Seminar

Renal cancer
Umberto Capitanio, Francesco Montorsi

The diagnosis and management of renal cell carcinoma have changed remarkably rapidly. Although the incidence of Published Online
renal cell carcinoma has been increasing, survival has improved substantially. As incidental diagnosis of small August 26, 2015
http://dx.doi.org/10.1016/
indolent cancers has become more frequent, active surveillance, robot-assisted nephron-sparing surgical techniques, S0140-6736(15)00046-X
and minimally invasive procedures, such as thermal ablation, have gained popularity. Despite progression in cancer
Department of Urology,
control and survival, locally advanced disease and distant metastases are still diagnosed in a notable proportion of Vita-Salute San Raffaele
patients. An integrated management strategy that includes surgical debulking and systemic treatment with well University (U Capitanio MD)
established targeted biological drugs has improved the care of patients. Nevertheless, uncertainties, controversies, and Division of Experimental
Oncology, URI, Urological
and research questions remain. Further advances are expected from translational and clinical studies. Research Institute, Renal
Cancer Unit
Introduction Pathophysiology and genetics (Prof F Montorsi FRCS),
Abdominal imaging is used for many different medical Renal cell carcinoma comprises a heterogeneous group of IRCCS San Raffaele Scientific
Institute, Milan, Italy
disorders (eg, hypertension, diabetes) and, therefore, cancers with different genetic and molecular alterations
Correspondence to:
incidental detection of renal masses is becoming underlying the many documented histological subtypes.18
Dr Umberto Capitanio,
increasingly common. A renal mass might be merely a Clear-cell, papillary (types 1 and 2), and chromophobe are Department of Urology,
simple renal cyst that requires no treatment or follow-up,1 the most common solid renal cell carcinomas within the San Raffaele Hospital,
but in a notable proportion of cases masses are benign kidney and account for 85–90% of all renal malignancies.18 Via Olgettina 60,
Milan 20132, Italy
renal lesions (eg, angiomyolipomas or oncocytomas) or Less common cancers include papillary adenoma, capitanio.umberto@hsr.it
malignant renal cell carcinomas that might require multilocular cystic clear-cell carcinoma, hybrid oncocytic
additional procedures or interventions.2 Although most chromophobe tumour, carcinoma of the collecting ducts
incidentally detected lesions are small low-grade tumours, of Bellini, renal medullary carcinoma, carcinoma
up to 17% of all renal cell carcinomas have distant associated with neuroblastoma, and mucinous tubular
metastases at the time of diagnosis.3 In this heterogeneous and spindle-cell carcinoma.18 The International Society of
clinical setting, developments in molecular biology, Urological Pathology Vancouver Consensus Statement
diagnostic techniques, surgery, and medical oncology are added five more epithelial tumour subtypes of renal cell
revolutionising the approach to this disease. carcinoma: tubulocystic, acquired cystic disease-
associated, clear-cell tubulopapillary, microphthalmia
Epidemiology family translocation, and hereditary leiomyomatosis–
In 2013, renal cell carcinoma was diagnosed in more renal cell carcinoma syndrome-associated.19
than 350 000 people worldwide, which made it the Although most renal masses are initially confined to
seventh most common site for tumours, and this cancer one organ, early haematogenic dissemination is
is associated with more than 140 000 deaths per year.4 responsible for metastatic disease at the time of
Incidence of renal cell carcinoma varies worldwide, diagnosis. The most frequent sites of distant metastases
being higher in developed countries than in developing are lungs, bone, and brain, but adrenal glands,
countries (appendix). Incidence predominates in men, contralateral kidney, and liver might be involved.20 See Online for appendix
with the male-to-female ratio being 1·5:1·0, and peaks at
age 60–70 years.5 Despite increased incidence overall,
improvements in relative survival rates have been Search strategy and selection criteria
reported over the past three decades,3,5 although these We identified data for this Seminar through searches of
might be skewed by disease stage migration.6–8 In Europe, PubMed and Web of Science. We included papers in core
mortality from renal cell carcinoma peaked at 4·8 per clinical journals that described studies in adults and were
100 000 in 1990–94 and had declined to 4·1 per published in English from 2004 to 2014. Search terms
100 000 (−13%) in 2000–04.5 In the USA, 5-year relative included “renal cancer” or “kidney cancer” in combination
survival rates at diagnosis increased from 50% in 1975–77 with the terms “epidemiology”, “genetics”, “pathophysiology”,
to 57% in 1987–89, and reached 73% in 2003–09.3 “diagnosis”, “biopsy”, “treatment”, “surgery”, “active
Established risk factors include smoking tobacco,9 surveillance”, “medical therapy”, or “targeted therapy”. We also
hypertension,10–12 and obesity.13,14 These associations might searched cited references from selected articles and previous
be biased by the probability that such patients undergo reviews to identify further relevant papers not retrieved by
routine imaging, which could increase the likelihood of this search, including those outside the time period of the
incidental detection of renal masses. Several other initial search. We also searched for updates on the main
associations have been suggested, for example, a features of renal cell carcinoma, with particular attention paid
protective effect of alcohol consumption,15 a negative to reports focusing on novel treatments, renal biopsy, new
effect of red meat consumption,16 and occupational imaging technologies, and minimally invasive techniques.
exposure to carcinogens,17 but the data are unclear.

www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X 1

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Renal cell carcinoma can be sporadic or hereditary, but Diagnosis

both forms are generally associated with structural
alterations of the short arm of chromosome 3.21
Translocation tumours are increasingly being identified
in adolescents and young adults.18 Many gene variants
have been associated with renal cell carcinoma. Somatic
mutations or epigenetic alterations of VHL, a tumour-
suppressor gene, are seen in more than 80% of clear-cell
subtypes. Specifically, the VHL tumour suppressor
protein is important in cellular oxygen sensing by
targeting hypoxia-inducible factors for ubiquitination
and proteasomal degradation.22 Sequencing studies have
identified other driver genes that are involved in the
pathogenesis of renal cell carcinoma, including PBRM1,23
BAP1,23 SETD2,24 TCEB1,24 and KDM5C.25 Studies
analysing the effects of these mutations on clinical
outcomes, however, are limited by small sample sizes,
short-term follow-up, and lack of assessment of multiple
markers in the same cohort.24,25 Hereditary forms of renal
cell carcinoma include von Hippel-Lindau syndrome
(VHL 3p25–26),26 hereditary papillary renal cell
carcinoma (MET 7q31–34),27 Birt-Hogg-Dubé syndrome
(FLCN 17p11),28 hereditary leiomyomatosis (FH 1q42–43),29
and tuberous sclerosis (TSC1 9q34 or TSC2 16p13).30
With the expansion of routine imaging for many disorders,
patients with renal cell carcinoma are increasingly being
identified by chance. Only 30% of patients are diagnosed
on the basis of symptoms. At all stages, renal cell
carcinoma might produce multiple hormone-like or
cytokine-like biologically active products that lead to
clinically important paraneoplastic syndromes (table 1).31
The findings of routine diagnostic blood tests might be
altered by renal cell carcinoma, but no change is
pathognomonic. Physical examination has a limited role
in diagnosis of renal cell carcinoma, but the presence of
a palpable abdominal mass, new-onset varicocele, or
lower extremity oedema should always prompt additional
imaging assessments for retroperitoneal neoplasia.
Standard imaging
Although renal cell carcinoma is frequently detected by
abdominal ultrasound scanning, limitations in specificity
and accuracy make it necessary to use CT or MRI to
confirm suspicious findings. The main goals of imaging
are to characterise the mass and possible abdominal
metastases, tumour extension, and venous involvement
for staging (appendix). Imaging might also be useful to

Occurrence among Proposed causes

Local symptoms
Acute or chronic flank pain
Gross haematuria
Palpable abdominal mass
Varicocele
Paraneoplastic disorders
Hypertension
Anaemia
Cachexia, weight loss
Pyrexia
Raised hepatic enzyme concentrations in
absence of liver metastases (Stauffer’s
syndrome)
Hypercalcaemia
Polycythaemia
Hypoglycaemia, neuromyopathy,
amyloidosis, vascular thrombosis, Cushing’s
syndrome, protein enteropathy,
galactorrhoea, gynaecomastia, decreased
libido, hirsutism, amenorrhoea, chills,
necrotising myopathy, immune
thrombocytopenic purpura
patients with
symptomatic RCC
Common Urinary system obstruction or infiltration, invasion of adjacent organs,
retroperitoneal space-occupying mass
Less frequent Urinary system infiltration
Less frequent Retroperitoneal space-occupying mass
Rare Increased venous pressure due to space-occupying mass or venous thrombus
Common Increased production of renin directly by tumour; compression or encasement of the
renal artery or its branches causing renal artery stenosis; or arteriovenous fistula
within the tumour, polycythaemia, hypercalcaemia, ureteral obstruction, and
increased intracranial pressure associated with cerebral metastases
Common Bleeding, abnormal production of prostaglandins, cytokines, and inflammatory
mediators
Common Abnormal production of prostaglandins, cytokines, and inflammatory mediators
Less frequent Abnormal production of prostaglandins, cytokines, and inflammatory mediators
Less frequent Non-specific hepatitis associated with a prominent lymphocytic infiltrate, raised
concentrations of interleukin-6 in serum
Less frequent Osteolytic metastatic involvement of bone, production of parathyroid-hormone-
like peptides, tumour-derived 1,25-dihydroxycholecalciferol, and prostaglandins
Rare Increased production of erythropoietin directly by the tumour or by the adjacent
parenchyma in response to hypoxia induced by tumour growth
Anecdotal Abnormal production of 1,25-dihydroxycholecalciferol, renin, erythropoietin,
prostaglandins, parathyroid-hormone-like peptides, lupus-type anticoagulant,
human chorionic gonadotropin, insulin, various cytokines or inflammatory
mediators

RCC=renal cell carcinoma.

Table 1: Most frequent local symptoms and paraneoplastic disorders associated with RCC

2 www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X


assess additional characteristics that could be important
if active management is planned (eg, bilateral renal
function, renal vascular supply, retroperitoneal anatomy).
If malignant renal cell carcinoma is suspected, additional
imaging (eg, thoracic and brain CT scan, total-body bone
scan) can be considered in symptomatic patients or in
cases of bulky abdominal disease.32–35
New imaging technologies
New technologies for cancer detection and character-
isation are being investigated for renal cell carcinoma; for
example, advanced MRI techniques, such as diffusion-
weighted and perfusion-weighted imaging, are being
explored for the assessment of renal masses.36 Although
PET might be useful for the diagnosis and follow-up of
renal cell carcinoma, this technique is not yet part of the
standard strategy.37 Some studies have suggested the use
of combined ¹²⁴iodine PET and CT for the detection of
labelled antibodies to the carbonic anhydrase IX antigen,
which is widely expressed in more than 90% of clear-cell
renal cell carcinomas but not in the normal kidney.38,39
Emerging role of renal biopsy
The use of renal biopsy has been limited by concerns
about accuracy and safety, and in the past has had little
effect on treatment decisions because the standard
treatment for solid renal masses was upfront removal.40
Increased active surveillance for small renal masses and
individualised targeted therapy for patients with
metastases, however, have pushed the scientific
community to improve expertise in biopsy performance
and pathological interpretation.41 Consequently, renal
biopsy is now used to establish the diagnosis of
radiologically indeterminate renal masses, obtain
histology of incidentally detected renal masses in patients
who are potential candidates for active surveillance, and
to select the most suitable targeted therapy for patients
with metastatic renal tumours.42
Accuracy of biopsy in detecting malignancy ranges from
38% to 100%.41 In one of the largest study cohorts reported
(n=345), histological subtype and Fuhrman grade were
correctly assessed at biopsy in 88% and 64% of cases,
respectively.43 Renal biopsy has low associated morbidity.
Contemporary series have revealed overall complication
rates (mainly bleeding, infection, and arteriovenous
fistula) in 0·3–5·3% of cases. Tumour seeding throughout
the biopsy tract, which had been reported anecdotally in
the past, is no longer a risk with modern biopsy
techniques.42 Although renal biopsy has a definite and
expanding role in the assessment and treatment of renal
masses, it remains substantially underused.40
Management
Notwithstanding advances in the understanding of renal
cell carcinoma biology, surgery remains the mainstay of
curative treatment. Although radical nephrectomy was
historically the standard of care for management of renal
www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X
Seminar
tumours, detection of small renal lesions44 and
accumulating evidence that surgically induced chronic
kidney disease can increase patients’ morbidity45 have led
to more conservative approaches.46 Specifically, nephron-
sparing surgery, active surveillance, and minimally
invasive techniques46 have been introduced into daily
clinical practice. These approaches limit invasiveness,
iatrogenic renal function impairment, and overtreatment.
Active surveillance
Management of localised renal cell carcinoma must take
into account competing causes of mortality, particularly
in elderly patients.47 This consideration has led to the
increasing use of active surveillance46 to avoid surgically
induced short-term and medium-term complications.
The rationale for active surveillance is that roughly 20%
of small renal masses harbour benign final pathology
and the median growth rate is usually slow
(2–3 mm/year).48 Moreover, the risk of metastatic
progression is very low (less than 1%), with virtually no
risk of cancer-specific mortality in well selected
patients.49–51 Biopsy might be useful before active
surveillance is started. Active surveillance has been
proposed for larger tumours to determine tumour
growth kinetics, especially if a patient has severe
competing risks and limited life expectancy.52 Absolute
cutoffs for tumour size and growth rate that should
prompt intervention during active surveillance are not
well defined. In various proposed protocols, imaging at
3 and 6 months initially, every 6 months during the next
2–3 years, and annually thereafter is suggested, but
cumulative radiation risk and increased costs are being
assessed.49,50,53 Data are needed from large cohorts with
long-term follow-up to better characterise clinical
indications and standardise protocols.
Minimally invasive techniques
Although surgery still represents the standard of care for
renal cell carcinoma, the use of minimally invasive
techniques to treat incidentally detected small tumours
has been increasing. Cryotherapy and radiofrequency
ablation (RFA) were initially contemplated only for
patients with one kidney or for those deemed unfit to
undergo a major procedure. Since preliminary reports
showed acceptable cancer control,37,54–57 the clinical
indications for these procedures has been extending. For
example, 8% of US patients are treated with cryotherapy
and RFA, compared with 4% in 1998.58
Renal ablative treatment uses the cell-destroying
properties of temperature (hot or cold) to cause apoptosis
in cancer cells.54 RFA induces thermal damage (50–120°C)
through frictional heating resulting from ionic oscillation
by a high-frequency alternating current (375–500 kHz).59
Cryotherapy stimulates tumour cell death directly by
damaging cell membranes and organelles and indirectly
by initiating vascular compromise through thrombosis
of small vessels,54 which leads to coagulative necrosis of
3
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the tissue. Potential complications after RFA and
cryotherapy are renal bleeding or abscess formation or
extrarenal effects in the bowel, pleura, spleen, pancreas,
and vasculature.
Most studies of outcomes after renal tumour
cryoablation consist of single-institution retrospective
reports with low numbers of patients and short follow-up.
An analysis of the Mayo Clinic Renal Tumor Registry that
included more than 1800 patients with primary cT1N0M0
renal tumours showed similar local recurrence-free
survival for patients treated with nephron-sparing
surgery, RFA, or cryotherapy (p=0·4). By contrast,
metastases-free survival was significantly better after
nephron-sparing surgery (p=0·005) and cryoablation
(p=0·02) than with RFA.60 Although this comparison
included a large number of cases, its retrospective nature,
the differing baseline characteristics between studies, and
other unmeasurable confounders make it difficult to
draw conclusions about cancer control.61 A meta-analysis
by Kunkle and colleagues56 suggested that recurrence-free
survival might be worse for RFA and cryoablation than
for partial nephrectomy, but showed no differences for
metastasis-free survival. Conversely, a systematic review
and meta-analysis of six clinical trials (one prospective
randomised and five retrospective cohort trials) showed
that recurrence-free survival and cancer-specific survival
were similar for patients treated with surgery or RFA,
with less postoperative decline in estimated glomerular
filtration rate in the RFA group.55 The overall complication
rate was significantly lower in the RFA group (7% vs 11%;
relative risk 0·55, 95% CI 0·31–0·97, p=0·04). The groups
had similar local recurrence rates of 3–4% (0·92,
0·4–2·14, p=0·8) and disease-free survival (hazard ratio
1·04, 95% CI 0·48–2·24, p=0·9).55
Surgery
Nephron-sparing surgery
Although radical nephrectomy involves removal of the
entire kidney, with nephron-sparing surgery only the
tumour is excised and as much of the normal renal
parenchyma as possible is maintained (figure 1). Although
initially reserved for imperative situations, according to
international guidelines, nephron-sparing surgery is now
the treatment of choice whenever a healthy part of kidney
can safely be spared. Nephron-sparing surgery has been
used increasingly since observations suggested
oncological control similar to radical nephrectomy62–64 but
with the additional benefit of renal preservation.65
Moreover, a long-term protective effect has been
suggested for nephron-sparing surgery relative to radical
nephrectomy for risk of cardiovascular events after
surgery (eg, new-onset hypertension, coronary artery
disease, vasculopathy, and cerebrovascular disease).45,66,67
Because patients with organ-confined renal cell carcinoma
that has been surgically treated are usually long-term
cancer survivors (85–96% cancer-specific survival 10 years
after surgery68), these functional outcomes are important.
4 www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X
Although many retrospective reports have suggested a
benefit in overall survival for patients treated with
nephron-sparing surgery relative to radical
nephrectomy,67,69 no improvements with nephron-sparing
techniques were found in a comparison of the two
techniques.70 However, many flaws undermined the study
(eg, low recruitment, selection and verification biases,
and being done at the beginning of the nephron-sparing
learning curve).70 Further efforts are needed to improve
understanding of which patients might benefit from
nephron-sparing surgery in terms of overall survival.
International guidelines include standard indications
for nephron-sparing surgery: absolute, indicating
patients with only one anatomical or functional kidney;
relative, indicating patients with a functioning opposite
kidney that is affected by a disorder that might impair
renal function in the future or with hereditary forms of
renal cell carcinoma who are at increased risk of
developing a tumour in the contralateral kidney; and
elective, indicating localised unilateral renal cell
carcinoma with a healthy contralateral kidney.37,58
Although nephron-sparing surgery has been proposed
for use even for locally advanced disease and metastatic
spread,71,72 further data are required before a conservative
approach can be approved in those settings.
Surgical excision of tumours is done by kidney
mobilisation, resection of the tumour (with or without a
rim of normal parenchyma, according to the anatomical
and tumour features), and final reconstruction
(renorrhaphy; figure 1). During resection of the tumour,
the main renal artery can be clamped temporarily (hilar
clamping) to minimise blood loss. Sustained hilar
clamping might cause impairment of renal function and,
therefore, limited duration of ischaemia is suggested,
although the functional long-term consequences are
controversial.73–75 If technically possible, techniques
without clamping or selective intraparenchymal
clamping (eg, clamping of only a branch of the main
artery) should be considered.76
Nephron-sparing surgery should be preferred unless
pre-existing disorders are likely to decrease the positive
effect of a conservative approach, such as frailty or short
life expectancy. Other risk factors are low surgical
expertise or volume of relevant surgeries, excessive
ischaemia time, use of non-conservative haemostasis
techniques, or large or anatomically complex renal
masses with a low percentage of nephrons that can be
spared. In such situations, the potential benefit in
functional outcomes might be jeopardised. Conservative
surgical techniques require substantial technical
expertise and might be associated with increased risk of
haemorrhage (3%) and urinary leakage (4%).77
Consequently, nephron-sparing surgery is still underused
for patients with renal cell carcinoma, especially in non-
academic hospitals.78–80
If the aim of the surgery is the preservation of the
normal renal parenchyma, the choice of surgical approach
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A
2
1

B C D

Figure 1: Procedures in robot-assisted nephron-sparing surgery to remove renal cell carcinoma

(A) In robot-assisted surgery, instead of directly moving the instruments, the surgeon performs the normal movements associated with the surgery, and the robotic
arms make those movements and use end-effectors and manipulators to perform the actual surgery on the patient. One arm is dedicated to the laparoscope and the
two others hold forceps, monopolar curved scissors, a cautery hook, and a large needle driver. The patient is positioned in a modified flank position. Port
configuration can vary based on tumour location to optimise the working angles. Surgical excision of the tumour is done by (B) kidney mobilisation, (C) tumour
resection (with or without a rim of normal parenchyma according to anatomical and tumour features), and (D) final reconstruction (renorrhaphy).

(open, laparoscopic, or robotic) depends largely on tumour
characteristics and the surgeon’s expertise. Tumour
features that dictate the feasibility of nephron-sparing
surgery versus radical nephrectomy include diameter,
location, depth, and proximity to hilar vessels and the
urinary collecting system. The three foremost anatomical
scores (PADUA,81 RENAL,82 and C-index83) may be used to
assess those features before surgery, with the aim of
improving selection of patients, surgical management,
research reporting, and outcome prediction.81–83
Robot-assisted nephron-sparing surgery is gaining
popularity because challenging cases can be approached
with a minimally invasive procedure (figure 1). In
hospitals that have acquired surgical robotic systems,
treatment with nephron-sparing surgery has increased
by 16–35% relative to hospitals without such technology.84
Conversely, laparoscopic nephron-sparing surgery might
be challenging and is usually limited to simpler cases or
done by experienced surgeons (appendix). Open
nephron-sparing surgery, which was the standard
approach until the early 2000s, is now used only in cases
where there are anatomical difficulties (eg, urinary tract
invasion or hilar or larger tumours) or for which
minimally invasive techniques are unavailable.
A meta-analysis of non-randomised studies including
2240 patients showed that robot-assisted compared with
laparoscopic nephron-sparing surgery was associated
with reduced rates of conversion to open surgery (relative
risk 0·4, 95% CI 0·2–0·9, p=0·02) and radical surgery
(0·19, 0·1–0·5, p=0·0006).85 Additionally, robot-assisted
nephron-sparing surgery resulted in significantly shorter
warm ischaemia, (weighted mean difference 3 min,
95% CI 1–5, p=0·005), although the clinical relevance of
this outcome was marginal, smaller change in estimated
glomerular filtration rate (standardised mean difference
0·2, 0·02–0·3, p=0·03), and shorter length of stay in
hospital (weighted mean difference 0·2 days, 0·1–0·4,
p=0·004).85 Moreover, no differences were noted in

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Figure 2: CT scan of a patient aged 55 years with a bulky right kidney tumour and caval thrombus invading
the right atrium
Images were taken before nephrectomy and venous thrombectomy, and are two slices from the same scan. Initial
presentation was a newly diagnosed right varicocele, followed by fatigue and dyspnoea. The right varicocele was
secondary to a venous thrombus occluding the vena cava and its branch, the right spermatic vein. Fatigue and
dyspnoea were secondary to initial heart failure and abnormal production of prostaglandins, cytokines, and
inflammatory mediators by the tumour.
operative outcomes, including complications with
Clavien-Dindo classification grades 1–2 (relative risk 1·1,
95% CI 0·9–1·3, p=06) and 3–5 (0·9, 0·6–1·5, p=0·8).85
Radical nephrectomy
If sparing the parenchyma is not possible and the aim of
the surgery is removal of the entire kidney, open radical
nephrectomy has been replaced in most cases by
laparoscopic nephrectomy, which is associated with
shorter stay in hospital, less perioperative blood loss,
fewer analgesic requirements, and shorter convalescence
time.86,87 Although randomised studies assessing
oncological outcomes have never been done, similar
oncological outcomes for laparoscopic and open radical
nephrectomy are suggested.86,87 Robot-assisted radical
nephrectomy results in increased medical expense
without improving morbidity compared with laparoscopic
procedures,88 but might still be worth considering for
selected cases (eg, when retroperitoneal lymphadenectomy
is thought to be required).
Lymph node dissection, adrenalectomy, and venous
thrombectomy
Adrenalectomy was historically viewed as an unavoidable
part of radical procedures. Removal of the ipsilateral
adrenal gland, however, is now optional if no macroscopic
invasion is suggested by preoperative imaging or found
during surgery.37,57,89
Irrespective of T stage, patients who have renal cell
carcinoma with nodal invasion (pN1) have poor cancer-
specific survival (20–30% at 3 years after surgery).90
Although lymphadenectomy provides the most accurate
6 www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X
and reliable staging of lymph node status, the value of
lymphadenectomy in renal cell carcinoma remains
controversial. A European Organisation for Research and
Treatment of Cancer randomised trial showed no survival
advantage for low-risk patients treated with nephrectomy
plus lymphadenectomy versus nephrectomy only,91
although several retrospective studies have suggested a
potential benefit with lymphadenectomy in intermediate-
risk and high-risk patients.92 Sentinel node biopsy is not
an option for renal cell carcinoma at present.93,94
Around 10% of patients with renal cell carcinoma have
venous tumour thrombosis in the renal vein, inferior
vena cava, or extending up to the right atrium (figure 2).
Although prognosis is worse in such cases and surgery
might be challenging and associated with an increased
complication rate, a case–cohort study suggested that
survival was better with surgical management than with
non-surgical management.95 Operative management is
dictated primarily by the extent of the thrombus. When
confined to the renal vein, minimum modification of the
standard surgical approach is required. As the thrombus
extends cranially, opening of the vena cava, liver
mobilisation, opening of the right atrium, and
cardiopulmonary bypass might be necessary.
Metastatic disease at diagnosis
Historically, patients with metastatic clear-cell renal
cell carcinoma were treated with systemic therapy based
on immune modulators, mainly interferon α and
interleukin-2, but outcomes were only slightly improved.96
In a few cases these agents have led to T-cell-mediated
tumour regression secondary to enhancement in
lymphocyte mitogenesis, lymphocyte cytotoxicity, and
activity of lymphokine-activated and natural killer cells.97
Immunotherapy with high-dose interleukin 2 has been
associated with durable complete response in less than
10% of patients and has been associated with severe
treatment-related toxic effects.97 Subsequently, combined
data from 99 study groups show an overall chance of
partial or complete remission in only 13% of patients,
compared with 3–4% in placebo or non-immunotherapy
control groups.98 Aldesleukin and interferon α (associated
with bevacizumab) remain the only immune-modulating
drugs approved for selected cases of metastatic renal cell
carcinoma.57
Several non-randomised studies had suggested a
response to systemic therapy and improved survival in
patients who had undergone nephrectomy and, therefore,
two randomised clinical trials were planned at the end of
1980s to test the effect of surgery on survival in patients
with metastatic renal cell carcinoma. 331 patients overall
were randomly assigned treatment with nephrectomy
plus interferon α-2b or interferon α-2b alone.99,100 A
combined analysis of the findings showed a 31% decrease
in the risk of death with surgery compared with
interferon α-2b alone (median survival 13·6 months,
95% CI 9·7–17·4 vs 7·8 months, 5·9–9·7).101 Several
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hypotheses were formed to explain the observed benefits
of nephrectomy: reduction of disease burden; decrease of
immunosuppression and improved clinical response to
cytokines; decreased growth-factor secretion (mainly
VEGF); and inhibited tumour microenvironment
secondary to surgically induced chronic metabolic
acidosis.102
Over the past decade, the main advance in the
treatment of metastatic renal cell carcinoma has been the
development of treatments that affect specific targets in
biological pathways. Agents targeting the VEGF/PDGFR/
mTOR pathway continue to be the mainstays of
treatment (table 2). Although improved target specificity
has lessened the risk of toxic effects associated with these
drugs, durable complete responses remain the exception.
Seven targeted drugs have been approved by European
Medicines Agency and the US Food and Drug
Administration for management of renal cell carcinoma
(table 2, figure 3). Sunitinib and sorafenib were associated
significant benefits in progression-free survival and
overall survival compared with placebo in two phase 3
trials,103,104 as was, temsirolimus in high-risk patients
when compared with IFN monotherapy.110 In contrast, in
patients with metastatic renal cell carcinoma who
progressed after treatment with sunitinib, overall survival
was shorter with temsirolimus than with sorafenib.111
Everolimus was associated with a significant benefit in
progression-free survival relative to placebo in patients
with metastatic renal cell carcinoma who progressed
after sunitinib or sorafenib.112 Everolimus has been
approved by the US Food and Drug Administration as
the first drug to be used specifically to treat non-
cancerous kidney tumours (renal angiomyolipomas) in
patients with tuberous sclerosis complex.30

Mechanism Administration route Setting Treatment Main findings

Sunitinib PDGFR and VEGFR Capsules Treatment naive Sunitinib vs interferon α PFS, 11 months (95% CI 10–12) vs 5 months (95% CI 4–6),
inhibitor (n=750) HR 0·42 (95% CI 0·32–0·54), p<0·001103
Sorafenib PDGFR, VEGFR-2, and Capsules Second-line therapy Sorafenib vs placebo PFS, 5·5 vs 2·8 months, HR 0·44 (95% CI 0·35–0·55),
MAPK/MEK/ (n=903) p<0·00001;104 OS, 17·8 vs 15·2 months, HR 0·74 (95% CI
ERK inhibitor 0·74–1·04), p=0·146;104 OS after censoring,* 17·8 vs 14·3 months,
HR 0·78 (95% CI 0·62–0·97), p=0·029104
Bevacizumab Recombinant Intravenous injection Treatment naive Bevacizumab plus interferon PFS, 10·2 vs 5·4 months, HR 0·63 (95% CI 0·52–0·75), p<0·001;105
humanised (n=649) vs interferon plus placebo OS, 23·3 vs 21·3 months, HR 0·91 (95% CI 0·76–1·10), p=0·33106†
monoclonal antibody
directed against
VEGF-A
Treatment naive Bevacizumab plus interferon PFS, 8·5 vs 5·2, HR 0·72 (95% CI 0·61–0·83), p<0·001;107 OS, 18·3
(n=732) vs interferon alone (95% CI 16·5–22·5) vs 17·4 (95% CI 14·4–20·0), HR 0·86 (95% CI
0·73–1·01), p=0·069108
Temsirolimus mTOR inhibitor Intravenous injection Treatment naive Temsirolimus plus PFS, 9·1 vs 9·3 months, HR 1·1 (95% CI 0·9–1·3), p=0·8;109
(791) bevacizumab vs interferon OS, 25·8 vs 25·5 months, HR 1·0, p=0·6109
plus bevacizumab
Treatment naive Temsirolimus vs interferon PFS, 3·8 vs 1·9 months, p<0·0001; OS, 10·9 vs 7·3 months,
(poor-risk, n=626) HR 0·73 (95% CI 0·58–0·92), p=0·008110
Second line after Temsirolimus vs sorafenib PFS, 4·3 months (95% CI 4·0–5·4) vs 3·9 months
sunitinib (n=512) (95% CI 2·8–4·2), HR 0·87 (95% CI 0·71–1·07), p=0·19;111
OS, 12·3 months (95% CI 10·1–14·8) vs 16·6 months (95% CI
13·6–18·7), HR 1·31 (95% CI 1·05–1·63), p=0·01111
Everolimus mTOR inhibitor Capsules Second-line therapy Everolimus vs placebo PFS, 4·0 months (95% CI 3·7–5·5) vs 1·9 months (95% CI
(n=410) 1·8–1·9), HR 0·30 (95% CI 0·22–0·40), p<0·0001112
Pazopanib VEGFR/PDGFR/c-Kit Capsules Treatment naive Pazopanib vs placebo PFS, 11·1 vs 2·8 months, HR 0·40 (95% CI 0·27–0·60),
inhibitor (n=233) p<0·0001;113 OS, 22·9 months (95% CI 17·6–25·4) vs 23·5 months
(95% CI 12·0–34·3), HR 1·01 (95% CI 0·72–1·42)114
Treatment naive Pazopanib vs sunitinib PFS, 8·4 months (95% CI 8·3–10·9) vs 9·5 months (95% CI
(n=1110) 8·3–11·1);115 OS, 28·3 months (95% CI 26·0–35·5) vs 29·1 months
(95% CI 25·4–33·1), HR 0·92 (95% CI 0·79–1·06), p=0·24116
Cytokine refractory Pazopanib vs placebo PFS, 7·4 vs 4·2 months, HR 0·54 (95% CI 0·35–0·84), p<0·0001;113
(n=202) OS, 22·7 months (95% CI 19·3–28·3) vs 18·7 months (95% CI
14·2–26·3), HR 0·82 (95% CI 0·57–1·16)114
Axitinib VEGFR (1–3), PDGFR, Capsules Treatment naive Axitinib vs sorafenib PFS, 10·1 month (95% CI 7·2–12·1) vs 6·5 months (95% CI
and c-Kit inhibitors with mRCC (n=288) 4·7–8·3), HR 0·77 (95% CI 0·56–1·05), p=0·038117
Second-line therapy Axitinib vs sorafenib PFS, 6·7 months (95% CI 6·3–8·6) vs 4·7 months
for mRCC (n=723) (95% CI 4·6–5·6), HR 0·66 (95% CI 0·54–0·81), p<0·0001118

PFS=progression-free survival. HR=hazard ratio. OS=overall survival. mRCC=metastatic renal cell carcinoma. *After crossover of placebo patients. †Unblinded after interim analysis and crossover and use of other
antineoplastic therapies allowed.

Table 2: Phase 3 trials of targeted therapies approved for management of mRCC

www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X 7

 Seminar

Immune modulation Blood vessel

Interferon α
NK cell T cell

Sunitinib
PDGFR Sorafenib
CTLA4 Pazopanib
Aldesleukin

Angiogenesis
PD-1
(Ipilimumab))
(Rilotumumab) Axitinib
(Nivolumab)
FGF
PDGF
Paracrine
PD-L1 growth
HGF FGFR
stimulation
VEGFR
(Brivanib)
MET/HGFR (Dovitinib Temsirolimus VEGF
AKT Everolimus
(Erlotinib)
Bevacizumab
PI3K mTORC1–2
PTEN
EGF
HIF1α Autocrine
growth stimulation
Nucleus
EGFR

VHL
MAPK/ERK TGFα
pathway Gene expression,
cell growth, proliferation, survival

Tumour cell

Figure 3: Biological pathways related to development of renal cell carcinoma and treatment targets
NK=natural killer.

Pazopanib is an oral inhibitor of the VEGFR/ Bevacizumab is a recombinant humanised monoclonal

PDGFR/c-Kit pathway that has shown a significant benefit
in progression-free survival compared with placebo in
treatment-naive patients (table 2).113 The difference in final
overall survival between patients treated with pazopanib
or placebo was not significant, partly because of early and
frequent crossover from placebo to pazopanib.113 In a
phase 3 trial, similar efficacy was found with pazopanib
and sunitinib, with slightly lower incidence of toxic effects
(palmar-plantar erythrodysaesthesia and fatigue) but with
higher incidence of liver function test abnormalities.115,116 A
randomised crossover trial revealed a significant
preference for pazopanib over sunitinib by patients and
physicians (70% vs 22%, p<0·001),119 mainly because of a
better adverse event profile for fatigue, improved quality
of life,119 and reduced cost.120
Axitinib is a potent, selective, second-generation
inhibitor of VEGFR 1, 2, and 3. In patients with treatment-
naive metastatic renal cell carcinoma, progression-free
survival was not significantly increased with axitinib
compared with sorafenib (table 2), although adverse
events of any grade were less common in the axitinib
group by an average of 10%.117 Conversely, among patients
treated with a cytokine-containing regimen before
axitinib, progression-free survival was longer than in
those who received sorafenib (table 2).118
antibody directed against VEGF. In two phase 3 trials of
bevacizumab plus interferon compared with interferon
plus placebo105 or interferon alone,106 bevacizumab was
superior in terms of progression-free survival. One of the
studies was unblinded because a clinically meaningful
significant benefit was found in an interim analysis.105 In
the final overall survival analyses of both trials, however,
no significant differences were found between treatment
groups (table 2), probably because of the confounding
effect of crossover after the interim analysis and the use
with other targeted drugs as salvage therapies in the
interferon groups. 107,108
The introduction of targeted therapies has set a new
benchmark for the treatment of metastatic renal cell
carcinoma, but most patients included in trials have had
clear-cell metastatic disease. The results, therefore, might
not be universally applicable to all histological types. A
contemporary analysis of patients with metastatic renal
cell carcinoma treated with VEGF-targeting agents showed
median overall survival of 18·8 months (95% CI 17·6–21·4)
with a remarkable peak at 43·2 months for patients in the
most favourable risk group (appendix).121 The most
informative clinical variables to predict the outlook of
patients with metastatic renal cell carcinoma treated with
targeted therapies include haemoglobin (p<0·0001),

8 www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X


serum corrected calcium (p=0·0006), Karnofsky
performance status (p<0·0001), time from initial diagnosis
to the start of treatment (p=0·009), absolute neutrophil
count (p<0·0001), and platelet count (p=0·012).122
The most common treatment-related adverse events
associated with targeted therapies for metastatic renal
cell carcinoma are fatigue, hypertension, nausea,
diarrhoea, dysphonia, and palmar-plantar erythro-
dysaesthesia.123 Grade 3 or 4 adverse events are expected
in around a third of patients, with profiles improving
slightly for the new-generation targeted therapies (eg,
pazopanib).123 Clinical and translational studies are
needed to identify the phenotypic predictors of response
for each of the drugs.
Controversies, uncertainties, and research
questions
Despite progress in the understanding of renal cell
carcinoma, uncertainties, controversies, and research
questions remain. Advances are expected over the next
few years from translational and clinical studies. Novel
tissue and genetic markers are expected to improve
accuracy of renal biopsy in characterising histology and
disease aggressiveness at diagnosis (indolent mass vs
clinically relevant malignancy). This approach could be
crucial to the selection of patients who will benefit from
active surveillance and other non-surgical approaches.
Data are too immature to validate universal use of
minimally invasive techniques (cryotherapy and RFA) for
renal cell carcinoma. Only case series, unmatched
retrospective studies, and chart reviews with short follow-
up are available. Longer follow-up data and well designed
comparative trials are needed to confirm oncological
results, standardise techniques, and to recommend
alternatives to surgery, especially for small renal masses.
In terms of the potential use of radiotherapy as part of
a multimodal approach, renal cell carcinoma had been
viewed as a radioresistant tumour because of poor
outcomes with low-dose radiotherapy.124 This notion has
been challenged by emerging evidence that stereotactic
body radiotherapy with a high-fraction dose has an effect
in primary tumours and oligometastatic disease.124
Randomised trials of radiotherapy regimens and
radiotherapy combined with targeted drugs are awaited
to confirm the potential clinical implications.
Medical and integrated therapies, identification of new
target pathways, and optimum sequencing and
combination of existing targeted agents are areas of
active study.125 Molecular markers that seem to be
predictive of response to sunitinib in patients with
metastatic renal cell carcinoma have been identified.
Prediction is based on molecular subtypes and suggests
that tailored and personalised treatment is feasible.126
Upcoming results of ongoing trials testing novel drugs
will increase the choice for urologists and oncologists
treating locally advanced and metastatic disease. A
promising avenue of clinical research, for example, is
www.thelancet.com Published online August 26, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00046-X
Seminar
the use of immune checkpoint inhibitors. These
treatments work by targeting molecules that serve as
checks and balances on immune responses. By blocking
inhibitory molecules or activating stimulatory molecules,
it is hoped that pre-existing anticancer immune
responses will be restored. Nivolumab, for instance, is a
fully human IgG4 monoclonal antibody that binds to the
PD-1 receptor and restores T-cell immune activity. This
drug has shown promising results in the treatment of
metastatic renal cell carcinoma.127 Many other new drugs
are being investigated, and tivozanib128,129 dovitinib,130
cabozantinib,131 erlotinib,132 and sirolimus133 are being
tested as potential treatments (figure 3). Additionally,
two phase 3 studies are assessing the role of cytoreductive
nephrectomy in the context of novel systemic therapies
and the best treatment sequencing for surgery and
targeted drugs (NCT01099423).134 The role of adjuvant
therapy after surgery is also being investigated. Past
attempts to prove clinical benefit with adjuvant
immunotherapy (interferon α and interleukin-2) system-
atically failed.135–137 Five phase 3 trials including more
than 6000 patients with non-metastatic renal cell
carcinoma are being done to assess the role of targeted
therapies in the adjuvant setting,138 no benefit has yet
been found with adjuvant VEGF inhibitors (sorafenib or
sunitinib) in patients at high risk of recurrence
(NCT00326898).
Surgical metastasectomy has been gaining popularity
as part of a multimodal approach to treating patients
with oligometastatic renal cell carcinoma and has shown
acceptable morbidity in selected patients.139–141 Partial or
complete removal of the metastatic lesions was associated
with improved overall survival, especially in patients with
adequate performance and functional statuses.139–142
Patients are being recruited into randomised clinical
trials to assess the efficacy of a multimodal approach
based on targeted therapy after surgical metastasectomy
(NCT00918775 and NCT01444807).
Conclusions
Renal cell carcinoma provides one of the best examples
in oncology of how innovative basic research, novel
clinical findings, and improved surgical techniques can
converge to improve the care of patients. Alternative
management strategies, such as active surveillance or
cryotherapy, can be considered for an increasing number
of patients. For patients who are candidates for surgical
excision, the development of minimally invasive
techniques, such as robot-assisted laparoscopic nephron-
sparing surgery, has decreased the risk of surgically
induced functional impairment. Additionally, extended
understanding of biological pathways and novel targeted
therapies has led to improved survival outcomes in
patients with metastatic disease. Further developments
in translational research and findings from trials are
expected to integrate surgical and systemic treatments to
enhance cancer control.
9
 Seminar
Contributors
Both authors did the literature search, wrote the drafts, and reviewed the
contents of the paper.
Declaration of interests
UC has received consultancy and lecturer honoraria and FM has
received research support, consultancy fees, and lecturer honoraria from
Recordati.
Acknowledgments
We thank Jeni Crockett-Holme for editorial support and Nicola Spreafico
for graphics support.
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