Comparison of cytoreductive partial versus radical nephrectomy in metastatic renal cell carcinoma: To be on the horns of a dilemma

Abstract

Background:

Cytoreductive radical nephrectomy (cRN) with immunotherapy is the treatment of choice in patients with metastatic renal cell carcinoma (mRCC). Limited data are available on the role of cytoreductive partial nephrectomy (cPN) in mRCC. This study is a systematic review and meta-analysis of the evidence regarding survival rates comparing cPN versus cRN.

Methods:

PubMed/Medline, Scopus, Google Scholar, EMBASE, and the Cochrane Library were reviewed in December 2021 according to PRISMA. Four articles including 2669 patients were selected to enroll in the study. The identified reports were reviewed and their methodological quality was subjected to total quality assessment. The outcomes were cancer specific survival (CSS) and overall survival rate (OS).

Results:

Totally 2669 patients, 542 in cPN and 2127 in cRN groups enrolled in final analysis. Of the preoperative data, there were significant differences in preoperative size of tumor between cRN and cPN patients (p < 0.001), however Fuhrman grades were comparable between groups (low grade: p = 0.51, high grade: p = 0.76). There were comparable results in 1-year (p = 0.07), 2-year (p = 0.08), and 3-year (p = 0.71) CSS rates between cPN versus cRN. There was no significant difference between cPN versus cRN in OS rate (p = 0.61).

Conclusion:

There are comparable results between cPN and cRN in CSS and OS rate. However, due to a lack of data, future study will need to do more extensive studies using prospectively recorded patient features to evaluate the cPN and cRN in the metastatic setting.

Keywords

Cytoreductive partial nephrectomy metastatic renal cell carcinoma

Introduction

Renal Cell Carcinoma (RCC) accounts for around 2%–3% of all adult cancers.¹ One-third of newly diagnosed RCC patients may acquire metastatic disease, whereas 20%–40% of individuals with clinically localized RCC develop metastatic cancer.² Although the introduction of immunotherapy increased progression-free survival and, in rare cases, sustained clinical responses in metastatic RCC,^3,4 long-term findings revealed only a 10%–20% response rate and a less than 5% 10-year survival rate.⁵

Founding a poor prognosis in advanced RCC has sparked a significant amount of study in the hopes of discovering methods to enhance long-term survival rates, such as immunotherapy and surgical combinations. The role of cytoreductive radical nephrectomy (cRN) in combination of interferon has been proved^3,6 but lessons from outcomes of partial nephrectomy (PN) in localized RCC, create a new concept that whether cytoreductive PN (cPN) could be consider in management of mRCC. The necessity for additional potentially nephrotoxic treatments in metastatic condition makes the maintenance of renal function even more important. Aside from renal function preservation, further advantages of PN may include better postoperative performance status, elimination of paraneoplastic symptoms, and eradication of the source of future metastases.⁷

Till now only few studies, evaluate the outcomes of cytoreductive partial nephrectomy in mRCC patients and the data are scarce. As our knowledge, this is the first systematic review and meta-analysis which conducted to shed the light on the role of cPN on mRCC patients.

Methods and materials

This systematic review and meta-analysis conducted in December 2021 in multiple databases. The Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (www.prisma-statement.org) was used for the study design, search strategy, data abstraction (Table 1). Only articles written in English were chosen to enroll.

Table 1.

Study design.

Patients	Patients underwent cytoreductive radical or partial nephrectomy for the treatment of metastased renal cell cancer
Literature search	Keyword search in PubMed, Google Scholar, and Scopus
Databases	Pubmed, Ovid, MEDLINE, EMBASE, the Cochrane Controlled Trials Register, HealthSTAR, CINAHL, Google, and Google Scholar
Limits	Only comprehensive articles without time limit Humans In English
Keywords	Cytoreductive radical nephrectomy Cytoreductive partial nephrectomy Metastasis Renal cell cancer
Eligibility criteria	Article in full-text (no abstracts) Unique publication (no duplicate articles) Reported each of the interested outcomes (1-, 2-, and 3-year cancer-specific survival and overall survival) Original report as determined from reading the abstract or if necessary the full text Outcome reported in a usable form (each surgical approach was reported as a separate cohort, no additional confounding treatments, no missing or unreliable data; could not have >10% difference in values between text and tables)
Exclusion criteria	Duplicate patient population, where some or all of the same patients were included in a different study reporting on the same parameters (prevents double counting) Early case experience (prevents bias toward approaches with more experienced surgeons)
Data abstraction	Articles needed to report which contain each of outcome of interest to be included in the analysis.
Data abstraction	Data were abstracted by two individuals into a custom database table including list of variables. Fifty percent of articles were abstracted by one reviewer and other 50% with other one. The data for 50% of the articles was double-entered by a second individual, and any discrepancies were resolved through repeated review and discussion prior to data analysis. All outcomes were then double-checked and any discrepancies resolved variables in four types were abstracted from each study: those necessary to determine inclusion and exclusion criteria, baseline patient characteristics, and clinical outcomes. In order to use all data as possible, if only median and range were reported in an article, we substituted the median for the mean (if sample size was greater than 25), and the Range/4 (for moderately sized samples (15 < n ⩽ 70)) or Range/6 (for large samples (n > 70)) for the standard deviation. All studies were reviewed by two independent reviewers using the total quality assessments (QASs) (Table 2) to assess the methodological quality of the studies that were included. Although the QASs were reported for each study, they were not used to weight the studies in the meta-analysis.
Primary outcomes	1-, 2-, and 3-year cancer-specific survival Overall survival
Controls for publication bias	Performed a funnel plot analysis

CSS: cancer specific survival; OS: overal survival.

Original articles reporting on cytoreductive treatment of renal cell carcinoma were selected and conference abstracts because of lack of data were not enrolled in peer review.

Total quality assessment (QAS) was used to assess the methodological quality of the studies, by two independent reviewers. However, QASs scores, were not used to weight the studies in the meta-analysis (Table 2).

Table 2.

Quality assessment items and possible scores.

A. Was the assigned treatment adequately concealed prior to allocation?
2 = method did not allow disclosure of assignment
1 = small but possible chance of disclosure of assignment or unclear
0 = quasi-randomized or open list/tables

B. Were the outcomes of participants who withdrew described and included in the analysis (intention-to-treat)?
2 = withdrawals well described and accounted for in analysis
1 = withdrawals described and analysis not possible
0 = no mention, inadequate mention, or obvious differences and no adjustment

C. Were the outcome assessors blinded to treatment status?
2 = effective action taken to blind assessors
1 = small or moderate chance of unblinding of assessors
0 = not mentioned or not possible

D. Were the treatment and control groups comparable at entry? (likely confounders may be age, partial or total rupture, activity level, acute or chronic injury)
2 = good comparability of groups, or confounding adjusted for in analysis
1 = confounding small; mentioned but not adjusted for
0 = large potential for confounding, or not discussed

E. Were the participants blind to assignment status after allocation?
2 = effective action taken to blind participants
1 = small or moderate chance of unblinding of participants
0 = not possible, or not mentioned (unless double-blind), or possible but not done

F. Were the treatment providers blind to assignment status?
2 = effective action taken to blind treatment providers
1 = small or moderate chance of unblinding of treatment providers
0 = not possible, or not mentioned (unless double-blind), or possible but not done

G. Were care programes, other than the trial options, identical?
2 = care programes clearly identical
1 = clear but trivial differences
0 = not mentioned or clear and important differences in care programes

H. Were the inclusion and exclusion criteria clearly defined?
2 = clearly defined
1 = inadequately defined
0 = not defined

I. Were the interventions clearly defined?
2 = clearly defined interventions are applied with a standardized protocol
1 = clearly defined interventions are applied but the application protocol is not standardized
0 = intervention and/or application protocol are poorly or not defined

J. Were the outcome measures used clearly defined? (by outcome)
2 = clearly defined
1 = inadequately defined
0 = not defined

K. Were diagnostic tests used in outcome assessment clinically useful? (by outcome)
2 = optimal
1 = adequate
0 = not defined, not adequate

L. Was the surveillance active, and of clinically appropriate duration?
2 = active surveillance and appropriate duration
1 = active surveillance, but inadequate duration
0 = surveillance not active or not defined

All the data extracted by two independently authors and agreement reached after discussion. For any disagreement, consultation with the senior authors performed. The data collected from all manuscripts regarding treatment groups included the cytoreductive nephrectomy surgical approach (partial vs radical), publication year, duration of follow-up, patient characteristics (number, age, gender, tumor size, Furman grade, histology), cancer specific survival (CSS), and overall survival rate (OS).

Statistical methods

The meta-analysis done with the Review Manager version 5.2 (downloaded from http://community.cochrane.org/tools/review-production-tools/revman-5). Mean and standard deviation (SD) was considered for continuous data and proportions or risks and the treatment effect which reported as odds ratios (OR) with a 95% confidence interval (95% CI) were used for dichotomous data. If only median and range were reported in an article, the median was substituted for the mean when the sample size was greater than 25. For SD, range/4 (for moderately sized samples (15 < n ⩽ 70)) or range/6 (for large samples (n > 70)) were used.⁸

Chi-squared test and I² statistic were used to assess the Heterogeneity between studies and p-value of <0.1 and an I² value >50% were considered as statistical heterogeneity, prompting a random-effects modeling estimate. A non-significant chi-squared test result (p ⩾ 0.1 and I² ⩽ 50%) suggested that there was no evidence of heterogeneity and a Fixed-Effect model was used. Publication bias also showed in Funnel plots, and the more asymmetric the funnel plot was, the higher the potential bias was.

Results

This systematic review and meta-analysis four articles included 2669 patients, 542 undergoing cPN, 2127 undergoing cRN (Table 3). Of the preoperative data, there were significant differences in preoperative size of tumor between cRN and cPN patients (p < 0.001), however Fuhrman grades were comparable between groups (low grade: p = 0.51, high grade: p = 0.76). Clear cell carcinoma was the commonest post-operative pathology with no significant difference between groups (p = 0.83)

Table 3.

Included study which divided in to two comparison groups.

Study	Type of surgery	Number of patients	Age (year)	Gender	Tumor size (cm)	Fuhrman grade, N (%)	Histology, N (%)	Mean follow-up (median)Range	QAS
Capitanio et al.	RN	1997	61.0 (25–95)	M: 1366 (68.4) F: 631 (31.6)	9.3 (0.6–25)	Low grade: 384 (19.2) High grade: 808 (40.5) Missing values: 805 (40.3)	Clear cell: 1782 (89.3) Papillary: 64 (3.2) Chromophobe: 10 (0.5) Collecting duct: 4 (0.2) Other: 137 (6.9)	23.5 (12) 1–202	9
Capitanio et al.	PN	46	63.3 (42–82)	M: 29 (63.0) F: 17 (37.0)	5.1 (1.0–18)	Low grade: 13 (28.9) High grade: 18 (40.0) Missing values: 15 (33.3)	Clear cell: 41 (89.1) Papillary: 3 (6.5) Chromophobe: 0 Collecting duct: 0 Other: 2 (4.3)	24.7 (15.5) 1–161
Lenis et al.	RN	9,763	60.9 (9.9)	M: 6772 (69.4)F: 2991 (30.6)	9.6(5.1)	Low grade: 1719 (17.6)High grade: 6361 (65.2)Missing values: 1683 (17.2)	Clear cell: 7756 (79.4) Papillary: 429 (4.4) Chromophobe: 111 (1.1)Sarcomatoid component: 862 (8.8)Other: 605 (6.2)	17.47.2–34.3	11
Lenis et al.	PN	381	60.3 (9.6)	M: 275 (72.2)F: 106 (27.8)	6.5(3.8)	Low grade: 108 (28.4)High grade: 193 (50.7)Missing values: 80 (21.0)	Clear cell: 285 (74.8) Papillary: 43 (11.3)Chromophobe: 10(2.6)Sarcomatoid component: 29(7.6)Other: 14 (3.7)	23.710.8–39.9
Chen et al.	RN	149	72.34 (5.93)	M: 98 (65.8%)F: 51 (34.2%)	<4: 20 (13.4%)4–7: 61 (40.9%)>7: 65 (43.6%)Unknown: 3 (2%)	Low grade:33 (22.1)High grade: 96 (64.4)Missing values:20 (13.4)	Clear cell: 112 (75.2%)Papillary: 12 (8.1%)Chromophobe: 0%Collecting duct: 1(0.7%)Sarcomatoid component: 8 (5.4%)Other: 16 (10.7%)		8
Chen et al.	PN	59	71.39 (5.04)	M: 43 (72.9%)F: 16 (27.1%)	<4: 13 (22.0%)4–7 : 20 (33.9%)>7: 25 (42.4%)Unknown: 1(1.7%)	Low grade: 14 (23.7%)High grade: 38 (64.4)Missing values: 7 (11.9)	Clear cell: 47 (79.7%)Papillary: 7 (11.9%)Chromophobe: 0%Collecting duct: 0%Sarcomatoid component: 3 (5.1%)Other: 2 (3.4%)
Hutterer et al.	RN	99	62.4 (42–86)	M: 71 (71.7%)F: 28 (28.3%)	–	Low grade: 60 (60.6%)High grade: 39 (39.4%)	Clear cell: 98 (99%)Papillary: 1 (1%)Chromophobe: –Collecting duct: –	34.8	9
Hutterer et al.	PN	38	62.5 (45–83)	M: 26 (68.4%)F: 12 (31.6%)	-	Low grade: 24 (63.2%)High grade: 14 (36.8)	Clear cell: 37 (97.7%)Papillary: –Chromophobe: 1 (2.6)%Collecting duct: –	22.8

Cancer specific survival rate

There was no significant heterogeneity between studies in 1-year CSS (I² = 0%; p < 0.51, Figure 1), but in 2- and 3-year CSS significant heterogeneities between studies were found between cPN and cRN methods (I² = 84%, 81%; p = 0.01, 0.02); thus, fixed effect for 1-year CSS and random effect were used to analyze 2- and 3-year CSS. There were comparable results in 1-year (OR: 0.1; 95% CI: −0.01 to 0.21; p = 0.07; Figure 2), 2-year (OR: 1.61; 95% CI: 0.94–2.75; p = 0.08; Figure 2), and 3-year CSS rates between cPN versus cRN (OR: 1.28; 95% CI: −0.34 to 4.88; p = 0.71; Figure 2).

Figure 1.

Funnel plot of 1-year cancer specific survival rate showed no significant heterogeneity between cytoreductive partial versus radical nephrectomy.

Figure 2.

Forest plot of overall survival (a), 1-year (b), 2-year (c), and 3-year (d) cancer-specific survival rates showed no significant difference in patient underwent cytoreductive radical versus partial nephrectomy in treatment of metastatic renal cell carcinoma.

Overall survival rate

There was significant heterogeneity between studies in OS rate (I²= 100%; p < 0.001). Therefore, random effect was used to analyze. There was no significant difference between cPN versus cRN in OS rate (OR: 4.39; 95% CI: −12.47 to 21.24; p = 0.61; Figure 2).

Discussion

This systematic review and meta-analysis is the greatest collection of thorough research on cytoreductive partial versus radical nephrectomy to date. Because of the lack of randomized clinical trials, variations in patient characteristics between surgery cohorts may explain disparities in results between treatment groups. Statistical techniques cannot adequately correct these disparities. Furthermore, unidentified discrepancies in the characteristics of the patients and physicians, as well as the therapies used, may contribute to the varied outcomes between trials. Caution is suggested when interpreting the findings of this meta-analysis in light of the above factors.

Traditionally, cRN with immunotherapy was the treatment of choice for mRCC patients. Nowadays, the concept of cytoreductive partial nephrectomy has gain a power in status of metastasis. The efficacy and safety of cPN have been called into doubt due to concerns about its technical difficulties, risk of complications, and unclear survival benefits over cRN.

The main goal in treatment of cancer is disease control. Our study showed cPN has a comparable result in CSS compared to cRN during 3-year follow-up. We supported the findings of Capitanio et al,⁹ and Hutter et al.⁷ studies. However, Hellenthal et al.¹⁰ noted the patients who underwent cPN had a 0.49 reduced chance of dying from RCC than those who had cRN. This discrepancy might be due to limitations of their study respectively. The patient in cPN group had a significantly smaller tumor and this decreased overall tumor burden in cPN group which is known to impact survival rates in mRCC patients could affect the survival rate.¹¹ It is predictable that patients with a single and resectable metastasis are expected to have higher cancer-specific survival than those with many and unresectable metastases, and possibly, patients treated with cPN may have had a more favorable metastatic profile than RN patients. Furthermore, the lymph node status is a substantial predictor of failure to achieve either an objective immunotherapy response or an increase in survival when immunotherapy is employed as an adjuvant treatment. Therefore, to investigate the absolute equivalency of PN and RN in the metastatic patient, additional extensive evaluations with prospectively documented patient data are unquestionably required.

Considering the preservation of renal function, and as consequence expecting higher overall survival rate, cPN has got more preference in the treatment of mRCC. Our findings showed no difference between OS rate between cPN compared to cRN. In contrast, Lenis et al.¹² showed that patients who underwent cPN had a 19% lower risk of dying from any cause than those who received cRN. However, when they stratified the data by tumor size, they found this benefit to be isolated to small renal tumors (less than 4 cm). Chen et al.¹³ also showed survival advantage of patient who underwent cPN versus cRN. After subgroup analysis they also confirmed that OS was superior only in male patients with ⩽7 cm tumor, N0 and isolated metastasis and even in the N1 stage, cPN results was worse than cRN. Recently published study¹² showed the treatment in high-volume center, papillary and chromophobe histology, and more recent year of treatment were all associated with higher chance of receiving a cPN. Conversely, age ⩾80 years, no medical insurance, high tumor grade, and 4–7 cm tumor were all associated with decreased odds of receiving acPN. Therefore, this discrepancy between our findings and above studies might be because of heterogeneity and selection bias between the studies. Furthermore, mostly the benefit of cPN in OS is in small sized tumor and because of the lack of data we couldn’t analyzed the survival rates in order of size of tumor and other independent factors like as performance status and laboratory results (hemoglobin, LDH, calcium).¹⁴

This meta-analysis contained the biggest sample size of comprehensive studies that evaluated the two surgical procedures for treatment of metastatic RCC in terms of survival rate results. Nevertheless, there were some limitations. The only English literatures were included. Studies that did not identify the mean and SD approximated them using the median and range, which may have deviated somewhat from the true numbers. Due to lack of data, we were not able to do sub-group analysis in order to tumor size, grade, performance status, comorbidities, prior systemic therapy, and laboratory results which all may affect the survival rates.

Conclusion

The results of this meta-analysis should be considered with care in light of the concerns previously mentioned. The quality of the papers included influences the quality of the outcomes of systematic reviews and meta-analyses. As the quality of the studies included in the current analysis was assessed using a questionnaire, it was discovered that some studies were of poor quality, and a well-powered study with a large number of candidate articles is recommended to better compare the outcomes of the two surgical approaches. Future trials with more extensive analysis and prospectively documented patient data are undoubtedly necessary to assess the PN and RN in the metastatic situation.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Hamidreza Shemshaki

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