The effect of cytoreductive partial nephrectomy in elderly patients with metastatic renal cell carcinomaa systematic review

Background To explore the survival value of cytoreductive partial nephrectomy (cPN) in elderly metastatic renal cell carcinoma (EmRCC).Methods RCC patients aged ≥65 years from 2010 to 2015 in The Surveillance, Epidemiology and End Result database (SEER) were analyzed using Kaplan-Meier (K-M) method and multivariate COX analysis. Propensity score matching (PSM) was performed to balance effects of confounding factors such as general features and pathological features. We were committed to study the long-term survival advantages of cPN patients, explore the appropriate population of cPN, and try to establish a Nomogram model to predict individual survival.Results In EmRCC patients, especially in male patients with tumors size ≦7cm, N0 stage, or isolated metastases, cPN brought a better survival than cytoreductive radical nephrectomy (cRN). Tumor size and N stage were independent risk factors affecting the survival of cPN patients, cPN in patients with tumor size >7cm or N1 stage may present a higher risk of death.Conclusions The implementation of cPN in EmRCC patients who meet specific clinical characteristics like tumors size ≦7cm, N0 stage, or isolated metastases seems to help improve the tumor outcomes.


Background
With the aggravation of global aging, the proportion of the elderly in renal cell carcinoma (RCC) patients is increasing [1]. Authoritative guide provides a lot of guidelines for the management of RCC patients, but the treatment recommendations for elderly patients are often the same as for young people, ignoring the elderly with low glomerular filtration rate baseline, high proportion of cardiovascular disease and low drug toxicity tolerance. It needs to strengthen the individualized guidance for the management of cancer in this part of the population.
The release of CARMENA trial results challenged the role of cytoreductive nephrectomy (CN) in metastatic RCC (mRCC) [2]. But it is undeniable that the trial has been criticized for some selection bias with slow and incomplete recruitment and incorporating too many high-transfer cases and patients with poor prognosis [3,4]. Therefore, the trial could not reduce the value of CN in mRCC patients with intermediate-risk disease [5,6].
Cytoreductive radical nephrectomy (cRN) and cytoreductive partial nephrectomy (cPN) are two major surgical methods of CN, and the application of cPN in mRCC has been increasing year by year [7]. It is generally believed that compared with cRN, cPN can not only reduce tumor burden equally [8], but also better protect renal function, reduce the occurrence of long-term cardiovascular diseases, and increase patients' tolerance to systemic therapy drugs, which is conducive to long-term survival [9,10]. However, the risk of increased perioperative complications and prolonged operative time is equally worrying. As a result, elderly metastatic renal cancer (EmRCC) is often considered to have worse long-term survival and lower resistance to surgical risks, so it is directly abandoned for surgery or rarely considered for cPN treatment [11].
Up to now, there is a lack of systematic prospective studies on the treatment of EmRCC population, and the retrospective analysis of a single center often has the defect of a small number of cases [12]. Based on the extensive representation of SEER database, this study attempts to explore the value of cPN in EmRCC from the perspective of population epidemiology beyond clinical trials.

Methods
Patients aged ≥65 was defined as the elderly [1,12], and EmRCC population was searched from the Surveillance, Epidemiology and End Result database (SEER) between 2010-2015, eliminating patients diagnosed of "autopsy" or "death certificate", "source information unknown" and "incomplete follow-up information".
Cell classification was performed according to Fuhrman grade and TNM staging was conducted according to AJCC 2007th edition. Histologic type was divided into two categories: "clear cell renal cell carcinoma (ccRCC)" and "other". According to the metastasis of liver, lung, bone and brain, metastasis sites were divided into two parts: "isolated site group" and "multiple sides group".
With the help of IBM SPSS Statistics 24.0 software, the Kaplan-Meier (K-M) method was applied to perform single-factor survival analysis of variables, and screened variables with the P<0.05 into Cox regression model to evaluate independent risk factors for overall survival (OS). Propensity score matching (PSM) was used to balance effects of confounding factors such as general features and pathological features, and to compare the difference of OS between cPN and cRN [13]. The Nomogram model was constructed using the R language (version 3.5.1; R Foundation; Foreign package, survival package and rms package) to estimate the survival rate and internal verification was conducted [14].  Table 1

Discussion
With the progress of global aging, the number of elderly patients in metastatic renal cancer is increasing. Older patients have many characteristics of their own, such as visceral reserve dysfunction, more toxic side effects and poorer tolerance on drug treatment, as well as shorter natural lifespan, seemingly unable to enjoy the benefits of long-term survival of cPN [1]. Although the authoritative guidelines have various norms for the treatment of RCC, they often confuse the elderly with the young patients and lack more personalized guidance for the elderly. It is urgent to increase the research on this part of patients.
The release of the CARMENA trial has weakened the value of CN in the age of vascular targeted therapy [2]. However, due to the limitations of patient selection bias in this trial, and considering that some patients lack a good economic basis to bear the high cost of vase-targeted drugs, CN still has a unique position in the treatment of metastatic renal cancer [3][4][5]. In recent years, cPN has replaced cRN in the treatment of RCC with tumor size ≤4cm, becoming the gold standard for surgical treatment. Even in tumor size >7cm of RCC, some scholars have tried PN to achieve clinical efficacy comparable to RN [15]. Due to poorer baseline kidney function in elderly patients, PN can lead to better long-term renal function protection [9,16], which not only reduce the risk of chronic kidney disease progression and the incidence of cardiovascular events [8,17], but also enable patients to better tolerate the toxic side effects of systemic drug therapy such as vascular targeted therapy, immunotherapy, and thus may have better prospects in metastatic RCC [18].
Our study found that the long-term survival of surgical patients in EmRCC was better than that of non-surgical patients, which was consistent with other research results [19][20][21].
Moreover, all the subjects were EmRCC patients who underwent CN in the database, which Admittedly, retrospective analysis based on SEER database has certain limitations. For example, there is a lack of physical function scores such as Karnofsky score or ECOG score, as well as information related to simultaneous or subsequent targeted vascular therapy and immunotherapy, which makes our conclusion biased to some extent. However, due to the lack of large-scale prospective studies for CN treatment in EmRCC population, and our research is based on a large epidemiological database, the conclusions are still of special value, which can assist in the development of clinical practice, research trials and guidelines for this special population.

Conclusions
In our study, we found that: 1. In EmRCC, the MST of cPN seems to be superior to cRN, especially in males, tumor size ≦7cm, N0 stage or isolated metastasis.