovascular complications, metabolic and endocrinology disorders, and infections, as well as impaired organ function (kidney, liver and heart). Additional new drugs will be launched, but no predictive biomarkers are available. Head-to-head studies to evaluate the safety of the different drugs are rare. In this quite complex scenario, we believe that a decision-making approach focused on the patient may represent a suitable strategy.
Until recently, immunotherapy was the only treatment available for metastatic renal cell carcinoma (mRCC). Following the introduction in the oncology therapeutic setting of the new-targeted agents, the oral active multikinase inhibitors (tyrosine kinase inhibitors; TKIs) sorafenib and sunitinib have represented a breaking point and a fundamental step forward in the treatment of mRCC. Paradoxically, we now have plenty of choice thanks to the longawaited availability of seven new therapeutic approaches [1] that have dramatically changed the possibility of treating this disease. Following approval by the US FDA and EMA in 2006 of sorafenib and sunitinib, which were the first two TKIs used for the treatment of mRCC, other different and important agents, such as mTOR inhibitors temsirolimus and everolimus, the monoclonal VEGF antibody bevacizumab, and, more recently, the two TKIs pazopanib and axitinib, have widened the therapeutic armamentarium [2–8]. Unfortunately, often these targeted therapies are not curative for mRCC patients. Despite considerable delayed tumor progression, complete and long-lasting responses are observed in less than 1% of cases [9]. Analyses of different 10.2217/FON.13.150 © 2013 Future Medicine Ltd
studies have shown that no targeted agent seems to be superior to another in terms of overall survival in a first-line setting [10,11]. In this situation, it is likely that a strategy based on the administration of the most suitable agent for a patient, with the aim of assuring the best compliance, could offer a good quality of life while improving efficacy. To reach this goal, the patient must be considered as the center of the decision-making process, rather than planning a sequential strategy for all patients. Of note, a large proportion of mRCC patients are elderly and often present with a number of comorbidities; therefore, we believe that special recommendations on how to best manage elderly patients in clinical practice are required. In our opinion, a strategy that is not only based on guidelines and algorithms but that also highlights the clinical evaluation of the patient may be considered in the decision-making process. We have analyzed data from literature and matched them with the experience gained at our institution in daily clinical practice. We took into consideration information concerning age and comorbidities of the patients, and the toxicity profile of every agent. Future Oncol. (2013) 9(11), 1599–1607
Keywords elderly patient n metastatic renal cell carcinoma n sorafenib n sunitinib n targeted therapy n toxicity n
part of
ISSN 1479-6694
1599
Perspective
Verzoni, de Braud, Fabiani, Grassi, Testa & Procopio
Evidence acquisition
Data collection was based on a search of the PubMed and Medline databases for articles published up to 31 December 2012. Electronic early-release publications were also included. Only articles published in English were considered. The search method included terms used to describe the following topics: elderly patients, cardiac complications, hypertension, thromboembolism, infections, and liver and kidney function alterations. Papers were restricted to the treatment of mRCC with the following drugs: sunitinib, sorafenib, temsirolimus, bevacizumab plus interferon, everolimus and pazopanib. Elderly population
Elderly patients represent a consistent number of the cases of mRCC observed in clinical practice. They include patients who are 65 years of age or older and constitute 20–30% of the entire mRCC population. Despite this, elderly patients have been generally under-represented in Phase III clinical trials, which usually include a selected population of patients with a good performance status (0–1), no concomitant diseases and a median age of approximately 60 years. Therefore, the results collected in those trials are not immediately applicable to elderly patients. To our knowledge, so far no prospective clinical trials including this patient population have been designed. However, the safety profile plays a critical role when treating the elderly. In contrast to younger patients, even mild toxicities may represent obstacles to the therapy, especially when they develop at the same time. Table 1 summarizes the efficacy and all-grade safety data available regarding the use of new targeted agents in elderly patients. The experience acquired with sorafenib is the largest in clinical practice. The first published evidence concerns a post hoc analysis of a Phase III trial comparing 787 patients >70 years of age with 115 patients ≥70 years. A similar overall clinical benefit independent of age was identified in these two subgroups treated with sorafenib, and adverse events (AEs) were predictable and manageable regardless of age [3]. A second analysis of data from the American EAP trial, which evaluated 736 mRCC patients 70 years or older, with different histologies, ethnic groups and lines of treatment, did not show any statistically significant differences in terms of safety and progression-free survival. The frequency of treatment discontinuations, dose reductions, drug-related AEs and cardiotoxic events was similar in the two groups [12]. The 1600
Future Oncol. (2013) 9(11)
most frequent grade 3–4 AEs were rash/desquamation (5% in both groups), hand–foot skin reaction (8% in patients ≥70 years vs 10% in those
