Download Current management of renal cell cancer

KIDNEY DISEASE
21
Current management of
renal cell cancer
LAVINIA SPAIN AND SAMRA TURAJLIC
The last decade has seen
significant treatment
advances in the management
of renal cell cancer, from
the availability of oral,
targeted therapies to
the recent introduction
of immunotherapy. In
this article the authors
cover the risk factors
for renal cancer and its
different histological types,
as well as the staging and
management of both early
and late-stage disease.
T
he diagnosis of renal cell cancer (RCC)
has increased in frequency since the
1990s. This has been attributed to more
widespread use of imaging techniques
such as computed tomography (CT) and
magnetic resonance imaging (MRI) that
can detect incidental lesions. Lifestyle
factors such as obesity, as well as improved
life expectancy, may have also contributed
to this rise.1
RCC is more common in men than in
women. In their lifetime, 1 in 52 men will
be diagnosed with RCC.1 Its incidence in
men in the UK between 2008–2010 was
13–16 per 100 000 persons – an incidence
twice that of women.1 In 2014, RCC was
the fifth most common cancer diagnosed
in men and the tenth most common in
women.1 Mortality rates in men are also
twice as high as in women.2
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MARCH/APRIL 2017
a
b
Figure 1. Primary renal cell carcinoma: (a) external view;
(b) transected view (photographs courtesy of Dr Samra Turajlic)
RISK FACTORS
Smoking, obesity and hypertension are
well-documented risk factors for the
development of RCC.3 Occupational
trichloroethylene exposure has also been
implicated, although the evidence is less
compelling.4 Whether these environmental
factors act as triggers for the development
of cancer on the background of an
underlying genetic vulnerability is not yet
confirmed. Patients with end-stage kidney
disease, especially those on haemodialysis,
are also at increased risk of developing RCC.5
There are several inherited, autosomal
dominant genetic conditions that predispose
to RCC development. These include Von
Hippel-Lindau (VHL) syndrome, hereditary
papillary cancer, hereditary leiomyomatosis
and renal cell cancer (HLRCC) syndrome,
and Burt-Hogg-Dubé syndrome, among
others. Taking a family history is important,
especially in young patients.
CLINICAL PRESENTATION OF RCC
Early-stage RCC may be picked up
incidentally on imaging or due to symptoms
of the primary tumour, such as back pain,
blood in the urine, a palpable mass in the
Lavinia Spain, Clinical Research Fellow,
Royal Marsden NHS Foundation Trust,
London; Samra Turajlic, Consultant
Oncologist, Royal Marsden NHS
Foundation Trust and The Frances Crick
Institute, London
www.trendsinmenshealth.com
KIDNEY DISEASE
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Tumour
Lymph nodes
Metastases
Estimated
5-year survival
Stage I
T1
Tumour ≤7cm, confined to
kidney
N0
None clinically enlarged or
pathologically involved
M0
No distant sites of tumour
spread
81%
Stage II
T2
Tumour >7cm, confined to
kidney
N0
M0
74%
Stage III
T3
Tumour invades major blood
vessels or fat around kidney
(but not into adrenal gland or
beyond Gerota’s fascia)
T1 or T2
N0 or N1
No involved lymph nodes (N0)
OR presence of involved lymph
nodes (N1)
M0
53%
N1
M0
T4
Tumour invades beyond
Gerota’s fascia or into adrenal
gland
Any
Any N
M0
Any
M1
Tumour spread to distant site(s)
Stage IV
8%*
*Probably underestimates current five-year survival rates (see Treatment for Stage IV).
Table 1. American Joint Committee on Cancer TNM staging system for renal cell cancer and estimated five-year prognosis
abdomen, fever and systemic malaise.
Late-stage RCC may also be detected in this
manner or due to symptoms of secondary
tumours, such as bone pain or cough.
TRACERx program (http://tracerx.co.uk/
studies/renal/) is dedicated to studying
the genes that drive both sporadic and
inherited forms of RCC.
TYPES OF RENAL CANCER
There are several histological types of
RCC. The most common is clear cell
(ccRCC), accounting for up to 90% of
cases.6 The next most frequent type is
papillary RCC, with chromophobe RCC
and rarer types (eg collecting duct,
translocational and medullary tumours)
comprising the rest. Any histological type
may exhibit sarcomatoid features, which
are associated with a more aggressive
clinical course and poor response to
drug therapy.
STAGING AND PROGNOSIS
As with many other cancers, the extent
of RCC is defined according to how large
the primary tumour is, whether it has
invaded local lymph nodes and whether
it has spread to more distant sites. This
governs the approach to treatment and,
along with other factors, informs the risk
of recurrence. Staging according to the
‘tumour, node, metastasis’ (TNM) system is
summarised in Table 1. 8
Clear cell, papillary and chromophobe
RCCs all demonstrate different underlying
gene mutation profiles that impact
multiple growth pathways.7 Alterations
in the VHL gene and loss of the short arm
of chromosome 3 define ccRCC, even in
non-inherited cases.7 The UK-based Renal
www.trendsinmenshealth.com
The anatomical extent of disease is one of
the best prognostic factors for early-stage
RCC. Five-year survival rates are included
in Table 1. A scoring system derived by
Leibovich et al may also be applied to
primary ccRCC and incorporates clinical
information as well as findings from
surgery in Stage I-III disease.9 The Furhman
grade is another prognostic measure
based on the appearance of the nucleus
in the tumour cells (Figure 2).10 In Stage IV
disease, the overall prognosis is predicted
by patients’ risk category and determined
by the efficacy of drug therapy. This is
further discussed below.
TREATMENT FOR STAGE I–III CANCER
Most RCCs are diagnosed at an early
stage, enabling definitive treatment of
the primary tumour.
Surgery
There are several surgical approaches
that may be pursued, depending on
the location and size of the tumour.
‘Radical’ nephrectomy, where the entire
kidney is removed, may be performed
laparoscopically (ie via keyhole surgery)
or with an open approach, and is
recommended for tumours >7cm.
Partial nephrectomy, often favoured
where conserving kidney function is a
priority, may require an open procedure.
Enlarged local lymph nodes are typically
removed at surgery.
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KIDNEY DISEASE
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Local therapies for small renal masses
In patients who have renal masses <3cm
in a peripheral location, ablative therapies
using heat (radiofrequency ablation; RFA)
or cold (cryo-ablation) may be employed.
Active surveillance
Given that many small primary RCCs
are incidentally picked up and can
demonstrate an indolent course of growth,
active surveillance of such lesions may be
the most appropriate course of action in a
patient whose risk of anaesthesia may not
justify early surgery.
TREATMENT FOR STAGE IV CANCER
When RCC spreads beyond the kidney it
typically goes to both local and distant
lymph nodes and to the bones, lungs,
liver and brain. Surgery to remove the
primary tumour, called a cytoreductive
nephrectomy (CN), is often undertaken
even in the setting of distant secondary
tumours, especially if it is causing pain or
bleeding. Very occasionally, spontaneous
regression of secondary tumours may
occur after a CN. Drug treatments are
the cornerstone of management in most
people with Stage IV disease.
Drug treatments
Much progress has been made in the
treatment of advanced (Stage IV) RCC
in the last 10 years. Prognostic scoring
systems have been developed based
on blood test results and the time to
development of secondary lesions.11,12
These classify patients into favourable,
intermediate and poor risk groups that
correlate with outcome in patients on
targeted therapies.
Oral tyrosine kinase inhibitors (TKIs),
such as sunitinib (Sutent) and pazopanib
(Votrient), improve survival in patients with
Stage IV RCC in comparison to the older,
more toxic interferon-alpha regimens.13,14
They target the vascular endothelial growth
factor (VEGF) receptor that allows tumours
to perpetuate growth by formation of new
blood vessels. There are other anti-VEGF
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Figure 2. Haematoxylin and eosin (H&E) staining of clear cell renal cell cancer. High grade
(left) and low grade (right) (photographs courtesy of Dr Samra Turajlic and Dr Jose Lopez)
oral therapies, namely axitinib (Inlyta) and
cabozantinib (Cometriq), that are effective
in patients whose tumours have progressed
on sunitinib or pazopanib.15,16 Side-effects
of the anti-VEGF TKIs include fatigue,
diarrhoea, high blood pressure, rash and
thyroid dysfunction. Many of these can
be managed with supportive medication,
dose interruptions or dose reductions. The
anti-VEGF TKIs are most effective in ccRCC;
responses in other types are inferior.17
Temsirolimus (Torisel) and everolimus
(Afinitor) are drugs that block the mammalian
target of rapamycin (mTOR) pathway, also
implicated in RCC development. Temsirolimus
has a demonstrated benefit in poor-prognosis
RCC compared to interferon-alpha.
Everolimus was previously the standard of
care for second-line treatment; however, its
use in this setting has now been superseded
by cabozantinib and nivolumab (Opdivo).
Side-effects of the mTOR inhibitor class
include lung inflammation, rash, poor
wound healing and diabetes.
Nivolumab is an immunotherapy that
helps expose RCC to the patient’s immune
system. Its use at present is in the second
or third line of treatment after progression
on an anti-VEGF TKI. The key advantage is
that, in a proportion of patients, durable
responses may occur beyond cessation of
treatment. Nivolumab is well tolerated,
although immune-related side-effects such
as colitis and hepatitis can occur.18
More specific information on the efficacy
of these drug treatments is summarised
in Table 2.
The median overall survival for metastatic
RCC is around 29 months; however, this
is likely to increase with the full range of
therapies now available.22 Whether there
is a gender difference in outcomes in the
metastatic population remains to be explored.
Other treatments for advanced disease
Radiotherapy may be effective to treat
bone pain or brain metastases. Occasionally,
RFA may also be used in the treatment
of lung metastases. In patients with low
volume advanced disease who fall into a
‘good’ prognostic category, a ‘watch and
wait’ approach may be adopted, with serial
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KIDNEY DISEASE
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Line of therapy
Drug
Mechanism of action
Proportion of patients
with tumour shrinkage
by ≥30%
Median duration of
therapeutic benefit
(months)
First
Sunitinib19
Anti-VEGF
24%
9.5
Anti-VEGF
31%
8.4
Temsirolimus
(in poor-prognosis RCC)
mTOR inhibition
9%
5.5
Axitinib15
Anti-VEGF
19%
6.7
Cabozantinib16
Anti-VEGF
(with anti-MET activity)
21%
7.4
Nivolumab18
Anti-PD-1
24%
4.6*
Lenvatinib with
everolimus21
Anti-VEGF with mTOR
inhibition
43%
14.6
Everolimus18
mTOR inhibition
5%
4.4
Nivolumab
Anti-PD-1
As for second line
As for second line
Cabozantinib
Anti-VEGF
(with anti-MET activity)
As for second line
As for second line
Pazopanib19
20
Second
Third
*Given the issues with use of standard response criteria in immunotherapy-treated patients, this figure likely underestimates the true
duration of benefit.
Table 2. Drug treatments for advanced renal cell cancer licensed in the UK
imaging to enable early initiation of drug
treatments upon any worrying progression.23
Adjuvant therapy
‘Adjuvant’ therapy in oncology aims to
reduce any microscopic cancer cells that
may remain after definitive treatment
(usually surgery) removes all visible disease.
Recent studies involving sunitinib have
shown conflicting results, and at present
there is no standard of care.24,25
Conclusion
RCC is one of the more common types of
cancer affecting men and may be silent
for a long period of time, leading to late
detection. Although drug treatments for
the control of advanced disease have
improved greatly in the last decade,
capturing early tumours amenable to
surgical resection gives the greatest
chance of long-term cure. Men and their
healthcare professionals should be aware
that persistent flank pain, blood in the
www.trendsinmenshealth.com
urine and unexplained malaise or weight
loss should prompt review, especially in the
context of a family history of RCC.
Declaration of interests: none declared.
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