EUROPEAN UROLOGY 72 (2017) 6475

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Platinum Priority Collaborative Review Kidney Cancer

Editorial by Ithaar H. Derweesh, Riccardo Autorino, Karim Bensalah and Umberto Capitanio on pp. 7677 of this issue

Collaborative Review of Risk Benefit Trade-offs Between Partial

and Radical Nephrectomy in the Management of Anatomically
Complex Renal Masses

Simon P. Kim a,b, Steven C. Campbell c, Inderbir Gill d, Brian R. Lane e, Hein Van Poppel f,
Marc C. Smaldone g, Alessandro Volpe h, Alexander Kutikov g,*
a
University Hospital Case Medical Center, Case Western Reserve University School of Medicine, Seidman Cancer Center, Urology Institute, Center of
Healthcare Outcomes and Quality, Cleveland, OH, USA; b Cancer Outcomes and Public Policy Effectiveness Research Center, Yale University, New Haven, CT,
USA; c Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA; d
USC Institute of Urology, University of Southern California, Los
Angeles, CA, USA; e Spectrum Health Medical Group, Urology, Grand Rapids, MI, USA; f Department of Urology, University Hospitals of Katholieke Universiteit
g
Leuven, Leuven, Belgium; Division of Urologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, Temple University Health System,
h
Philadelphia, PA, USA; University of Eastern Piedmont, Maggiore della Carita Hospital, Novara, Italy

Article info Abstract

Article history: Background: While partial nephrectomy (PN) is the recommended treatment for many
Accepted November 29, 2016 small renal masses, anatomically complex tumors necessitate a clear understanding of
the potential risks and benefits of PN and radical nephrectomy (RN).
Associate Editor: Objective: To critically review[1_TD$IF] the comparative effectiveness evidence of PN versus RN;
Stephen Boorjian to describe key trade-offs involved in this treatment decision; and to highlight gaps in
the current literature.
Evidence acquisition: A collaborative critical review of the medical literature was
Keywords: conducted.
Partial nephrectomy Evidence synthesis: Patients who undergo PN for an anatomically complex or large mass
may be exposed to perioperative and potential oncologic risks that could be avoided if
Radical nephrectomy
RN were performed, while patients who undergo RN may forgo long-term benets of
Renal cell carcinoma renal preservation. Decision-making regarding the optimal treatment with PN or RN
Renal masses among patients with anatomically complex or large renal mass is highly nuanced and
Surgery must balance the risks and benets of each approach. Currently, high-quality evidence
on comparative effectiveness is sparse. Retrospective comparisons are plagued by
selection biases, while the one existing prospective randomized trial, albeit imperfect,
suggests that nephron-sparing surgery may not benet all patients.
Conclusions: For anatomically complex tumors, PN preserves renal parenchyma but
may expose patients to higher perioperative risks than RN. The risks and benets of each
surgical approach must be better objectied for identication of patients most suitable
for complex PN. A prospective randomized trial is warranted and would help in directing
patient counseling.
Patient summary: Treatment decisions for complex renal masses require shared deci-
sion-making regarding the risk trade-offs between partial and radical nephrectomy.
# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Division of Urologic Oncology, Fox Chase Cancer Center, Temple University
Health System, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
E-mail address: alexander.kutikov@fccc.edu (A. Kutikov).

http://dx.doi.org/10.1016/j.eururo.2016.11.038
0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
 EUROPEAN UROLOGY 72 (2017) 6475
1. Introduction
More than 60 000 patients in the USA and >100 000 patients
in Europe are diagnosed annually with kidney cancer
[1,2]. With cross-sectional imaging now ubiquitous, the
incidence of localized renal masses is increasing [3,4]. The
majority of patients who currently present with stage I renal
cell carcinoma (RCC)clinical T1a (<4 cm) or T1b (47 cm)
are surgically treated with partial nephrectomy (PN) or
radical nephrectomy (RN) [5]. Clinical practice guidelines
recommend PN for T1 tumors that are amenable to nephron-
sparing surgery (NSS) with the goal of preserving healthy
renal parenchyma without compromising cancer control
[69]. These guidelines are based on a growing number of
observational studies that suggest better overall survival
(OS) and renal function for patients who undergo PN [9]. As a
result, several population-based studies have demonstrated
that the clinical paradigm has shifted towards higher
utilization of PN in the surgical management of localized
renal tumors [1012].
While little controversy exists regarding the utility and
prudence of PN for patients with small and anatomically
simple renal tumors, patients who undergo complex NSS for
large and/or anatomically complex masses may be exposed
to perioperative and potential oncologic risks that would be
avoided if RN were performed. Issues of additional surgical
complexity are especially salient in the elderly and patients
with comorbidities, while oncologic safety is crucial for all,
particularly the young and robust individuals. Thus, deci-
sion-making regarding the optimal treatment with PN or RN
among patients with large and/or anatomically complex
renal masses is highly nuanced and must balance the risks
and benefits of each approach. Risk trade-offs in this space
are particularly complex given that advanced treatment
technologies have evolved to include a variety of surgical
approaches, ranging from conventional open surgery to
minimally invasive surgery via laparoscopy or robotics using
both transperitoneal and retroperitoneal approaches [1318].
In this collaborative review, we critically evaluate the key
elements of decision-making for patients presenting with
large/anatomically complex, localized renal masses. We
highlight gaps in the current literature and outline the
clinical challenge of determining which mass in which
patient is most appropriate for PN versus RN.
2. Evidence acquisition
MEDLINE, EMBASE, and Scopus were used to search the
English literature from inception to January 2016 using the
following terms: renal mass/tumor, partial nephrec-
tomy, radical nephrectomy, and nephron-sparing current clinical practice guidelines are largely predicated on
surgery in conjunction with large, complex, compli- the growing number of observational studies suggesting
cations, renal function, or survival. The authors further better outcomes with respect to renal function and OS
reviewed the reference lists of relevant articles identified
by this search. The full text of selected studies that focused
on pertinent topics for this manuscript was reviewed by
the first and senior authors. Co-authors then added or
removed articles via consensus as part of draft revisions.
After reaching agreement regarding the structure of the
65
manuscript, an initial draft was written and circulated by
the first and senior authors. After a number of iterations,
consensus regarding the content of the manuscript was
reached among the authors. In the process of writing this
critical review, the most recent pertinent studies were also
added as references.
3. Evidence synthesis
3.1. Quantification of the anatomic complexity or renal masses
A strong argument can be made, with some data providing
support, that PN for a small peripheral renal mass is
associated with similar perioperative risks as RN [19]. Nev-
ertheless, risks associated with PN increase with tumor size
and anatomic complexity [20]. Indeed, tumor anatomic
complexity is one of the key predictors of risk associated
with PN. Tumor excision and reconstruction are inherently
more challenging for larger, endophytic, central, and hilar
tumors when compared to smaller, peripheral, polar lesions
[20]. Several validated scoring systems have been devel-
oped to quantitate the anatomic complexity of localized
renal tumors to facilitate objective reporting, allow
meaningful comparisons between series, and help objectify
surgical decision-making [2124]. These scoring systems
for anatomic complexity, now often collectively termed
nephrometry, quantitate renal mass attributes such as
tumor size, endophytic versus exophytic location, nearness
to the collecting system, centrality, proximity to the hilar
vessels, and renal contact surface area [25,26].
The literature contains many reports from numerous
institutions demonstrating that higher tumor complexity
scores are associated with greater perioperative risks
among patients undergoing cancer-directed renal surgery
[27]. Importantly, there is evidence that tumor anatomic
complexity correlates with more aggressive renal tumor
biology [28]. Figure 1 highlights several examples of large,
endophytic, and/or central masses, with some in challeng-
ing locations, that most renal surgeons would consider
complex for resection using PN. Although many nephro-
metry scoring systems offer low, intermediate, and high
groupings for anatomic complexity score, the score cutoffs
are admittedly arbitrary. Thus, thresholds for how tumor
anatomic complexity affects risk balance and clinical
decision-making continue to depend on a surgeons skill
and opinion.
3.2. Potential benefits of PN over RN
Recommendations for PN for localized renal tumors in
compared to other treatment options, in particular RN
[68]. PN was first introduced as a surgical treatment for
renal masses with imperative indications such as a solitary
kidney, bilateral renal masses, or pre-existing chronic
kidney disease (CKD) because of the deleterious impact
on quality of life and mortality of worsening renal function
66 EUROPEAN UROLOGY 72 (2017) 6475
[(Fig._1)TD$IG]

Fig. 1 Examples of renal masses of high anatomic complexity for which the risk trade-off between partial nephrectomy (PN) and radical nephrectomy
(RN) is unclear and must be carefully considered. (A) Axial cut from the nephrographic phase of a post-contrast computed tomography (CT) scan
showing a large, endophytic, and central 8-cm right renal mass with a RENAL nephrometry score of 3 + 2 + 3 + p + 3 = 11p (arrow). The patient
underwent RN. (B) Coronal cut from the excretory phase of a triphasic CT scan showing an entirely endophytic 3-cm renal mass with RENAL score of
1 + 3 + 3 + a + 3 = 10a (arrow). The patient underwent PN. (C) Axial cut from the corticomedullary phase of a post-contrast CT scan showing a 3.5-cm
posterior hilar left renal mass with RENAL score of 1 + 2 + 3 + p + 3 h = 9 ph (arrow) that can be difficult to reach using a transperitoneal approach.
The patient underwent PN. (D) Sagittal cut from the nephrographic phase of a post-contrast CT scan showing a kidney with two renal masses (orange
arrows). The larger 4.2-cm mass (RENAL score 2 + 2 + 3 + x + 1 = 8x) has invasion of the sinus (black arrow), which was identified as a small,
segmental renal-vein thrombus at the time of PN.

and the risk of hemodialysis [2934]. Over time, however,
utilization of PN gradually expanded to patients with a
normal contralateral kidney and normal estimated glomer-
ular filtration rate (eGFR) to reduce the risks of developing
CKD, thereby potentially improving all-cause mortality
(ACM) while still achieving similar oncologic outcomes as
RN.
3.2.1. Impact of PN and RN on renal functional outcomes
Better renal function following NSS represents the most
widely accepted clinical benefit of PN compared to RN. The
first studies to suggest this benefit used single-institution
and retrospective cohorts that demonstrated better renal
function for PN compared to RN among patients undergoing
surgery for a renal mass [30,35,36]. For instance, Huang et al
[37] reported a significantly lower probability of eGFR
<60 ml/min/1.73 m2 for patients undergoing PN in compar-
ison to those undergoing RN (80.0% vs 35.0%; p < 0.001).
Several other historical cohort studies using institutional
data reported similar renal function benefits of PN over RN
[3840].
Other studies using either population-based cohorts or a
higher level of evidence support the benefits of PN with
respect to lower risk of CKD following surgery for a renal
mass. In a systematic review and meta-analysis of
31 729 and 9281 patients surgically treated with RN and
PN, respectively, patients undergoing PN had a significantly
lower risk of developing stage IIIV CKD (hazard ratio [HR]
0.39, 95% confidence interval [CI] 0.330.47) [9]. A recent
meta-analysis focusing on masses >4 cm demonstrated
similar findings [41]. In one population-based cohort study,
Medicare beneficiaries with T1a tumors also had lower
adjusted HRs for adverse renal outcomes, such as dialysis or
kidney transplantation, when undergoing PN compared to
RN (16.4% vs 21.8%; adjusted HR 0.74; p < 0.001) [42]. Better
renal function in PN patients may translate into down-
stream metabolic benefits. For example, a retrospective
cohort study of Medicare beneficiaries found lower rates of
anemia due to chronic disease among older patients after
PN compared to RN [43]. Other studies have also reported
lower incidence of anemia due to CKD and lower use of
erythropoiesis-stimulating agents [44]. Furthermore, retro-
spective data suggest that patients undergoing PN have a
lower risk of developing osteoporosis [45].
Level I evidence confirms that patients with normal renal
function who undergo PN are less likely to develop CKD
 EUROPEAN UROLOGY 72 (2017) 6475
compared to those who have the entire kidney removed.
European Organization for Research and Treatment of
Cancer (EORTC) trial 30904 was a multicenter phase
3 clinical trial that randomized 273 patients to RN and
268 patients to PN with ACM as the primary endpoint
[46,47]. Patients eligible for inclusion presented with a
renal mass 5 cm, an anatomically normal contralateral
kidney, and World Health Organization performance status
of 02. The investigators reported that patients undergoing
PN had a markedly lower risk of developing any chronic
kidney disease (eGFR <60 ml/min/1.73 m2) compared to RN
(64.7% vs 85.7%; p < 0.001) at median follow-up of 6.7 yr
[48]. However, an important point to note is that in this
prospectively randomized cohort of patients with a largely
normal contralateral kidney, there was no significant
difference in the incidence of renal failure (eGFR <15 ml/
min/1.73 m2) between the RN and PN cohorts (1.5% vs 1.6%;
difference 0.1%, 95% CI 2.2 to 2.1) [48].
Challenges in detecting harm due to RN in patients with
normal renal function are underscored by recent data from
the renal transplant literature. In a cohort of more than
96 000 renal donors from the USA between 1994 and 2011,
the rate of end-stage renal disease was 30.8 per
10 000 patients (95% CI 24.338.5). Although this was
nearly an eightfold increase in risk compared to non-donor
controls, the absolute risk was extremely low, with fewer
than 100 of nearly 100 000 patients requiring dialysis after
donating a renal unit [49].
Compelling evidence is emerging that the etiology of
CKD is a strong predictor of future GFR decline. The Kidney
Disease: Improving Global Outcomes group recently
updated its CKD classification schemata, which, along with
GFR and albuminuria, now also includes etiology in the CKD
definition [50]. Important work has been carried out in
recent years to demonstrate that the risk of GFR decline
markedly differs between nephron loss due to surgical and
medical causes. Campbell, Lane and colleagues recently
proposed CKD categories in patients undergoing renal
surgery based on CKD etiology [51]. Patients with CKD due
to medical causes who do not have renal cancer are
identified as CKD-Medical (CKD-M). Patients with CKD
before PN or RN and then undergo resection are classified as
CKD-medical/surgical (CKD-M/S). Meanwhile, patients with
normal baseline renal function who have eGFR <60 ml/min/
1.73 m2 only after surgical resection are classified as CKD-
surgical (CKD-S) [52]. Consistent with data from EORTC
30904, renal function in patients with CKD-S appears to
largely remain stable following an initial drop after renal
resection, while CKD-M/S and CKD-M cohorts experience a
progressive GFR decline [52,53]. Regardless of preoperative
GFR, a marked GFR decrease following surgery to <45 ml/
min/1.73 m2 appears to be linked to a higher risk of
progressive GFR reduction [53]. It has long been recognized
that a GFR decrease to <45 ml/min/1.73 m2 is a significant
predictor of risk, and this threshold is used to differentiate
CKD 3b from 3a in the latest CKD classification system
[37]. Thus, patients with compromised preoperative eGFR
whose new baseline eGFR will fall below 45 ml/min/1.73 m2
if RN is performed should be strongly considered for PN
67
[50]. However, accurate prediction of post-RN GFR remains
elusive to date.
While baseline CKD is highly prevalent among patients
presenting with renal masses, improvement in preoperative
risk stratification for patients with normal baseline renal
function is also needed, as these patients represent the
majority of individuals who present with kidney tumors
[37,5456]. Clinically actionable predictive biomarkers are
emerging. For example, preoperative proteinuria appears to
be a risk factor for post-renal surgery GFR decline [57,54]. It
was recently found that urokinase-type plasminogen
activator receptor (suPAR) was a predictor of future GFR
decline in a cohort of patients undergoing cardiovascular
catheterization who had normal renal function [58]. Adop-
tion of suPAR for decision-making and prognostication for
patients undergoing renal surgery is likely in the near
future. Further studies are needed to validate these
biomarkers in predicting GFR decline for patients present-
ing with localized renal tumors and to identify how best to
integrate the data into clinical practice.
3.2.2. Impact of PN versus RN on survival outcomes
To date, most observational studies comparing PN and RN
have reported that NSS is associated with better OS not only
in patients with pre-existing CKD but also in those with a
normal contralateral kidney and good baseline renal
function. The literature has largely ascribed this apparent
survival benefit to the downstream metabolic sequelae of
renal function preservation [5962]. Initial single-institu-
tion studies focused on patients with poor renal function or
a solitary kidney, for whom PN yielded long-term oncologic
control and survival [30]. With the gradual expansion of PN
into the elective setting, observational studies suggested
that PN was associated with lower ACM [35,63,64]. Popula-
tion-based studies using Surveillance, Epidemiology, and
End Results (SEER)Medicare data supported the lower
ACM for PN, presumably because of lower CKD incidence,
although there is mixed evidence regarding whether NSS
reduced the rate of cardiovascular events [42]. More
recently, systematic reviews and meta-analyses pooling
all the existing evidence revealed that PN is associated with
significantly lower HRs for ACM when compared to RN
[9,41]. The more recent systematic review and meta-
analysis by Mir et al [41] that was restricted to patients with
T1b and T2 renal tumors confirmed these findings. Other
institutional studies have also demonstrated better OS for
PN compared to RN for patients with large renal masses
[65,66].
Existing retrospective and observational data supporting
a survival advantage for PN compared to RN are potentially
subject to selection bias. For instance, several studies using
population-based cohorts and systematic reviews and
meta-analyses have suggested that PN also paradoxically
lowers cancer-specific mortality [9,41]. This controversial
finding suggests that some of the OS benefit is due in part to
patient selection, whereby more favorable renal tumors
(in terms of size and/or location) are surgically treated with
PN. Second, most of the aforementioned studies provided
little detail about salient tumor and patient characteristics
68 EUROPEAN UROLOGY 72 (2017) 6475
that are central to critical clinical decision-making in
urologic practice and that serve as the basis for patient
selection for PN versus RN [67]. For instance, urologic
surgeons are inherently more likely to select less anatomi-
cally complex tumors for PN, and more central and hilar
tumors for RN [67]. Given the correlation between tumor
complexity and tumor biology, patients with favorably
located tumors are more likely to be selected for PN than RN
at many, but not all, centers [28]. In addition, more robust
patients are also more likely to undergo a more complex
operation such as PN, so it is also likely that selection bias
occurs in this domain [67]. Thus, many inherent imbalances
with regard to unmeasured confounders in cohorts used to
compare the effectiveness of PN and RN probably amplify
the treatment effect measured for PN.
Complex statistical methodologies and modeling have
been adopted in attempts to adjust for such differences and
potential biases. The most rigorously performed observa-
tional study to date used an instrumental variable
approach to effectively pseudo-randomize patients to renal donors represent a far healthier patient population
treatment arms and reduce unmeasured confounding via
instrumental variable (IV) analysis. Tan and colleagues [68]
reported that PN was associated with better long-term
survival among Medicare beneficiaries with low-stage
tumors when distance to PN provider was used as the IV.
This study was strengthened by the fact that measured
confounders were successfully balanced using the IV
methodology and, more importantly, the paradoxical
higher cancer-specific survival (CSS) for PN in the retro-
spective effectiveness analyses was eliminated [69]. One
concern, however, is that the use of statistical methods
such as IV for cohorts undergoing cancer-directed surgery
may not be valid because of unacceptably large variability
for the treatment effect estimator and reliance on
assumptions that cannot be verified [70,71]. In fact, in
the same SEER-Medicare cohort that underwent renal
surgery for T1a renal cancers, the benefit of PN was only
observed in the first 3 yr, suggesting that the apparent
advantages of NSS may largely stem from profound
differences in preselected cohorts, whereby patients who
are destined to live longer are chosen to undergo PN. At
5 and 10 yr after surgery, PN did not appear to yield a
survival advantage, contradicting the usual assumptions
that the delayed benefit of nephron preservation is due to
the superior metabolic and cardiovascular profile in PN
versus RN patients [72]. These data are supported by work
by Shuch et al [73], who highlighted that SEER-Medicare
patients chosen for PN have longer OS than nonrenal
cancer control groups.
Finally, the shortcomings of drawing conclusions from
observational data are perhaps best highlighted by results
from EORTC 30904, a prospective trial that randomized
patients with renal masses of 5 cm and a normal
contralateral kidney to PN or RN. Reported in 2011, these
data show that patients randomly allocated to RN in fact
had unanticipated better OS compared to those undergoing
PN in the intention-to-treat analysis. In the final report, the
10-yr OS was higher for RN than for PN patients (81.1% vs
75.7%; HR 1.51; p = 0.02) at median follow-up of 9.3 yr.
However, it is relevant to note that for patients with
pathologically confirmed renal cell carcinoma, the differ-
ence in 10-yr OS did not reach significance (p = 0.07)
[47]. The study had notable limitations. For instance, the
actual patient accrual was markedly underpowered from
the initial study design, which was intended as a
noninferiority trial with a target cohort of 1300 patients
for a one-sided p value. EORTC 30904 only accrued
541 patients from 45 medical centers over a period of a
decade (1 person per year per institution) with significant
crossover following randomization, further complicating
the ability to fully determine the benefit of PN compared to
RN [69]. Despite some significant shortcomings, EORTC
30904 suggests that not all patients benefit from NSS.
Robust data for renal transplant donors, who, like patients
in EORTC 30904, all have a normal contralateral renal unit,
dovetail with these findings. In fact, appropriately selected
patients largely appear to be unharmed by RN during long-
term follow-up [74,75]. However, it should be noted that
than patients with renal cell carcinoma. For instance,
donors are typically 1020 yr younger and are specifically
screened to exclude comorbidities (diabetes, cardiac
disease, hypertension), thus potentially rendering the loss
of an entire renal unit less consequential.
Identifying subgroups of patients who will benefit the
most from PN over RN is arguably the most imperative
challenge in this clinical domain. In accordance with
EORTC 30904 and the renal transplant literature, recent
retrospective data for patients undergoing cancer-directed
kidney surgery suggest that nephron reduction correlates
with poorer survival only among patients with abnormal
preoperative renal function (CKD-M/S) and not those with
normal GFR before surgery (CKD-S), unless the surgery will
substantially reduce GFR to <45 ml/min/1.73 m2 [51,53].
Younger patients may be more likely to benefit from
nephron preservation than older individuals. For instance,
retrospective administrative data, when adjusted using
both IV and propensity scorebased strategies, reveal little
advantage of nephron preservation among patients older
than 75 yr [68,76]. SEER-Medicare data also suggest that
patients with comorbidities may benefit more from NSS
than those with no comorbidities; however, given the
limited granularity of the data set, adjusting for pre-
existing renal insufficiency is not currently possible
[68,69]. Thus, given the marked heterogeneity of pre-
selected cohorts, meaningful and granular analyses
comparing the effectiveness of PN and RN are currently
lacking, and the question regarding who benefits most
from NSS remains a matter of debate.
3.3. Potential risks of PN over RN
The risks of PN are attributable to factors such as renal mass
complexity and patient-specific variables. Thus, it is
essential to critically assess each of these variables in
determining whether future renal function preservation
outweighs the immediate risks of complications of surgery
and potential oncologic compromise.
 EUROPEAN UROLOGY 72 (2017) 6475
3.3.1. Perioperative complications of PN and RN
Critically assessing the risks of perioperative morbidity and
complications represents a key facet in the decision-making
process for complex renal tumors. Irrespective of tumor
complexity, PN is associated with a higher risk of blood loss
and a need for blood transfusion compared to RN. For
instance, in EORTC 30904, patients undergoing PN had
higher rates of perioperative bleeding than those undergo-
ing RN [47].
Beyond blood loss, PN is associated with a nontrivial
complication rate, especially in patients with large and
anatomically complex tumors [20,7780]. In fact, common
postoperative complications have been well documented
for PN that are less likely or do not occur with RN. These
complications specific to PN include renal parenchymal
bleeding, longer operative times, urine leaks, renal artery
aneurysm/arteriovenous malformation, longer hospital
stay, and higher risk of mortality [81,82]. Although
complications after PN occur infrequently and are readily
manageable, it is essential to recognize that the likelihood of
complications is related to tumor anatomic complexity and
patient characteristics [83,84]. For instance, in some series,
tumors with high anatomic complexity (RENAL nephro-
metry score 1012) were associated with higher estimated
blood loss and a threefold greater incidence of major
complications when compared to tumors of low complexity
(RENAL score 46) [20].
Patients with more complex renal tumors, such as a
completely endophytic tumor abutting the collecting system
or a tumor in a kidney with an intrarenal pelvis, have a
higher risk of post-PN urine leaks [85,86]. Bruner et al [87]
reported that each nephrometry score point correlated with
a 35% increase in the likelihood of urine leakage following PN
in a Mayo Clinic series of patients with T1 renal tumors. A
recent five-institution, retrospective cohort study showed
higher rates of perioperative and postoperative complica-
tions following PN for higher complexity renal masses,
although most complications were minor (grade I or II)
[88]. For instance, low-, intermediate- and high-complexity
tumors were associated with higher perioperative (9.0% vs
15.8% vs 18.0%; p = 0.02) and postoperative (10.9% vs 18.0%
vs 23.0%; p = 0.009) complications. The above notwithstand-
ing, it is important to recognize that urinary fistulae after PN
occur infrequently (in 5% of patients), are typically
temporary and resolve spontaneously or with conservative
measures, and almost never result in reoperation or renal
unit loss [89,90]. Recent reports from high-volume centers
suggest that rates of fistula are becoming rarer with the use
of modern surgical techniques [91].
Along with tumor anatomic complexity, appraisal of
patient and surgeon-related clinical factors is essential for a
sound oncologic and patient-centered treatment plan
(Table 1). Appropriate patient selection for elective PN is
imperative based on the patients perceived ability to
tolerate potential complications. Older patients may be at
higher risk of surgical and medical complications following
PN compared to RN, and their ability to make a strong
recovery may also be compromised. For example, a
population-based cohort study of Medicare beneficiaries
69
Table 1 Key surgical and clinical factors that [4_TD$IF]likely impact
surgical treatment decisions between partial nephrectomy (PN)
and radical nephrectomy (RN) a
Patient factors
Age
Functional status
Comorbidity status
Dependence on anticoagulation and antiplatelet agents
Previous surgical history
History of previous malignancy
Previous history of renal mass/genomic syndrome status
Patient preferences/risk tolerance
Renal function
Estimated (or measured) glomerular ltration rate
Proteinuria magnitude
Status of the contralateral kidney (normal, impaired, absent)
Comorbidities associated with development or progression of chronic
kidney disease, including moderate to severe hypertension, diabetes
mellitus, recurrent urolithiasis, morbid obesity
Tumor factors
Tumor size
Tumor anatomic complexity
Tumor hilar location
Tumor growth pattern (inltrative vs well circumscribed)
Posterior versus anterior location
Tumor focality
Surgical factors and approaches
Surgeon skill set and experience with RN versus PN
Medical center experience with PN and advanced renal surgery
Surgeon experience with laparoscopic/robotic surgery versus open surgery
Surgeon experience with transperitoneal versus retroperitoneal approach
Surgeon preferences/risk tolerance
a
Adapted from [5_TD$IF]Smaldone et al [[6_TD$IF]67].
with T1 renal tumors surgically treated via laparoscopic or
open PN or laparoscopic RN revealed that the PN group had
higher rates of medical or surgical complications among
patients aged >65 yr [92]. Similarly, Tomaszewski et al [93]
found that advanced age was a strong predictor of
complications among patients undergoing PN and RN for
T1 and T2 localized tumors [93].
The impact of comorbidity status must also be factored
into treatment decisions and should be considered during
comparative effectiveness assessments of cancer treat-
ments [94]. Comorbidity status affects patient life expec-
tancy and outcomes following diagnosis and treatment of
cancer [95]. Indeed, as one would expect, the preoperative
comorbidity profile affects complication rates following
renal surgery [96]. Therefore, a critical appraisal of patient
comorbidity and functional status is crucial in selecting
patients with complex renal tumors for PN due to the
inherent risks of such surgery. The National Surgical Quality
Improvement Program has developed a publically available
and objective risk calculator to predict complications of
general or vascular surgeries among older patients
[97]. Nevertheless, it is yet to be determined whether this
calculator can appropriately adjust for the clinical hetero-
geneity of renal tumors and accurately predict postopera-
tive complications following PN and RN [98].
3.3.2. Oncologic efficacy of PN
According to the literature, most urologists believe that PN
and RN confer similar oncologic efficacy. However, it is
70 EUROPEAN UROLOGY 72 (2017) 6475
important to recognize that most of the data available
have[2_TD$IF] limitations. Specifically, most series are retrospective
analyses of preselected cohorts, with considerable poten-
tial for selection bias [65,66,99105]. In fact, as mentioned
above, recent meta-analyses revealed superior CSS for PN
compared to RN, a paradoxical finding that can only be
explained by surgeons choosing anatomically less complex
(and thus potentially biologically less aggressive) tumors
for PN and selecting patients with more complex masses
that appear more aggressive on imaging for RN [9,41].
Tumor anatomic complexity is strongly linked to both
treatment choice and tumor biology [28,67,106109].
However, the majority of studies comparing the effec-
tiveness of PN and RN largely lack clinical information
about salient anatomic features of the tumors, making
unbiased, meaningful comparisons difficult [9]. Some
authors have attempted to retrospectively control for
tumor anatomic complexity; however, it is unlikely that
routine statistical manipulation would appropriately
adjust for marked differences in these preselected patient
groups [66].
Another major limitation of the data available stems
from the large number of patients and the likely long
follow-up required to adequately power a robust compari-
son of oncologic effectiveness between PN and RN. This is
also related to the marked heterogeneity of clinical behavior
for renal tumors, whereby the vast majority of masses are
relatively biologically inert. In fact, some older patients with
larger renal masses (T1b, T2) who have significant medical
comorbidities can do well from an oncologic standpoint
even when tumors are left unresected, at least during short-
or intermediate-term follow-up [110,111]. Thus, indolent
tumors, in a sense, may wash out the potential signal from
masses for which PN may potentially be an inferior option
compared to RN. Furthermore, the long follow-up needed to
detect local recurrence following PN adds to the challenge
of identifying patients who may be harmed by NSS [90].
Oncologic considerations, including pathologic upstaging
and positive margins and their potential significance, should
be discussed with patients before choosing complex PN
[112114]. The rate of positive surgical margins has been
estimated at 4% in the USA [115]. The clinical significance of
positive surgical margins for patients surgically treated with
PN remains controversial [116]. This is again probably a
reflection of the heterogeneity in clinical behavior of renal
tumors and the degree of surgical margins involved
(microscopic vs macroscopic residual disease). As a conse-
quence, studies have been decidedly mixed about whether
positive surgical margins are associated with a higher risk of
recurrence. More recently, however, a retrospective multi-
institutional analysis indicated that positive surgical mar-
gins were independently associated with a higher risk of
distant recurrence, particularly in the lung [117]. Interest-
ingly, such recurrences most commonly occurred within the
first 2 yr after surgery. In this study, the risk of recurrence
was low overall (5.6%), and was nearly doubled among
patients with adverse pathologic features. Similarly, a recent
population-based study suggested that positive surgical
margins were associated with lower long-term survival
[118]. The risks of high-grade disease, advanced tumor stage,
and recurrence increase with tumor size [119121]. Whether
RN affords an oncologic advantage over PN in patients with
high-risk tumors is currently unknown.
Overall, it is worth noting that the prospective random-
ized EORTC 30904 trial confirmed the oncologic equiva-
lence of PN and RN for renal masses 5 cm in size, as there
was no significant difference in the 10-yr progression rate
(4.1% after PN vs 3.3% after RN; p = 0.48), cancer-specific
mortality (p = 0.23), and 10-yr OS (p = 0.07). Until additional
high-quality data become available, this level I evidence
from EORTC 30904 inspires confidence in the oncologic
efficacy of PN for RCC, at least for smaller renal masses
(<5.0 cm), and should help to inform preoperative patient
counseling in this setting.
3.4. Potential impact of multifocality on treatment choice
between PN and RN
Any discussion of clinical choices regarding renal mass
management must acknowledge the issue of tumor multi-
focality and the additional dimension that this brings to
clinical decision-making. Concurrent additional tumors in
the ipsilateral kidney may render PN more technically
complex, while synchronous or metachronous tumors in
the contralateral kidney arguably make NSS more appeal-
ing. Although multifocality is often associated with
hereditary syndromes, it can occur sporadically [122]. In
patients with a sporadic renal mass, multifocality can be
synchronous or metachronous, and ipsilateral or contralat-
eral [123,124]. The incidence of ipsilateral synchronous
multifocality is estimated at 7%, while bilateral tumors are
present in up to 11% of patients at presentation [125]. Im-
portantly, how to best integrate the risk of future recurrence
in the ipsilateral and contralateral renal unit into decision-
making regarding PN versus RN remains a matter of opinion
in the literature [122]. In clinical practice, the <5% risk of
metachronous contralateral tumor development should be
discussed during decision-making and patient counseling
regarding PN versus RN.
3.5. Potential impact of surgical approach on treatment choice
between PN and RN
Yet another variable that can influence clinical decision-
making between PN and RN among patients with an
anatomically complex renal mass is the surgical approach
using open, laparoscopic, or robotic surgery. For instance, at
many centers without advanced robotic expertise, patients
with a complex renal mass face a decision between
relatively low-impact surgery such as laparoscopic/robotic
RN and an open PN, with the latter necessitating more
prolonged postoperative recovery.
Traditionally, NSS lay exclusively in the realm of open
surgery [29,30,36,63]. However, the introduction of laparo-
scopic and robotic surgery over the past two decades has
markedly changed this clinical landscape. During the early
days, when minimally invasive surgery was emerging,
laparoscopic RN initially stunted widespread adoption of
 EUROPEAN UROLOGY 72 (2017) 6475
NSS [12,126]. However, more recently, the evolution of and
growing surgical confidence with robotic PN has fueled
more widespread adoption of NSS [1618,127]. Robotic PN
can be performed via either a transperitoneal or retroperi-
toneal approach, thus extending the minimally invasive
repertoire to confidently address virtually the entire
spectrum of PN surgery, including anatomically challenging
intrarenal or hilar tumors and patients with a solitary
kidney or prior abdominal surgery, using clamped and
unclamped approaches [128131]. Nevertheless, some
experts continue to believe that for patients with complex
renal masses and imperative indications for NSS, open
surgical techniques offer a lower risk of renal unit loss.
The availability of newer surgical options results in
additional complexity when deciding between PN and a
more straightforward RN. Although the literature on
comparative effectiveness is rich in retrospective data on
perioperative and functional outcomes between laparo-
scopic, robotic, and open PN, how these data are integrated
into critical clinical decision-making for complex renal
masses depends on the expertise and experience of the
individual surgeon and on patient preference [81,132
134]. Nevertheless, most guidelines have advocated that
management decisions regarding selection of surgery (eg,
PN vs RN) should take precedence over choice of surgical
modality, which represent secondary considerations.
3.6. Future directions
In the future, more granular data sets will allow for more
meaningful retrospective comparisons of RN and PN
cohorts; however, the true benefits and risks of NSS in
patients with complex tumors are unlikely to be clearly
delineated until another randomized trial is performed. In
this spirit, Campbell and colleagues have proposed that
[(Fig._2)TD$IG]
patients with tumors of 410 cm who are amenable to PN
Fig. 2 Proposed clinical trial assessing the comparative effectiveness of
partial nephrectomy (PN) and radical nephrectomy (RN) [135].
71
be randomized to PN or RN with a primary outcome of OS at
5 and 10 yr (Fig. 2). Proposed secondary outcomes of the
trial would be disease-specific survival and renal and
cardiac functional sequelae [135]. Appropriate trial accrual
would require robust physician and patient education
regarding the trade-offs of each treatment and the
uncertainties associated with each therapeutic approach.
4. Conclusions
Treatment decisions regarding surgical management of
anatomically complex renal masses are multifaceted and
must weigh potential benefits against risks for PN compared
to RN. Limitations of the treatment effect, potential
complications, and oncologic considerations based on
tumor complexity must be integrated with variables such
as contralateral renal function, patient age, and comorbidity
profile. At present, most studies that have evaluated the
comparative effectiveness of PN versus RN are retrospective
with inherent selection biases and incomplete clinical data.
The only prospective randomized trial in this space leaves
the specific question regarding PN versus RN for anatomi-
cally complex tumors largely unanswered. Without addi-
tional high-quality prospective data supporting a benefit of
one approach over the other, the RN versus PN debate will
continue to be dominated by patient and surgeon opinion.
In the meantime, patients with an absolute indication for
NSS who also have an anatomically complex renal mass
should be considered for referral to a tertiary center with
expertise in advanced PN surgery to maximize the chances
of a favorable outcome.
Author contributions: Simon P. Kim had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Kim, Campbell, Gill, Lane, Van Popell,
Smaldone, Volpe, Kutikov.
Acquisition of data: Kim, Kutikov.
Analysis and interpretation of data: Kim, Campbell, Gill, Lane, Van Popell,
Smaldone, Volpe, Kutikov.
Drafting of the manuscript: Kim, Kutikov.
Critical revision of the manuscript for important intellectual content: Kim,
Campbell, Gill, Lane, Van Popell, Smaldone, Volpe, Kutikov.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: Kim, Campbell, Gill, Lane,
Van Popell, Smaldone, Volpe, Kutikov.
Supervision: Kim, Campbell, Gill, Lane, Van Popell, Smaldone, Volpe,
Kutikov.
Other: None.
Financial disclosures: Simon P. Kim certies that all conicts of interest,
including specic nancial interests and relationships and afliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/afliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents led,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Simon P. Kim is supported by a career development
award from the Conquer Cancer Foundation of the American Society of
72 EUROPEAN UROLOGY 72 (2017) 6475
Clinical Oncology. We would like thank Hillary Sedlacek for her help and
contributions to this study.
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