Abstract
Background/Aim: The role of cytoreductive nephrectomy (CN) for metastatic renal cell cancer (mRCC) is not clearly understood after the approval of targeted therapies, particularly in the elderly population. The aim of this study was to compare survivals between patients who did and did not receive CN. Patients and Methods: The SEER-18 database was utilized in order to identify elderly patients with mRCC to compare overall survival (OS) and cancer-specific survival (CSS) between patients who did or did not receive CN between February 2006 and 2012. Kaplan–Meier curve and log rank test were used to compare OS and CSS between these two arms. Cox proportional hazard model was used for multivariate analysis and statistical significance was defined as p≤0.05. Results: There was a significant survival benefit for those who received CN compared to those who did not receive CN (median OS: 18 months vs. 4 months, p<0.001; median CSS: 21 months vs. 5 months, p<0.001). Conclusion: CN offered significant survival benefit, even in elderly patients with metastatic renal cell cancer.
People older than 65 years are the fastest growing segment of the population in the United States of America. This segment is projected to reach 21 percent by 2050 (1). Renal cell carcinoma (RCC) is a disease of elderly and is most frequently diagnosed among patients between 65-74 years of age (2, 3). In the interferon era, cytoreductive nephrectomy (CN) was associated with a significant survival benefit when used in combination with interferon immunotherapy in patients with metastatic renal cell carcinoma (mRCC). This benefit was demonstrated in two randomized controlled trials (4, 5). A combined analysis of these two major prospective trials (4, 5) performed by Flanigan et al. demonstrated a median survival of 13.6 months for the nephrectomy plus interferon group vs. 7.8 months for the interferon group alone (1).
However, the role of CN in mRCC patients is not clearly understood following the approval of targeted small-molecule tyrosine kinase inhibitors in the early 2000s. In this targeted era, rates of CN have steadily declined and older age has been identified as an independent factor associated with decreased receipt of CN (6, 7). To our knowledge, the role of cytoreductive nephrectomy in elderly patients has never been investigated at a population level. Considering renal cell carcinoma (RCC) occurs predominantly in the elderly population (2), survival outcomes (CN vs. no CN) among elderly patients with mRCC at a population level in the targeted era were evaluated.
Patients and Methods
The National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) database is a population-based database and embodies approximately 28% of the United States population (8). The SEER-18 registry includes Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah, Los Angeles, San Jose-Monterey, Rural Georgia, Alaska Native, Greater California, Greater Georgia, Kentucky, Louisiana, and New Jersey Tumor Registries. Since the registry contains de-identified dataset, local institutional Review Board approval was waived.
The SEER-18 database was utilized to identify elderly (≥65 years of age) patients with mRCC as the first primary malignancy. “Renal carcinoma” was selected from the ICCC site recode extended ICD-3-/WHO 2008 and ICD-3-0 histological code 8050/3, 8260/3, 8310/3, 8312/3, 8317/3, 8318/3 and 8319/3 to identify patients with papillary, clear cell, chromophobe, sarcomatoid and collecting duct carcinoma types of RCC. Inclusion criteria were: patients whose disease was histologically confirmed, were actively followed, had a known age and were included in the research database. Patients whose diagnosis was made from a death certificate or at autopsy along with those still living but with no survival data were excluded. See Figure 1 for CONSORT diagram.
To limit the heterogeneity with targeted agent use, the targeted era was defined as February 2006 to December 2011 as sunitinib was approved for use in mRCC by the Food and Drug Administration in January 2006.
The design of the study was a retrospective, population-based, case-control study. The treatment arm included patients receiving CN, while the control arm included patients not receiving CN (no CN). Patients were considered to have received CN if they had partial, subtotal, total, radical nephrectomies or nephrectomy NOS. Patients with segmental resection or wedge resection were coded with the same code for site specific surgery as local tissue destruction in the SEER database so this subset were not included in cytoreductive nephrectomy group. Kaplan-Meier curve (3-year) and log rank test were used to compare overall survival (OS) and cancer-specific survival (CSS) between these two arms. Cox proportional hazard model was used for multivariate analysis and statistical significance was defined as p≤0.05.
Results
In total, 3,376 elderly patients with mRCC who met the inclusion criteria were identified in the SEER database between 2006 and 2012 and analyzed. Of them, only 32.8 % (n=1,110) received CN. The demographics of the study are summarized in Table I.
There was a significant survival benefit for those who received CN as compared to those who did not receive CN (Median OS: 18 months vs. 4 months, p<0.001; Median CSS: 21 months vs. 5 months, p<0.001) (Figure 2). After adjusting for age, sex, race, T-stage, N-stage, histology subtype and year of diagnosis, patients receiving CN had significantly better 3-year OS and 3-year CSS compared to patients not receiving CN with a Hazard Ratio (HR) of 0.43, 95%CI=0.39-0.47, p<0.001 and HR of 0.44, 95%CI=0.39-0.49, p<0.001 respectively. Among patients who received CN, younger age at diagnosis, race other than Caucasians and African Americans and zero nodal (N0) stage were found to be independent factors predicting better OS (Table II).
Discussion
Our study demonstrates a substantial survival benefit with CN in elderly patients with mRCC in the targeted era, after adjusting for other factors. To our knowledge, this is the largest population-based study to date showing survival benefit with CN specifically in the elderly population. Two retrospective studies utilizing the National Cancer Data Base (NCDB) and the SEER database also showed a significant survival benefit with cytoreductive nephrectomy in targeted therapy era (10, 11). However, these studies did not look at survival benefit specifically for the elderly population.
Despite lack of sound evidence, elderly patients are perceived to be less able to tolerate standard treatment by their providers. Overall CN is generally a safe procedure with excellent reported perioperative outcomes (12). A study utilizing US-based Nationwide Inpatient Sample registry showed that patients with advanced age (≥75 years) were more likely to acquire operative mortality (13). However, this study had a significant limitation of lack of adjustment for case complexity and performance status. Matin et al. suggested that for patients undergoing laparoscopic urological surgery, age ≥65 years does not increase the risk of intraoperative, postoperative or late operative complications (14). Furthermore, Burdjis et al. demonstrated that advanced age (≥75 years) alone was not associated with significant mortality and morbidity as compared to younger patients (15).
There are other studies suggesting older age as an independent factor for perioperative complications (16, 17). Elderly patients with low physiological reserve, multiple comorbidities and poor performance status are more likely to have worse operative outcomes. Physiological age, underlying comorbidities and performance status should therefore be the guiding factors for selecting patients for CN and not just the chronological age.
CARMENA (Clinical Trial to Assess the Importance of Nephrectomy) and SURTIME (Immediate surgery or surgery after sunitinib malate in treating patients with metastatic kidney cancer) are two large randomized phase III trials that are investigating the role of CN in the targeted era. Elderly patients with ECOG performance status of 0-1 and life expectancy of at least 3 months are included in these trials (22, 23). The final results of these trials will potentially give us definitive guidance about the role of CN in the elderly population. Interestingly though, results of the Checkmate-214 study comparing the combination immunotherapy nivolumab and ipilumumab to sunitib in the front line setting of mRCC are available now and may change the treatment paradigm of mRCC in the near future (24). The study showed superiority of immunotherapy over sunitinib in terms of ORR and PFS and OS in the intermediate and poor risk groups. Future studies analyzing the benefits of CN with the use of immunotherapy are likely to be needed.
The SEER database is large and comprehensive. It includes approximately 28% of the United States population and is comparable to the general United States population with regard to measures of poverty and education (18). Because of its generalizability, we were able to evaluate the impact of treatment at a population level outside of randomized clinical trials. These are the major strengths of our study.
Our study is limited by lack of prospective randomization, a product of its retrospective study design. It is important to note that allocation of patients to CN is not randomized, potentially leading to selection bias and hence overestimating the benefit of CN. Moreover, patients with mRCC are more likely to have one or more adverse prognostic factors including poor performance status, elevated LDH, anemia, hypercalcemia, bone metastasis and more than one sites of metastasis (19-21) and the SEER database lacks individual patient information on these parameters.
In summary, our data support that CN remains an independent predictor of OS in the targeted era even in the elderly population over the age of 65. It should be a serious consideration in elderly patients, particularly with excellent performance status.
Footnotes
Conflicts of Interest
No Authors have relevant disclosures to report.
- Received March 15, 2018.
- Revision received March 27, 2018.
- Accepted March 28, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved