Transcript
Guideline for Management
of the Clinical Stage 1
Renal Mass
Renal Mass Clinical Panel Members:
Consultants:
Andrew C. Novick, MD, Chair
Steven C. Campbell, MD, PhD, Co-Chair
Martha M. Faraday, PhD
Linda Whetter, DVM, PhD
Michael Marberger, MD
Arie Belldegrun, MD
Michael L. Blute, MD
George Kuoche Chow, MD
Ithaar H. Derweesh, MD
Jihad H. Kaouk, MD
Raymond J. Leveillee, MD, FRCS-G
Surena F. Matin, MD
Paul Russo, MD
Robert Guy Uzzo, MD
AUA Staff:
Heddy Hubbard, PhD, FAAN
Edith Budd
Michael Folmer
Katherine Moore
Kadiatu Kebe
Dedication to Andrew C. Novick, M.D.
Consensus is always difficult. Even in the setting of level I evidence, competing
interpretations, experiences and interests present challenges to the best-intentioned analyses.
Consensus requires commitment to the process, time, a spirit of collaboration and, above all,
leadership.
For many, Andy Novick’s career was both the quintessence of leadership and the
embodiment of the best in academic urology. Andy’s clinical and intellectual contributions in
the fields of kidney transplantation and renovascular surgery provided the underpinning upon
which surgical and functional renal preservation in cases of kidney cancer is based. He brought
forward many of the concepts and techniques for nephron-sparing surgery. Perhaps most
importantly, Andy facilitated the recognition that nephron-sparing surgery was safe, feasible and
oncologically sound through the systematic study and publication of his work as well as
thoughtful review of the work of colleagues. He moved the field forward by believing that
technology could improve care, but insisting on responsible application and repetitive
reassessment of the data as a means of doing so. Andy was an ardent supporter of basic and
translational science in urology in both word and deed. He was a passionate educator and served
our national organizations such as the American Board of Urology with pride and conviction. In
the midst of all this, he mentored hundreds of students, residents and fellows, cared for thousands
of patients and developed one of the premier urologic programs in the world.
Andy had an enormous set of expectations of himself and those around him, recognizing
that great achievements are within each of our own capacities. People who knew Andy were
most drawn to his profound dedication to the values of the medical profession. He understood
that deserved admiration was a responsibility. Andy engendered loyalty not to himself, but to the
best within one’s self.
We therefore dedicate this document and our efforts herein to Andrew C. Novick. As a
compendium of the data regarding the treatment of localized renal masses, it represents his
passion, his high standards and a roadmap for future generations of caregivers and investigators
interested in relieving suffering from kidney cancer. It reflects the best that Andy was so
consistently able to bring forth in all of us.
Chapter 1: Management of the Clinical Stage 1 Renal Mass:
Diagnosis and Treatment Recommendations
Contents
Mission Statement ........................................................................................................................... 1
Introduction ..................................................................................................................................... 1
Background ..................................................................................................................................... 1
Epidemiology .............................................................................................................................. 1
Etiology ....................................................................................................................................... 2
Major Pathologic Subtypes ......................................................................................................... 2
Presentation and Diagnosis ............................................................................................................. 2
Presentation ................................................................................................................................. 2
Diagnosis .................................................................................................................................... 3
Imaging techniques
3
Role of Renal Mass Biopsy
4
Tumor Characteristics ................................................................................................................. 5
Staging
5
Grading
5
Other Prognostic Indicators ........................................................................................................ 6
Tumor Size
6
Necrosis
6
Microvascular Invasion
6
Sarcomatoid Features
6
Collecting System Invasion
6
Symptoms and Performance Status
7
Clinical and Biological Indicators .................................................................................................. 7
Molecular Studies ....................................................................................................................... 7
Overview of Treatment Alternatives .............................................................................................. 8
Surveillance ................................................................................................................................ 8
Radical nephrectomy .................................................................................................................. 8
Open Radical Nephrectomy (ORN)
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Laparoscopic Radical Nephrectomy (LRN)
8
Partial Nephrectomy (PN) .......................................................................................................... 9
Open Partial Nephrectomy (OPN)
9
Laparoscopic Partial Nephrectomy (LPN)
9
Robotic-Assisted Laparoscopic Partial Nephrectomy
10
Ablative therapies ..................................................................................................................... 10
Novel treatments ....................................................................................................................... 11
METHODOLOGY ....................................................................................................................... 11
Literature Searches and Article Selection ................................................................................. 12
Data Extraction and Evidence Combination ............................................................................. 12
Statistical Model ....................................................................................................................... 13
Limitations of Available Data................................................................................................... 13
Limitations of study design
13
Confounding variables
14
RESULTS OF THE OUTCOMES ANALYSIS .......................................................................... 14
Descriptive Information ............................................................................................................ 14
Patient Age Varies Across Interventions
14
Tumor Size Varies Across Interventions
15
Follow-Up Durations Vary Across Interventions
15
Number of studies in which RCC was confirmed
16
META-ANALYTIC FINDINGS .................................................................................................. 16
Major Urological Complications .............................................................................................. 17
Major Nonurological Complications ........................................................................................ 19
Perioperative Events ................................................................................................................. 19
Conversions
19
Transfusions
22
Reinterventions
22
Survival ..................................................................................................................................... 23
Total Recurrence-Free Survival ................................................................................................ 24
Local Recurrence-Free Survival ............................................................................................... 24
Metastatic Recurrence-Free Survival........................................................................................ 25
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Cancer-Specific Survival .......................................................................................................... 26
Overall Survival ........................................................................................................................ 27
Grading the recommendations .................................................................................................. 28
Summary of the Treatment Options for the Clinical Stage 1 Renal Mass .................................... 28
Active Surveillance ................................................................................................................... 28
Radical Nephrectomy ............................................................................................................... 30
Open Partial Nephrectomy........................................................................................................ 32
Laparoscopic Partial Nephrectomy ........................................................................................... 34
Thermal Ablation ...................................................................................................................... 35
Cryoablation.............................................................................................................................. 35
Radiofrequency Ablation .......................................................................................................... 37
Novel Treatment Modalities of the Clinical Stage 1 Renal Mass............................................. 38
Overview
38
High intensity focused ultrasound
39
Radiosurgery (“Cyberknife”)
39
Other modalities
40
Limitations of the Literature ......................................................................................................... 41
Panel Consensus Regarding Treatment Modalities ...................................................................... 42
Treatment Guideline Statements ................................................................................................... 45
For All Index Patients ............................................................................................................... 45
New Research/Future Directions .................................................................................................. 51
Conflict of Interest Disclosures .................................................................................................... 55
Acknowledgements and Disclaimers: Guideline for Management of the Clinical Stage 1 Renal
Mass: Diagnosis and Treatment Recommendations ..................................................................... 56
References ..................................................................................................................................... 57
Consultants:................................................................................................................................... 72
Abbreviations and Acronyms ....................................................................................................... 73
Glossary ........................................................................................................................................ 76
Copyright © 2009 American Urological Association Education and Research, Inc.®
Mission Statement
Detection of clinical stage 1 (< 7.0 cm), solid, enhancing renal masses has increased in frequency
and is now a common clinical scenario for the practicing urologist. The biology of these tumors
is heterogeneous, and there are multiple management options available, ranging from
observation to radical nephrectomy (RN). Approximately 20% of clinical stage 1 renal masses
are benign, and only 20% to 30% of malignant tumors in this size range demonstrate potentially
aggressive features, with substantial variance based on patient age, gender and tumor size.1, 2
Current practice is divergent and, in some cases, potentially discordant with what the existing
literature supports. The American Urological Association (AUA) commissioned this Panel to
develop guidelines for the management of the clinical stage 1 renal mass that would be useful to
physicians involved in the care of these patients.
Introduction
It is estimated that in 2008, approximately 54,390 new cases (33,130 men and 21,260 women) of
kidney cancer will be diagnosed in the United States (U.S.), resulting in 13,010 deaths.3 Renal
parenchymal tumors (renal cell carcinoma, RCC) account for approximately 85% of kidney
cancers diagnosed in the U.S., while most of the remainder (12%) are composed of upper tract
urothelial cancers.4
Renal cell carcinoma, which represents 2% of all adult cancers, is the most lethal of
common urologic cancers, with approximately 35% of patients dying from the disease at the 5year mark.4 Approximately 17.9 new cases per 100,000 of the population were diagnosed in
2008..5
Average age at diagnosis for renal cell carcinoma is in the early 60s.4 Childhood RCC is
uncommon, representing only 2.3% to 6.6% of all pediatric renal tumors.6-10
Background
Epidemiology
Renal cell carcinoma incidence rates have risen steadily each year during the last three decades
in most of the world, with an average increase of 2% to 3% per year.11 Most renal masses,
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particularly clinical stage T1 tumors, are now discovered incidentally during imaging prompted
by nonspecific or unrelated symptoms.
Etiology
Tobacco use and obesity are the most consistently identified risk factors for RCC, accounting for
about 20% and 30% of cases, respectively.4, 12 Hypertension has also been demonstrated to
increase the risk of RCC development.4, 13 Nonsteroidal anti-inflammatory agents and dietary
factors have not been found to play significant etiologic roles in RCC development.4, 14 Moderate
alcohol,15, 16 fruit and vegetable17, 18 and fatty fish19 consumption have been reported to reduce
the risk of RCC development. No consistent data are available to support occupational risk
factors for RCC development.4 Family history is associated with increased risk for RCC
development, with inherited forms of RCC accounting for approximately two to four percent of
cases.4
Major Pathologic Subtypes
Renal tumors are subdivided based on cell of origin and morphologic appearance. Classification
schemes have changed over time, and certain histologic subtypes have fallen out of favor. RCC
subtypes now include clear cell, papillary, chromophobe, collecting duct and unclassified RCC20
with granular cell and sarcomatoid RCC no longer considered distinct entities. Sarcomatoid
features can be present in all histologic subtypes and portend a poor prognosis.21, 22
Clear cell RCC frequently presents with higher stage and grade than papillary and
chromophobe subtypes, and therefore the disease-specific survival (DSS) is worse.23, 24
Presentation and Diagnosis
Presentation
Incidental detection accounts for more than 50% of RCC cases, and these tumors are more likely
to be organ confined and associated with an improved prognosis.25, 26
Symptoms associated with RCC can be the result of local tumor growth, hemorrhage,
paraneoplastic syndromes or metastatic disease. Flank pain is usually due to hemorrhage or
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obstruction (ureteral, vascular or thromboembolic), although it also may occur with locally
advanced or invasive disease. The classic triad of flank pain, gross hematuria and palpable
abdominal mass is now uncommon25 and invariably denotes advanced disease.
Physical exam has a limited role in diagnosing RCC, but may be valuable in detection of
signs of advanced disease such as a palpable abdominal mass, lymphadenopathy, nonreducing
varicocele or bilateral lower extremity edema. Paraneoplastic syndromes are found in about 20%
of patients with RCC, the most common being hypertension, polycythemia and hypercalcemia.27,
28
Diagnosis
Imaging techniques
Discovery of a renal mass with ultrasound (US) or intravenous pyelography should be further
investigated with a high-quality computed tomography (CT) scan both prior to and following
intravenous contrast medium, presuming adequate renal function. Differential diagnosis of a
renal mass includes: RCC, renal adenoma, oncocytoma, angiomyolipoma, urothelial carcinoma,
metastatic tumor, abscess, infarct, vascular malformation or pseudotumor. Approximately 20%
of small, solid, CT-enhancing renal masses with features suggestive of RCC prove to be benign
oncocytoma or atypical, fat-poor angiomyolipoma after surgical excision.29 The incidence of
benign histology is higher in young women as well as in older patients.2, 30 Tumors less than 3
cm may be more likely to be benign 2,31 and the aggressive potential of RCC increases
dramatically beyond this size. 32 With the exception of fat-containing angiomyolipoma, no
current scanning methods can distinguish between benign and malignant solid tumors or between
indolent and aggressive tumor biology. Oral and intravenously based abdominal CT scanning
characterizes the renal mass, provides information about contralateral renal morphology and
function, assesses extrarenal tumor spread (venous and regional lymph node involvement) and
determines the status of the adrenal glands and the liver.
Magnetic resonance imaging (MRI) may be reserved for the clinical settings of locally
advanced malignancy, possible venous involvement, renal insufficiency or allergy to intravenous
contrast. However, recent studies have raised concern about the routine use of MRI. The U.S.
Food and Drug Administration (FDA) is currently investigating a potential link between
nephrogenic systemic fibrosis (NSF) and gadolinium exposure. NSF is a condition characterized
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by progressive fibrosis of the skin and other organs leading to significant disability and increased
mortality. Initially reported most commonly in end-stage renal disease (ESRD) patients, it is
also described in advanced chronic kidney disease (CKD) not requiring dialysis. No clearly
effective therapies exist. Current FDA recommendations for utilization of gadolinium are to
consider: (a) utilization only if clearly necessary in patients with advanced CKD and (b)
institution of prompt dialysis in patients with advanced renal dysfunction who receive
gadolinium contrast. MRI can be used selectively in the evaluation of patients with clinical stage
1 renal masses, primarily for patients at risk for contrast nephropathy or those who are allergic to
conventional intravenous contrast. In these settings, a balanced discussion of the potential risks
of NSF should be considered.
Routine metastatic evaluation should include liver function tests, abdominal/pelvic CT
and chest radiography. Bone scan should be obtained for patients with elevated serum alkaline
phosphatase, bone pain or decline in performance status,33 and chest CT should be obtained for
patients with pulmonary symptomatology or an abnormal chest radiograph.34 Most brain and
bone metastases are symptomatic at time of diagnosis, and therefore, routine imaging of these
sites is generally not indicated.
Role of Renal Mass Biopsy
Percutaneous renal biopsy or fine needle aspiration (FNA) has traditionally served a limited role
in the evaluation of renal masses because of the relatively high diagnostic accuracy of crosssectional imaging such as CT or MRI and concern about a high false-negative rate and potential
complications associated with renal mass biopsy.35-38 Biopsy or aspiration was thus primarily
reserved for patients suspected of having renal metastasis, abscess or lymphoma, or when needed
to establish a pathologic diagnosis of RCC in occasional patients presenting with disseminated
metastases or unresectable primary tumors.35
In recent years, the potential role of biopsy for localized renal tumors has been revisited,
in part driven by the recognition that 20% clinical stage T1 renal masses may represent benign
disease and could be considered for less aggressive management.2,31,32,40 In addition, accuracy
and safety of renal mass biopsy has improved substantially due to further refinements in CT- and
MRI-guided techniques.39-46 A review of studies since 2001 demonstrates that the false-negative
rate with renal mass biopsy is now only 1%, and the incidence of symptomatic complications is
relatively low, with only a very small percentage (< 2%) requiring any form of intervention.40,48
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Needle-tract seeding also appears to be exceedingly rare, assuming appropriate patient selection.
While another 10% to15% of renal mass biopsies are indeterminate, this is much less concerning
than a false negative, which would lead to observation of a malignancy. Given the significant
heterogeneity in the biological aggressiveness of clinical stage 1 renal masses and the wide range
of treatment options now available, renal mass biopsy is now being used increasingly for patient
counseling and clinical decision making. This approach is appropriate for patients in whom a
wide range of management options are under consideration, ranging from surgery to observation.
Renal mass biopsy is not indicated, however, for healthy patients who are unwilling to accept the
uncertainty associated with this procedure or for older patients who will only consider
conservative management options regardless of biopsy results. Incorporation of molecular
analysis has shown great promise to further improve accuracy of renal mass biopsy/aspiration
and remains a research priority.41,43
Tumor Characteristics
Staging
The 2002 tumor, nodes, metastasis (TNM) stage classification system proposed by the
International Union Against Cancer, which defines the anatomic extent of disease more
explicitly than previously, is recommended for clinical and scientific use.49 T1 tumors are those
that are confined to the kidney and ≤ 7 cm in greatest dimension. The T1 substratification (T1a:
≤ 4 cm in greatest dimension; T1b: > 4 cm but ≤ 7 cm in greatest dimension), introduced in
2002,48 has been validated by a number of studies49-51 with estimated five-year cancer-specific
survival (CSS) rates by the 2002 tumor classification of 95.3% to 97% and 87% to 91.4% in
patients with pT1a and pT1b RCC, respectively.49, 50
Grading
Over the past century, multiple grading systems for RCC have been proposed. In the early 1980s,
Fuhrman and colleagues presented a landmark series of 100 patients after nephrectomy.52 Four
nuclear grades were defined based on increasing nuclear size and irregularity and nucleolar
prominence. While concerns over interobserver variability persist, the Fuhrman grading system
remains the most widely used system in the U.S. today.53, 54 Higher Fuhrman grade is associated
with larger tumor size and advanced stage.55 Several large series have demonstrated that
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Fuhrman grade is an independent predictor of survival for conventional clear cell RCC.24, 56 For
patients with pT1 clear cell lesions, the 5-year disease-specific survival (DSS) rate was 94.2%
for patients with Grade 1-2 disease and 89.8% for patients with Grade 3-4 disease179. For cases
of papillary tumors, type I and type II designation is more appropriate and for chromophobe181
and other nonclear cell RCC, high or low grade (not Fuhrman) is appropriate.180
Other Prognostic Indicators
Tumor Size
The 2002 American Joint Committee on Cancer TNM system changed the classification system
of T1 tumors to incorporate size, stratifying T1 tumors into T1a (≤ 4 cm) and T1b (> 4 cm and
< 7 cm).57 While this has been independently validated, the threshold cutpoints of 4 cm and 7 cm
have generated controversy, and the current literature suggests that tumor size provides optimal
prognostic information when used as a continuous rather than a dichotomous variable.58-61
Necrosis
Tumor necrosis in RCC can be microscopic or macroscopic. The majority of analyses deal with
microscopic coagulative necrosis. This feature is associated with higher stage, grade and tumor
size and is more common in papillary and clear cell subtypes.62, 63 One recent analysis suggests
that tumor necrosis is an independent predictor of poor outcomes in pT1 RCC.
Microvascular Invasion
Presence of microvascular invasion of neoplastic cells within an endothelial-lined vessel is
associated with higher stage, grade and tumor size and has been shown to be an independent
predictor of poor survival in clinically localized RCC. 64-66
Sarcomatoid Features
While once considered a separate entity, sarcomatoid features can be found in all histologic
subtypes.20, 67 Sarcomatoid features represent an aggressive, de-differentiated component of the
primary tumor.68 Most tumors with sarcomatoid features present at an advanced stage, 182 and
response to systemic therapy is poor.21, 69-71
Collecting System Invasion
Invasion into the collecting system occurs in less than 10% of T1 tumors. However, in this
subgroup of patients, this finding indicates a poor prognosis.72, 73
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Symptoms and Performance Status
Incidentally detected tumors are lower stage and grade.74, 75 Patients with incidentally detected
tumors have improved DSS; however, whether this association persists after controlling for
larger size, stage and grade is unclear.76-78 Performance status is a qualitative measure of the
disease burden and functional status of a patient that has closely correlated with prognosis for
patients with all stages of RCC.
Clinical and Biological Indicators
A variety of clinical and biological indicators is associated with tumor progression and may
influence survival in RCC. For instance, anemia, preoperative thrombocytosis and elevated
erythrocyte sedimentation rate or C-reactive protein are all markers of poor prognosis in RCC.7983
Molecular Studies
Molecular markers are the future to understanding RCC prognosis and response to therapy and
will likely be incorporated into renal mass biopsy to improve patient counseling in the near
future. Many important genes and proteins involved in key pathways are now known to be
potential prognostic markers. Most prominent among these are various alterations in the vhl gene
and altered expression of carbonic anhydrase IX (CAIX) or the B7H1 molecule, which is a
costimulatory molecule involved in immune responses to RCC. Other potential molecular
prognostic markers for RCC include cell cycle regulators such as p27, cyclin D1, pRb and p53
and markers of cellular proliferation such as Ki-67. Expression levels of important members of
the hypoxia-inducible pathway such as HIF1α, VEGF and the VEGF receptors may also
correlate with outcomes for RCC.84, 85
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Overview of Treatment Alternatives
Surveillance
Patients diagnosed with a clinical T1 renal mass with radiologic characteristics consistent with
RCC may be candidates for active surveillance (AS) with delayed or, alternatively, no treatment
rendered. Indications for AS include elderly patients, those with decreased life expectancy or
those with medical comorbidities that would be associated with increased risk if a therapeutic
intervention were to be undertaken. Alternatively, a strategy of observation with delayed
intervention as indicated may be elected in order to determine the growth rate or to obtain
alternative diagnostic imaging. A judicious period of AS appears to be associated with a low
risk of size or stage progression while maintaining most therapeutic options.86
Radical nephrectomy
For decades, RN has been the mainstay of treatment for all renal masses including clinical stage
1 tumors. This includes removal of the entire kidney including Gerota’s/Zuckerkandel’s fascia,
regional lymph nodes and the adrenal gland. CSS, local tumor control and progression-free
survival have been extremely high with this approach. The main concern with RN is the
negative impact on renal function and association with CKD.130 RN is currently greatly
overutilized for the management of clinical stage T1 renal masses, particularly stage T1a.87
Open Radical Nephrectomy (ORN)
At one time, ORN was the gold standard for treatment of all renal masses. Currently, with the
advent of minimally invasive approaches, the indications for ORN are diminishing, particularly
in patients with clinical stage 1 renal masses. Urologic surgeons should still be skilled in ORN
for situations where minimally invasive approaches may not be possible or if conversion to an
open approach is required.
Laparoscopic Radical Nephrectomy (LRN)
In an effort to reduce patient morbidity, urologic surgeons adapted the minimally invasive
technique of laparoscopy to perform kidney removal. First described in 1991,88 there have been
multiple adaptations of the operation, including entrapment with morcellation, intact extraction
and hand-assisted laparoscopic nephrectomy. The literature includes many reports of the
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advantages of these approaches with virtually unanimous agreement that there is reduced
perioperative and postoperative morbidity while maintaining equivalent short- and long-term
oncologic efficacy, particularly in patients with small, localized tumors.
Partial Nephrectomy (PN)
The understanding of increased risk of CKD with RN and recent data highlighting the
association between CKD and cardiovascular morbidity and mortality has led to the desire to
preserve as much normal renal parenchyma as possible.130, 132 PN is now widely accepted as a
treatment alternative which yields virtually identical oncologic outcomes as RN for appropriately
selected patients. While PN was initially reserved for absolute indications such as patients with a
solitary kidney, renal insufficiency whereby dialysis would likely ensue or in those with
inheritable forms of renal cancer, PN is now considered the treatment of choice for most clinical
T1 renal masses, even in those with a normal contralateral kidney.
Open Partial Nephrectomy (OPN)
Open partial nephrectomy is generally recognized as one of the standards of care for localized
renal masses. Potential problems unique to PN include inadequate surgical margins,
hemorrhage, warm ischemia and urine leak. Steps taken to avoid these complications include the
use of frozen section of tumor base when indicated, hilar vessel clamping (artery alone or
artery/vein), manual compression, use of diuretics and free radical scavengers, cold ischemia and
meticulous closure of the collecting system and capsule. Multiple published series demonstrate
OPN to be safe, effective and reproducible for the treatment of clinical T1 renal masses.
Laparoscopic Partial Nephrectomy (LPN)
Similar to the introduction of LRN with its equivalent oncologic outcomes and improved
morbidity profile, LPN attempts to achieve equivalence with OPN. Initially reserved for
superficial cortical tumors, with the advent of improved laparoscopic surgical instrumentation,
LPN is now often performed utilizing the same surgical techniques as its open counterpart
(vascular control, watertight closure of the collecting system and capsule, use of surgical
bolsters, etc.). Shortcomings currently are the need for advanced laparoscopic techniques, such
as suturing, and extensive experience. Although oncologically comparable to OPN for localized
renal masses, most series demonstrate that LPN is associated with greater warm ischemia time
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and an increased risk of postoperative hemorrhage when compared to OPN. Hence, LPN has
largely been confined to centers of surgical excellence where high volume of cases is the rule.
However, with further improvements in laparoscopic instrumentation and greater dissemination
of expertise, more widespread application of LPN is anticipated in the future.
Robotic-Assisted Laparoscopic Partial Nephrectomy
Very recently, robotic-assisted LPN has been offered to patients at various practices. While
robotic instrumentation has been used for treatment of prostate cancer for several years, its use
for PN is a recent application. Currently, only a few small, single-institution reports offer limited
information regarding this procedure, including whether robotic-assisted LPN offers any
advantages over other forms of nephron-sparing surgery (NSS). At present there are insufficient
data to evaluate outcomes. 89-91
Ablative therapies
Renal ablative techniques were developed in an effort to improve patient procedural tolerance
and reduce the potential for complications. A variety of generators, ablation probes and energy
delivery systems are now commercially available. Energy-based tissue-ablative techniques
include radiofrequency ablation (RFA) and cryoablation. Controversy exists about which
technology is superior. The primary requirement for an ablative technology to be efficacious is
that it must deliver a lethal treatment to the cancer cells, leaving no viable cancer cells within the
treated zone. Of equal importance, the physician must be able to localize, control and predict the
area of treatment while avoiding inadvertent ablation of surrounding healthy tissue. Renal tumor
ablations can be performed through open incisions or via laparoscopic or percutaneous routes
under image guidance (US, MRI, CT). Although ablative therapies show promise of efficacy,
long-term oncologic follow-up is not yet available. Surrogate outcome measures such as
radiographic demonstration of loss of contrast enhancement have come into question. Available
data suggest that local control may be suboptimal when compared to surgical excision, and
surgical salvage may be difficult. While it is likely that outcomes associated with ablative
modalities will improve with further advances in technology and application, judicious patient
selection remains of paramount importance.
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Novel treatments
The literature reflects the evolution of novel treatment modalities which include high intensity
focused ultrasound (HIFU), radiosurgery, microwave thermotherapy (MWT), laser interstitial
thermal therapy (LITT), pulsed cavitational ultrasound (PCU), as well as other new technologies.
Clinical outcomes are limited to a small number of patients with short-term follow-up, and these
modalities remain investigational.
METHODOLOGY
The Panel’s goals were to: conduct a systematic literature review of the relevant scientific
evidence; identify descriptive information about samples and procedures relevant to interpreting
existing evidence; identify outcomes relevant to patients, families, and practitioners; estimate
outcome effect sizes for the most commonly used treatments and approaches; complement the
available evidence with expert opinion; and determine what additional evidence is needed to
further evidence-based management of the clinically localized renal mass. The Panel also
carefully considered other important factors that may affect treatment options such as patient
preferences and the availability of particular facilities or expertise.
The evidence review process included literature searches, extraction of descriptive
information about samples and procedures and extraction of outcomes data. The management
options evaluated were: AS; cryoablation (cryo in tables); RFA; LPN; OPN; LRN; and ORN.
The descriptive information considered included: patient age; tumor size; follow-up
duration; and numbers of studies with/without pathological validation of tumor type. These data
were used to describe the subpopulations treated with the different interventions and to interpret
effect sizes across interventions when major patient variables (i.e., age, tumor size, follow-up
duration) differed across interventions.
The outcomes examined were: major urological complications; major nonurological
complications; perioperative events (conversions, transfusions and reinterventions); total
recurrence-free survival (RFS); local RFS; metastatic RFS; CSS; and overall survival (OS).
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Literature Searches and Article Selection
Literature searches on English-language publications were performed using the MEDLINE
database from January 1, 1996 to September 30, 2007 using the terms “renal carcinoma” and
“renal mass” in conjunction with the interventions evaluated. Pediatric studies, studies with
sample size less than five, editorials and reviews were eliminated. Studies that focused primarily
on surgical techniques without detailed outcomes information and studies in which more than
50% of patients were dialysis patients, solitary kidney patients, patients with recurrent RCC or
patients with hereditary RCC syndromes were eliminated. Studies that reported descriptive or
outcomes information collapsed across multiple interventions were also excluded. Multiple
reports on the same patient group were carefully examined to ensure inclusion of only
nonredundant outcomes data. For the survival analyses, studies had to meet the additional
criteria that the diagnosis of RCC was validated pathologically and that survival outcomes for
RCC patients were separable from outcomes for patients diagnosed with benign tumors. One
exception was made to this rule: AS patients were included in metastatic RFS analyses. This
exception was made because of the clinical importance of estimating the probability of
metastases in patients for whom no intervention was undertaken.
All extracted articles used adult human subjects. A total of 114 articles met inclusion
criteria and underwent data extraction.
All authors, consultants and the panel manager self-reported potential conflicts of interest
(COI) in accordance with AUA policy. The panel chair and facilitator reviewed the COI
disclosures, and the disclosures were made available to all panel members in hard copy prior to
all meetings. Staff reviewed the AUA COI policy requiring recusal in the event of potential
biases or conflicts prior to every meeting.
Data Extraction and Evidence Combination
Quantitative information about samples, procedures and outcomes was extracted by the
methodologist into Excel spreadsheets. All entered data were double checked for accuracy.
Most studies examined one treatment group; some studies compared two treatment
groups. All intervention groups were treated as single arms that estimated the outcome or other
variable in the population of interest, regardless of the number of groups in a particular study.
This approach maximized statistical power and the use of available information. Table 1 lists the
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total number of arms for each intervention and the number of studies of each type used to
generate descriptive information and used in the meta-analyses.
Table 1: Study Types for Descriptive Information and Meta-Analyses
AS
12
Cryo
16
AS
12
Total Number of Study Arms
RFA
LPN
OPN
21
26
29
Single-Arm Observational Studies
RFA
LPN
OPN
18
20
13
Cryo
13
Cryo vs. RFA
Cryo vs. LPN
2
1
Two-Arm Observational Studies
RFA vs.
LPN vs.
LPN vs.
OPN vs.
OPN
OPN
LRN
LRN
1
4
1
1
LRN
17
LRN
10
OPN vs.
ORN
10
ORN
17
ORN
2
LRN vs.
ORN
5
The effect size calculated was a point estimate with 95% confidence intervals. The point
estimate for a given outcome includes all study arms that reported that particular outcome. Most
of the data involved the occurrence of an event (i.e., a complication, a recurrence, a death),
resulting in point estimates that are estimates of the event rate for a particular outcome in the
population of interest bounded by 95% confidence intervals. In the tables, the event rates are
expressed as percentages.
Statistical Model
A random effects model was used to calculate the effect size for each study and to generate the
overall effect sizes for particular interventions.a This model assumes that the true effect could
legitimately vary from study to study following a normal distribution and that some variability
across studies is variability in true effect that is not error. This model produces conservative
estimates of effect sizes and is the most appropriate given the type of data available.
Limitations of Available Data
Limitations of study design: The overwhelming majority of studies available to the Panel were
observational, retrospective, reported findings on samples of convenience that were not
a
All effect size calculations and analyses were run using Comprehensive Meta-Analysis (CMA) software, version 2.0 (Biostat,
Inc.).
Copyright © 2009 American Urological Association Education and Research, Inc.®
13
randomized to treatments and involved only one treatment group. There are inherent, unknown
and unquantifiable biases within each study because of the lack of randomization. The Panel
weighed this issue carefully in its deliberations and concluded that meta-analysis was valuable to
describe the existing literature and to determine what types of information are needed to further
evidence-based management of the clinical stage 1 renal mass.
Confounding variables: Interpreting statistically significant differences in outcomes across
interventions requires thorough consideration of other variables that could account for
differences. Three confounding variables that differed across interventions were focused on in
detail: patient age, tumor size and follow-up duration. For most outcomes, the influence of
confounding variables could not be separated from possible intervention effects, making
interpretation of statistically significant differences difficult. For this reason, only comparisons
for which confounding variables appear to exert minimal influence are presented. The possible
impact of these factors is addressed in the sections that follow and must be weighed carefully in
interpreting the point estimates.
RESULTS OF THE OUTCOMES ANALYSIS
This section summarizes the evidence evaluated by the Panel, including the descriptive
information examined and results from meta-analyses.b
Descriptive Information
Patient Age Varies Across Interventions: Table 2 presents the mean and median patient age for
each intervention type. Patients treated with AS, cryoablation and RFA generally were older
than those treated with OPN, LPN, ORN or LRN.
b
Not all studies reported all descriptive information. The tables contain data from the study subsets that reported the variable of
interest.
Copyright © 2009 American Urological Association Education and Research, Inc.®
14
Table 2: Patient Age - Number of Studies and Patients
Intervention Type
# of Studies
# of Patients
12
15
19
26
28
17
16
390
644
745
2245
6418
1581
6235
Active Surveillance
Cryoablation
Radiofrequency Ablation
Partial Nephrectomy – Lap
Partial Nephrectomy – Open
Radical Nephrectomy – Lap
Radical Nephrectomy – Open
Mean/Median
Age (yrs)
67.1 / 68.2
66.9 / 66.3
68.5 / 70.0
60.5 / 60.1
60.1 / 60.0
60.9 / 61.0
62.5 / 63.0
Tumor Size Varies Across Interventions: Table 3 presents the mean and median tumor size for
each intervention type. AS, cryoablation, RFA, LPN and OPN were used to treat relatively small
tumors. LRN and ORN were used to treat larger tumors.
Table 3: Tumor Size - Number of Studies and Patients
Intervention Type
Active Surveillance
Cryoablation
Radiofrequency Ablation
Partial Nephrectomy – Lap
Partial Nephrectomy – Open
Radical Nephrectomy – Lap
Radical Nephrectomy – Open
# of Studies
# of Patients
12
15
19
26
25
15
14
390
644
745
2245
5596
1391
5849
Mean/Median
Tumor Size (cm)
2.7 / 2.2
2.6 / 2.6
2.7 / 2.7
2.6 / 2.6
3.2 / 3.0
4.8 / 5.1
5.0 / 5.4
Follow-Up Durations Vary Across Interventions: Table 4 presents the mean and median
follow-up duration (mos) for each intervention type. AS, cryoablation, RFA, LPN and LRN had
the shortest follow-up periods; OPN and ORN had the longest follow-up periods.
Table 4: Follow-Up Duration -- Number of Studies and Patients
Intervention Type
Active Surveillance
Cryoablation
Radiofrequency Ablation
Partial Nephrectomy – Lap
Partial Nephrectomy – Open
Radical Nephrectomy – Lap
Radical Nephrectomy – Open
# of Studies
# of Patients
12
10
10
17
22
8
13
390
463
528
1639
5057
795
5294
Mean/Median
Follow-Up (mos)
29.6 / 29.0
19.5 / 16.7
22.9 / 19.4
20.8 / 15.0
55.5 / 46.9
30.2 / 17.7
60.8 / 58.3
Copyright © 2009 American Urological Association Education and Research, Inc.®
15
Number of studies in which RCC was confirmed: Table 5 presents the number of studies in
each intervention category with and without pathological validation of tumor type.
Table 5: Studies with and without RCC confirmation
Number of Studies
Patients with pathology-confirmed
No biopsy, no pathology, incomplete
RCC identifiable; outcomes
pathology, or outcomes not
attributable to patients with RCC
attributable to patients with RCC
Intervention Type
Active Surveillance
3
9
Cryoablation
9
7
RFA
12
9
Partial Nephrectomy – Lap
23
3
Partial Nephrectomy – Open
29
2
Radical Nephrectomy – Lap
17
2
Radical Nephrectomy – Open
16
0
META-ANALYTIC FINDINGS
Interpretation Cautions: The findings presented below must be interpreted with full
understanding of two issues. First, the data source was observational studies. The data are likely
to contain, therefore, unknown and uncontrolled biases, including selection bias and other
problems inherent in nonrandomized retrospective designs. Second, the descriptive data indicate
that patient age, tumor size and follow-up durations varied widely across the interventions
considered. Therefore, interpretation of the percentages presented in the tables (the point
estimate effect sizes and confidence intervals) is limited by these issues. For most outcomes, the
influence of confounding variables could not be separated from possible intervention effects,
making interpretation of statistically significant differences difficult. For this reason, the only
comparisons presented are those for which confounding variables appear to exert minimal
influence. Overall, the findings presented below are best understood as accurately describing the
available literature. Limited conclusions can be made regarding true differences among
interventions. Differences that are most likely to be unconfounded are emphasized.
Tables and Sections: The tables summarize the meta-analyzed data by intervention type for all
studies that reported extractable data in a particular category. The column labeled “Percent” is
the point estimate effect size calculated using a random effects model, taking into account all
studies that reported a particular outcome and met criteria for the analysis. The lower and upper
limits represent 95% confidence intervals. Possible confounding variables are presented in
Copyright © 2009 American Urological Association Education and Research, Inc.®
16
additional columns (i.e., patient age and tumor size for complications and perioperative events;
age, tumor size and follow-up duration for survival). These numbers differ somewhat from the
information presented in Tables 2, 3 and 4 because they are derived from the group of studies
that met criteria for a particular analysis and the subset of these studies that provided descriptive
information. The sections labeled “Interpretation” emphasize the potential role of confounding
variables. Sections that include comparisons among interventions have an additional section
labeled “Comparisons” that describes statistically significant differences with an accompanying
table.
Major Urological Complications
Table 6a summarizes the major urological complications data. Major urologic complications
include postoperative hemorrhage requiring transfusion or other intervention, urinary leak or
fistula, abscess, unanticipated loss of renal function or other local complications potentially
related to the procedure. Complication types are defined in Table 14. Conversions were not
counted as complications.
Table 6a:
Major Urological Complications
Study
Type
Cryo
RFA
LPN
OPN
LRN
ORN
# of
studies
15
20
22
15
13
6
Percent
4.9
6.0
9.0
6.3
3.4
1.3
Lower
Limit
3.3
4.4
7.7
4.5
2.0
0.6
Upper
Limit
7.4
8.2
10.6
8.7
5.5
2.8
Mean/Median
Patient Age
(yrs)
67.0 / 66.7
68.5 / 70.0
60.4 / 59.9
59.5 / 59.0
60.7 / 61.0
62.7 / 62.3
Mean/Median
Tumor Size
(cm)
2.6 / 2.6
2.7 / 2.7
2.6 / 2.6
3.2 / 3.0
4.8 / 5.1
4.9 / 5.2
Table 6b:
Major Urological
Complications: Significant
Comparisons (p<0.05)
LPN
OPN OPN
Cryo Cryo
RFA RFA
LRN
ORN
Comparisons: Table 6b presents statistically significant differences among interventions.c Major
urologic complication rates following laparoscopic partial nephrectomy were significantly higher
(p < 0.05) than cryoablation, RFA, LRN and ORN rates, but statistically indistinguishable from
c
Interventions in the same column have statistically similar rates; column order reflects relative magnitude with the highest
values in the far left column and the lowest values in the far right column. Statistically significant differences are present when
adjacent column and row entries do not overlap. ORN appears only in the last column; its rate is significantly lower than all other
interventions. LPN appears only in the first column; its rate is significantly higher than all other interventions except for OPN,
which also is present in the first column.
Copyright © 2009 American Urological Association Education and Research, Inc.®
17
OPN rates. OPN rates were statistically indistinguishable from cryoablation and RFA rates but
significantly higher (p < 0.05) than LRN and ORN rates. Cryoablation, RFA and LRN rates were
statistically indistinguishable. ORN major urological complication rates, however, were
significantly lower (p < 0.05) than rates for all other interventions.
Interpretation: Statistically significant differences must be interpreted in the context of patient
age and tumor size differences. The higher LPN major urological complication rate may
represent a valid finding because potential confounding variables would be expected to reduce
the LPN complication rate. Specifically, among studies that treated smaller tumors
(cryoablation, RFA, OPN, LPN), LPN major urological complication rates were significantly
higher than ablation rates even though LPN patients were younger than ablation patients.
Among studies that treated relatively young patients (LPN, OPN, LRN, ORN), LPN major
urological complication rates were significantly higher than LRN and ORN rates despite the fact
that LRN and ORN patients had larger tumors.
The relatively high major urological complication rate for OPN patients, though of less
magnitude than the LPN rate, may also represent a valid finding because confounding variables
would be expected to reduce the rate. OPN major urological complication rates were similar to
ablation rates even though OPN patients were younger. OPN major urological complication
rates were significantly higher than LRN and ORN rates even though LRN and ORN patients
had larger tumors. In addition, a single randomized controlled trial compared OPN and ORN
complication rates92and reported similar patterns. In 242 OPN patients, there was a 4.1% urinary
fistula rate, and 12% of patients had a blood loss of 0.5 liters or greater. In comparison, in 287
ORN patients, there were no urinary fistulas and 5.2% of patients experienced a greater than 0.5
liter blood loss. These data were not included in the meta-analysis but lend validity to the higher
urological complication rate for OPN compared to ORN suggested by the meta-analyzed data.d
The higher major urological complication rates for the ablation therapies compared to
ORN are more difficult to interpret given that these patients were older than ORN patients and
d
This study was the only randomized controlled trial (RCT) in the relevant literature. Conservative meta-analytic procedures
stipulate that RCT data, because of the stronger study design, should be considered separate from and not combined with
observational study data. Because this study reported complications in a way that did not fit the complications definitions used
by the Panel, it was not possible to calculate a point estimate that would be comparable to those calculated for the observational
studies. The RCT findings, however, are informative in that they parallel findings of the observational studies.
Copyright © 2009 American Urological Association Education and Research, Inc.®
18
generally had comorbidities that may have increased the potential for complications. This
difference should not be overinterpreted.
The higher major urological complication rate for LRN patients compared to ORN
patients also may represent a valid finding. LRN major urological complication rates were
significantly higher than ORN rates even though LRN and ORN were used to treat patients of
similar ages and with similar tumor sizes.
Overall, the higher major urological complication rates for the PN and laparoscopic
interventions may reflect the technical complexity of these procedures. A learning curve for
laparoscopic procedures during this era may have contributed to these findings.
Major Nonurological Complications
Table 7a summarizes the major nonurological complications data.
Study
Type
Cryo
RFA
LPN
OPN
LRN
ORN
# of
studies
15
20
22
14
13
6
Table 7a:
Major Nonurological Complications
Mean/Median
Lower Upper
Patient Age
Percent Limit
Limit
(yrs)
67.0
/ 66.7
5.0
3.5
7.2
68.5 / 70.0
4.5
3.2
6.2
60.4 / 59.9
4.6
2.9
7.1
59.5 / 59.0
2.2
1.2
4.0
60.7 / 61.0
8.3
5.5
12.4
62.7 / 62.3
5.9
3.4
10.2
Mean/Median
Tumor Size
(cm)
2.6 / 2.6
2.7 / 2.7
2.6 / 2.6
3.2 / 3.0
4.8 / 5.1
4.9 / 5.2
Interpretation: Given that the interventions treated patients of different ages and tumor sizes,
meaningful comparisons were not possible. For example, although LRN and ORN had the
highest rates, these patients had larger tumors than the other interventions.
Perioperative Events
Conversions: Conversions were defined as any change from the planned renal surgical approach
or procedure to a different renal surgical approach or procedure. Studies in which the authors
specifically stated that no conversions were necessary were included in these analyses. Studies
in which the authors did not address the occurrence of conversions were not included. Table 8a
Copyright © 2009 American Urological Association Education and Research, Inc.®
19
summarizes the conversion data. ORN studies were not included because conversions were not
relevant to this intervention.
Table 8a: Conversions
Study
Type
Cryo
RFA
LPN
OPN
LRN
# of
Studies
15
19
24
11
14
Percent
3.5
1.6
3.9
0.5
3.0
Lower
Limit
2.2
0.9
3.0
0.2
2.1
Upper
Limit
5.6
3.0
5.1
1.2
4.1
Mean/Median
Patient Age
(yrs)
67.0 / 66/7
68.9 / 70.2
60.4 / 60.1
59.1 / 59.0
61.0 / 61.0
Mean/Median
Tumor Size
(cm)
2.6 / 2.6
2.7 / 2.7
2.6 / 2.6
3.1 / 3.1
4.8 / 5.1
Table 8b:
Conversions –
Significant
Comparisons
(p<0.05)
LPN
Cryo Cryo
LRN LRN
RFA
OPN
Comparisons: Table 8b presents statistically significant comparisons.e OPN patients had the
lowest conversion rate at less than 1%; this rate was significantly less (p < 0.05) than rates for all
of the other interventions. RFA rates were significantly less (p < 0.05) than those for LPN.
Rates for LPN, cryoablation and LRN were statistically similar; rates for cryoablation, LRN and
RFA were statistically similar.
Interpretation: In the context of interventions used to treat small tumors in relatively young
patients (LPN and OPN), the significantly higher conversion rate for LPN may reflect the greater
technical challenge of laparoscopic procedures and may be a valid difference. It should be noted
that an occasional and timely conversion from a laparoscopic to an open procedure should not
necessarily be considered an adverse event. The higher conversion rates for the ablation
therapies and LRN are more difficult to interpret because they may be influenced by the older
patient population and larger tumor sizes treated, respectively, by these interventions. The very
low rate for OPN also is difficult to interpret and may reflect the young patient population, the
relatively small tumor sizes treated and/or the technical advantages of the open surgical
approach.
e
Interventions in the same column have statistically similar rates; column order reflects relative magnitude with the highest
values in the far left column and the lowest values in the far right column. Statistically significant differences are present when
adjacent column and row entries do not overlap. For example, OPN appears only in the last column; its rate is significantly lower
than all other interventions. LPN appears in the first column with cryoablation and LRN; its rate is statistically similar to
cryoablation and LRN rates but significantly higher than RFA and OPN rates.
Copyright © 2009 American Urological Association Education and Research, Inc.®
20
Additional Information: The number of studies that reported the occurrence of conversions, the
reason for conversion and the procedure to which the operation was converted are detailed in
Tables 8c and 8d (e.g., of the 11 conversions reported in cryoablation studies, nine were
converted to open cryoablation, and two were converted to ORN). Each column indicates the
number of studies that reported the occurrence of a conversion, the total number of studies that
addressed conversions, and the total number of procedures that were performed. Of 109
conversions, the most commonly reported conversion reason was bleeding (38 reports). In 23
instances, the reason for the conversion was not reported.
Table 8c: Reason for Conversion
Conversion Reason
Bleeding
Perirenal fat, renal vessel or hilum involvement
Access or adhesions
Positive margins
Proximity to other intra-abdominal structure
Cutting into tumor or tumor fracture
Respiratory difficulty
Bowel injury
Multiple masses
Need to remove >50% of kidney
Not reported
TOTAL
Cryoablation
(conversions
occurred in 4
of 15 studies;
total of 727
procedures)
RFA
(conversions
occurred in 1
of 19 studies;
total of 837
procedures)
2
1
6
0
0
0
2
0
0
0
0
11 (1.5%)
0
0
0
0
1
0
0
0
0
0
0
1 (0.12%)
LPN
(conversions
occurred in
13 of 24
studies; total
of 2067
procedures)
18
4
11
12
2
1
0
0
1
1
12
62 (3.0%)
OPN
(conversions
occurred in 1
of 11 studies;
total of 2216
procedures)
0
0
0
1
0
0
0
0
0
0
0
1 (0.045%)
LRN
(conversions
occurred in
9 of 14
studies; total
of 1387
procedures)
18
1
3
0
0
0
0
1
0
0
11
34 (2.45%)
Table 8d: Original and Converted-To Procedures
Original Procedure
Converted to
Cryoablation
Open Cryo
Open RFA
LPN
OPN
LRN
ORN
TOTAL
9
n/a
0
0
0
2
11 (of 727
procedures;
1.5%)
RFA
n/a
1
0
0
0
0
1 (of 837
procedures;
0.12%)
LPN
n/a
n/a
n/a
38
22
2
62 (of 2067
procedures;
3.0%)
OPN
n/a
n/a
n/a
n/a
0
1
1 (of 2216
procedures;
0.045%)
Copyright © 2009 American Urological Association Education and Research, Inc.®
LRN
n/a
n/a
n/a
n/a
n/a
34
34 (of 1387
procedures;
2.45%)
21
Transfusions: Table 8e summarizes the transfusion data. ORN studies were not included in this
analysis because these studies did not consistently report transfusion use.
Table 8e: Transfusions
Study
Type
Cryo
RFA
LPN
OPN
LRN
# of
Studies
15
19
21
9
11
Percent
3.2
2.4
6.0
8.1
2.1
Lower
Limit
2.0
1.4
4.1
4.7
0.9
Upper
Limit
4.9
4.0
8.9
13.7
4.8
Mean/Median
Patient Age
(yrs)
67.0 / 66.7
68.9 / 70.2
60.6 / 60.0
57.9 / 58.4
60.5 / 61.0
Table 8f:
Transfusions –
Significant
Comparisons
(p<0.05)
OPN
LPN
Cryo
LRN
RFA
Mean/Median
Tumor Size
(cm)
2.6 / 2.6
2.7 / 2.7
2.5 / 2.6
3.1 / 2.9
5.1 / 5.1
Comparisons: Table 8f presents statistically significant comparisons.f OPN and LPN patients
had the highest transfusion rates; these rates were significantly higher (p < 0.05) than the rates
for cryoablation, RFA and LRN patients.
Interpretation: Because OPN and LPN were used to treat younger patients with smaller tumors,
the significantly higher transfusion rates may be valid differences and may reflect the technical
challenges of PN procedures.
Reinterventions: Reinterventions were defined as any unplanned operation that occurred during
or after the planned renal surgery. Table 8g summarizes the reintervention data.
Table 8g: Reinterventions
Study
Type
Cryo
RFA
LPN
OPN
LRN
ORN
# of
Studies
15
20
22
14
13
6
Percent
2.6
3.2
3.4
1.6
2.0
1.1
Lower
Limit
1.5
1.9
2.7
1.0
1.2
0.6
Upper
Limit
4.3
5.1
4.4
2.7
3.2
2.1
Mean/Median
Patient Age
(yrs)
67.0 / 66.7
68.5 / 70.0
60.4 / 60.0
59.0 / 59.5
60.7 / 61.0
62.0 / 62.3
Mean/Median
Tumor Size
(cm)
2.8 / 2.6
2.7 / 2.7
2.6 / 2.6
3.0 / 2.9
4.8 / 5.1
5.0 / 5.4
Table 8h:
Reinterventions –
Significant
Comparisons
(p<0.05)
LPN
RFA RFA
Cryo Cryo Cryo
OPN OPN
LRN LRN
ORN
f
Interventions in the same column have statistically similar rates; column order reflects relative magnitude with the highest
values in the far left column and the lowest values in the far right column. Statistically significant differences are present when
adjacent column and row entries do not overlap. For example, OPN and LPN have statistically similar rates that are significantly
higher than rates for cryo, LRN, and RFA.
Copyright © 2009 American Urological Association Education and Research, Inc.®
22
Comparisons: Table 8h presents statistically significant comparisons.g LPN patients had
significantly higher (p < 0.05) rates than OPN, LRN and ORN patients. RFA patients had
significantly higher (p < 0.05) rates than ORN patients. Rates for LPN and the ablation therapies
were statistically similar. Rates for the ablation therapies, OPN and LRN were statistically
similar. Rates for cryoablation, OPN, LRN and ORN were statistically similar.
Interpretation: The significantly higher reintervention rate for LPN may be a valid difference.
LPN and OPN patients were similarly aged and had similar-sized tumors, suggesting that the
higher LPN rate may be the result of the more technically difficult laparoscopic procedure. LPN
patients had smaller tumors than LRN and ORN patients, which would tend to decrease the LPN
reintervention rate if it were affected by tumor size. This difference may reflect the technical
challenge of the LPN procedure. The higher rate for RFA patients compared to ORN patients
should be interpreted with caution given that RFA patients were older than ORN patients but
also had smaller tumors.
Survival
The survival analyses -- total RFS, local RFS, metastatic RFS, CSS and OS -- were conducted on
the subset of studies that provided pathological confirmation of RCC and for which outcomes
could be attributed to RCC patients. These criteria eliminated many studies that had incomplete
pathological information or for which outcomes could not be attributed to RCC patients. One
exception was made to this criterion: the AS studies were included in evaluation of metastatic
RFS. The Panel made this exception because of the clinical priority to understand the probability
of metastases in patients for whom no surgical intervention was undertaken.
g
Interventions in the same column have statistically similar rates; column order reflects relative magnitude with the highest
values in the far left column and the lowest values in the far right column. Statistically significant differences are present when
adjacent column and row entries do not overlap. For example, LPN rates are statistically similar to ablation rates, but
significantly higher than OPN, LRN, and ORN rates.
Copyright © 2009 American Urological Association Education and Research, Inc.®
23
Total Recurrence-Free Survival
“Total recurrence” was defined as local recurrence plus metastatic or distant recurrence.h Table
9a summarizes the total RFS data. For the ablation studies, local recurrence was defined as any
localized disease remaining in the treated kidney at any point after the first ablation treatment.
Study
Type
Cryo
RFA
LPN
OPN
LRN
ORN
# of
studies
10
10
17
21
8
10
Table 9a: Total Recurrence-Free Survival
Mean/Median Mean/Median
Survival
Lower
Upper
Patient Age
Tumor Size
Rate
Limit
Limit
(yrs)
(cm)
67.0
/
66.5
2.5 / 2.6
87.6
80.9
92.2
67.6 / 70.0
2.8 / 2.7
85.2
81.3
88.5
61.2 / 61.0
2.6 / 2.6
98.3
97.0
99.0
60.4 / 60.0
3.3 / 3.1
95.1
93.6
96.3
60.7 / 61.0
4.6 / 4.6
95.3
93.4
96.6
62.6 / 62.6
4.6 / 4.8
88.8
83.9
92.4
Mean/Median
Follow Up
(mos)
26.2 / 18.3
39.3 / 32.8
25.8 / 16.0
46.8 / 40.0
32.8 / 37.1
44.8 / 45.3
Interpretation: Given the existence of multiple confounding factors, particularly substantial
differences in follow-up, meaningful comparisons among interventions were not possible. For
example, although the LPN total RFS rate appears high, it may be accounted for by short followup duration, by younger patient age and/or by relatively small tumors. ORN has a relatively low
total RFS rate, but the longest follow-up and treated some of the largest tumors. The low rates
for cryoablation and RFA are noteworthy given the relatively short follow-up and smaller tumor
size associated with these modalities. However, this finding must be interpreted in the context of
the conservative definition used to define local recurrence (i.e., any disease remaining in the
treated kidney after the first ablation; see Local RFS below).
Local Recurrence-Free Survival
“Local recurrence” was defined as any disease presence in the treated kidney or associated renal
fossa posttreatment. For the ablation studies, local recurrence was defined as any localized
disease remaining in the treated kidney at any point after the first ablation, in accordance with
the recommendations of the Working Group of Image-guided Tumor Ablation.93 Table 10a
summarizes the local RFS data.
h
Appearance of disease in the contralateral kidney was considered evidence of new disease and was not counted as
recurrence.
Copyright © 2009 American Urological Association Education and Research, Inc.®
24
Table 10a: Local Recurrence-Free Survival
Study
Type
Cryo
RFA
LPN
OPN
LRN
ORN
# of
studies
10
10
17
21
8
10
Percent
90.6
87.0
98.4
98.0
99.2
98.1
Lower
Limit
83.8
83.2
97.1
97.4
98.2
97.3
Upper
Limit
94.7
90.0
99.1
98.5
99.7
98.6
Mean/Median
Patient Age
(yrs)
67.0 / 67.0
67.6 / 70.0
61.2 / 61.0
60.5 / 60.0
60.7 / 61.0
62.6 / 63.0
Mean/Median
Tumor Size
(cm)
2.5 / 2.6
2.8 / 2.7
2.6 / 2.6
3.3 / 3.1
4.6 / 4.6
4.6 / 4.8
Mean/Median
Follow-Up
(mos)
19.5 / 18.2
22.9 / 19.4
20.8 / 15.0
55.5 / 46.9
30.2 / 17.7
59.3 / 58.3
Table 10b:
Local RFS –
Significant
Comparisons
(p<0.05)
LPN
OPN
LRN
ORN
Cryo
RFA
Comparisons: Table 10b presents statistically significant comparisons.i LPN, OPN, LRN and
ORN local RFS rates were statistically similar and were all significantly higher (p < 0.05) than
local RFS rates for cryoablation and RFA.
Interpretation: The most striking finding with regard to local RFS is the significantly lower rates
for the ablation therapies despite their short follow-up durations. These low local RFS rates
should be interpreted in the context of the definition for local recurrence used for this analysis,
which categorized re-ablation for remaining disease as a treatment failure. The high local RFS
rates of the other four interventions (which treated relatively young patients) are noteworthy
given the generally long follow-up durations and larger tumor sizes with the exception of LPN.
The consistency of local RFS rates for surgical excisional procedures despite differences in
follow-up and tumor size suggests that local recurrence may be minimally influenced by these
factors as long as complete surgical excision has been performed, but there is a need for long
term data on laparoscopic procedures to state this conclusion firmly.
Metastatic Recurrence-Free Survival
“Metastatic recurrence” was defined as any disease presence in the body other than in the treated
kidney or associated renal fossa posttreatment.j AS patients were included in this analysis
i
Interventions in the same column have statistically similar rates; column order reflects relative magnitude with the highest
values in the far left column and the lowest values in the far right column. Statistically significant differences are present when
adjacent column and row entries do not overlap. LPN, OPN, LRN, and ORN have statistically similar rates that are significantly
higher than rates for the ablation therapies.
j
A small number of patients had local and metastatic recurrence detected simultaneously; there were not enough cases to analyze
separately. These patients are contained in the Total Recurrence analyses; they are not included here or in the local recurrence
analyses.
Copyright © 2009 American Urological Association Education and Research, Inc.®
25
despite incomplete information about tumor pathology because of the clinical importance of
estimating the probability of metastases in patients for whom no intervention was undertaken.
Table 11a summarizes the metastatic RFS data.
Study
Type
AS
Cryo
RFA
LPN
OPN
LRN
ORN
# of
studies
12
10
10
17
21
8
10
Table 11a: Metastatic Recurrence-Free Survival
Mean/Median Mean/Median
Lower Upper
Patient Age
Tumor Size
Percent Limit
Limit
(yrs)
(cm)
67.1 / 68.2
2.7 / 2.2
97.7
95.5
98.9
67.0 / 66.5
2.5 / 2.6
95.3
91.1
97.5
67.6
/
70.0
2.8 / 2.7
97.8
95.5
98.9
61.2 / 61.0
2.6 / 2.6
98.8
97.8
99.4
60.4 / 60.0
3.3 / 3.1
96.7
95.6
97.5
60.7
/
61.0
4.6 / 4.6
95.7
93.9
97.0
62.6 / 62.6
4.6 / 4.8
89.8
85.3
93.1
Mean/Median
Follow-Up
(mos)
29.6 / 29.0
19.5 / 16.7
22.9 / 19.4
20.8 / 15.0
56.0 / 47.0
30.2 / 17.7
69.1 / 56.7
Interpretation: Overall, it is noteworthy that metastatic RFS rates are relatively high regardless
of intervention type, likely reflecting the indolent nature of many clinical stage T1 renal masses.
However, the presence of confounding factors precludes meaningful comparisons. The
interventions with the highest rates have short follow-up durations and treated relatively small
tumors. ORN rates are the lowest, but ORN patients had the largest tumors and the longest
follow-up durations. Until long-term follow-up data are available on all interventions, it is not
possible to draw conclusions about differences in metastatic RFS. As with all these data, the AS
data should be interpreted with caution due to concerns about patient selection. In addition, a
proportion of patients undergoing initial AS eventually underwent surgical intervention for
tumors that were increasing in size, and some tumors in the AS series were likely benign.
Cancer-Specific Survival
“Cancer-specific survival” was defined as the proportion of patients that did not die from RCC
during the follow-up period. Only studies in which survival could be attributed to patients with
RCC were included in this analysis. Table 12a summarizes the CSS data.
Copyright © 2009 American Urological Association Education and Research, Inc.®
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Study
Type
Cryo
RFA
LPN
OPN
LRN
ORN
# of
studies
6
8
17
21
8
12
Percent
95.2
98.1
98.8
97.2
98.2
89.1
Table 12a: Cancer-Specific Survival
Mean/Median Mean/Median
Lower Upper
Patient Age
Tumor Size
Limit Limit
(yrs)
(cm)
67.6 / 66.1
2.6 / 2.6
89.2
97.9
67.8
/
70.0
2.8
/ 2.7
95.2
99.2
61.2 / 61.0
2.6 / 2.6
97.6
99.4
60.4 / 60.0
3.3 / 3.1
96.0
98.0
60.7
/
61.0
4.6 / 4.6
96.7
99.0
62.5 / 62.6
4.8 / 5.2
84.0
92.8
Mean/Median
Follow-Up
(mos)
20.5 / 16.4
23.4 / 19.4
20.8 / 15.0
56.0 / 47.0
30.2 / 17.7
60.8 / 56.7
Interpretation: Overall, CSS rates are relatively high regardless of intervention type, again
possibly reflecting the indolent nature of many clinical stage T1 renal masses. However, the
presence of confounding factors precludes meaningful comparisons. The interventions with the
highest rates have short follow-up durations and treated younger patients and/or small tumor
sizes. ORN had the lowest rate, but has the longest follow-up and treated the largest tumors.
Until longer-term follow-up data are available on all interventions, it is not possible to draw
conclusions about differences in CSS.
Overall Survival
“Overall survival” was defined as the proportion of patients that did not die from any cause,
including RCC. Only patients known to have RCC were included in these analyses. Table 13a
summarizes the OS data.
Study
Type
# of
studies
Percent
Cryo
RFA
LPN
OPN
LRN
ORN
5
8
12
17
7
9
96.5
93.2
98.0
89.0
92.8
81.9
Table 13a: Overall Survival
Lower Upper Mean/Median
Limit Limit
Patient Age
(yrs)
85.5
99.2
65.9 / 65.2
82.2
97.6
67.8 / 70.0
96.1
99.0
60.6 / 60.2
85.3
91.8
60.0 / 59.1
86.4
96.3
60.7 / 61.1
65.5
91.5
62.7 / 64.0
Mean/Median
Tumor Size
(cm)
2.4 / 2.6
2.8 / 2.7
2.5 / 2.5
3.0 / 3.0
4.6 / 4.6
4.6 / 4.8
Mean/Median
Follow-Up
(mos)
23.0 / 20.5
23.4 / 19.4
16.4 / 13.5
55.5 / 47.0
31.8 / 16.1
58.4 / 58.3
Interpretation: As with the other survival analyses, the presence of confounding factors
precludes meaningful comparisons. Similar to the CSS data, the interventions with the highest
rates had short follow-up durations and treated younger patients and/or small tumors. ORN had
the lowest rate, but has the longest follow-up and treated the largest tumors. Until long-term
Copyright © 2009 American Urological Association Education and Research, Inc.®
27
follow-up data are available on all interventions, it is not possible to draw conclusions about
differences in OS. Some have hypothesized that the better overall survival for OPN compared to
ORN (the interventions with the longest follow-up) is related to a deleterious effect of CKD
associated with ORN, but selection bias may be a confounding factor. Studies that focus
specifically on post-procedure CKD are needed to definitively answer this question.
Grading the recommendations
The present statements are graded with respect to the degree of flexibility in application. A
"standard" is the most rigid treatment policy. A "recommendation" has significantly less rigidity,
and an "option" has the largest amount of flexibility. These terms are defined as follows:
1. Standard: A guideline statement is a standard if: (1) the health outcomes of the
alternative interventions are sufficiently well known to permit meaningful decisions,
and (2) there is virtual unanimity about which intervention is preferred.
2. Recommendation: A guideline statement is a recommendation if: (1) the health
outcomes of the alternative interventions are sufficiently well known to permit
meaningful decisions, and (2) an appreciable, but not unanimous majority agrees on
which intervention is preferred.
3. Option: A guideline statement is an option if: (1) the health outcomes of the
interventions are not sufficiently well known to permit meaningful decisions, or (2)
preferences are unknown or equivocal.
The draft was sent to 69 peer reviewers of whom 35 provided comments; the Panel
revised the document based on the comments received. The guideline was submitted first for
approval to the Practice Guidelines Committee of the AUA and then forwarded to the AUA
Board of Directors for final approval.
Summary of the Treatment Options for the Clinical Stage 1 Renal Mass
Active Surveillance
Surveillance of localized renal tumors is now performed increasingly in carefully selected
patients with a growing literature to support this management option.32, 39, 48, 94-102 A meta-
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analysis of this literature demonstrated an average growth rate of only 0.28 cm per year,48 and
the Panel’s review of the literature indicated that progression to metastasis was reported in only
about 1% (4/390) of patients. Meta-analysis of these data yielded a point estimate based on the
random effects model of about 2.3%. These favorable results are consistent with data about the
biological aggressiveness of clinical stage T1 renal masses -- many are benign (20%) or indolent.
Only about 20% to 30% of these tumors have potentially aggressive features.2, 32, 103 The
favorable results in AS series also likely reflect a selection bias for small tumors and favorable
radiographic characteristics. In addition, there is limited follow-up in most series (30 months
mean).48, 94 More adverse events and thus reduced RFS are expected with extended follow-up.
For incidental stage T1 renal masses, prolonged follow-up will be necessary, similar to low-risk
prostate cancer. Other important considerations in interpreting this literature are that some
patients eventually underwent surgery for increasing tumor size, and many tumors were not
biopsied, raising the possibility that a substantial portion may have been benign. In the metaanalysis by Chawla and colleagues,48 only 46% of tumors had pathologic confirmation of RCC.
These issues tend to bias results positively. It is also important to recognize that there are no
established protocols for AS for renal tumors. The current literature reports a wide variety of
surveillance protocols, none of which has been adequately substantiated.
Operational considerations can affect AS of localized renal masses and must be
recognized. First, estimation of tumor volume will more accurately reflect true tumor kinetics
and hence biological aggressiveness and should be considered for surveillance.101 Unfortunately,
tumor diameter rather than tumor volume is reported in most studies.48 In addition, for
measurements of tumor size, differences of < 3.1 mm for interobserver or < 2.3 mm for
intraobserver evaluations lie within the variability of measurement and should thus not be
attributed to tumor growth.104
There are many ongoing concerns about AS that should be conveyed during patient
counseling and the decision-making process. First, the growth rate of a renal mass does not
predict malignancy, as even tumors with zero growth rates have proven to be malignant.98 At
present there is no truly reliable way to distinguish benign vs. malignant or indolent vs.
potentially aggressive tumors based on clinical or radiographic features.2, 31, 48, 105, 106 One must
also recognize that a small subgroup of patients may demonstrate rapid growth and aggressive
behavior with AS. In the Volpe study,47 25% of the tumors doubled in volume in 12 months, and
Copyright © 2009 American Urological Association Education and Research, Inc.®
29
one patient developed metastatic disease. Clinical T1b tumors (> 4.0 cm and < 7.0 cm) in
particular may be at higher risk with AS. In the study by Sowery and colleagues,101 such tumors
demonstrated a rapid growth rate of 1.43 cm per year, and 1/9 patients developed metastasis.
This is consistent with our knowledge about the natural history and biological aggressiveness of
larger tumors.31, 32, 103 Several studies have shown increased biological potential for tumors > 3.0
cm,31, 32, 103 and Kunkle et al. 99 showed that the risk of synchronous metastasis goes up 22%
with each one centimeter increase in tumor size.
The other important concern is that AS could be associated with the loss of the window
of opportunity for NSS. There is only limited data about this issue in the current literature, and it
remains a valid concern.48, 86 Clearly, enhanced renal mass biopsy incorporating molecular
analyses holds promise for assessing aggressive potential and guiding decision making about AS;
however, further research will be required to define the utility and limitations of this approach.106
Until this field is more firmly established, AS remains a calculated risk that the patient must be
willing to accept.
Active surveillance is a reasonable option for patients with limited life expectancy or for
those who are unfit for or do not desire intervention. The patient should be counseled about the
small but real risk of cancer progression, possible loss of window of opportunity for NSS, lack of
curative salvage therapies if metastases develop, limitations of renal mass biopsy and
deficiencies of the current literature. Larger tumors and those with aggressive appearance, such
as substantial heterogeneity or infiltrative growth pattern, may be at higher risk and should be
treated proactively if the patient is a reasonable surgical candidate.
Radical Nephrectomy
Radical nephrectomy is still an appropriate treatment option for select clinical T1 renal tumors
not amenable to PN. ORN can be performed by a variety of surgical approaches, most commonly
the 11th or 12th rib resection flank or mini-flank (6-8 cm, without rib resection) incisions.107, 108
The component parts of the traditional ORN (e.g., regional lymphadenectomy or ipsilateral
adrenalectomy) are usually recommended at the time of RN, but their oncological efficacy has
never been tested in prospective trials. In today’s era of modern CT and MRI, it is extremely
uncommon that unsuspected regional nodal or ipsilateral adrenal metastases will be encountered
in patients with localized renal masses. LRN can be performed by intraperitoneal,
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30
extraperitoneal, and hand-assisted approaches.88, 109-117 The choice of ORN or LRN is largely
made by surgeon discretion and training background along with careful consideration of many
patient factors including body habitus; tumor size and location; comorbidities; and history of
prior abdominal or retroperitoneal operations. Given that oncologic efficacy appears to be
equivalent, a minimally invasive approach is preferred whenever feasible, given sensible patient
selection and adequate expertise.
Major urological complications and major nonurological complications related to ORN
occur in 1.3% and 5.9% of cases, respectively. Complications unique to LRN in particular and
laparoscopy in general have been reported from individual centers and are more likely to occur
earlier in a center’s experience.118 Open conversion occurs in approximately 2.9 - 5.9% of
cases.119-124, 144
Over the last 10 years, several important factors have led many urologic oncologists to
reconsider the routine use of RN for the management of localized renal masses. These factors
include: a) oncological outcomes are the same whether RN or PN is performed for renal cortical
tumors of less than 4 cm125, 126 and less than 7 cm127, 128 across all tumor histological subtypes; b)
in most contemporary series, despite state of the art imaging, approximately 20% of clinical T1
renal tumors are benign neoplasms (i.e., renal oncocytoma, fat-poor angiomyolipoma) and 60%
to 70% are indolent tumors with limited metastatic potential; c) concerns about late contralateral
recurrence following cure of the index tumor; and d) emerging evidence that RN is an
independent risk factor for the development of CKD.
The final item requires careful consideration as it underlies an overriding principle in the
management of clinical T1 renal masses -- nephron-sparing approaches should be used whenever
feasible. Reports comparing renal functional outcomes between patients undergoing PN or RN
for clinical T1 renal masses revealed that closely-matched patients undergoing RN were more
likely to have proteinuria and a serum creatinine > 2.0 mg/dl,126, 129 a finding that was later
confirmed using the calculation of estimated glomerular filtration rate (eGFR) obtained from the
Modification of Diet in Renal Disease formula.130 In addition, prior to tumor resection in
apparently healthy patients with an apparently normal contralateral kidney, it was reported that
26% of clinical T1a renal tumor patients had pre-existing CKD as defined by an eGFR of < 60
ml/min/1.73m2.130 After surgery, the three-year probability of mild CKD (GFR < 60
ml/min/1.73m2) was 20% after PN, but 65% after RN. Corresponding values for three-year
Copyright © 2009 American Urological Association Education and Research, Inc.®
31
probability of moderate CKD (GFR < 45 ml/min/1.73m2) were 5% for PN and 36% for RN.
Multivariate analysis indicated that RN remained an independent risk factor for the development
of new-onset CKD even after controlling for a variety of potential confounding factors. 130, 131
Even in the absence of end stage renal failure, it is now established that CKD
(eGFR 15-60 ml/min/1.73m2) is associated with increasing risks of cardiovascular events,
hospitalization and death, the likelihood of which increases as the eGFR decreases.132 Unlike the
carefully selected and much younger kidney transplant donors, renal tumor patients have a
median age of more than 60 years and often have comorbid medical conditions such as diabetes,
hypertension and peripheral vascular disease that can affect baseline kidney function. Recent
data demonstrates that RN is an independent risk factor for worse OS compared to PN when
utilized in matched patients undergoing resection of a clinical T1 renal tumor with a normal
contralateral kidney.133 In addition to the interplay between cardiovascular diseases and CKD,
there are quality of life data suggesting that patients undergoing elective NSS have a better
overall health-related quality of life than those undergoing radical nephrectomy with no
significant difference in hospital costs.134
Despite these compelling data, evidence from large cross-sectional national databases
indicates that RN is overutilized in the U.S. and abroad and still accounts for 80% to 90% of
operations for clinical T1 renal tumors.135-137 Overutilization of RN is an important quality of
care issue that must be carefully addressed through educational programs, and increased training
in both open and laparoscopic nephron-sparing operations, and referrals to surgeons with these
advanced nephron-sparing techniques.
Open Partial Nephrectomy
Open partial nephrectomy remains the nephron-sparing modality with the most substantial
supporting body of data and the most extensive clinical experience. The number of patients who
have undergone OPN reported in the literature exceeds the number of patients who have
undergone all other forms of treatment combined (excluding ORN) for the treatment of localized
RCC. OPN remains a standard of care in the treatment of localized RCC given its wide
application over the last two decades and the robustness of its operative and oncologic data.
The indications for OPN have been well described previously138 and include absolute,
relative and elective indications. As a surgical technique, OPN is versatile and reproducible.
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Moreover, the required skill set has traditionally been more easily transferred to trainees than
minimally invasive nephron-sparing techniques. Key concepts include excellent exposure, early
vascular control, wide excision with a negative surgical margin and reconstruction of the renal
remnant to minimize the risk of postoperative hemorrhage or urinary fistula. Ischemic times can
be kept acceptably low, and much of the uninvolved kidney can often be kept on ice during the
entire procedure. In addition, in many cases, manual compression may obviate the need for
vascular clamping. For more complex cases requiring difficult excisions and/or reconstructions,
longer periods of cold ischemia are readily achieved with excellent functional results.139 The use
of smaller incisions, perioperative epidurals, intercostal nerve blocks and patient-controlled
analgesia and/or potent anti-inflammatory agents (i.e., ketorolac) have all served to reduce
postoperative pain and hasten recovery following OPN.138
Postoperative serious adverse events with OPN are among the lowest of all nephronsparing options. Despite the higher risk profile of most demographic variables in OPN series
(older patients, larger mean tumor size, more centrally placed lesions),141 the risk of serious
adverse events remains acceptably low and comparable to all other treatment options. The
Panel’s meta-analysis indicated that total major urological complication rates for OPN were
6.3%, statistically similar to other forms of NSS such as LPN (9.0%), cryotherapy (4.9%) and
RFA (6.0%). Major nonurological complication rates for OPN were 2.2%, the lowest of all
interventions considered. OPN is associated with a very low reintervention rate (1.6%) and/or
retreatment rate. A randomized study by the EORTC comparing RN to OPN for small (< 5 cm)
renal tumors found a slightly higher rate of severe hemorrhage after NSS (3.1% vs. 1.2%) in
addition to a 4.4% rate of urinary fistulas.92However, the overall complication differences were
minimal in the context of the benefits of renal preservation in this study.
Physiologically, OPN is associated with the most robust data regarding preservation of
filtration function and the lowest risk of CKD, even in the elective setting.130 Moreover, unlike
minimally invasive and/or ablative treatment options, OPN allows definitive pathological
identification (i.e., stage, grade and histology) of the treated renal mass.140 Oncologically, OPN
produces very low rates of local and metastatic recurrence and high rates of CSS. In fact, as
measured by nearly all oncologic endpoints, OPN stands out as among the most effective means
of therapy for localized RCC, even when compared with RN. Given emerging data which
suggest that localized RCC has a prolonged natural history,48 the finding that OPN has three to
Copyright © 2009 American Urological Association Education and Research, Inc.®
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five times longer mean follow-up than any other nephron-sparing treatment modality is also
noteworthy.
Open partial nephrectomy is considered a standard of care for the treatment of the clinical
T1 renal mass, particularly in patients with compromised renal function but now also including
those with a normal opposite kidney.
Laparoscopic Partial Nephrectomy
Among nephron-sparing approaches, the Panel’s review indicated that LPN was primarily
utilized for the treatment of small cortical tumors (mean tumor size 2.6 cm, similar to those
treated by cryoablation). This would suggest that tumors treated by LPN were more likely to be
of lower pathologic stage than those treated by most other means.
In addition, LPN is associated with the second shortest mean duration of follow-up (20.8
months) with only cryoablation associated with shorter follow-up. There are limited studies143
addressing follow-up of at least five years. Pathological confirmation was available in all but a
small percentage of patients (< 2%) undergoing LPN
LPN is typically associated with longer warm ischemia times than other nephron-sparing
techniques. General conclusions about ischemia time cannot be offered based on the metaanalysis since few studies reported this information; however, in a combined study from major
centers with the greatest expertise, warm ischemic time was significantly shorter (20 min) for
OPN compared to LPN (31 min).141 Some studies suggest an advantage to routine hilar clamping
as a means to reduce blood loss, positive margins and operative time during LPN.145, 146 The
main concern is that increased warm ischemic times appear to be an independent predictor of
reduced renal function after PN.
LPN was associated with a statistically significant higher major urological complication
rate (9.0%) than any of the other treatment modalities except for OPN (6.3%). The LPN major
nonurological complication rate (4.6%) did not differ from other intervention types, however.
Conversion rates were highest for LPN at 3.9%, but these rates were statistically similar to those
for cryoablation (3.5%) and LRN (3.0%). In addition, Breda et al.147 reported the results of 855
LPNs from 17 centers and identified a 2.4% positive margin rate. These sobering statistics
emphasize the fact that LPN belongs in the hands of an experienced surgeon.
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34
Oncologic outcomes and survival rates reported with LPN performed for malignancy are
encouraging but very preliminary. More extended follow-up and more sophisticated analysis to
control for confounding factors will be required.
Patients with small peripheral lesions who meet criteria for OPN should be considered for
LPN. The potential benefits of minimally invasive surgery must be weighed against the higher
risk of complications and the possibility of longer periods of ischemia. However, with further
advances in laparoscopic instrumentation and greater dissemination of expertise, improved
outcomes and more widespread application of LPN is anticipated in the future.
Thermal Ablation
Probe-based thermal ablative modalities offer a proactive treatment approach associated with a
minimally invasive recovery profile. Ongoing concerns include increased local recurrence rates
when compared to surgical excision, controversy about radiographic parameters of success148
and difficulty with surgical salvage if required.149, 150 It is possible that outcomes associated with
ablative modalities will improve with further advances in technology and application and that
some of these concerns will be answered with more prolonged and informative outcomes data.
Nevertheless, even in their current iteration, cryoablation and RFA represent valid treatment
alternatives for many older patients or those with substantial comorbidities, presuming judicious
patient selection and thorough patient counseling. Given these concerns and the complexity of
the decision-making process, a primary role of the urologist in counseling and the informed
consent process is recommended.
Cryoablation
The clinical use of cryoablation for treatment of localized renal masses was initially developed
primarily by one institution using a stable technology platform via a laparoscopic approach and
applying standard patient selection criteria and follow-up regimens. Subsequent data on
cryoablation are largely from laparoscopic series (8 studies), but also include percutaneous MRIguided (2), percutaneous CT-guided (2 reports from the same institution), percutaneous USguided (1), open and laparoscopic (2 reports from the same institution), and 1 multi-institutional
study looking at all types of ablative therapy. Most reports are from the U.S., with only one from
Copyright © 2009 American Urological Association Education and Research, Inc.®
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Europe (Italy).151 There are no well-designed prospective studies comparing cryoablation to RFA
or to other forms of NSS. With one exception, no QOL measures are provided in these studies.
Overall, there is substantial variability in reported outcomes, treatment strategies and follow-up
methodologies. Some investigators did not routinely perform preoperative biopsy. Most
investigators did not perform routine postablation biopsies; however some investigators report
selective use of postablation biopsies to confirm recurrence152.
The major urological complication rate for cryoablation was 4.9%; this rate is similar to
rates for RFA, OPN and ORN and significantly lower than for LPN. The most common
complication reported with cryoablation is hemorrhage, usually due to renal fracture, 153,155 but
studies also report pancreatic injury and ureteral obstruction.154, 155 Cryoablation is associated
with good renal function preservation in the absence of complications, but renal loss has been
reported in the presence of complications. Interestingly, conversion rates for cryoablation
(3.5%) are similar to LPN rates (3.9%) and nearly twice as high as RFA rates (1.6%).
For the purpose of the Panel’s meta-analysis, a tumor was defined as incompletely
ablated if it required more than one ablation session to achieve elimination by radiographic
criteria in accordance with the recommendations of the Working Group on Image-Guided Tumor
Ablation.93 This is a point that is key to interpreting these data. Cryoablation was associated
with a significantly lower rate of incomplete ablation (4.8%) than RFA (14.2%). It is important
to note, however, that the laparoscopic vs. percutaneous techniques may be relevant variables to
consider. Specifically, most cryoablation studies were performed laparoscopically, and most
RFA studies were performed percutaneously. When ablation studies were compared based only
on technique, percutaneous studies had significantly higher incomplete ablation rates than
laparoscopic studies (13.9% vs. 2.1%). This pattern remained when percutaneous cryoablation
studies were compared to laparoscopic cryoablation studies (10.5% vs. 2.2%). While it is
tempting to conclude that technique or approach may impact outcomes, this information is based
on limited reports in the percutaneous cryoablation and laparoscopic RFA literature. In addition,
the influence of selection, technique and reporting biases may play a role in these differences.
Survival outcomes for cryoablation must be interpreted in the context of small sample
sizes, short follow-up duration and a limited number of studies. The longest published follow-up
of three years is based on two studies (Gill et al.152, Davol et al.153) which had similar CSS rates.
Overall, cryoablation total RFS rates were lower than rates for LPN, OPN and LRN, and
Copyright © 2009 American Urological Association Education and Research, Inc.®
36
relatively similar to RFA and ORN rates. This lower rate may reflect, in part, the definition used
for local recurrence as any disease remaining in the treated kidney after the first ablation. Local
RFS cryoablation rates were significantly lower than any other intervention except for RFA.
Metastatic RFS and CSS also were lower for cryoablation than for LPN; this difference may be
related to older patient age or other selection biases. Metastases are rare in this population, but a
few patients with small localized tumors went on to develop metastasis. This seemed to occur
primarily in those with untreated residual disease, substantiating an ongoing concern about this
type of clinical event.
Renal cryoablation may be a treatment option for the patient at high surgical risk who is
not a candidate for observation or who wants proactive treatment, and who accepts with full
understanding the need for lifelong radiographic surveillance and repeat biopsy after treatment.
This treatment option needs to be considered in light of the reduced RFS rates compared to
surgical excision. Biopsies (multiple cores in addition to FNA) are strongly encouraged prior to
therapy and also after therapy when recurrence or incomplete ablation is suspected (at the very
least) or as a routine in all cases.148 Recent data suggest that surgical salvage of cryoablation
failures can be difficult due to fibrotic reaction within the perinephric space and can be
associated with significant complications. 149
Radiofrequency Ablation
Radiofrequency ablation is one of the most recently developed treatment modalities for localized
renal tumors. Reflecting this, the RFA literature reviewed by the panel reported a mean followup of only 22.9 months. Nevertheless, published series emerging since 2002 have accumulated
more than 700 patients treated with RFA so far. The majority of RFAs are performed
percutaneously under CT-scan guidance with only a few centers using a laparoscopic approach.
Patients treated with RFA and cryoablation share similar demographics and selection criteria,
mainly for high surgical risk patients and renal tumor size of < 3 cm. The population treated with
ablation is older (mean, 68.5 years) and includes more solitary kidneys than any other treatment
modality. Moreover, RFA is now commonly utilized for salvage treatment of patients with
hereditary RCC because it can be performed percutaneously. To date, there are no randomized
studies to compare the laparoscopic and percutaneous approaches or to compare RFA and
cryoablation. All published series are retrospective observational studies.
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Radiofrequency ablation results in fewer conversions than other procedures with the
exception of OPN; however, patients may require reintervention more frequently than with other
treatment options. Complications associated with RFA are similar to those reported with other
treatment modalities. A large proportion of tumor pathology in the RFA group was
undetermined, most likely due to the common use of FNA rather than tissue core biopsy prior to
ablation.
Efficacy outcomes for RFA are 85.2% total and 87% local RFS, but this must be
interpreted within the context of a variety of confounding factors. Although CSS and metastatic
RFS after RFA did show favorable initial results, follow-up was too short in most reported series
to support definitive conclusions and comparisons. In accordance with the recommendations of
the Working Group on Image-Guided Tumor Ablation,93 RFA was defined as resulting in local
recurrence in our analysis if the original tumor was incompletely ablated at the initial ablation
session. This definition may have contributed to the high local recurrence rates associated with
RFA. As noted in the cryoablation section above, the percutaneous surgical approach produced
higher incomplete ablation rates than the laparoscopic approach. Moreover, rates of local RFS
and total RFS were significantly higher in the laparoscopic compared to the percutaneous
approach, respectively, when ablation studies were evaluated together.
In summary, RFA is a minimally invasive treatment option for localized renal masses,
especially for patients who represent a high surgical risk. Standard technique is lacking in the
current literature, and follow-up criteria are not well defined. Percutaneous renal core biopsy
with or without FNA are strongly encouraged in patients undergoing thermal ablation. The
percutaneous approach, although less invasive, has a higher incomplete ablation rate compared to
the laparoscopic approach, a phenomenon that may also be influenced by technique bias (see
Limitations of Literature). Recent data suggest that surgical salvage of RFA failures can also be
challenging and subject to significant complications. 150
Novel Treatment Modalities of the Clinical Stage 1 Renal Mass
Overview
The literature reflects the evolution of novel treatment modalities which include HIFU,
radiosurgery, MWT, LITT, PCU, as well as other new technologies. Clinical outcomes are
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limited to a small number of patients and short-term follow-up, and these modalities are best
considered developmental.
High intensity focused ultrasound
Although attractive as a noninvasive therapy of malignancies, transcutaneous HIFU has
limitations. Vallancien et al. reported the first feasibility study of HIFU involving eight patients
with renal tumors.156 They noted evidence of ablation in the treated areas after the specimens
were excised, but encountered skin burns in 10% of patients. Others have attempted HIFU for
palliative treatment with mixed results.157, 158 All studies have shown incomplete eradication of
tumor, i.e., viable tumor on excision or on follow-up imaging.159, 160 Since HIFU is ultrasound
based, artifacts (acoustic shadowing, reverberation and refraction) may affect its utility.
Additional disadvantages include the inability to monitor treatment progression in real time,
limited focal zone depth, risk of injury to or obstruction by air-filled viscera (colon) and
difficulty in synchronizing targeting with respiratory movements. Extracorporeal HIFU ablation
faces substantial technical challenges. Long treatment times (5.4 hours; range 1.5 to 9 hours),
small ablation zones (less than 10 mm) and side effects (treatment site discomfort/fevers, skin
burns) hamper its utility. HIFU technology is still being modified, the number of patients treated
and reported remains small (less than 100 treated), and it does not produce complete tumor
ablation reproducibly, therefore, there is insufficient evidence available to support HIFU beyond
experimental use at this point.
Radiosurgery (“Cyberknife”)
The literature review identified only one human Phase 1 study of radiosurgery involving three
patients who were treated with a radiation dose of 4 Gy/fraction x 4 fractions, followed eight
weeks later by RN or PN.161 No adverse events or toxicities were noted, with a mean follow-up of
12 months. Results showed one patient with necrotic tumor while the other two had pathologic
evidence of viable cancer cells. These results were certainly encouraging considering that in
animal models, ablation was not noted until a target of 40 Gy was obtained. Other preclinical data
found that 16 porcine kidneys with sequential histological evaluation demonstrated complete
fibrosis at the eight week mark. 162
In a retrospective study,163 the safety and local efficacy of radiosurgery in metastatic or
inoperable primary RCC was evaluated. Thirty patients with metastatic RCC or inoperable
primary RCC received high-dose fraction stereotactic radiation; 82 lesions were treated with
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varied dose/fractionation schedules (8 Gy x 4, 10 Gy x 4, 15 Gy x 2 or 15 Gy x 3) according to
target location and size. Local control, defined as radiologically stable disease or
partial/complete response, was obtained in 98% of treated lesions, although 19% of lesions had a
follow-up time of less than six months. A complete response was obtained in 21% of treated
lesions, with stable disease/partial response in 58% at a median 52 months (range 11 to 66) for
living patients and 18 months (range 4 to 57) for deceased patients. Side effects were low grade
and easily manageable in 90% of cases, and OS was 32 months.
In conclusion, radiosurgery in renal surgery is an experimental modality, and human trials
in patients with localized disease are just beginning. It is extracorporeal; multiple treatment
sessions are required; and it appears to be safe, with no acute toxicities reported. It is minimally
invasive but still requires a biopsy and placement of fiducial markers. The status of radiosurgery
for localized renal tumors remains experimental at this time.
Other modalities
Other energy ablative technologies such as MWT, LITT, and PCU are still in the developmental
stage.
Microwave thermotherapy. In MWT, energy is delivered through an antenna placed directly into
the lesion, generating an electromagnetic field that causes rapid ion oscillation and produces
frictional heat. MWT is similar in principle to RFA, but can generate heat 100 times faster and
may be less susceptible to heat sinks. In one in vivo rabbit model of RCC, MWT did not appear to
be effective. Carcinomatosis occurred most frequently after microwave therapy using this model.
164
Microwave ablation followed by nephrectomy has been evaluated in a single Phase 1 study in
which no skip areas were noted in the ablated zones. 165
Laser Interstitial Thermal Therapy. LITT delivers energy through the placement of a specialized
laser fiber directly into the lesion. Laser light is converted into heat > 55°C and causes tissue
necrosis. In one study by Deane and colleagues,166 LITT showed a reduction in enhancement
volume (percent of approximate tumor volume that is 'viable') from 73.7% to 29.5%, but the
clinical implications of this finding are not clear. 166
Pulsed Cavitational Ultrasound. The transcutaneous, nonthermal, mechanical effects of US waves
are thought to have an advantage over temperature-based ablation systems for which precise
targeting of the lesion is more dependent on local factors. PCU utilizes cavitational effects to
damage target tissues by varying acoustic parameters. No thermal collateral damage to surrounding
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tissue and skin or collecting system has been noted. A potential theoretical complication is the
dissemination of malignant cells from the shear forces generated by the procedure. Data about
PCU are limited to two preclinical studies involving an in vitro porcine model167 and an in vivo
study in rabbits. 168
Limitations of the Literature
The Panel identified major limitations of the available literature. Suboptimal study design was
the predominant limitation across all studies, with a near absence of prospective or randomized
data. Selection bias (e.g., differences in patient ages and tumor sizes) is evident across all
interventions. Widely divergent duration of follow-up for the various modalities is another major
confounding factor. Additional weaknesses include lack of standardized reporting and substantial
variability in applied techniques, definitions of success, reporting of complications and other
related outcomes. Complications were reported in variable ways or sometimes were completely
omitted. Renal function was typically reported as pre and posttreatment serum creatinine values
as opposed to eGFR or creatinine clearance as determined by a 24-hour urinary collection. Many
of the AS and ablative studies lacked pathologic data as did some surgical studies.
The nomenclature for renal mass anatomy is also highly variable among studies, limiting
the ability to compare outcomes among different institutions. Reporting and publication biases
probably also exist; studies with higher complication rates, recurrences or other inferior
outcomes tend not to be published. For example, few data regarding the morbidity of RN were
published until the advent of LRN. Limited clinical follow-up is available for many of the
studies, particularly for ablative therapies, LPN and AS, making their oncologic outcomes
subject to follow-up bias.
Finally, there is the problem of technique bias. This issue is most obvious for the
literature on ablative therapies, but is applicable to other interventions which lack
standardization. For example, percutaneous therapy is easily repeated whereas laparoscopic
therapy is not. This undoubtedly influences the behavior of the treating physician at the time of
therapy. In particular, because the percutaneous technique allows relatively straightforward
retreatment, the physician may use a more conservative approach. In contrast, because
retreatment is more difficult laparoscopically, the physician may be more aggressive and
thorough on the first procedure.
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As emphasized, there are multiple confounding factors that affect interpretation of the
meta-analytic results. The findings reported here must be appreciated within the context of these
limitations. In particular, the meta-analysis cannot account for or correct biases inherent in weak
study designs and lack of randomization. Future research endeavors must minimize the
limitations outlined above with prospective, randomized designs, homogeneous and transparent
selection criteria, standardized technical application and methodical reporting of outcomes.
Panel Consensus Regarding Treatment Modalities
Despite the above described limitations of the literature, the Panel was able to reach the
following consensus about the various treatment modalities:
● Nephron-sparing
surgery should be considered in all patients with a clinical T1 renal mass as an
overriding principle, presuming adequate oncologic control can be achieved, based on
compelling data demonstrating an increased risk of CKD associated with RN and a direct
correlation between CKD and morbid cardiovascular events and mortality on a longitudinal
basis. RN is still a viable option when necessary based on tumor size, location or radiographic
appearance if the surgeon judges that NSS is not feasible or advisable. A laparoscopic approach
to RN is now an established standard and should be considered if this procedure is required as it
is associated with a more rapid recovery.
● Active
surveillance is a reasonable option for the management of localized renal masses that
should be discussed with all patients and should be a primary consideration for patients with
decreased life expectancy or extensive comorbidities that would make them high risk for
intervention. For patients who are candidates for intervention, counseling about AS should
include a balanced discussion of the small but real risk of cancer progression, lack of curative
salvage therapies if metastases develop, possible loss of window of opportunity for NSS and
substantial limitations of the current AS literature. Larger tumors (> 3 to 4 cm) and those with
aggressive appearance, such as infiltrative growth pattern, may be associated with increased risk
and should be managed in a proactive manner, if possible.
● Thermal
ablation (cryoablation or RFA), either percutaneous or laparoscopic, is an available
treatment option for the patient at high surgical risk who wants active treatment and accepts the
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need for long-term radiographic surveillance after treatment.169 Tumor biopsy (core biopsy is
recommended for better diagnostic accuracy) should always be performed prior to treatment to
define histology and should also be considered after treatment, particularly if there is any
suspicion of recurrence. Counseling about thermal ablation should include a balanced discussion
of the increased risk of local recurrence when compared to surgical excision, potential need for
reintervention, lack of well-proven radiographic parameters for success, potential for difficult
surgical salvage if tumor progression is found and the substantial limitations of the current
thermal ablation literature. Larger tumors (> 3.5 cm) and those with irregular shape or
infiltrative appearance may be associated with increased risk of recurrence when managed with
thermal ablation.
● Surgical
excision by PN is a reference standard for the management of clinical T1 renal masses,
whether for imperative or elective indications, given the importance of preservation of renal
parenchyma and avoidance of CKD. This treatment modality is greatly underutilized. PN has
well established longitudinal oncologic outcomes data comparable to RN. Adequate expertise
and careful patient selection are important. A laparoscopic approach can provide more rapid
convalescence, but has been associated with an increased risk of major urologic complications
and longer warm ischemia times when compared to traditional OPN. In general, OPN is
preferred for complex cases such as tumor in the renal hilum, tumor in a solitary kidney or
multiple tumors.
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Treatment Algorithm
Patient with clinical T1 renal mass
Standards are presented in green boxes; Recommendations are
presented in yellow boxes; Options are presented in red boxes.
Key: AS, active surveillance; CKD, chronic kidney disease; CT, computed
tomography; FNA, fine needle aspiration; MRI, magnetic resonance
imaging; PN, partial nephrectomy; RFA, radiofrequency ablation;
RN, radical nephrectomy; TA, thermal ablation
EVALUATION
• High‐quality cross‐sectional imaging study (CT or MRI) with and without contrast (in the presence of adequate renal function) to assess contrast enhancement, exclude angiomyolipoma, assess for locally invasive features, define the
relevant anatomy and evaluate the status of the contralateral kidney
• Percutaneous renal mass core biopsy with or without FNA for patients in whom it might impact management, particularly patients with clinical or radiographic findings suggestive of lymphoma, abscess or metastasis
COUNSELING
• Review the current understanding of the natural history of clinical T1 renal masses, the relative risks of benign vs. malignant pathology and the potential role of AS
• Review the available treatment options and the attendant benefits and risks, including oncologic considerations, renal functional considerations and potential morbidities
• Discuss the potential advantages of a nephron‐sparing treatment approach in the imperative and elective settings, including the avoidance of dialysis and reduced risk of CKD with its attendant morbidity and mortality
INDEX PATIENT 1:
Healthy; Clinical T1a
STANDARD ‐ PN: Complete surgical excision
INDEX PATIENT 2:
Major comorbidities
Increased surgical risk
Clinical T1a
by PN is a standard of care and should be
strongly considered.
STANDARD ‐ RN: Should be discussed as
alternate standard of care if PN is not technically
feasible as determined by the urologic surgeon.
OPTION ‐ TA: Cryoablation or RFA should be
discussed as less‐invasive treatment options, but
local tumor recurrence is more likely, measures
of success are not well defined, and surgical
salvage may be difficult.
OPTION ‐ AS: AS with delayed intervention
should be discussed as option for patients
wishing to avoid treatment and willing to assume
oncologic risk.
STANDARD ‐ PN:
STANDARD ‐ RN:
Complete surgical
excision by PN should
be discussed as a
standard of care with
increased surgical risk in
this patient.
Should be discussed as
standard of care with
increased risk of CKD
and surgical
complications in this
patient.
RECOMMENDATION
‐ TA: Cryoablation or
RFA should be discussed as
less‐invasive treatment
options which may be
advantageous in this high
surgical risk patient,
acknowledging the
increased risk of local
tumor recurrence
compared to surgical
excision.
INDEX PATIENT 3:
Healthy; Clinical T1b
STANDARD ‐ RN: Should be discussed as
standard of care for patients with a normal
contralateral kidney.
STANDARD ‐ PN: Complete surgical excision
by PN should be discussed as an alternative
standard of care, particularly when there is a
need to preserve renal function.
as an acceptable approach
which can delay or avoid
the need for intervention
in this high‐risk patient.
STANDARD ‐ RN: Should be discussed as standard
of care for patients with a normal contralateral kidney,
although it can be associated with surgical morbidity
and an increased risk of CKD in this patient.
RECOMMENDATION ‐ PN: Complete surgical
excision by PN should be discussed as a recommended
modality when there is a need to preserve renal
function, although it can be associated with increased
urologic morbidity in this patient.
OPTION ‐ TA:
RECOMMENDATION
‐ AS: Should be offered
INDEX PATIENT 4:
Major comorbidities; Increased
surgical risk; Clinical T1b
Cryoablation or RFA
can/may be discussed as
a treatment option
which is less effective
due to an increased risk
of local recurrence. TA
may represent
suboptimal management
for this healthy patient.
OPTION ‐ AS: AS with
delayed intervention
can/may be discussed as an
option in patients who
want to avoid surgery and
are willing to accept an
increased risk of tumor
progression compared to
RN or PN. AS may
represent suboptimal
management for this
healthy patient.
Copyright © 2009 American Urological Association Education and Research, Inc.®
RECOMMENDATION ‐ AS: AS should be
discussed with patients who want to avoid surgery or
who are considered high risk for surgical therapy.
OPTION ‐ TA: Cryoablation or RFA can/may be
discussed as a treatment option which is less effective
due to an increased risk of local recurrence.
44
Treatment Guideline Statements
The Panel developed the following guideline statements from a careful assessment of the metaanalysis, the use of expert opinion when data were lacking or incomplete, and panel consensus.
These statements apply to the treatment of patients with clinical T1 renal masses. Inherent in
these guideline statements is the importance of individualizing patient diagnostic evaluation and
therapy. In an attempt to recognize commonly encountered clinical variations, each guideline
statement addresses a specific patient.
For All Index Patients
Standard: Physicians should obtain a high-quality cross-sectional imaging study
(CT or MRI) with and without contrast (in the presence of adequate renal function)
to assess contrast enhancement, exclude angiomyolipoma, assess for locally invasive
features, define the relevant anatomy and evaluate the status of the contralateral
kidney and its vasculature.
[Based on Panel consensus.]
Standard: Physicians should discuss with the patient the current understanding of
the natural history of clinical stage 1 renal masses, the relative risks of benign vs.
malignant pathology and the potential role of active surveillance.
[Based on Panel consensus.]
Overall, about 20% of clinical stage T1 enhancing renal masses are benign. In addition, a
potentially aggressive variant is only observed in 20% to 25% of all RCCs in this size range.
Tumor size and gender are important determinants of the risk of benign vs. malignant pathology.
Standard: Percutaneous renal mass core biopsy with or without fine needle
aspiration should be performed in all patients undergoing thermal ablation and in
patients for whom it might impact management, particularly patients with clinical
or radiographic findings suggestive of lymphoma, abscess or metastasis.
[Based on Panel consensus.]
Copyright © 2009 American Urological Association Education and Research, Inc.®
45
Standard: Physicians should review with the patient the available treatment options
and the attendant benefits and risks, including oncologic considerations, renal
functional considerations and potential morbidities.
[Based on Panel consensus.]
Standard: Physicians should counsel the patient about the potential advantages of a
nephron-sparing treatment approach in the imperative and elective settings. These
advantages include avoidance of the need for dialysis and a reduced risk of
developing chronic kidney disease with the attendant morbidity and mortality.
[Based on Panel consensus.]
Radical nephrectomy can lead to an increased risk of CKD, which is associated with increased
risk of morbid cardiac events and death according to population-based studies. Management
should focus on optimizing renal function rather than merely precluding the need for dialysis.
For Index Patient No. 1: A healthy patient with a clinical T1a (≤ 4.0 cm) enhancing renal mass
Standard: Complete surgical excision by partial nephrectomy is a standard of care
and should be strongly considered.
[Based on review of the data and Panel consensus.]
Both open and laparoscopic approaches to PN can be considered, dependent on tumor size,
location and the surgeon’s expertise. LPN can provide more rapid recovery, although this
approach has been associated with increased warm ischemic times and an increased risk of
urological complications including postoperative hemorrhage and urinary fistula. Most patients
with a solitary kidney, preexisting renal dysfunction, hilar tumor, multiple tumors or
predominantly cystic tumor are best managed with on open surgical technique. With improved
laparoscopic instrumentation and greater dissemination of expertise, improved outcomes and
more widespread application of LPN is anticipated in the future.
Standard: Radical nephrectomy should be discussed as an alternate standard of
care which can be performed if a partial nephrectomy is not technically feasible as
determined by the urologic surgeon.
[Based on review of the data and Panel consensus.]
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46
Radical nephrectomy can lead to an increased risk of CKD, which is associated with increased
risks of morbid cardiac events and death according to population-based studies. Management
should focus on optimizing renal function rather than merely precluding the need for dialysis.
PN is a greatly underutilized procedure that is often feasible even for central or hilar tumors,
given adequate surgeon expertise. Nevertheless, occasional localized renal tumors in this size
range are not amenable to PN, and RN should be considered an alternative standard of care. A
laparoscopic approach can provide reduced blood loss and more rapid recovery and should be
considered, presuming adequate surgeon expertise.
Option: Thermal ablation, such as cryoablation or radiofrequency ablation, should
be discussed as a less-invasive treatment option, but local tumor recurrence is more
likely than with surgical excision, measures of success are not well defined, and
surgical salvage may be difficult.
[Based on review of the data and Panel consensus.]
Thermal ablation is associated with a substantially increased risk of local recurrence, the
majority of which can be managed with a second attempt at thermal ablation. However, some
local recurrences are not amenable to this approach and require surgical salvage. In this setting
laparoscopic surgery and PN are often not possible due to extensive reactive fibrosis within the
perinephric space. In addition, measures of success for thermal ablation have come into question
with some studies demonstrating apparently viable cancer cells despite loss of contrast
enhancement. It is possible that outcomes associated with ablative modalities will improve with
further advances in technology and application; however, judicious patient selection and
counseling remain of paramount importance for these less-invasive technologies.
Option: Active surveillance with delayed intervention should be discussed as an
option for patients wishing to avoid treatment and willing to assume oncologic risk.
[Based on review of the data and Panel consensus.]
Approximately 80% of all clinical T1a renal masses are malignant, and of these, about 20% to
30% demonstrate potentially aggressive histologic features. The risk of tumor progression that
could preclude NSS or lead to unsalvageable systemic metastases is not well defined in the
current literature. Enhanced renal mass biopsy (incorporating molecular analyses) holds promise
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47
for assessing aggressive potential; however, further research will be required to define the utility
and limitations of this approach. Healthy patients considering AS must be willing to assume a
calculated risk of tumor progression.
For Index Patient No. 2: A patient with major comorbidities/increased surgical risk and a
clinical T1a (≤ 4.0 cm) enhancing renal mass
Standard: Complete surgical excision by partial nephrectomy should be discussed as
a standard of care with increased surgical risk in this patient.
[Based on review of the data and Panel consensus.]
Partial nephrectomy is associated with an increased risk of perioperative morbidity when
compared to RN, a relevant consideration for this patient with increased risk for surgical
intervention. Nevertheless, PN or other nephron-sparing approaches should be considered
whenever preservation of renal function is a primary issue. Both open and laparoscopic
approaches to PN can be considered, dependent on tumor size, location and the surgeon’s
expertise.
Standard: Radical nephrectomy should be discussed as a standard of care with an
increased risk of surgical complications and chronic kidney disease in this patient.
[Based on review of the data and Panel consensus.]
Radical nephrectomy is another standard of care in this high-risk patient population with
substantial comorbidities. However, RN can lead to an increased incidence of CKD with its
attendant risks, and some patients may have relative or imperative indications to avoid RN. A
laparoscopic approach to RN can provide reduced blood loss and more rapid recovery and should
be considered, presuming adequate surgeon expertise.
Recommendation: Thermal ablation should be discussed as a less-invasive treatment
option which may be advantageous in this high surgical risk patient, acknowledging
the increased risk of local tumor recurrence compared to surgical excision.
[Based on review of the data and Panel consensus.]
Copyright © 2009 American Urological Association Education and Research, Inc.®
48
Thermal ablation is a reasonable option for this high surgical risk patient that allows for
proactive treatment without the risks associated with major surgical intervention. However, an
increased risk of local recurrence should be discussed during counseling
Recommendation: Active surveillance should be offered as an acceptable approach
which can delay or avoid the need for intervention in this high-risk patient.
[Based on review of the data and Panel consensus.]
Active surveillance has been associated with relatively low rates of tumor growth and metastatic
progression during short-term (2 to 3 year) follow-up. Overall, about 20% of clinical T1a renal
masses are benign, and a potentially aggressive variant is only observed in 20%-30% of all RCCs
in this size range. AS should be a primary consideration in patients with decreased life
expectancy or those who are particularly high risk for proactive intervention.
For Index Patient No. 3: A healthy patient with a clinical T1b (> 4.0 cm to < 7.0 cm),
enhancing renal mass
Standard: Radical nephrectomy should be discussed as a standard of care for
patients with a normal contralateral kidney.
[Based on review of data and Panel consensus.]
Radical nephrectomy is associated with less perioperative morbidity than PN and remains a
standard of care for clinical T1b tumors, presuming a normal contralateral kidney. A
laparoscopic approach can provide reduced blood loss and more rapid recovery and should be
considered, presuming adequate surgeon expertise.
Standard: Complete surgical excision by partial nephrectomy should be discussed as
an alternative standard of care, particularly when there is a need to preserve renal
function.
[Based on review of data and panel consensus.]
Even in patients with a normal contralateral kidney, RN can lead to an increased risk of CKD,
which is associated with increased risks of morbid cardiac events and death based on populationbased studies. PN is an alternative standard of care for this patient, presuming favorable tumor
location and adequate surgeon expertise.
Copyright © 2009 American Urological Association Education and Research, Inc.®
49
Option: Thermal ablation can/may be discussed as a treatment option which is less
effective due to an increased risk of local recurrence.
[Based on Panel consensus.]
Tumors that are 4 cm to 7 cm in diameter are difficult to adequately treat with thermal ablation,
and the risks of local recurrence and complications are high in this patient population. Thermal
ablation may represent suboptimal management for this healthy patient, and this should be
emphasized during patient counseling.
Option: Active surveillance with delayed intervention can/may be discussed as an
option in patients who want to avoid surgery and are willing to accept an increased
risk of tumor progression compared to partial nephrectomy or radical
nephrectomy.
[Based on review of the data and Panel consensus.]
The risk of malignancy and potentially aggressive histologic features is substantially increased
for clinical T1b tumors. Hence, the risk of tumor progression that could preclude nephronsparing approaches or lead to unsalvageable systemic metastases is also increased. AS may
represent suboptimal management in this scenario and should only be considered in patients that
are willing to assume a high risk of adverse oncologic outcomes related to delayed intervention.
For Index Patient No. 4: A patient with major comorbidities/increased surgical risk and a
clinical T1b (> 4.0 cm to < 7.0 cm), enhancing renal mass
Standard: Radical nephrectomy should be discussed as a standard of care for
patients with a normal contralateral kidney, although it can be associated with
surgical morbidity and an increased risk of chronic kidney disease.
[Based on review of the data and Panel consensus.]
Radical nephrectomy is associated with less perioperative morbidity than PN, a relevant
consideration for this patient with increased risk for surgical intervention. RN thus remains a
standard of care, presuming a normal contralateral kidney. However, RN can lead to an
increased risk of CKD with its attendant risks, and some patients may have relative or imperative
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50
indications to avoid RN. A laparoscopic approach to RN can provide a more rapid recovery and
should be considered, presuming adequate surgeon expertise.
Recommendation: Complete surgical excision by partial nephrectomy should be
discussed as a recommended modality when there is a need to preserve renal
function, although it can be associated with increased urologic morbidity. [Based on
review of the data and Panel consensus.]
Partial nephrectomy can be associated with an increased risk of urologic morbidity, an important
consideration in this high-risk patient. Nevertheless, PN or other nephron-sparing approaches
should be considered whenever preservation of renal function is a primary issue.
Recommendation: Active surveillance should be discussed with patients who want to
avoid surgery or who are considered high risk for surgical therapy.
[Based on review of the data and Panel consensus.]
The risk of tumor progression that could preclude nephron-sparing approaches or lead to
unsalvageable systemic metastases may be increased in this patient. Nevertheless, AS should be
a primary consideration in patients with limited life expectancy or those who are particularly
high risk for proactive intervention.
Option: Thermal ablation can/may be discussed as treatment option which is less
effective due to an increased risk of local recurrence.
[Based on Panel consensus.]
Clinical T1b tumors are difficult to adequately treat with thermal ablation, and the risks of local
recurrence and complications are high in this patient population.
New Research/Future Directions
Application of evidence-based medicine: In general, future studies attempting to compare
different treatment modalities and their outcomes should be prospectively designed, have
uniform selection criteria, standardized treatment protocols and consistent follow-up strategies
using tissue-based markers of success and ideally be performed in randomized fashion.170
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51
Markers of clinical success that could be used to supplement radiographic findings are needed.
As newer ablative and noninvasive modalities become available, it will become increasingly
unacceptable to await the long-term results of radiographic evaluations. QOL outcomes should
be incorporated in the evaluation of treatments of localized renal masses.171
Oncological outcomes/translational research: The classification of RCC into separate types with
differing morphology, genotype and probable clinical outcome has led to a re-evaluation of
prognostic parameters. Further refinements of staging and prognostication await the discovery
of new molecular markers for the various RCC morphotypes.172 The indications for AS should
be defined for each patient, and their age and comorbidity index should be reported. Additional
studies of AS with long-term follow-up are needed to define the true risks associated with this
approach. Research into the role of renal mass biopsy enhanced by molecular profiling, with
correlation with pathologic findings and long-term outcomes, should be a top priority in this
field.173
Further efforts to elucidate the long-term metabolic side effects of decreased functioning
nephron mass as a consequence of RN for RCC may not only enhance the understanding of the
plieotrophic effects of progressive renal disease in the setting of RN, but may provide a further
rationale for the adoption of nephron-sparing strategies for treatment of RCC. Such studies will
expand our understanding of risk factors and consequences of precipitous declines in functional
nephron mass.133 In addition, novel forms of ischemic protection (pharmacologic, immunologic)
should be further investigated as a way to minimize renal damage and thus potentially enhance
the feasibility and safety of NSS.174
Copyright © 2009 American Urological Association Education and Research, Inc.®
52
Surgical technology: Use of the DaVinci Robot for robotic-assisted LPN is being currently
evaluated at centers of excellence,158, 175 with the emergence of the robot as a platform for imageguided therapies as well. Furthermore, promising new developments such as single-port access
surgery and natural-orifice translumenal endoscopic surgery might add to the surgical
armamentarium for minimally invasive renal surgery.176, 177
Targeted molecular therapy: Improved understanding of the biology of RCC has resulted in the
development of novel targeted therapeutic agents that have altered the natural history of this
disease. In particular, the hypoxia-inducible factor/vascular endothelial growth factor pathway
and the mammalian target of rapamycin signal transduction pathways have been exploited.
Sunitinib malate, sorafenib tosylate, bevacizumab /interferon alfa and temsirolimus have
improved clinical outcomes in randomized trials of patients with metastatic RCC by inhibiting
tumerigenic pathways, ushering in a new age for systemic treatment.178 Recently reported and
ongoing clinical trials will help further define the role of these agents as therapy for RCC.
Currently, these and other emerging agents are being investigated as adjunctive agents for
higher-risk localized or locally-advanced disease, and these agents could potentially facilitate
nephron-sparing approaches by downsizing localized RCC. However, there currently is no role
for targeted molecular therapy in the treatment of localized disease outside of a clinical trial.
Copyright © 2009 American Urological Association Education and Research, Inc.®
53
Table 14. Classification of Complications Listed in the Literature*
Urologic Complications
Major
Minor
Nonurologic Complications
Major
Chronic renal failure requiring
dialysis
Bladder outlet obstruction
Abscess
Intra‐abdominal complications
Dialysis ‐ temporary
Hematuria
Arrythmia/dysrrhythmia
Intraoperative transfusion
Minor
Abnormal labs ‐ transient
Atrial fibrillation
Ischemic colitis
Hemorrhage‐minor
Hydrocalicosis
Perinephric hematoma ‐ no
transfusion
Perirenal fluid
Renal thermal injury
Atrial flutter
Bowel abrasion
Liver infarct
Myocardial infarction
Anterior abdominal wall paresthesia ‐
transient
Anterior abdominal wall weakness ‐
persistent
Atelectasis
Bowel serosal tear
Hydronephrosis
UTI
Bowel obstruction
Needle or electrode track seeding
Dermatitis
Cardiovascular complications
Chronic respiratory failure
Coagulopathy
Colitis
Neurological complication
Neuropathy
Nonrenal vascular injury
Pancreatic injury
Elevated myoglobin ‐ transient
Esophagitis
Fatigue
Genitourinary complication
Colonephric fistula
Pancreatitis
Gout
Colonic ischemia
Colonic perforation
Death
Duodenal perforation
Duodenal ulcer
DVT
Elevated creatinine ‐ persistent
Elevated myoglobin requiring
treatment
Embolus
Fistula
GI complication
GI hemorrhage
Gluteal compartment syndrome
Gluteal fasciotomy
Heart failure
Hernia
Infection
Ileus
Injury to diaphragm
Injury to nonrenal intra‐abdominal
structures
Persistent pain
Pneumonia
Pneumothorax
Pseudoaneurysm
Psoas muscle laceration
Pulmonary complications
Pulmonary embolism
Hypertension ‐ transient
Narcotic or sedative reaction
Nonspecific EKG changes
Pain during procedure
Pleural effusion
Rash associated with contrast
Subcutaneous emphysema
Rehospitalization
Transient hyperthermia
Retained vessel loop
Retroperitoneal fibrosis
Retroperitoneal hematoma
Splenic hematoma
Splenic injury
Stroke
Thermal injury ‐ other
Thrombus
Transfusion
Trochar site infection
Wound complications
Transient pain
Hemorrhage‐major
Interstitial nephritis
Kidney infarct
Kidney loss
Parietal abscess
Perinephric hematoma ‐
requiring transfusion
Renal fracture
Renal hemorrhage
Renal insufficiency
Renal ‐ other
Renal vascular injury
Ureter injury
Ureteral obstruction
Ureteropelvic junction injury
Urine leak
Urinoma
*The complications presented in this table were drawn directly from the articles included in the meta-analysis; the terms listed are the terms chosen by the authors to describe particular
adverse events. These terms were sorted by the Panel into the categories of major and minor urological and nonurological complications. The variety of terms presented here highlights the
lack of standardized complications reporting in this literature and demonstrates the difficulty inherent in synthesizing evidence across studies that used different terminologies.
Copyright © 2009 American Urological Association Education and Research, Inc.®
54
Conflict of Interest Disclosures
All panel members completed Conflict of Interest disclosures. Those marked with (C) indicate
that compensation was received; relationships designated by (U) indicate no compensation was
received.
Consultant or Advisor: Paul Russo, Wilex AG (C); Arie Belldegrun, Galil Medical (C), Wilex
AG (C), Bayer (C), Pfizer (C), ROEI Medical (C); Surena Matin, Johnson & Johnson Wound
Management (C); Michael Marberger, GSK (C), R. Wolf (U), GP-Pharma Barcelona (C),
MSD (C); Steven C. Campbell, Pfizer (C), Sanofi Aventis (C); Investigator: Arie Belldegrun,
Pfizer (C), Amgen (C); Steven C. Campbell, Pfizer (U), Novartis (U); Scientific Study or Trial:
Raymond J. Leveillee, Pluromed (U), LMA Urology-Suisse (U), Boston Scientific (U); Michael
Marberger, MDS (U), GSK (U), Focus Surgery (U); Meeting Participant or Lecturer: Jihad
Kaouk, Endocare (C); Steven C. Campbell, Sanofi Aventis (C); Robert G. Uzzo, Pfizer (C),
Bayer (C); Raymond J. Leveillee, ACMI (C), Applied Medical (C), ValleyLab (C), Ethicon (U);
Michael Marberger, GSK (C), MSD (C); Board Member, Officer, Trustee: Arie Belldegrun,
Agensys (C), Hana Biosciences (C), Cougar Biotechnology (C); Other: Jihad Kaouk, Intuitive
Surgical (C); Steven C. Campbell, Aventis Pharmaceuticals (C); Raymond J. Leveillee, ACMI
(U), Ethicon (U), Intuitive Surgical (C); Linda Whetter, Zola Associates (C).
Copyright © 2009 American Urological Association Education and Research, Inc.®
55
Acknowledgements and Disclaimers: Guideline for Management of the
Clinical Stage 1 Renal Mass: Diagnosis and Treatment Recommendations
The supporting systematic literature review and data analysis and the drafting of this document
were conducted by the Renal Mass Guideline Panel created in 2006 by the American Urological
Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of
the AUA selected the Panel chair who in turn appointed the Panel facilitator and members,
urologists with specific expertise in this disease. The mission of the Panel was to develop either
analysis- or consensus-based recommendations, depending on the type of evidence available, to
support optimal clinical practices in the management of the clinical stage 1 renal mass. This
document was submitted to 69 urologists and other health care professionals for peer review.
After revision of the document based upon the peer review comments, the guideline was
submitted to and approved by the PGC and the Board of Directors of the AUA. Funding of the
Panel and of the PGC was provided by the AUA, although Panel members received no
remuneration for their work. Each member of the PGC and of the Panel furnished a current
conflict of interest disclosure to the AUA.
The final report is intended to provide medical practitioners with a current understanding
of the principles and strategies for the management of the clinical stage 1 renal mass. The report
is based on an extensive review of available professional literature, as well as on clinical
experience and expert opinion.
This document provides guidance only, and does not establish a fixed set of rules or
define the legal standard of care. As medical knowledge expands and technology advances, the
guideline will change. Today the guideline statements represent not absolute mandates but
provisional proposals or recommendations for treatment under the specific conditions described.
For all these reasons, the guideline does not preempt physician judgment in individual cases.
Also, treating physicians must take into account variations in resources, and in patient tolerances,
needs and preferences. Conformance with the guideline reflected in this document cannot
guarantee a successful outcome.
Copyright © 2009 American Urological Association Education and Research, Inc.®
56
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Appendix 1: Small Renal Mass Guideline Panel Members and Consultants
(2008)
Members:
Andrew C. Novick, M.D., Chair
Cleveland Clinic Foundation
Cleveland, Ohio
Steven Charles Campbell, M.D., Ph.D., Co-Chair
Cleveland Clinic Foundation
Cleveland, Ohio
Raymond J. Leveillee, M.D., FRCS-G
PGC Representative
University of Miami School of Medicine
Miami, Florida
Arie Belldegrun, M.D.
UCLA School of Medicine
Los Angeles, California
Michael L. Blute, M.D.
Mayo Clinic
Rochester, Minnesota
George Kuoche Chow, M.D.
Mayo Clinic
Rochester, Minnesota
Ithaar H. Derweesh, M.D.
University of Tennessee
Memphis, Tennessee
Jihad H. Kaouk, M.D.
Cleveland Clinic Foundation
Cleveland, Ohio
Surena Fazeli Matin, M.D.
MD Anderson Cancer Center
Houston, Texas
Paul Russo, M.D.
Memorial Sloan-Kettering Cancer Center
New York, New York
Robert G. Uzzo, M.D.
Fox Chase Cancer Center
Philadelphia, Pennsylvania
Consultants:
Martha M. Faraday, Ph.D.
Linda E. Whetter, Ph.D., D.V.M.
Michael Marberger, M.D.
Copyright © 2009 American Urological Association Education and Research, Inc.®
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Abbreviations and Acronyms
AS
=
active surveillance
AUA
=
American Urological Association
CAIX
=
carbonic anhydrase IX
CKD
=
chronic kidney disease
cm
=
centimeter
COI
=
conflict of interest
cryo
=
cryoablation
CSS
=
cancer-specific survival
CT
=
computed tomography
dl
=
deciliter
e.g.
=
for example
eGFR
=
estimated glomerular filtration rate
et al.
=
and others
etc.
=
et cetera; and the rest
FNA
=
fine needle aspiration
GFR
=
glomerular filtration rate
Gy
=
Gray
HIFU
=
high intensity focused ultrasound
i.e.
=
that is
lap
=
laparoscopic
LITT
=
laser interstitial thermal therapy
LPN
=
laparoscopic partial nephrectomy
Copyright © 2009 American Urological Association Education and Research, Inc.®
73
LRN
=
laparoscopic radical nephrectomy
m2
=
meters squared
mg
=
milligrams
min
=
minute
ml
=
milliliter
mm
=
millimeter
mos
=
months
MRI
=
magnetic resonance imaging
MWT
=
microwave thermotherapy
N/A
=
not applicable
NSS
=
nephron-sparing surgery
OPN
=
open partial nephrectomy
ORN
=
open radical nephrectomy
OS
=
overall survival
p
=
p-value
PCU
=
pulsed cavitational ultrasound
PN
=
partial nephrectomy
QOL
=
quality of life
RCC
=
renal cell carcinoma
RFA
=
radiofrequency ablation
RFS
=
recurrence-free survival
RN
=
radical nephrectomy
SRM
=
sorenal mass(es)
Copyright © 2009 American Urological Association Education and Research, Inc.®
74
TNM
=
tumor, nodes, metastasis cancer stage classification system
U.S.
=
United States
US
=
ultrasound
vhl
=
von Hippel-Lindau gene
vs.
=
versus
°C
=
Celsius
Copyright © 2009 American Urological Association Education and Research, Inc.®
75
Glossary
Cancer-specific survival – the proportion of patients diagnosed with renal cell carcinoma that
did not die from renal cell carcinoma within a specified follow-up period
Conversion – any change from the planned renal surgical approach or procedure to a different
renal surgical approach or procedure
Local recurrence – any disease presence in the treated kidney or associated renal fossa at any
point after the initial procedure; for ablation studies, local recurrence would include any disease
remaining in the treated kidney at any point after the first ablation.
Local recurrence-free survival – the proportion of patients diagnosed with renal cell carcinoma
that did not experience a local recurrence within a specified follow-up period.
Metastatic recurrence – any disease presence in the body other than in the treated kidney or
associated renal fossa post-treatment
Metastatic recurrence-free survival - the proportion of patients diagnosed with renal cell
carcinoma that did not experience a metastatic recurrence within a specified follow-up period
Overall survival - the proportion of patients diagnosed with renal cell carcinoma that did not die
from any cause within a specified follow-up period
Reintervention – any unplanned procedure or operation that occurred during or after the
planned renal surgery.
Total recurrence - the sum of local recurrence events plus metastatic recurrence events
Total recurrence-free survival – the proportion of patients diagnosed with renal cell carcinoma
that did not experience a local or metastatic recurrence within a specified follow-up period
Copyright © 2009 American Urological Association Education and Research, Inc.®
76