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167 Indian J Urol, April-June 2010, Vol 26, Issue 2
Role of surgery in advanced/metastatic renal cell
carcinoma
Suresh Bhat
Department of Urology, Medical College, Kottayam-686 008, Kerala, India
ABSTRACT
Metastatic renal cell cancer (RCC) is a malignant disease without curative treatment. These patients are usually symptomatic
and desperate for effective palliative treatment. Radiotherapy, chemotherapy, and hormonal therapy are not effective
in these patients. A multimodal approach consisting of cytoreductive nephrectomy, systemic therapy (which includes
cytokines or targeted molecules), and metastasectomy have been shown to be useful in prolonging the survival and
improving the quality of life in a select group of patients with metastatic renal cancer. Patients with oligometastatic
disease, good performance status, and delayed presentation of the secondaries have better results following this integrated
approach. Although there is some controversy regarding the order in which nephrectomy and systemic therapy are to be
instituted, well-controlled studies like the South West Oncology Group and European organization research and treatment
of cancer have shown that upfront nephrectomy gives better survival compared to neoadjuvant systemic therapy followed
by nephrectomy. This order is the standard presently. Of late, with better understanding of the genetic basis and the
biology of the various subtypes of renal cell carcinoma, targeted molecular therapies have emerged as an equally effective
alternative therapy to cytokines. Recent reports have proven that targeted therapy is more effective with comparable
side effects. Metastasectomy in a subgroup of patients improves survival and quality of life specifi cally in those with lung
secondaries and painful bone metastases.
Key words
Key words: Cytoreductive nephrectomy, immunotherapy, metastasectomy, metastatic renal cancer, targeted molecular
therapy
DOI: 10.4103/0970-1591.65381
INTRODUCTION
Renal cell carcinoma (RCC) is a serious and life-
threatening disease. It accounts for about 2% of all
cancers with a worldwide annual increase of 1.5-5.5%.
This is mainly due to enhanced detection of tumors
by increased use of imaging techniques.[1] RCC is the
most lethal among the urinary tract tumors. It has a
highly variable natural history and biological behavior.
Approximately 30-40% patients with malignant
renal cortical tumors will either present with or later
develop metastatic disease.[2] After radical or partial
nephrectomy, metastases develop in about 2 years.[3]
About 90% of the metastases are from the conventional
(clear cell) RCC.[3] The 5 year survival for all stages of
RCC has continued to improve. Disease-free interval
(DFI) of up to 30 years has been reported. Patients with
untreated metastatic disease have a 5 year survival of
0-18%.[4]
Kidney cancer is not a single disease; it is made up of a
number of different types of cancers, each with a different
histology, different clinical course, and caused by alteration
of different genes. Metastases have been reported to almost
all the organs in the body. The common sites include
lungs, liver, bones, adrenals, pancreas, brain, thyroid, skin,
and ureter. Conventional RCC metastasizes commonly to
the lungs, whereas papillary and chromophobe variety
to the lymph nodes and the liver, respectively.[4] Median
patient survival for patients with metastasis is about 10-12
months.
[5] Patients with metastatic disease have an 18%
chance of surviving 2 years.[6] However, subsets of patients
with advanced disease have shown improved survival. The
following factors predict the risk of metastasis following
radical nephrectomy (RN) for clinically localized RCC viz:
size and stage of primary tumor, extent of regional lymph
node involvement, if any, tumor histology, presence or
absence of necrosis, and presence or absence of vascular
invasion.
A decade ago, patients with metastatic RCC (mRCC) had very
dismal prognosis. Now, the outlook has changed remarkably
thanks to the tremendous advancements in the fi eld of
medical management of mRCC especially immunotherapy
(IT), targeted therapy, and the better understanding of the
For correspondence: Dr. Suresh Bhat, Medical College,
Kottayam, Kerala, India. E-mail: drsureshbhat@yahoo.com
Review Article
Review Article
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Indian J Urol, April-June 2010, Vol 26, Issue 2 168
role and timing of cytoreductive nephrectomy (CRN) as
well as expertise in minimally invasive surgery. Surgical
intervention in any patient with mRCC has one of the two
aims viz: (1) complete metastasectomy to render the patient
clinically free of all sites of metastases or (2) cytoreductive
nephrectomy to remove the primary tumor either before
or after the initiation of systemic therapy. Whether to
proceed with metastasectomy depends on multiple factors
like the sites and number of metastases, resectability, surgical
expertise, and patient compliance and general condition.
The decision to perform metastasectomy is often empirical.
Surgery in the setting of mRCC may be in the form of
palliative nephrectomy, nephrectomy as a component of
adoptive immunotherapy, cytoreductive nephrectomy, and
metastasectomy.
SURGICAL CONSIDERATIONS IN PATIENTS WITH
mRCC
Radical nephrectomy in the setting of mRCC, commonly
called cytoreductive nephrectomy, is usually advocated as
part of multimodality treatment approach. Over the years,
several arguments have been put forward to support the
concept of radical nephrectomy for mRCC. It is common
knowledge that nephrectomy in a patient with mRCC almost
certainly cannot bring cure and that these patients die of
their metastases than the primary tumor. In 1978, deKernion
and colleagues showed that nephrectomy alone had a
minimal effect on survival in mRCC patients.[7] In fact, the
only rationale could be, it may bring about a survival benefi t
and improvement in quality of life (QOL). However, with
the advent of modern targeted molecular therapy (TMT), a
critical reevaluation of the approach to the management of
patients with mRCC is becoming increasingly signifi cant.
The role of palliative nephrectomy
In general, palliative nephrectomy alone for metastatic
disease without adjuvant therapy is not useful. As the
general condition of the patient is poor most of the time,
surgery may be associated with morbidity and mortality.
It should only rarely be done in patients with intractable
pain, bleeding, uncontrolled hypertension, symptoms
due to paraneoplastic syndromes such as uncontrolled
hypercalcemia, erythrocytosis, if usual measures fail.
However, the systemic effects attributed to RCC may be
produced by the metastases and not necessarily due to the
primary tumor itself. Hence, palliative nephrectomy may
not bring relief for the problem which it was intended to
palliate. Walther and colleagues in 12 patients with mRCC
and hypercalcemia found that after nephrectomy, calcium
decreased in only 7 patients, it increased in 4 patients and
remained unchanged in 1 patient.[8] In addition, patients
who had reduction in serum calcium did not fare better than
those who did not show any reduction in the calcium ,in that
both groups had median survival of 6 months. As minimally
invasive procedures like angioinfarction of the tumor
result in equally effective palliation, the role of palliative
nephrectomy may be limited. However, the quality of life in
selected patients after palliative nephrectomy appears better.
Nephrectomy as a component of adoptive immunotherapy
Adoptive immunotherapy involves transfer of antitumor
cells into the host to mediate tumor regression. Nephrectomy
is required to harvest tumor antigens or tumor infi ltrating
lymphocytes (TILs). University of California at Los Angeles
(UCLA) has reported some encouraging results with this
modality.[9] In 55 patients, an overall partial response (PR)
rate of 25.5% and complete response (CR) of 9.1% was noted.
There was a survival advantage of 15 months in those patients
receiving tumor infi ltrating lymphocytes and interleukin
2 (IL-2). In a multicenter trial, combination of tumor
infi ltrating lymphocytes with low dose IL-2 was compared
with IL-2 alone. Treatment with CD8+ tumor infi ltrating
lymphocytes did not improve response rate or survival in
patients treated with IL-2 post-nephrectomy.[10] Although
the results of adoptive immunotherapy are disappointing,
with proper informed consent, more patients need to be
enrolled into clinical trials. Future trials are needed to
document the effi cacy of adoptive immunotherapy.
CYTOREDUCTIVE NEPHRECTOMY
Biologic rationale for cytoreductive nephrectomy
RCC is an immunogenic tumor as evidenced by the
expression of multiple tumor antigens notably CA IX
(carbonic anhydrase). RCC has the ability to manipulate
and suppress the host’s natural immunity leading to
immunological dysfunction. The primary tumor might
suppress the antitumor effect of the host defense mechanism.
It suppresses the cell-mediated immunity. The primary
tumor acts as an ‘immunogenic sink’ whereby it diverts the
circulating macrophages, lymphocytes, and immunoglobulins
away from the distant metastases.
[11] Lymphocytes from
patients with mRCC have been shown to have defective
T-cell receptors, enhanced apoptosis, and defective signal
transduction with tumor infi ltrating lymphocytes showing
greater dysfunction than peripheral lymphocytes.[12]
RCC produces high levels of proinfl ammatory and T-cell
inhibitory substances such as IL-8, IL-6, IL-10,TNF, and
TGFb-1 all of which suppress immunologic responses.[12]
The primary tumor also lacks response to immunotherapy.
Hence, removal of this large load of immunosuppressive
tumor may improve the host’s immune surveillance. A
reduction in the tumor burden increases the likelihood of
response. Additional immunotherapy can augment the host
immune mechanisms thereby producing better survival and
quality of life.
This is typifi ed by the occasional and rare phenomenon of
spontaneous disappearance of the metastases, especially in
the lungs. The lungs are rich in macrophages, lymphocytes,
and immunoglobulins. This spontaneous regression is due
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169 Indian J Urol, April-June 2010, Vol 26, Issue 2
to host-mediated cytotoxicity. This occurs in 0.4-0.8%
of patients. In the national cancer institute (NCI) series
of 91 patients, 4 patients showed complete regression
of metastases after nephrectomy.[13] However, most of
these lesions were not biopsy proven and could have been
old granulomas, fungal lesions, or pulmonary infarcts.
Spontaneous regression is a rare event and nephrectomy
should not be done for this purpose alone. Another aim
of nephrectomy in mRCC is to improve the quality of life
by obtaining relief of symptoms like hematuria, pain and
systemic symptoms. Mostly, however, the pain is due to
involvement of the nerves and the bones, and surgical
treatment is usually inadequate. Some patients may have
psychological benefi t with a feeling that the cancer has
been removed. Another benefi t of nephrectomy is removal
of source of metastases. This results in resetting of the clock,
for accumulation of lethal tumor burden.
There is some controversy regarding the timing of
nephrectomy in the multimodal approach. There are authors
who prefer upfront nephrectomy and others who perform
nephrectomy, only after systemic therapy. Both have their
own pros and cons.
Nephrectomy before systemic therapy
Cytoreductive nephrectomy (debulking nephrectomy) has
an important role in the multi-modal management of mRCC.
Even though there is a controversy regarding the timing of
nephrectomy, most of the authors feel that it is benefi cial
to perform the cytoreductive nephrectomy before the
planned systemic therapy. Proceeding with cytoreductive
nephrectomy in patients with good performance status
(PS) and easily resectable primary is reasonable and much
followed option.
Cytoreductive nephrectomy appears to be benefi cial for
many patients with mRCC. However, it is not curative and
should not be done indiscriminately. Nephrectomy alone
offers no benefi t, however, when done as part of multimodal
treatment approach, it does have a complementary role.
When evaluating the controversial issue of nephrectomy
before immunotherapy or TMT, the following issues need
to be looked into. They are (a) after nephrectomy, will the
patient be stable enough to receive the systemic therapy and
(b) will initial nephrectomy improve the objective response
of systemic therapy at metastatic sites. Obviously, patient
selection is the most crucial factor in this. Patients with other
comorbidities like compromised cardiac and pulmonary
function cannot be part of this protocol. Patients who are
most likely to benefi t from cytoreductive nephrectomy
include those with substantial tumor burden, (in excess
of 75%) in the affected kidney, good performance status,
and no central nervous system or liver metastases.
[14]
Removing the primary tumor may also prevent further
seeding of metastases and eliminate potential source of
pain and hemorrhage. Cytoreductive nephrectomy leaves
behind a smaller volume of cancer cells which are easier
to be managed with systemic therapy. These form the
basis of performing the nephrectomy fi rst. Patients with
normalization of the C-reactive protein after nephrectomy
have a better survival.[15] Factors that may militate against
nephrectomy include comorbidities that increase the risk
of surgery and high volume of metastatic disease. Kader
et al
maintain that it is the physiological age and not the
chronological age that should be considered before taking
up patients for cytoreductive nephrectomy.[16]
Potential disadvantages of cytoreductive nephrectomy
are perioperative morbidity and mortality, and delay in
starting systemic therapy. Many patients due to the ensuing
complications become unfi t to receive the systemic therapy
and most patients do not respond to immunotherapy.[17]
The mortality of cytoreductive nephrectomy varies from
6 to 11% and the morbidity is around 20%.[17] In the South
West Oncology Group (SWOG) trial, there was only one
death in the perioperative period.[18] Expert surgeons can
now perform even challenging resections using laparoscopic
techniques. This may reduce the complication rate. Reports
by Bennet and associates, National Cancer Institute and
Cleveland Clinic showed that a significant number of
patients (22-77%) could not receive immunotherapy.[19-21]
In the SWOG trial, only 2% patients were unable to receive
interferon after nephrectomy.[18]
The best support for the pre-immunotherapy nephrectomy
came from two prospective, randomized studies by the SWOG
and European organization research and treatment of cancer
(EORTC) groups. In the SWOG study, the median survival
for the cytoreductive nephrectomy + immunotherapy group
was 11.1 months compared to 8.1 months in the interferon
(IFN) only group. This represents a 31% reduction in the
risk of death (
P
=0.002). Thus, cytoreductive nephrectomy
appears to signifi cantly improve overall survival in patients
with mRCC treated with IFN-α. This effect was independent
of performance status, site of metastases, and the presence
of measurable disease. Although the result is statistically
significant, the overall survival advantage is only 5.8
months.
[18] In the EORTC study, the survival was 17 and
7 months, respectively.[22] Flanigan and colleagues did a
combination analysis of these two studies and found a median
survival of 13.6 months for the combination group and 7.8
months for the immunotherapy alone patients. There was a
survival advantage of about 6 months for the cytoreductive
nephrectomy + immunotherapy group.[23] Unlike other
series, operative mortality in the combined experience was
only 1.5% and only 5.6% of patients did not receive IFN.
A provocative study from the SWOG hypothesized that
the survival advantage could be due to the post-operative
azotemia resulting from cytoreductive nephrectomy and
not due to the removal of the tumor.[24] Many tumors
acidify their peritumoral microenvironment as a means of
overcoming the negative effects of the intracellular acidosis
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Indian J Urol, April-June 2010, Vol 26, Issue 2 170
that results from tumor cell hypoxia and increased glycolytic
metabolism. Unilateral nephrectomy may alter the dynamics
of the tumor host interface and further acidify the tumor
pH suffi ciently to exceed the tolerance of the tumor cells,
slowing or reversing tumor growth and invasion. In this
SWOG study, patients developing increase in blood urea
nitrogen (BUN) and creatinine had a signifi cantly improved
survival compared with those who did not (17 vs 4 months).
According to Bromwich and colleagues, this advantage could
be due to referral pattern, surgical judgments, and patient
selection.[25] In their group of 20 patients, who underwent
cytoreductive nephrectomy, 13 received immunotherapy,
yet the median survival was only 9.5 months. Kassouf and
associates have shown that cytoreductive nephrectomy
followed by systemic therapy is equally good for non-clear
histology mRCC also.[26] These patients compared to the
clear cell mRCC subtype were younger, had higher lymph
node involvement, and sarcomatoid variety. That is why,
after metastasis, the non-clear variety has worse prognosis
than the clear cell type.
Walther
et al
used laparoscopic techniques for cytoreductive
nephrectomy in an effort to reduce the morbidity so that
systemic therapy could be initiated earlier.[27] They compared
open nephrectomy, lap-assisted nephrectomy, and lap
morcellation in relation to starting the immunotherapy.
For open surgery patients, it took a median time interval of
67 days (56-151 days), whereas for lap-assisted patients, it
was 60 days (47-63 days). The group that benefi ted the most
was those who had morcellation. In these patients, systemic
therapy could be started at a median of 37 days (37-57 days).
The authors concluded that laparoscopy offered a reasonable
method of performing nephrectomy in preparation for
immunotherapy.
A Cochrane-based analysis concluded that in fi t patients
with metastases at diagnosis and minimal symptoms,
nephrectomy followed by IFN-α gives the best survival
strategy for fully validated therapies.[28] So far, only,
cytoreductive nephrectomy followed by immunotherapy
is authoritatively evaluated and approved. It constitutes
standard therapy currently.[29]
Nephrectomy after systemic therapy
Many clinicians feel that nephrectomy be performed only
on those patients who show response to systemic therapy.[30]
The plus points are avoidance of morbidity, mortality, and
cost-associated with nephrectomy. Experimental evidence
shows that surgery itself can lead to immunosuppression
and decreased response to immunotherapy. Platelet-derived
growth factor and TGF released during surgery can augment
the tumor growth. Some studies have shown that tumor
progresses after nephrectomy in 22% of patients.[31] This
has been hypothesized to be due to the loss of angiostatin,
an angiogenic inhibitor secreted by the primary tumor.
This might have been inhibiting the growth of metastases
partially.
Other advantages of this approach include earlier initiation
of the systemic therapy, the potential for reduction of
metastatic and primary tumor burden before surgery, early
identifi cation of patients who will benefi t from surgical
removal of the primary tumor, and the opportunity to
examine the effects of systemic therapy on urological
tumors.
It is prudent to delay nephrectomy to assess the response to
a course of systemic therapy. The most signifi cant benefi t
of the neoadjuvant approach in the treatment of mRCC
is that it can act as a litmus test to select patients who are
responding to therapy and most likely to benefi t from
the proposed cytoreductive nephrectomy. Some tyrosine
kinase inhibitors (TKI) even downstage the primary tumor
rendering subsequent nephrectomy technically easier.[32]
The downside of TMT is that it may increase the surgical
morbidity and postoperative complications. This is mainly
due to the inhibition of the vascular endothelial growth
factor receptors and related pathways. These proangiogenic
pathways have important role in tissue integrity. Hence,
any disturbance in these could lead to increased incidence
of delayed wound healing, fascial disruption, and incisional
hernia. This might also cause impairment in the natural
regeneration of the microvasculature and predispose the
patient to postoperative bleeding and thrombotic events.
[33]
Tyrosine kinase inhibitors are very costly. A course of
1 month therapy costs about rupees 2 lakhs. This is one of
the factors which may militate against this therapy.
Rackley and associates found that patients treated with initial
immunotherapy had slightly higher objective response
rates and longer median survival rates when compared
to patients who had initial nephrectomy and adjunctive
immunotherapy.[21] They reported on 62 patients, 37 of
whom underwent nephrectomy prior to immunotherapy
and 25 patients who received IFN ± IL-2. Three of the 25
patients responded to the immunotherapy and proceeded
onto nephrectomy. Of these 3, 2 patients were alive at 18
and 42 months. In this small series, prior nephrectomy group
had an 8% response rate and 12 months median survival,
whereas, in the initial immunotherapy group, the response
rate was 12% and median survival was 14 months.
Krishnamoorthy
et al.
from Cleveland treated 14 patients
with mRCC initially with immunotherapy and later 9
patients responding to this with nephrectomy. IL-2 alone or
in combination with IFN was given in this study. All patients
were then rendered disease free by surgical excision of both
residual metastatic disease and primary tumor. Cancer-
specifi c survival at 3 years was 81.5%.[34] Overall, cytokine
therapy before nephrectomy did not yield comparable
results.
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171 Indian J Urol, April-June 2010, Vol 26, Issue 2
Targeted therapies are dramatically changing the landscape
of advanced kidney cancer. Although several studies
demonstrated that targeted agents are generally well
tolerated, there are limited data on the safety of surgical
resection in patients after targeted therapy. Thomas and
associates recently reported neoadjuvant targeted therapy
followed by nephrectomy.[35] They treated 19 patients with
targeted molecules. Ten patients had prior nephrectomy.
A median of 4 cycles of sunitinib was given to 12 patients,
sorafenib to 3 patients, and bevacizumab to 4 patients.
The indication for neoadjuvant-targeted therapy was
unresectable primary tumor or the inability to perform
nephron sparing surgery in those with bilateral disease.
9, 3, 6, and 3 patients underwent nephrectomy, partial
nephrectomy, local recurrence excision, and metastasectomy,
respectively. In these two patients with extensive bilateral
disease, partial nephrectomy could be done due to the
downsizing of the tumor by the targeted therapy. Three
patients (16%) had major complications like perioperative
hemorrhage, disseminated coagulation, and anastamotic
leak. Two patients had minor wound complications. At
a median follow-up of 8 months, 16 patients were alive
and 8 patients showed disease progression. Margulis and
coworkers from the MD Anderson cancer center treated
44 patients with neoadjuvant-targeted molecules.[36] Fifteen
patients received sunitinib, 12 patients sorafenib, and 17
patients bevacizumab. Upfront nephrectomy was done
in 58 well-matched patients. At analysis around 1 year,
18.2% of patients in the fi rst group and 31% patients in
the second group died of RCC. Complications were seen
in 32.4%. Withholding targeted therapy for at least two to
three half lives before and after surgery may help prevent
the adverse effects of these agents on microvasculature and
tissue integrity. Half life of temsirolimus is 17 h, sorafenib
is 1-2 days, sunitinib is 4 days, and bevacizumab is 17 days.
The terminal half life of these agents and their metabolites
would suggest that interrupting therapy for 7-10 days before
and after surgery would reasonably reduce surgical risks.
In addition, the meticulous surgical technique and good
hemostasis go a long way in curtailing the side effects.
Most systemic therapy protocols for mRCC were tried
before the availability of targeted therapies. They utilized
immunotherapy which did not affect the primary tumor.
With the recent availability of powerful tyrosine kinase
inhibitors which have been shown to reduce the size of the
primary tumor, ‛medically selected’ patients (neoadjuvant
systemic therapy) for cytoreductive nephrectomy may have
better survival. This needs further documentation using
randomized controlled studies.
ROLE OF NEPHRON SPARING SURGERY
The role of nephron sparing surgery (NSS) has been
recently examined in the metastatic setting. Besides the
preservation of renal function, the additional benefi ts of
NSS include improved performance status, elimination of
paraneoplastic syndromes, and eradication of the source of
new metastases. Kranbeck
et al,
recently showed that the
survival in 14 patients with mRCC who had NSS and 40
patients who had radical nephrectomy was comparable.
[37]
The sample size was small in this study and selection
bias might have crept in. More recently, Hutter and
colleagues have shown in a well-matched study that NSS
did not undermine the RCC-specifi c survival.[38] This study
included 38 patients having NSS and 99 patients who had
radical nephrectomy. The median actuarial survival of
the NSS vs radical nephrectomy patients was 5.1 vs 3.3
years. Krishnamoorthy
et al
, from Cleveland, reviewed
the outcome in 15 patients with mRCC who had NSS and
surgical or systemic treatment of metastases. All cases were
technically successful and the need for renal replacement
was found in only one patient.[39] These studies showed
a survival advantage for the NSS group. This may partly
be due to the preservation of the renal function. Recent
studies have shown that chronic kidney disease (CKD)
is present in 26% of apparently normal patients with
small renal tumors and normal serum creatinine. Casual
nephrectomy can lead to worsening of the renal function.
Patients who had nephrectomy had a reduced survival
due to increased mortality from cardiovascular causes The
likelihood of developing chronic kidney disease with a GFR
of <45 ml/min/1.73 m2 after partial nephrectomy is <5%,
whereas after radical nephrectomy it is 36%.[40]
THE ROLE OF METASTASECTOMY IN MRCC
Patients with mRCC usually have a dismal prognosis.
However, with the introduction of TMT the outlook has
dramatically changed. Favorable subgroups include solitary
metastases and DFI to metastases of >1 year. Complete
resection of isolated metastases was associated with 5 year
survival rates of between 35 and 60%. Findings from Mayo
clinic, Memorial Sloan Kettering Cancer Center (MSKCC),
and from Martin Luther university showed a 5-year survival
of 30-50% following metastasectomy. Interestingly, even
when the likelihood of complete resection was low,
metastasectomy still maintained its benefi cial effect.[41]
Prognostic variables
Features adversely associated with survival in patients
with mRCC of clear cell variety include constitutional
symptoms at nephrectomy, metastases to bones or liver,
multiple metastases, metastases at nephrectomy or within
2 years of nephrectomy, tumor thrombus level 1-4, nuclear
grade 4, and coagulative necrosis. Complete resection of all
metastases was associated with improved survival.
Patients with liver metastases are more likely to die of RCC
compared to metastases to bone (69% vs 35%). A study by
Han
et al,
showed that the number of metastases rather than
the site of metastases is more important regarding survival.[42]
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Complete resection of metastases was associated with
a twofold decreased risk of death from RCC. A recent
algorithm by Motzer
et al,
has suggested that the Karnofsky’s
performance status (KPS), lactate dehydrogenase (LDH)
level, hemoglobin(Hb) level, serum creatinine, and time
from the diagnosis to immunotherapy were signifi cantly
associated with survival.[43]
In a study of 670 patients with mRCC treated at MSKCC,
the following factors were considered to be associated with
poor survival: low KPS (<80%), high LDH (>1.5 x upper limit
of normal), low Hb(lower than the lower limit of normal),
high corrected serum calcium (>10 mg/dl), and absence
of nephrectomy.[43] Median survival ranged from 4 to 13
months. For patients without any of the above risk factors
the median time to death was 22.1 months. For patients with
only one of the factors the time to death was 12 months and
with multiple factors, only 5 months.
Role of lymphadenectomy
Parker has demonstrated that the primary regional drainage
of kidney is predicatable.[44] On the right side, the regional
nodal drainage is to the lateral caval, pre-caval, post-caval,
and inter-aortocaval nodes. On the left side, para-aortic,
pre-, post-, and inter-aortocaval nodes. However, the
secondary drainage is variable and unpredicatable. Despite
the predicatable nature of the renal lymphatic drainage,
patterns of lymph node metastasis in patients undergoing
surgery for RCC are rarely predicatble. Because the role
of lymph node dissection in mRCC is less well studied
than in localized and node only disease, the decision for
lymphadenectomy (LND) is heavily influenced by the
experience and the bias of the surgeon. For patients with
lymph node (LN) metastases, the median survival was 5
months longer for patients who had LND than for patients
who did not. This difference was statistically signifi cant.
While the primary intent of LND in localized RCC is to
increase the detection of nodal micrometastases thereby
improving staging accuracy, in N + M0 disease, the principal
goal is complete disease resection and cure. However, only
a small group of patients have lymph node only disease
(4-10%). Giuliuni and coworkers reported a 5 year and 10
years survival of 47.9% and 31.9%, respectively, for N + M0
disease following an extended LND.[45] In another study by
Peter and colleagues, the 1 and 5 years survival following
extended LND was 87.5% and 43.75%, respectively. Without
LND, the rate declined to 56.5% and 25.69%, respectively.[46]
In advanced disease, the presence of lymph nodes with
wide spread metastases portends a grave scenario. In a study
by Peter and Brown, patients with mRCC were subjected
to nephrectomy + lymphadenectomy, nephrectomy, and
no surgery.[46] The survival at 1 and 5 years for the three
groups were as follows: 81%, 47.7%, and 32.3% for the fi rst
category, 28.9%, 9.1%, and 11.4%, respectively. An UCLA
study also reported similar benefi ts.[47] Recently, Patard
and coworkers reported complete LND after sunitinib in
a patient who was initially found to have unresectable
lymph nodes. There was no recurrence at 6 months.[48] In
patients undergoing LND, the most frequent complication
was bleeding (>1 L) which occurred in 10% of patients.
Other complications included pleural damage, infection,
and lymph leak. The overall complication rate was 25.7%.
Because, nodal positive disease represents an aggressive
phenotype of RCC, these patients are in desperate need of
an effective adjuvant therapy.
Accumulated evidence is in favor of adding LND in lymph
node only disease (which is rare) or when there are limited
and resectable metastases elsewhere.
Lung metastases
Lungs are the most common sites of metastases in RCC
patients. Resection of pulmonary metastases (LM) is
associated with higher survival rates and results are better
when compared to other anatomical sites. Factors generally
agreed upon to impart longer survival postoperatively
are fewer pulmonary metastases, lack of lymph node
involvement, pathological evidence of complete resection,
and the synchronous or metachronous nature. The number
of resected lung metastases has little infl uence on survival
when the resection is complete. Surgery for lung metastases
related to primary RCC is safe and curative in one-third of
patients. The most important predictive factor for a long-
time survival is the completeness of resection. The fi rst
resection of a pulmonary metastasis in a patient with RCC
was performed by Barney and Churchill in 1939.[49] Since
then surgery remained the only effective treatment for
patients with isolated lung metastases. The published 5-year
survival rates after metastasectomy of renal origin range
from 36 to 54%. Patients who developed metachronous
metastases had far superior survival rates than those who
had synchronous metastases (5-year survival of 56.7 months
vs 15.3 months). Hoffman
et al,
suggested that pulmonary
metastases resection can be done if the DIF was long and the
number of metastases upto 6 and good functional status.[50]
Repeat metastasectomy for recurrent pulmonary metastases
appears to be effi cacious in certain patients since the group
from the Mayo Clinic reported that the 5-year overall survival
in this subgroup was similar to that in patients without
recurrence.[51] Zagoria and colleagues treated lung metastases
with radiofrequncy ablation.[52] At 1-year follow-up there
was no recurrence. Thoracoscopic techniques are being
routinely used nowadays for resection of the metastases.
Soga and associates treated 39 patients with unresectable
pulmonary metastases with RFA. The recurrence free
survival rates were 92% at 1 year, 23% at 2 years, and 23%
at 5 years.[53] Radiofrequency ablation is considered safe
and effective treatment modality for prolonging survival
in patients with unresectable secondaries. As the 5-year
survival after metastasectomy of lung nodules is 36-54%,
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173 Indian J Urol, April-June 2010, Vol 26, Issue 2
resection of the secondaries should be considered whenever
feasible.
Pulmonary metastases are shown to be significantly
more susceptible to IFN treatment compared to other
sites. However, no activity of IFN has been found in this
adjunct setting and treatment has often resulted in increased
morbidity. Therefore, adjunct IFN therapy cannot be
routinely recommended after treatment of pulmonary
metastases.[54]
Adrenal metastases
The incidence of ipsilateral adrenal metastases from RCC
varies from 1.1 to 10%.[55] The higher incidence of metastases
are seen in patients with upper pole tumor, left sided tumors,
and larger tumors. Adrenals can be involved in different
ways viz: directly via the Gerota’s fascia, through the vessels
piercing the Gerotas fascia, lymphatics, and directly as
arterial emboli and retrograde venous embolization.
Many cases of ipsilateral and contralateral adrenal metastases
were reported even with small lower pole tumors.[56]
Therefore, the sensitivity, specifi city, and predictive value
of the predisposing factors are insuffi cient to defi ne all the
cases at risk. CT scan has been shown to be highly sensitive
for the diagnosis of adrenal metastases. If a preoperative
CT scan shows normal adrenal, then the chance of adrenal
metastases is very low and probably does not need to be
resected except in large upper pole tumors.[57]
In patients without any systemic spread and intra-adrenal
metastases only, the median long term survival was 11.7
years. Patients with adrenal metastases and systemic spread
had a survival of 16 months. Patients with RCC and a single
contralateral adrenal metastasis should be considered as
having solitary metastases. These patients are recommended
radical nephrectomy, ipsilateral adrenal exploration, and
contralateral adrenalectomy as long as there are no other
metastases. The ipsilateral adrenal should only be removed
if there is any suspicion of metastasis.[58] Patients with
synchronous contralateral adrenal metastasis are suitable
for ipsilateral adrenal preservation. Right-sided lesions are
more amenable for preservation as opposed to left in view
of lower frequency of metastasis and different anatomical
relationship. Patients with bilateral synchronous adrenal
metastases should be considered to have disseminated
disease. Yu
et al,
in a recent report showed that patients
who had bilateral adrenalectomy, on an average died within
6 months.[59] Radical nephrectomy in these patients is
only palliative. Paul
et al,
reported a new algorithm to
determine the risk of adrenal metastasis.[60] Adrenalectomy
was considered unnecessary if the maximum diameter of
the tumor was <8 cm, and staging examinations did not
show organ or lymph node metastases. The clinical value
of adrenalectomy is as low as LND. Recent studies indicate
adrenal involvement to be a poor prognostic indicator.[61]
Metastases to bones
Metastases to bones from RCC is common (30-40%).[62]
These are usually highly vascular and destructive lesions.
They pose unique surgical challenges due to the risk of
life-threatening bleeding and resistance to other forms of
treatment. Osseous metastases in RCC bring about with
them poor performance status due to the intractable pain and
pathological fracture. The surgical procedures done in these
patients included curettage and cementing, internal fi xation,
en bloc resection, amputation, and nailing. Only patients
with good performance status and solitary metastases usually
underwent surgery. Surgery for patients with spinal and
pelvic metastases is usually associated with higher morbidity
when compared with long bone metastases which can be
done with a minimally invasive method.[63] Toyada
et al,
have proposed two prognostic factors in the treatment of
bone metastases with RCC and accordingly categorized
these patients into good prognosis group and bad prognosis
group.
[63] The two factors are the time interval from
nephrectomy to the appearance of the bone metastases and
the presence of extra-osseous metastases. If the metastases
developed within 2 years, the prognosis was bad. In their 50
patients, they found that those with poor prognostic factors
had a median survival of 5 months while those in the good
category had 30 months’ median survival.
Yuvraj
et al,
found that the number of metastases and the
synchronous or metachronous nature of the metastases also
are important.[64] In their study of patients with mRCC and
solitaty metastases to the bone, 6 patients had synchronous
and 13 patients had metachronous metastases to the bones.
The former had a median disease free survival of 25 months
and the later group had 63 months.
Hence, it appears that the most important prognostic factors
in these patients are the number of metastases, time from
nephrectomy, and presence or absence of extraosseous
metastases. The data available from published reports
indicate that in patients with limited disease, with the
presence of a solitary metastasis, with present or impending
pathological fracture or intractable pain and neurological
symptoms, surgical treatment not only gives effective relief
but also signifi cantly improves prognosis in a selected group
of patients.
Liver metastases
Involvement of the liver occurs either by contiguous
extension or hematogenus spread. A large renal tumor
may indent or compress the liver but actual invasion is rare.
Hematogenous spread is more common. When intrahepatic
metastases are present, 98% of patients have other metastases
as well. Most of these patients are symptomatic, however,
the liver function in most are normal. Partial hepatectomy
in direct extension gives a good survival. Complete resection
of metachronous liver metastases can be achieved in the
majority of patients. However, signifi cant morbidity and
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Indian J Urol, April-June 2010, Vol 26, Issue 2 174
mortality as well as the limited prognosis even after R0
resection strongly suggest careful patient selection. The
prognosis of patients with either metastatic disease stage
IVb or contiguous spread of renal cell carcinoma to adjacent
organs (stage IVa) has been uniformly poor, with a 1%
3-year survival rate and less than a 5% 5-year survival rate,
respectively.[7] Two recent reports of RCC metastases to liver
had a complication of 31-36%. The 2-year survival was 56%.
Small sized metastases, evidence of complete resection, and
shorter DFI were favorable in terms of survival.[65]
Patients with hepatic secondaries are considered for other
modalities of ablative therapy only if they are not candidates
for surgical resection, have <4 metastases, and lesions are
<5 cm. Most studies are retrospective, short-term reports
and no definite conclusions regarding survival can be
made.
[66] Radiofrequency ablation has been the most studied
in hepatic secondaries. However, radiofreqency ablation
provides effective palliation for these patients.
Metastases to brain
The largest recent series of patients with RCC undergoing
surgical resection of brain metastases was presented by
the group from MSKCC. In this study the mean survival
after metastasectomy was 12 months.[67] Notably longer
DFI was not associated with improved survival. Recently,
Vecil and Lang reviewed the M D Anderson Cancer Center
experience with a specific subset of patients, that is those
with intraventricular brain metastases who underwent
metastasectomy.[68] Of the 35 patients, 16 had RCC, which
is more than any other histology that was identified. The
operative complication rate was12% and there was no
perioperative mortality. The median survival in patients
with a single metastasis was 13.6 months. Bevacizumab is
contraindicate in patients with brain metastases because of
its tendency to cause increased bleeding. Not uncommonly,
patients with mRCC present with metastases exclusively
in the choroid plexus. Most of these patients present with
intraventricular bleed and consequent neurological defi cits.
CT and MRI scans are useful in diagnosing this condition.
Almost all cases reported were solitary lesions. Resection
of the lesion, steriotactic surgery, and chemotherapy have
produced good results, and survival up to 5 years have been
reported.[69]
Metastases to thyroid
Thyroid is a highly vascular organ yet the incidence
of metastases in the thyroid is rare. Thyroid receives
approximately half the volume of arterial blood received
by the entire liver. RCC is the most common source of
secondaries in the thyroid (56%). The probable reasons for
the rarity of metastases in the thyroid are initial fi ltration
of the malignant cells by the lungs; even if they reach the
thyroid, due to the high volume of high velocity blood
fl ow, the tumor cell may not be able to get a foothold
there; high concentration of oxygen and iodine inhibits the
proliferation of fi xed tumor cells. If a patient with a history
of nephrectomy for RCC subsequently has a solitary thyroid
mass, one should consider isolated thyroid metastasis as
well as a primary thyroid tumor. After thyroidectomy or
lobectomy for metastases from RCC, 60% were disease free at
6 years. In a report by Isalymph nodeieks and associates, the
overall 5 year survival rate in 45 patients following thyroid
metastasectomy was 51%.[70] Nineteen patients died during
the study. According to these authors, the overall survival of
patients undergoing thyroidectomy for metastases from RCC
is affected rather by the general health of the patient than
the tumor-related factors. There is a signifi cant coincidence
of thyroid and pancreatic metastases of RCC.
Pancreatic metastases
Pancreas is a rare target for metastases from RCC. About
50% of the metastases to the pancreas are asymptomatic.
Metastases move to the pancreas via lymphatics and the
venous channels. Nagakawa has shown lymphatics from
the head of the pancreas to the dorsal aspect of the renal
artery.
[71] Lore
et al,
proposed that diseases of the pancreas
can lead to alterations in the portal blood fl ow and opening
up of the renal portals from the pancreas.[72] In the absence
of other metastases and solitary metastases to the pancreas,
the 5 year survival is about 31%.[73] Mortize
et al,
reported 10
month survival for patients after various pancreatic surgeries
for patients with metastases from RCC.[74] LND is usually not
required as no cases of lymph node metastases have been
reported in this setting. The usual surgeries done in these
patients include classical Whipple’s, total pancreatectomy,
and distal pancreatectomy. Short-term survival (upto 1
year) has been reported after ablation of the pancreatic
secondaries using radiofrequency energy.[75]
Metastases to other organs
Renal cell carcinoma can metastasize to almost any organ in
the body even as late as 20 years. Oligometastases and long
interval from radical nephrectomy are favorable indicators
of survival following metastasectomy.
CONCLUSION
Patients with mRCC are mostly symptomatic and badly
in need of effective palliative therapy. As the natural
course of the disease is highly variable, therapy needs to
be individualized. The management of these patients has
undergone dramatic changes mostly due to the introduction
of TMT. The natural history of the disease can be changed
by a range of these agents. The era of TMT has only begun.
Many more drugs are in the pipeline and these may have a
greater impact on the survival.
A multimodal approach is the current standard of
treatment for patients with mRCC. Selected patients with
oligometastatic diseases, long period of interval from
radical nephrectomy to the development of metastases,
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175 Indian J Urol, April-June 2010, Vol 26, Issue 2
and good performance status are the most important factors
that have an impact on the survival of these patients.
Even though cure is not possible, improved survival and
quality of life can be achieved with combination therapy
using cytoreductive nephrectomy and systemic therapy.
Laparoscopic resections are being increasingly done to
reduce the morbidity. Alternative ablative methods such as
radiofrequency ablation, cryosurgery, etc may play a greater
role in these patients in the future. Currently, upfront
cytoreductive nephrectomy followed by systemic therapy
is the standard. However, in the days to come, planned and
well-controlled clinical trials using TMT in the neoadjuvant
setting may completely change this, hopefully, providing
better survival and quality of life.
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How to cite this article: Bhat S. Role of surgery in advanced/metastatic
renal cell carcinoma. Indian J Urol 2010;26:167-76.
Source of Support: Nil, Confl ict of Interest: None declared.
Bhat: Surgery in metastatic renal cancer
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