Cytoreductive Partial Nephrectomy: Framework for Patient Selection
Kyrollis Attalla1, Jatin S. Gandhi,2, Robert J. Motzer, MD, MS, FACP3, David Jones, MD4, Paul Russo, MD1
1 Department of Surgery, Urology Service;
2 Department of Pathology;
3 Department of Medicine;
4 Department of Surgery, Thoracic Service;
Memorial Sloan Kettering Cancer Center New York, New York 10065
ABSTRACT
Cytoreductive nephrectomy in metastatic renal cell carcinoma has demonstrated
a significant survival benefit in properly selected patients, however the role of
cytoreductive partial nephrectomy in this setting and whether it undermines
oncologic efficacy is not well defined. Indeed, cytoreduction coupled with nephron preservation
to both optimize cancer control and abate the renal and cardiovascular morbidities
of chronic kidney disease represents the preferred approach in patients with
imperative indications for renal preservation. We present a case of a cytoreductive partial
nephrectomy in a patient with metastatic disease in the context of a small renal mass
and pre-existing chronic kidney disease and describe a framework for patient selection.
INTRODUCTION
Renal cell carcinoma (RCC) accounts
for 3% of adult malignancies and is the
eighth leading cause of cancer in the
United States1. Up to 30% of patients
diagnosed with RCC present with
synchronous metastases and recurrence
is seen in 30% of patients after complete
resection of the primary tumor2,3.
Although the 5-year survival of earlystage
RCC is 93%, patients presenting
with metastatic disease have dismal
5-year survival rates of approximately
12%, and at least half of patients with
RCC will eventually require systemic
therapy4. Metastatic RCC (mRCC)
can have an unpredictable and highly
variable natural history which can
range from indolent with years of small
volume metastatic disease off treatment
to rapid progression and death within
months5.
Distinct clinical variables,
including performance status, serum
hemoglobin, corrected calcium, and
serum LDH can segregate patients
into risk strata associated with overall
survival6. Identifying patients likely
to derive benefit from cytoreductive
nephrectomy poses a significant clinical
challenge. Careful selection of patients
for cytoreductive operations based on
these prognostic models is key with
avoidance of poor risk and debilitated
patients unlikely to benefit who are
referred instead for upfront systemic
therapies7. Cytoreductive radical
nephrectomy (cRN) classically involves
radical nephrectomy, yet metastatic
disease has been reported in 0.5-8% of
patients with small renal masses which
usually are of high grade with renal
sinus, perinephric fat, or branched renal
vein extension (T3a)8,9,10. Two published
prospective active surveillance series
report metastatic rates of tumors
<4cm ranging from 0-1.1%11,12. In such
patients, the role of cytoreductive
partial nephrectomy (cPN) and whether
it undermines oncologic efficacy is illdefined.
We herein describe cPN in a
patient with mRCC, a small renal mass,
and pre-existing chronic kidney disease
(CKD) and discuss the contemporary
experience with cPN.
Case Presentation
A 57-year-old male initially presented
with a one-month history of an enlarging,
painless right chest wall mass. His
medical and surgical history is significant
for hyperlipidemia and diverticulitis
for which he previously underwent
a sigmoid resection. His family history
is remarkable for maternal aunts with
non-small cell lung cancer, ovarian cancer,
a maternal grandfather with bladder
cancer, and a father who died of
metastatic prostate cancer. He endorses
a 7.5 pack-year smoking history but is
not a current smoker.
Work-up of the right chest wall mass
included a CT chest which demonstrated
an expansile destructive right rib lesion
measuring 5.8 x 4.1 x 6.5 cm and a nonspecific
3mm pulmonary nodule (Figure
1). A CT-guided biopsy of the chest
wall mass was most consistent with
clear cell RCC (Figure 3). Subsequent
CT of his abdomen demonstrated a 3.9
x 4.2 x 4.0 cm heterogenous exophytic
right renal mass (Figure 2). The patient
denied gross hematuria, unintentional
weight loss, constitutional symptoms,
and pain. His physical exam was
remarkable for a palpably firm right
chest wall mass, and lab data revealed
normal serum hemoglobin, absolute
neutrophil count, platelets, and calcium.
With his excellent performance status
and normal lab results he was assigned
to the intermediate risk group as per the
International Metastatic RCC Database
Consortium (IMDC) prognostic
model13. Notably, he had mild baseline
chronic kidney disease with a serum
creatinine of 1.5 and an estimated
glomerular filtration rate was 48.2 ml/
min/1.78 m2.
He was taken to the operating
room for thoracoscopy, chest wall
mass resection, and cPN. Thoracoscopy
revealed an approximately 6cm oval,
lobulated soft tissue mass involving
the lateral portion of the right ninth
rib, and a small nodule in the right
lower lobe superior segment. A right
lower lobe wedge resection and right
chest wall resection, including partial
ninth rib and adjacent intercostal tissue,
was performed without complication.
The chest wall was reconstructed
with the use of surgical mesh and a
chest tube was placed. The right renal
mass was approached via a separate
8 cm mini-flank incision and a cPN
was successfully performed using a
completely off clamp (no ischemia)
approach. Total estimated blood loss
for the combined resections was 300cc.
The patient had an uneventful hospital
course and was discharged on day 4
with a serum creatinine at baseline
of 1.5. He has made a near complete
recovery and at 6 weeks is being
reassessed by the medical oncology
team for either careful interval followup
or the initiation of systemic therapy
depending on an upcoming extent of
disease evaluation.
Histopathologic examination of
the partial nephrectomy specimen
revealed a 5.5 cm clear cell RCC with
negative surgical margins, Fuhrman
Grade 3. Metastatic RCC was present in
the right lower lobe wedge (0.25cm) as
well as the chest wall resection (7.4cm)
which involved bone, skeletal muscle,
and fibroadipose tissue (Figure 4). All
surgical margins were negative, and
a pathologic stage of pT1bNxM1 was
assigned.
Discussion
Partial nephrectomy is a standard
of care approach in select patients with
localized renal tumors and provides the
same local tumor control compared to
radical nephrectomy while at the same
time preserving renal function and
preventing or delaying cardiovascular
ill-effects of CKD14,15. However, a
paucity of data exists regarding partial
nephrectomy in the metastatic setting. As
recently developed systemic therapies
have extended life expectancies in
patients with metastatic disease16,
surgical approaches need to consider
baseline renal function, avoidance of
development of concomitant serious
medical renal disease which carries its
own distinct potential for cardiovascular
morbidity and mortality, and improve
patient’s ability to tolerate additional
therapies. The surgical approach in this
case was driven by two salient features,
namely, his pre-existing CKD and the
exophytic position of his small renal
mass. Assuming that each renal unit in
this patient contributes half to his overall
renal function, a radical nephrectomy
would potentiate his renal impairment
to stage IV CKD (GFR 15-29) per the
CKD-EPI creatinine equation17.
At baseline, CKD is more prevalent
in the RCC patient, with 26% of patients
having GFRs <60 despite normal serum
creatinine18. CKD has been found to
be an independent risk factor for the
development of kidney cancer19. The
benefit of partial nephrectomy in the
management of the small renal mass
was brought to light in a 2006 study
from our institution; the incidence
of new-onset CKD in patients with
normal serum creatinine and two
functioning kidneys who underwent
nephron sparing surgery and radical
nephrectomy for small renal masses was
found to be 17% and 69%, respectively
for a eGFR of a 60181. The effect was more remarkable at a GFR cutoff of 45
(2.9% vs. 35.9% respectively for PN VS.
RN respectively).
Tumor size is an important predictor
of survival in the localized setting,
however limited data is available
regarding the role of tumor size as a
predictor of survival in the metastatic
setting. In a report from our center,
the impact of tumor size on survival in
patients with mRCC at diagnosis who
underwent CN was assessed20. Our
cohort was comprised of 304 patients; 21
patients with tumors < 4 cm (8 patients
underwent cPN; 13 patients underwent
cRN), with an IMDC validation cohort
(n=778). Extent of metastatic disease
sites was directly related to primary
tumor size. Smaller tumors were found
to have fewer metastatic sites, a finding
that was specific to tumors of clear cell
histology. A significant difference in
overall survival was observed when
using a 4 cm size cutoff to distinguish
small vs. large masses, and a subgroup
analysis stratified patient into clear
cell and non-clear cell histology,
demonstrating that tumor size was a
significant prognostic factor only in
patients with clear cell RCC.
In 2006 and in 2007, two papers
reported cause-specific survival data
in metastatic RCC patients treated with
cPN. In the first report from the Mayo
Clinic, patients undergoing cPN (n=16)
did not demonstrate inferior cancerspecific
survival rates compared to those
undergoing cRN (n=404)21. Although
early and late complications were higher
with cPN, there were no differences in
complications in M1 pts undergoing cPN
compared to a matched cohort of nonmetastatic
patients undergoing partial
nephrectomy. One critical confounder in
this study was that 87.5% of the patients
in the cPN group underwent complete
resection of all metastatic disease (like
our patient did) compared to only
22.5% in the cRN group. The second
paper from the University of Montreal
Health Center included larger patient
numbers (cRN: 732 patients; cPN: 45
patients), and detected a 1.5-fold, albeit
statistically nonsignificant, increase in
cancer-specific mortality for cRN cases
(p=0.2), confirming the non-inferiority
cPN described in the previous study22.
Given the multi-institutional nature of
the study, differences in surgical and
adjuvant treatments could have affected
the results of this study.
The first retrospective study to
demonstrate a survival benefit with cPN
was published in 2013 from Roswell
Park Cancer Center, which included
2,880 patients who underwent cRN and
70 patients who underwent cPN from
the Surveillance, Epidemiology, and
End Results (SEER) database23. Patients
undergoing cPN were 0.54 times less
likely to die and 0.49 times less likely to
die of RCC than those who underwent
cRN (95% CI 0.3–0.73, p<0.001 and 95%
CI 0.35–0.69, p<0.001; respectively).
The largest single institution study
of cPN from MD Anderson Cancer
Center reported in 2014 identified the
indications for and outcomes of cPN
with particular attention paid to cPN
subgroups24. A total of 33 patients
were included; 8 patients had bilateral
synchronous tumors, 20 patients had
metachronous contralateral tumors,
and 5 patients had unilateral renal
tumors. Although all patients had
metastatic disease before PN, not all
had metastatic disease at the original
diagnosis; 17 (52%) presented with
M1 disease, and 16 (49%) developed
metastases after original diagnosis
but before cPN. Twelve patients (36%)
experienced 17 early postoperative
complications within 3 months after
surgery, ranging from Clavien grade 1
to 4a (the commonest complications
including urine leak (n=5), acute kidney
injury (n=2), and wound infection
(n=2)). Patients who underwent cPN
for a metachronous contralateral renal
mass and a renal mass < 4cm had the
best overall survival (61 and 42 months,
respectively). A significant difference
was observed in median overall survival
in patients presenting with M1 vs. M0
disease27; vs. 63 months, respectively
(p=0.003). These findings suggest
that metastasis at original diagnosis
and the timing of presentation of the
index lesion have an important role in
survival.
Figure 4: (A) Gross image of the right
interpolar renal neoplasm having a
circumscribed orange yellow appearance.
(B) Microscopic images showing a
characteristic clear cell renal cell carcinoma
histology. (C) Gross and (D) microscopic
image from the chest wall soft tissue tumor
deposit with infiltration into the adjacent
9th rib. (E) Microscopic tumor deposit
within the lung parenchyma measuring
0.25cm.
The most recent addition to
the literature was a report from the
National Cancer Database (NCDB)
which examined the trends in usage
of cPN and effect on overall survival
in 10,144 patients with mRCC (9,764
patients undergoing cRN, 381 patients
undergoing cPN)25. Rates of cPNc
increased over the 2006-2013 study
period, from 1.8% to 4.3%. Survival
curves were constructed for a matched
cohort, and overall survival was
significantly improved in patients
undergoing cPN compared to cRN,
with a 1-year overall survival of 67%
and 76% in the cRN and cPN cohorts,
respectively. When stratified by
tumor size, cPN conferred a survival
advantage only in patients with tumors
<4 cm, and in a multivariate analysis,
cPN was found to be independently
associated with improved overall
survival (HR = 0.81; 95% CI: 0.71–0.93;
p=0.002). As with all registry-based
analyses, these data are limited by
lack of important prognostic variables
used in risk stratification, the extent of
metastatic burden, and the systemic
therapies received.
Our institutional practice is
to recommend nephron sparing
approaches when technically feasible.
In this case the indication for cPN
must be considered imperative given
the patient’s pre-existing CKD. In the
cytoreductive setting, consideration
for cPN is given to patients with
pre-existing CKD, and is prioritized
in patients with an anatomically or
functionally solitary kidney and those
with bilateral renal masses. Careful
preoperative assessment of tumor
complexity is critical, and patient
counseling should include the potential
for post-operative complications
including bleeding events and urinary
fistulae (greater in the partial compared
to radical nephrectomy), understanding
that such events could potentially delay
the start of systemic therapy and/
or enrollment onto a clinical trial. In
patients in whom renal preservation is
non-imperative (i.e. small renal mass
with a normal contralateral kidney
and no pre-existing CKD), cPN may be
performed when technically feasible.
Conclusions
The role of partial nephrectomy in
mRCC is currently supported by retrospective
series which suggest the
non-inferiority of cPN compared to
cRN. Indeed, the framework for patient
selection for cPN should prioritize
those in whom renal preservation is imperative
to prevent the further progression
of CKD and its associated potential
for cardiovascular morbidity and mortality
and obviate the potential for end
stage renal disease and dialysis. Partial
nephrectomy in both the localized and
metastatic settings demonstrate higher
surgical complication rates compared
to radical nephrectomy, and such risks,
particularly for non-imperative indications,
must be weighed against the benefits
of nephron sparing approaches in
properly selected patients.
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Correspondence: Paul Russo, MD, FACS. Department of Surgery, Urology Service, Memorial
Sloan Kettering Cancer Center, New York, NY 10065. Email: russop@mskcc.org
Disclosures: None