Abstract
Introduction: Epidemiological outcomes of renal cell carcinoma (RCC) remain sparse. This study aims to compare preoperative characteristics, surgical outcomes, and oncological outcomes of RCC patients at a urology unit in Singapore.
Methods: A retrospective cohort analysis of 137 RCC patients in the National University Hospital of Singapore who had undergone partial nephrectomy between 2009 and 2020 was conducted. χ2 tests (Chi-Square Test, Fisher’s Exact Test) and one-way analysis of variance (ANOVA) were used for comparing categorical and continuous variables respectively. Kaplan-Meier estimates were used for survival analysis.
Results: In total, 137 patients were identified (Chinese [n=82], Malay [n=19], Indian [n=15], Others [n=21]). Indian patients were diagnosed at an earlier age (52.13±10.52 years, P=0.018). A larger percentage of Malay patients (78.9%, P<0.001) were operated on before 2016, prior to the center’s adoption of the robotic surgical technique. More Malay and Indian patients underwent laparoscopic surgery (36.8% and 46.7%, P=0.008), experiencing higher rates of intra-operative conversions compared to the Chinese and other ethnicities (5.3% and 13.3% vs. 0%, P=0.011). They also had longer post-operative stays compared to Chinese (7.42±6.46 days; 7.40±7.69 days vs. 4.88±2.87 days, P=0.036). Malays were much less likely to undergo robotic partial nephrectomy compared to Chinese patients (OR=0.295, 95% CI=0.102-0.856) and had the highest rate of metastatic recurrence (10.5%, P=0.023).
The global distribution of renal cell carcinoma (RCC) is notable, comprising 3.5% of all malignancies. It is the third most common cancer of the urinary tract, accounting for over 400,000 new diagnoses in 2020. Despite numerous advancements in diagnosis and treatment,1 it has been rising in incidence globally amidst the increasing prevalence of risk factors such as smoking, obesity, hypertension, and chronic kidney disease (CKD); the routine use of abdominal imaging in many settings has also contributed to higher detection rates.2,3 Within the local context, the situation is likewise - Singapore witnesses one of the highest mortality rates from RCC within the Asian region (3.3 per 100,000).4 Although outcomes of RCC in Singapore have been previously described in the literature,3,5 there is a paucity of studies reporting on ethnicity-stratified outcomes.6 This is of particular relevance to the multi-racial, multi-cultural society upon which Singapore prides itself. Our nation is enriched with a diversity of ethnic groups – namely the Chinese (74.3%), Malays (13.5%), Indians (9.0%), and the respective minority ethnicities (3.2%). Hence, ethnicity-centric studies serve to supplement the local healthcare system with up-to-date epidemiological data that translate into optimal healthcare services for the population. By identifying pertinent disparities, authorities are better able to then make informed choices and strive towards creating equitable healthcare access for all. As the epidemiological prevalence of RCC and its outcomes within Singapore remain sparse, we aimed to describe the preoperative characteristics and surgical and oncological outcomes of patients with localized RCC managed in a tertiary urology unit (National University Hospital) in Singapore, across different ethnicities.
Methods
Domain Specific Institutional Review Board approval was obtained for the conduct of this study (Reference Number 2016/01304). Clinical information of 137 patients who underwent partial nephrectomy for diagnosed RCC at the National University Hospital, Singapore, between October 2009 and December 2019, were retrospectively collected. The inclusion criteria was localized RCC (cT1 to T3) managed with partial nephrectomy. All partial nephrectomies were performed by either an open manner or laparoscopically, either with or without the assistance of a Da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA). Data obtained included baseline patient demographics (age at diagnosis, gender, ethnicity), clinical (pre-operative kidney function), surgical (operative approach, operative time, blood loss, post-operative complications), and oncological (pathological size and stage, histology) characteristics, as well as recurrence and survival outcomes.
Patients were followed up until death or until the last documented follow-up visit according to surveillance protocol recommended by the European Association of Urology based on the UCLA Integrated Staging System for Renal Cell Carcinoma. Imaging was performed with computed tomography scans of the abdomen and pelvis, together with a computed tomography scan of the chest or a chest radiography. When clinical recurrence was suspected, further evaluation of the possible metastases was performed with radionuclide bone scans or fluorodeoxyglucose (FDG)-positron emission tomography scans. All patients were categorized based on their ethnicity (Chinese, Malay, Indian, Others). Minority groups included Vietnamese, Filipinos, Arabs, and Sikhs. Clinical, surgical, and oncological end-points were compared across all racial groups.
Statistical Analysis
Data are presented as mean (standard deviation [SD]) for continuous variables and frequencies with percentages (%) for categorical variables. Chi-squared test (or Fisher’s Exact Test, where applicable) were used for comparison of categorical variables, while one-way analysis of variance (ANOVA) was used to compare between continuous variables. Survival estimates were assessed using Kaplan-Meier survival curves. Additionally, binomial logistic regression was conducted to identify significant predictors of access to minimally invasive (robotic) surgery, presented as odds ratios (ORs) with 95% confidence intervals (95% CI). All statistical analyses were performed on SPSS version 26.0 (IBM, Armonk, New York, USA).
Results
A total of 137 RCC (Chinese [n=82], Malay [n=19], Indian [n=15], Others [n=21]) patients who had undergone partial nephrectomy were included in the study. Baseline characteristics are detailed in Table 1. The mean follow-up period was 27.4 months. Indians were diagnosed at earlier age compared to other ethnicities (52.13 ± 10.52 years). There were no significant differences in other pre-operative aspects (American Society of Anesthesiology scoring) and pre-morbid characteristics (gender, body mass index, co-morbidities) across all ethnicities.
Baseline characteristics
Oncological features were similar as well (Table 2). Anatomical complexity of the tumors, assessed by the RENAL nephrometry score,6 did not vary significantly across all groups. Majority of RCCs were pT1a, and no one ethnicity saw a greater proportion of higher pathological tumor staging. Histologically, most tumors were clear-cell RCCs (Chinese, 80.5%; Malay, 78.9%; Indian, 80%; Others, 76.2%: P=0.634) and largely had negative surgical margins upon resection (Chinese, 86.6%; Malay, 78.9%; Indian, 86.7%; Others, 76.2%: P=0.218).
Comparison of oncological characteristics
Surgical characteristics and post-operative outcomes are detailed in Table 3. When comparing operative approach, a higher proportion of Malays and Indians underwent laparoscopic surgery (36.8% and 46.7%, respectively; P=0.008), subsequently experiencing a greater rate of intra-operative conversions compared to the Chinese and other ethnicities (5.3% and 13.3% vs. 0%; P=0.011). Though operative time did not differ significantly across all racial groups, Malays experienced marginally longer operative duration (251.16 ± 67.91 minutes). Likewise, intra-operative blood loss amounts were comparable across all ethnicities. Interestingly, even though rates of post-operative complications (defined by Clavien-Dindo classification) were not significantly higher in any particular ethnicity and were seen in approximately a third or more of patients within each group, Malays and Indians had longer post-operative lengths of hospital stay (7.42 ± 6.46 days and 7.40 ± 7.69 days, respectively; P=0.036). Post-operative changes in biochemical parameters (estimated glomerular filtration rate, creatinine, urea, hemoglobin) were consistent across all groups.
Comparison of surgical characteristics and oncological outcomes
Pertaining to long-term oncological outcomes, four patients (one Chinese, two Malay, one Indian) experienced local recurrence of disease while three patients (two Malay, one Indian) had metastatic recurrence. The rates of metastatic recurrence within each group differed significantly, with the Malay ethnicity demonstrating highest systemic recurrence rates (10.5%, P=0.023). There were four deaths, two of which died of causes directly attributable to RCC, two of whom passed away of unrelated causes of metastatic colorectal carcinoma and ischemic heart disease. Overall survival (P=0.079), local recurrence-free (P=0.304), and systemic recurrence-free survival (P=0.103) did not demonstrate statistically significant differences between all ethnic groups. Kaplan-Meier survival curves of these endpoints are depicted in Figures 1, 2, and 3 accordingly. Median time to local and systemic recurrence was 19.2 months and 26.5 months respectively.
Overall survival
Local recurrence-free survival
Metastasis-free survival
From 2016 onwards, the adoption of robotic-assisted surgery within our center began to take flight, witnessing a gradual rise in robotic cases. This was met with a corresponding decline in open and solely laparoscopic surgery. However, beyond the surgical benefits that robotic surgery confers to both the surgeon and the patient, well-documented drawbacks include cost affordability, thus inequality in patient care. As such, we sought to hypothesize if ethnicity might be a significant predictor of access to robotic surgery, contextualized to a first-class healthcare institution within Singapore. Table 4 details the logistic regression analysis of possible predictor variables. Of all, ethnicity and the year of surgery were statistically significant for patients’ access to robotic surgery. Patients undergoing surgery for RCC after 2016 were 18.954 times more likely to undergo robotic surgery compared to patients who were operated on prior to 2016 (OR: 18.954, 95% CI: 7.626 – 47.112). In general, Malays were much less likely to undergo robotic partial nephrectomy compared to the Chinese, which is taken as the reference standard (OR: 0.295, 95% CI: 0.102 – 0.856).
Predictors of access to robotic partial nephrectomy
Discussion
This retrospective cohort study provides a comprehensive review of the landscape of partial nephrectomies for RCC in a single institution, across a 10-year period. The ethnic composition of 59.9% Chinese, 13.9% Malay, 10.9% Indian, and 15.3% other races differs slightly from the population estimates of Singapore (74.3% Chinese, 13.5% Malay, 9.0% Indian, and 3.2% other races).7 Moreover, a study of RCC in Singaporean patients from 2001 to 2010 reported a cohort of 80.8% Chinese, 6.5% Malay, 4.6% Indian, and 8.1% other races.8 The relatively higher number of patients from other races and lower percentage of Chinese patients in our study could be due to medical tourism from regional countries, but the proportion of Chinese patients still trended as the majority ethnicity, similar to that of the general population.
The incidence of significant post-operative complications (as defined by Clavien-Dindo classification grades III-V) was 9.5% across all racial groups. Although no differences between ethnicities were observed, this was notably higher than the rates reported in a multicenter Italian cohort of 979 patients that underwent partial nephrectomy9 (3.5%).9 The complication rate for the laparoscopic approach has been estimated at 23%10 and that of the robotic approach at 5.6%.11 Although information on specific complications were unavailable, this may reflect the learning curve required for robotic surgery, which formed the majority of our cohort (54.7%).12,13 Moreover, the longer duration of postoperative hospital stay for Malays and Indians may be attributed to the relatively higher rates of conversion to open surgery, which entails a higher morbidity and corresponding adverse impact on post-operative recovery.
On the other hand, overall survival in this study ranged from 94.7%–100% at 1 year and 89.5%–100% at 5 years, which is numerically on par with recent studies in the literature.14-16 There was also no significant all-cause mortality difference between ethnicities, showing that similar outcomes were achieved despite the disparities in access to robotic surgery. Of the deaths in this study, only two were attributed to RCC; the low rates of local recurrence (four patients, 2.9%) and metastasis (three patients, 2.2%) also suggest that most tumors achieved adequate resection margins. The first robotic urological surgery in Singapore was performed in 2003,17 but subsidization for such procedures at our center only began in 2016. The presence of such subsidies likely led to the higher rates of robotic partial nephrectomy observed in our cohort after that year. Similar subsidies have been seen in other Asian countries such as Hong Kong and Malaysia.18 The introduction of these subsidies in the public sector has alleviated the burden of medical bills on patients. In turn, more patients are opting for robotic surgery, and this had led to higher caseloads for surgeons trained in the procedure. Given that a learning curve exists for robotic nephrectomy, this is likely to lead to improvements in postoperative outcomes for patients with increasing institutional experience.12,13 Interestingly, some ethnicity-specific disparities were seen in access to robotic partial nephrectomy. This may be attributed to a heterogeneous make-up of each ethnic cohort, comprising not only local citizens but also foreigners as well. Consequently, their nationality may serve as a barrier to accessing relatively costlier options like robotic surgery. For instance, within the context of Singapore, government subsidies for robotic operations are available to citizens or permanent residents but not foreigners, which may lead them to opt for an open nephrectomy instead. Nonetheless, it is hoped that improvements in healthcare services and increased governmental support for medical subsidies will smooth out these differences and provide more equitable care.
This study was not without limitations. Our cohort was derived from a single tertiary center in Singapore, and the outcomes of this study may not be generalizable to patients in other countries. Given the differing institutional expertise, available equipment, and sources of financial aid available in various countries, the prevalence and outcomes of minimally invasive techniques such as laparoscopic or robotic surgery are expected to differ. Moreover, the small sample size of this study precludes in-depth analysis of outcomes such as intraoperative conversion, local recurrence, systemic metastasis, and cancer-specific mortality, given that some outcomes had zero patients reaching the endpoint. Although this may be truly reflective of advancements in surgical technique and in-hospital care, larger cohorts are needed to conclusively support this point.
Conclusion
In conclusion, this retrospective single-institution study of partial nephrectomy for RCC provides a comprehensive survey of the clinical, operative, and postoperative characteristics stratified by ethnicity. Although there were some differences in age of diagnosis, access to robotic surgery, and length of hospitalization, outcomes were generally favorable with low rates of post-operative complications, local or metastatic recurrence, and overall mortality.
- Received December 6, 2022.
- Revision received May 10, 2023.
- Accepted May 17, 2023.
References
- 1.↵Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, Bray F. International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol. 2015;67(3):519-530. doi:10.1016/j.eururo.2014.10.002.
- 2.↵Rossi SH, Klatte T, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol. 2018;36(9):1341-1353. doi:10.1007/s00345-018-2286-7.
- 3.↵Lim EJ, Fong KY, Li J, Clinicopathological features of non-conventional renal cell carcinoma histological subtypes: Learning points from a large contemporary series spanning over three decades. Investig Clin Urol. 2022;63(2):151-158. doi:10.4111/icu.20210373.
- 4.↵Capitanio U, Bensalah K, Bex A, Epidemiology of Renal Cell Carcinoma. Eur Urol. 2019;75(1):74-84. doi:10.1016/j.eururo.2018.08.036.
- 5.↵Yip SK, Cheng WS, Tan BS, Li MK, Foo KT. Partial nephrectomy for renal tumours: the Singapore General Hospital experience. J R Coll Surg Edinb. 1999;44(3):156-160.
- 6.↵Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol. 2009;182(3):844-853. doi:10.1016/j.juro.2009.05.035
- 7.↵Singapore Department of Statistics (SingStat). Singapore Department of Statistics Census of Population 2020. Available at: https://www.singstat.gov.sg/-/media/files/publications/cop2020/sr1/cop2020sr1.ashx. Accessed 21 June 2022.
- 8.↵Ezenwa EV, Tan YH. Ethnic variation of the histological subtypes of renal cell carcinoma in Singapore. African Journal of Urology. 2014;20(4):184-188. doi:10.1016/j.afju.2014.08.006.
- 9.↵Mari A, Antonelli A, Bertolo R, Predictive factors of overall and major postoperative complications after partial nephrectomy: Results from a multicenter prospective study (The RECORd 1 project). European Journal of Surgical Oncology (EJSO). 2017;43(4):823-830. doi:10.1016/j.ejso.2016.10.016.
- 10.↵Tachibana H, Takagi T, Kondo T, Ishida H, Tanabe K. Robot-assisted laparoscopic partial nephrectomy versus laparoscopic partial nephrectomy: A propensity score-matched comparative analysis of surgical outcomes and preserved renal parenchymal volume. Int J Urol. 2018;25(4):359-364. doi:10.1111/iju.13529.
- 11.↵Connor J, Doppalapudi SK, Wajswol E, Postoperative Complications After Robotic Partial Nephrectomy. J Endourol. 2020;34(1):42-47. doi:10.1089/end.2019.0434.
- 12.↵Zeuschner P, Meyer I, Siemer S, Three Different Learning Curves Have an Independent Impact on Perioperative Outcomes After Robotic Partial Nephrectomy: A Comparative Analysis. Ann Surg Oncol. 2021;28(2):1254-1261. doi:10.1245/s10434-020-08856-1.
- 13.↵Motoyama D, Matsushita Y, Watanabe H, Initial learning curve for robot-assisted partial nephrectomy performed by a single experienced robotic surgeon. Asian J Endosc Surg. 2020;13(1):59-64. doi:10.1111/ases.12683.
- 14.↵Haas NB, Song Y, Willemann Rogerio J, Disease-free survival as a predictor of overall survival in localized renal cell carcinoma following initial nephrectomy: A retrospective analysis of Surveillance, Epidemiology and End Results-Medicare datac. Int J Urol. 2023;30(3):272-279. doi:10.1111/iju.15104.
- 15.Kim SH, Choi MG, Shin JH, Kim YA, Chung J. A Real-World, Population-Based Retrospective Analysis of Therapeutic Survival for Recurrent Localized Renal Cell Carcinoma After Nephrectomy. Front Oncol. 2021;11:693831. doi:10.3389/fonc.2021.693831
- 16.↵Dursun F, Elshabrawy A, Wang H, Survival after minimally invasive vs. open radical nephrectomy for stage I and II renal cell carcinoma. Int J Clin Oncol. 2022;27(6):1068-1076. doi:10.1007/s10147-022-02153-5.
- 17.↵Chan ES, Matsuda T, eds. Endourology Progress: Technique, technology and training. Springer: 2019. ISBN: 9811334641 doi:10.1007/978-981-13-3465-8
- 18.↵Yip SKH, Sim HG. Robotic radical prostatectomy in east Asia: development, surgical results and challenges. Curr Opin Urol. 2010;20(1):80-85. doi:10.1097/MOU.0b013e3283337bf0.
