Advanced Age May Not Be an Absolute Contraindication for Radical Nephroureterectomy in Patients with Upper Tract Urothelial Carcinoma: A Single-Center Case Series and a Systematic Review with Meta-Analyses

Objective: This study aims to investigate whether advanced age is an absolute contraindication for radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) through a single-center case series and a systematic review with meta-analysis. Materials and methods: In the single-center case series, 588 UTUC patients who underwent RNU between May 2003 and June 2019 in West China Hospital were enrolled, and cancer-specific survival (CSS) was the primary outcome of interest. In the systematic review with meta-analysis, PubMed, Scopus, Embase, and Cochrane databases were systematically searched for related articles for further analysis. The endpoints for meta-analyses were overall survival (OS) and CSS. Results: The single-center case series included 57 (9.7%) octogenarians. The CSS of octogenarians after RNU was comparable to that of younger people. Advanced age (≥80) was not an independent risk factor for poor CSS (HR, 1.08; 95% CI, 0.48, 2.40). In a systematic review with meta-analysis, the cut-off value of advanced age is 70, and the results showed that advanced age was associated with inferior OS (pooled HR, 1.55; 95% CI, 1.29, 2.01) and CSS (pooled HR, 1.37; 95% CI, 1.08, 1.65). However, the subgroup analysis of countries found no positive correlation between advanced age and CSS (pooled HR, 1.33; 95% CI 0.92, 1.74) in Chinese. Conclusions: Advanced age may no longer be an absolute contraindication for RNU. RNU can be safely and effectively performed on UTUC patients of advanced age after a comprehensive presurgical evaluation.


Introduction
Urothelial carcinoma (UC) is the fourth most common malignancy in developed countries, and upper tract urothelial carcinoma (UTUC) only accounts for 5-10% of UC, with an estimated annual incidence of approximately 2 people per 100,000 [1,2].Radical nephroureterectomy (RNU), with or without adjuvant therapy, serves as the gold standard treatment for high-risk organ-confined UTUC, providing durable local control and maximizing survival expectations [2].Moreover, as upper tract urothelial carcinoma (UTUC) is most common in patients aged 70-90 years, the number of UTUC patients of advanced age worldwide is gradually increasing in the context of global aging.
Great advancements in anesthesia, surgical techniques (especially laparoscopy and robotics), and nursing during hospitalization have contributed to the theoretical and practical foundation of operations on elderly patients [3][4][5].Recently, a growing number of studies have reported similar survival outcomes between younger and older patients after surgery [6,7].However, whether RNU is a suitable and promising choice for patients of advanced age is heavily debated and remains unclear.
Therefore, the present study aims to investigate whether advanced age is an absolute contraindication for RNU by reporting the survival outcomes of UTUC patients with advanced age after RNU in Southwest China and placing our findings within the context of the literature by performing a systematic review and meta-analysis of studies on the topic of age and UTUC prognosis after RNU.

Methods and Materials
2.1.Single-Center Case Series 2.1.1.Patients and Data Our study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (2021-1209), and the informed consent was allowed to be waived because of the retrospective nature, anonymous patients, and data.We retrospectively collected UTUC patients who had undergone RNU between May 2003 and June 2019 in the West China Hospital of Sichuan University.We excluded those with incomplete long-term prognostic information, those with non-urothelial carcinoma confirmed by RNU pathology, and we also excluded those who had a previous neoadjuvant therapy history.Ultimately, 588 patients were eligible for inclusion in further analysis (Figure 1a).
Great advancements in anesthesia, surgical techniques (especially laparoscopy and robotics), and nursing during hospitalization have contributed to the theoretical and practical foundation of operations on elderly patients [3][4][5].Recently, a growing number of studies have reported similar survival outcomes between younger and older patients after surgery [6,7].However, whether RNU is a suitable and promising choice for patients of advanced age is heavily debated and remains unclear.
Therefore, the present study aims to investigate whether advanced age is an absolute contraindication for RNU by reporting the survival outcomes of UTUC patients with advanced age after RNU in Southwest China and placing our findings within the context of the literature by performing a systematic review and meta-analysis of studies on the topic of age and UTUC prognosis after RNU.

Patients and Data
Our study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (2021-1209), and the informed consent was allowed to be waived because of the retrospective nature, anonymous patients, and data.We retrospectively collected UTUC patients who had undergone RNU between May 2003 and June 2019 in the West China Hospital of Sichuan University.We excluded those with incomplete long-term prognostic information, those with non-urothelial carcinoma confirmed by RNU pathology, and we also excluded those who had a previous neoadjuvant therapy history.Ultimately, 588 patients were eligible for inclusion in further analysis (Figure 1a).We collected clinical and pathological data from our hospital database.Clinical data included chronological age in the year of surgery, gender, body mass index (BMI), hemoglobin and albumin within 1 week before RNU, the American Society of Anesthesiologists (ASA) score, the history of adjuvant systemic chemotherapy, and surgical techniques.Pathological data included tumor location, tumor size, pathological tumor stage and grade, lymph node status, lymphovascular invasion (LVI), tumor architecture and multifocality, and surgical margin.The pathological tumor stage and grade were both derived by an independent review of RNU specimens by our professional urogenital pathologists, according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system and the WHO/ISUP recommendation grading system, respectively.

Follow-Up and Endpoints
Approximately 2 to 3 weeks after RNU is the rational time for first follow-up, at which time the pathological reports of the RNU specimen, including the general report and immunohistochemical report, have been completed.The main project was to analyze the nature of the primary tumor and make individual therapy plans.Generally, the protocol of subsequent follow-up was in accordance with the European Association of Urology guidelines.The patients were followed up every 3 months in the first year, every 6 months in the second year, and then once every 2 years if there were no recurrence or We collected clinical and pathological data from our hospital database.Clinical data included chronological age in the year of surgery, gender, body mass index (BMI), hemoglobin and albumin within 1 week before RNU, the American Society of Anesthesiologists (ASA) score, the history of adjuvant systemic chemotherapy, and surgical techniques.Pathological data included tumor location, tumor size, pathological tumor stage and grade, lymph node status, lymphovascular invasion (LVI), tumor architecture and multifocality, and surgical margin.The pathological tumor stage and grade were both derived by an independent review of RNU specimens by our professional urogenital pathologists, according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system and the WHO/ISUP recommendation grading system, respectively.

Follow-Up and Endpoints
Approximately 2 to 3 weeks after RNU is the rational time for first follow-up, at which time the pathological reports of the RNU specimen, including the general report and immunohistochemical report, have been completed.The main project was to analyze the nature of the primary tumor and make individual therapy plans.Generally, the protocol of subsequent follow-up was in accordance with the European Association of Urology guidelines.The patients were followed up every 3 months in the first year, every 6 months in the second year, and then once every 2 years if there were no recurrence or uncommon symptoms.The routine contents of follow-up included a physical examination, routine blood and urine tests, a contrast-enhanced computed tomography scan of the chest and abdomen, and cystoscopy.
Cancer-specific survival (CSS), defined as the time from RNU to death related to UTUC, and cancer-specific mortality were included in our study as the endpoints.

Statistical Analysis
Analysis was performed using the software packages R 4.3.2(http://www.R-project.org; accessed on 21 September 2023, The R Foundation, Boston, MA, USA) and Empow-erStats 4.0 (http://www.empowerstats.com;accessed on 21 September 2023 X and Y Solutions, Inc., Boston, MA, USA).Continuous variables were expressed as medians with interquartile ranges (IQRs), and categorical variables were expressed as numbers with percentages.Significant differences between groups were determined by the χ 2 test and Mann-Whitney U test.CSS was calculated using Kaplan-Meier analysis, and the log-rank test was used for comparison.Cox proportional hazard models were used to investigate the associations of clinicopathological information with CSS by calculating HRs (95% CI).All statistical assessments were two-tailed and considered statistically significant at p < 0.05.

Systematic Review and Meta-Analysis
The conduct and reporting form of this meta-analysis were in accordance with the Meta-Analysis extension of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-NMA) reporting guidelines [8].The PRISMA checklist was provided in Supplementary Table S1.

Search Strategy and Selection Criteria
The PubMed, Scopus, Embase, and Cochrane databases were systematically searched for related articles.The predefined search terms are "UTUC," "upper tract urothelial carcinoma," "upper tract urinary carcinoma," "urothelial carcinoma," "renal pelvis and ureter tumor," "radical nephroureterectomy" and "RNU".Synonyms were combined by the Boolean operator (OR), and paratactic terms were combined by the Boolean operator (AND).
Population, intervention, comparison, outcomes, and study (PICOS) principles were used during the screening process [9], where PICOS stands for: population (P)-patients diagnosed with UTUC; intervention (I)-RNU surgery; comparison (C)-octogenarians and younger patients; outcomes (O)-cancer-specific mortality and CSS; and study designs (S)-retrospective comparative studies.The exclusion criteria were as follows: (a) age was regarded as a continuous variable; (b) not all patients had received RNU; (c) included patients with neoadjuvant therapy; and (d) there was no specific information on CSS.The specific screening flow chart is shown in Figure 1b.
The risk of bias was assessed independently by two investigators (JJY and XYL) using the Newcastle Ottawa Scale (NOS).The risk of bias was grouped into three categories, including "high quality" (points range: 7-9), "moderate quality" (points range: 4-6), and "low quality" (points range: 0-3).The disagreement was addressed by consulting with the co-authors.

Data Consolidation
We completed the complicated data synthesis process using StataMP 17 software.The HRs and 95% CIs of OS and CSS were obtained and pooled for analysis.The heterogeneity among studies was evaluated by the I 2 value.If the I 2 value was greater than 50%, the heterogeneity was considered to be significant, and a random effects model was used.Egger's and Begg's tests were utilized to evaluate the publication bias of our study.Subgroup analyses were performed on regions as well.The significant cut-off values of the p value were 0.05 for pooled results and 0.10 for publication bias.
There were 57 patients in the octogenarian group, with a median age of 83 (IQR: 81-85).There were 531 patients in the younger group, with a median age of 67 (IQR: 59-73).The octogenarian group had a significant association with lower BMI (p = 0.042), lower albumin (p = 0.019), a higher ASA score (p < 0.001), and an earlier tumor stage (p = 0.023).No significant differences were found for other characteristics (all p > 0.05).
Detailed clinicopathologic and laboratory characteristics are given in Table 1.

Survival Outcomes and Cox Regression
The median follow-up time was 59 months (IQR: 32-83).During this period, 220 (37.4%) patients died from UTUC.The Kaplan-Meier plots showed that, compared with the younger group, the patients in the octogenarian group showed no significant difference in CSS (p = 0.37) (Figure 2a).Similar results were also found in the subgroup analysis of tumor stage (p = 0.63 for pT < 3; p = 0.64 for pT ≥ 3) (Figure 2b,c).As shown in Table 2, tumors with advanced stage and grade, tumor size 3, papillary architecture, LNM, positive surgical margin, ureter location, a tients with anemia, lower albumin, and without adjuvant systemic chemothe were associated with poor CSS in the univariate Cox analysis (all p < 0.05).Th as many clinical indicators as possible, we included all variables whose p val As shown in Table 2, tumors with advanced stage and grade, tumor size greater than 3, papillary architecture, LNM, positive surgical margin, ureter location, as well as patients with anemia, lower albumin, and without adjuvant systemic chemotherapy history were associated with poor CSS in the univariate Cox analysis (all p < 0.05).Then, to include as many clinical indicators as possible, we included all variables whose p values were less than 0.10 in the multivariate Cox regression, and the results indicated that tumor stage, size, site, grade, and lymph node status were independently associated with CSS (all p < 0.05).However, age was not a significant risk factor in univariate or multivariate analysis (HR, 0.80, 95% CI, 0.50, 1.30, p = 0.376; and HR, 1.08, 95% CI, 0.48, 2.40, p = 0.853, respectively).

Systematic Review
The systematic search yielded a total of 2074 studies, of which 42 were found to be eligible after full-text evaluation (Figure 1b).The main characteristics of the included studies are summarized in Table 3.Among the 42 studies, the sample sizes ranged from 24 to 3544 patients, and a total of 22,490 UTUC patients after RNU were included.These studies were published between 2006 and 2023, and the patient recruitment periods ranged from 1987 to 2021.The median age ranged from 61.0 to 74.5 years, and the median follow-up time was between 18.0 and 82.8 months.
Interestingly, nearly all of the included studies (35/42, 83.3%) were Asian studies; three studies were global.It is noteworthy that only five studies (5/42, 11.9%) focused on the influence of the specific cut-off value of age on survival outcomes, while in others, age was just a baseline characteristic and happened to be a categorical variable.Although the age variable was noncontinuous in all the included studies, there was still a large difference among studies that emphasized dichotomous or multicategorical variables and their cut-off values.

Quality Assessment
NOS was used to evaluate the quality of the included studies, and the results are shown in Supplementary Table S2.High quality was determined to be high in 39 studies, moderate in 3 studies, and no study was marked as low quality.

Meta-Analysis
Considering the aim of the present study and the number limitation of the included studies with the same age cut-off value, we finally chose 70 as a relatively appropriate value, and the corresponding studies were subjected to meta-analysis.
Among the ten studies on CSS, two studies with similar regions and institutions and one study with information on cancer-specific mortality rather than CSS were excluded.Then, data from the remaining studies and data from our single-center case series (HR, 0.81, 95% CI 0.61-1.05)were used for meta-analysis, and the results indicated a significant association between age greater than 70 and poor CSS (pooled HR, 1.37, 95% CI 1.08-1.65).Significant heterogeneity was observed in the primary analysis (p = 0.001; I 2 = 70.0%)(Figure 3b).Interestingly, to explore the influence of region on the association of age with CSS, we extracted five studies from China, and the pooled HR estimate for CSS was 1.33 (95% CI, 0.92-1.74),indicating no clear correlation between age and CSS; there was high heterogeneity among these studies (p = 0.001; I 2 = 78.0%)(Figure 3c).
Due to the number restriction of the included studies, we utilized Egger regression to evaluate publication bias, and no obvious publication bias was observed in those studies (p = 0.193 for OS, p = 0.900 for CSS, p = 0.861 for sub-CSS).

Discussion
Population aging has posed a substantial challenge for the management of UTUC around the world.The increase in UTUC patients, characterized by localized lesions on first diagnosis, has been attributed to the strengthening of health awareness and widespread use of CT [1].In addition, advances in minimally invasive therapies (especially in laparoscopic and robotic technology) have assuaged concerns about conventional surgery, offered advantages associated with less blood loss, decreased pain, and faster operation time, and created an opportunity to perform surgery on elderly patients [52,53].However, the RNU for the aged UTUC patients is still controversial.
In the present study, we conducted a retrospective analysis to compare the survival outcomes (CSS) between octogenarians and younger patients and placed our findings in an international context by systematically reviewing the relevant literature.In our center, octogenarians with UTUC who underwent RNU showed a comparable outcome to younger UTUC patients.Further review of previous studies and meta-analyses indicated that advanced age (>70 years) tended to be related to poor OS and CSS.However, there was no significant association between advanced age and CSS in China.
Our results are in concordance with several single-and multi-institutional studies in which a negative association between the advanced age and prognosis of UTUC patients after RNU has been found [47,54].In contrast, several previous studies have shown that age was an independent predictor of long-term survival for UTUC patients, and advanced age was found to be associated with worse outcomes [55,56].However, few studies have been conducted on the topic of patient age, and our systematic review only found five studies on this topic.In 2009, a multicenter study of 1453 patients after RNU found that being older at the time of RNU was associated with inferior CSS, which was also observed by Stanley et al. in 2011 even after adjusting for tumor stage, grade, and treatment [12,56].In contrast, the latest publication, studied by Koterazawa et al., retrospectively included 283 UTUC patients after laparoscopic RNU and demonstrated that no significant difference in the incidence of postoperative complications and 5-year OS, CSS, and RFS was observed between octogenarians and younger patients [51].
There might be several sources of the between-study heterogeneity observed herein.First, the majority of the previous studies only investigated chronological age, and few studies have considered anesthetic risk, biological age, comorbidities, and other potential factors.In 2018, biological age, evaluated by the categories of hemoglobin and white blood cells, was reported to show a stronger relationship with outcomes than chronological age in UTUC patients, especially elderly patients [57].However, clinically, less aggressive, and nonstandard treatment regimens were recommended to patients based on their advancing age, and a patient's chronological age alone may prevent them from receiving the best care for their disease.According to the American Society of Clinical Oncology guidelines, geriatric assessment (GA) should be used as intended to guide treatment decisions for elderly patients (≥65 years old) with cancer to identify vulnerabilities [58].A recent study investigated the effects of age, ASA grading, and the Charlson Comorbidity Index (CCI) on UTUC outcomes and suggested that RNU should be a promising choice even among elderly patients who are eligible after GA [59].However, Phaibulvatanapong et al. reported that CCI might not be suitable for assessing the comorbidity of cancer patients because cancer is one of the grading factors, which could result in patients with metastatic disease receiving an unjustified high score [60].More future studies are needed to further explore and evaluate this in clinical practice.
In addition, the basic characteristics, such as race and region, may also cause selection bias.For UTUC, men in Europe and America typically have a 1.5-2.5 times higher risk than women, while in Asia, women have a 1.3 times higher risk than males [61][62][63].Furthermore, being male was found to be associated with adverse outcomes in China rather than America, and the black race was found to be relevant to adverse outcomes in America [55,64].This may partly explain the result of the pooled analysis that advanced age was significantly related to poor CSS, but the relationship disappeared when the region was restricted to China.However, in the above analysis, we failed to take gender and race into consideration.Sex in our center did not appear to be an independent predictor of CSS (HR 1.07; 95% CI 0.82, 1.40; p = 0.612), which was in line with most earlier studies.Interestingly, Kobayashi et al. evaluated the impact of gender-adjusted age on prognosis in upper tract urothelial carcinoma patients following RNU and demonstrated that older age was significantly associated with CSS independently of pathological features in male patients but not in female patients [28].Moreover, in 2013, Liu et al. reviewed the data from 285 men and 136 women treated with RNU for UTUC, and the results showed that the impact of gender on UTUC outcomes is age-specific [65].Females aged ≥59 years had worse outcomes than their male counterparts, while women <42 years and 42-58 years had better outcomes than men.Sex hormones and their receptors were thought to be the cause of gender differences in outcomes.Therefore, further research is needed to confirm whether sex-or age-specific sex has an effect on UTUC outcomes and to elucidate the molecular mechanism.
According to the EAU guidelines, the curative therapy for UTUC remains RNU, while nephron-sparing surgery or several novel technologies, such as ablation, are a choice for low-risk UTUC and patients with solitary kidney or severe renal impairment [2].Older patients should not be denied potentially curative surgery based solely on their age; instead, we should make every effort to assess the overall condition of older patients.Recently, other studies have also demonstrated that indicators that reflect preoperative inflammation or nutritional status, such as the neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio, are associated with worse outcomes in patients with carcinoma [66,67].Therefore, an authoritative evaluation system or nomogram aimed at identifying a special population of elderly patients who can benefit from RNU is urgently needed to guide clinical practice.
Notably, the strength of our study was that we provided a comprehensive reference about the relationship between the chronological age of UTUC patients at the time of RNU and survival outcomes and suggested that advanced age may not be an absolute contraindication for RNU by combining our single-center findings with a systematic review as well as a meta-analysis.Nonetheless, our study had some limitations.For our cases, the small size of octogenarians and the absence of specific comorbidities, due to the retrospective setting, are the most notable.Moreover, studies that focused on the influence of age were scarce, and age tended to be a continuous variable in most studies.The cut-off value for age in the pooled analysis was 70, which was limited by the number of included studies.However, it is relatively common for patients with newly diagnosed UTUC to be older than 70 years, whereas we were interested in the age of 80 years, which limits the external application of the conclusions of our study.Admittedly, in this single-center case series, we only chose the ASA score to reflect the general condition of patients from the perspective of tolerance to anesthesia.However, some novel indicators, which were determined by preoperative status and previously reported to influence the prognosis of UTUC patients, were not included in our analysis.These indicators included body composition based on computed tomography scans (e.g., iliopsoas muscle area, visceral fat density, intermuscular fat area, muscle attenuation, etc.), preoperative nutrition and inflammatory status (e.g., Naples prognostic score, controlling nutritional status score, prognostic nutritional index, etc.), and other indexes (e.g., CCI, modified frailty index, etc.).We are conducting a prospective, multicenter study with improved baseline balance and more complete basal characteristics to address these limitations.

Conclusions
Our single-center case series and the systematic review indicated that advanced age may not be an absolute contraindication for RNU in UTUC patients.RNU can be a safe and effective choice for UTUC patients of advanced age after a comprehensive presurgical evaluation.

Figure 1 .
Figure 1.(a) The specific screening flow chart of included patients.(b) The specific screening flow chart of included studies.

Figure 2 .
Figure 2. Survival rates for the octogenarians and younger patients: (a) in the whole tumor stage < T3; (c) tumor stage ≥ T3.

Table 1 .
The clinical and pathological characteristics of patients.

Table 2 .
Univariate and multivariate analyses of cancer-specific survival.

Table 3 .
The characteristics of the included studies.