Uro-Oncology Symposium: Moving to a New Horizon - EUA guidelines In Renal Carcinoma

2018-10-16 07:31:39 |

Provides up to date information with based evidence mangment fo diagnosing and mangment of renal tumours

EAU GUIDELINES ON RENAL CELL

CARCINOMA

Epidemiology

The use of imaging techniques such as ultrasound (US) and computerised tomography (CT) has increased the detection of asymptomatic renal cell cancer (RCC). The peak incidence of RCC occurs between 60 and 70 years of age, with a 3 : 2 ratio of men to women. Aetiological factors include lifestyle factors, such as smoking, obesity and hypertension. Having a first-degree relative with RCC is associated with a significantly increased risk of RCC.

Staging system

The current UICC 2017 TNM (Tumour Node Metastasis) classification is recommended for the staging of RCC (Table 1).

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Table 1: The 2017 TNM staging classification system

T - Primary Tumour

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

T1 Tumour ≤ 7 cm or less in greatest dimension, limited to the kidney

T1a	Tumour ≤ 4 cm or less
T1b	Tumour > 4 cm but ≤ 7 cm

T2 Tumour > 7 cm in greatest dimension, limited to the kidney

T2a	Tumour > 7 cm but ≤ 10 cm
T2b	Tumours > 10 cm, limited to the kidney

T3 Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia

T3a	Tumour grossly extends into the renal vein or
	its segmental (muscle-containing) branches, or
	tumour invades perirenal and/or renal sinus fat
	(peripelvic), but not beyond Gerota fascia
T3b	Tumour grossly extends into the vena cava below
	diaphragm
T3c	Tumour grossly extends into vena cava above the
	diaphragm or invades the wall of the vena cava

T4 Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)

N - Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in regional lymph node(s)

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M - Distant Metastasis

M0	No distant metastasis
M1	Distant metastasis
TNM stage grouping
Stage I		T1	N0	M0
Stage II		T2	N0	M0
Stage III		T3	N0	M0
		T1, T2, T3	N1	M0
Stage IV		T4	Any N	M0
		Any T	Any N	M1

Clinical Diagnosis

Many renal masses remain asymptomatic until late disease stages. The classic triad of flank pain, visible haematuria, and palpable abdominal mass is rare and correlates with aggressive histology and advanced disease.

Paraneoplastic syndromes are found in approximately 30% of patients with symptomatic RCCs. A few symptomatic patients present with symptoms caused by metastatic disease, such as bone pain or persistent cough.

Imaging

Computed tomography imaging, before and after intravenous contrast, can verify the diagnosis and provide information on the function and morphology of the contralateral kidney and assess tumour extension, including extra-renal spread, venous involvement, and enlargement of lymph nodes (LNs) and adrenals.

Abdominal US and magnetic resonance imaging (MRI) are supplements to CT. Contrast-enhanced US can be helpful in specific cases (e.g., chronic renal failure with a relative contraindication for iodinated or gadolinium-based

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contrast media, complex cystic masses, and differential diagnosis of peripheral vascular disorders such as infarction and cortical necrosis).

Magnetic resonance imaging can be used in patients with possible venous involvement, or allergy to intravenous contrast. Chest CT is the most accurate for chest staging and is recommended in the primary work–up of patients with suspected RCC.

In patients with hereditary RCC who are worried about the radiation exposure of frequent CT scans, MRI may be offered as alternative for follow-up imaging.

Biopsy

Percutaneous renal tumour biopsies are used:

to obtain histology of radiologically indeterminate renal masses;
to select patients with small renal masses for active surveillance;
to obtain histology before, or simultaneously with, ablative treatments;
to select the most suitable form of medical and surgical strategy in the setting of metastatic disease.

In patients with any sign of impaired renal function, a renal scan and total renal function evaluation using estimated glomerular filtration rate should always be undertaken to optimise the treatment decision.

Renal biopsy is not indicated for comorbid and frail patients who can be considered only for conservative management (watchful waiting) regardless of biopsy results.

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Recommendations for the diagnostic	Strength rating
assessment of renal cell cancer
Use multi-phasic contrast-enhanced	Strong
computed tomography (CT) of abdomen
and chest for the diagnosis and staging of
renal tumours.
Use magnetic resonance imaging to better	Weak
evaluate venous involvement, reduce
radiation or avoid intravenous CT contrast.
Use non-ionising modalities, mainly	Weak
contrast enhanced ultrasound, for further
characterisation of small renal masses,
tumour thrombus and differentiation of
unclear renal masses.
Do not routinely use bone scan and/or	Weak
positron-emission tomography (PET) CT
for staging of RCC.
Perform a renal tumour biopsy before	Strong
ablative therapy and systemic therapy
without previous pathology.
Perform a percutaneous biopsy in select	Weak
patients who are considered for active
surveillance.
Use a coaxial technique when performing	Strong
a renal tumour biopsy.
Do not perform a renal tumour biopsy of	Strong
cystic renal masses.
Use a core biopsy technique rather than	Strong
fine needle aspiration for histological
characterisation for solid renal tumours.

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Histological diagnosis

A variety of renal tumours exist, and about 15% are benign. All kidney lesions require examination for malignant behaviour.

Histopathological classification

The new WHO/ISUP classification will replace the Fuhrman nuclear grade system in due time but will need validation.

The three most common RCC subtypes, with genetic and histological differences, are: clear cell RCC (80-90%), papillary RCC (10-15%), and chromophobe RCC (4-5%). The various RCC types have different clinical courses and responses to therapy.

Prognostic factors

In all RCC types, prognosis worsens with stage and histopathological grade. Histological factors include tumour grade, RCC subtype, sarcomatoid features, microvascular invasion, tumour necrosis, and invasion of the perirenal fat and collecting system. Clinical factors include performance status (PS), local symptoms, cachexia, anaemia, platelet count, neutrophil/lymphocyte ratio, C-reactive protein and albumin.

Recommendations	Strength rating
Use the current Tumour, Node, Metastasis	Strong
classification system.
Use grading systems and classify RCC	Strong
subtype.
Use prognostic systems in the metastatic	Strong
setting.
In localised disease, use integrated	Strong
prognostic systems or nomograms to
assess risk of recurrence.

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Disease Management

Treatment of localised RCC

Localised renal cancers are best managed with partial nephrectomy (PN) rather than radical nephrectomy (RN), irrespective of the surgical approach. Partial nephrectomy is unsuitable in some patients with localised RCC due to:

locally advanced tumour growth;

unfavourable tumour location;

significant health deterioration.

If pre-operative imaging and intra-operative findings are normal, routine adrenalectomy is not indicated. Lymphadenectomy should be restricted to staging because the survival benefit of extended LN dissection is unclear in patients with localised disease. In patients who have RCCs with tumour thrombus and no metastatic spread, prognosis is improved after nephrectomy and complete thrombectomy.

Nephron-sparing surgery versus radical nephrectomy Based on current available oncological and quality of life outcomes, localised renal cancers are best managed by nephron-sparing surgery (NSS) rather than RN, irrespective of the surgical approach. Before routine nephrectomy, tumour embolisation has no benefit. In patients unfit for surgery with massive haematuria or flank pain, embolisation can be a beneficial palliative approach.

Recommendations	Strength rating
Offer surgery to achieve cure in localised	Strong
RCC.
Offer partial nephrectomy to patients with	Strong
T1 tumours.

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Do not perform ipsilateral adrenalectomy if	Strong
there is no clinical evidence of invasion of
the adrenal gland.
Consider an extended lymph node	Weak
dissection in patients with adverse clinical
features including a large diameter of the
primary tumour.
Offer embolisation in patients unfit for	Weak
surgery presenting with massive
haematuria or flank pain.
Radical- and partial nephrectomy techniques

Summary of evidence		LE
Laparoscopic RN has lower morbidity than open		1b
surgery.
Oncological outcomes for T1-T2a tumours are		2a
equivalent between laparoscopic and open RN.
Partial nephrectomy can be performed, either with an		2b
open, pure laparoscopic- or robot-assisted approach,
based on surgeon’s expertise and skills.
Partial nephrectomy is associated with a higher		3
percentage of positive surgical margins compared
with RN.

Recommendations	Strength rating
Offer laparoscopic radical nephrectomy (RN)	Strong
to patients with T2 tumours and localised
masses not treatable by partial
nephrectomy.

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Do not perform minimally invasive RN in	Strong
patients with T1 tumours for whom a partial
nephrectomy is feasible by any approach,
including open.
Do not perform minimally invasive surgery	Strong
if this approach may compromise
oncological, functional and perioperative
outcomes.

Alternatives to surgery

Surveillance

Elderly and comorbid patients with incidental small renal masses have a low RCC-specific mortality and significant competing-cause mortality. In selected patients with advanced age and/or comorbidities, active surveillance (AS) is appropriate to initially monitor small renal masses, followed, if required, by treatment for progression. The concept of AS differs from the concept of watchful waiting. Watchful waiting is reserved for patients whose comorbidities contraindicate any subsequent active treatment and who do not require follow-up imaging, unless clinically indicated.

Cryoablation and radiofrequency ablation

Currently there are no data showing oncological benefit of cryoablation or radiofrequency ablation (RFA) techniques over PN.

Recommendations	Strength rating
Offer active surveillance, radiofrequency	Weak
ablation and cryoablation to elderly and/or
comorbid patients with small renal masses.

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Treatment of locally advanced RCC

Management of clinically positive lymph nodes (cN+)

In the presence of clinically positive LNs (cN+), LND is always justified but the extent of LND is still controversial.

Low level data suggest that tumour thrombus in the setting of non-metastatic disease should be excised. Adjunctive procedures such as tumour embolisation or inferior vena cava filter do not appear to offer any benefits in the treatment of tumour thrombus.

In patients unfit for surgery, or with non-resectable disease, embolisation can control symptoms, including visible haematuria or flank pain. At present there is no evidence for the use of adjuvant therapy following surgery.

Treatment of advanced/metastatic RCC

Management of RCC with venous tumour thrombus

Recommendations	Strength rating
In patients with clinically enlarged lymph	Weak
nodes, perform lymph node dissection for
staging purposes or local control.
In case of venous involvement, remove the	Strong
renal tumour and thrombus.

Cytoreductive nephrectomy

Tumour nephrectomy is curative only if all tumour deposits are excised. This includes patients with the primary tumour in place and single- or oligo-metastatic resectable disease. For most patients with metastatic disease, cytoreductive nephrectomy is palliative and systemic treatments are necessary.

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Summary of evidence	LE
Cytoreductive nephrectomy combined with	1a
interferon-alpha (INF-α) improves survival in patients
with metastatic RCC and good performance status.
Deferred cytoreductive nephrectomy with presurgical	2b
sunitinib in intermediate-risk patients with clear-cell
metastatic RCC leads to a survival benefit in
secondary endpoint analysis and selects out patients
with inherent resistance to systemic therapy.
Cytoreductive nephrectomy for patients with	3
simultaneous complete resection of a single
metastasis or oligometastases may improve survival
and delay systemic therapy.
Patients with IMDC poor risk (≥ four risk factors) do	2b
not benefit.

Recommendations	Strength rating
Offer cytoreductive nephrectomy to	Weak
favourable- and intermediate-risk patients
with metastatic RCC (mRCC).
Do not offer cytoreductive nephrectomy	Weak
in IMDC poor-risk patients with ≥ four risk
factors.
Perform immediate cytoreductive	Weak
nephrectomy in patients with
oligometastases when complete resection
can be achieved.
Offer deferred cytoreductive nephrectomy	Weak
to intermediate-risk patients with clear-cell
mRCC who require systemic therapy with
sunitinib.

IMDC = The Metastatic Renal Cancer Database Consortium.

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Local therapy of metastases in metastatic RCC (mRCC)

A systematic review of the local treatment of metastases from RCC in any organ was undertaken. The heterogeneity of the data will only allow for cautious recommendations.

Summary of evidence	LE
All included studies were retrospective	3
non-randomised comparative studies, resulting in a
high risk of bias associated with non-randomisation,
attrition, and selective reporting.
With the exception of brain and possibly bone	3
metastases, metastasectomy remains by default the
only local treatment for most sites.
Retrospective comparative studies consistently point	3
towards a benefit of complete metastasectomy in
mRCC patients in terms of overall survival, cancer-
specific survival and delay of systemic therapy.
Radiotherapy to bone and brain metastases from RCC	3
can induce significant relief from local symptoms
(e.g. pain).

Recommendations	Strength rating
Offer local therapy for metastatic disease	Weak
(including metastasectomy) to patients
with a favourable disease profile in whom
complete resection is achievable or when
local symptoms need to be controlled.
Offer stereotactic radiotherapy for clinically	Weak
relevant bone or brain metastases for local
control and symptom relief.

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Systemic therapy for advanced/metastatic RCC Chemotherapy

Summary of evidence	LE
In metastatic RCC, 5-fluorouracil combined with	1b
immunotherapy has equivalent efficacy to INF-α.
In metastatic RCC, chemotherapy is otherwise not	3
effective with the exception of gemcitabine and
doxorubicine in sarcomatoid and rapidly progressive
disease.

Recommendation	Strength rating
Do not offer chemotherapy as first-line	Strong
therapy in patients with clear-cell
metastatic RCC.

Immunotherapy

Interferon-α may only be effective in some patient subgroups, including patients with clear-cell RCC (ccRCC), favourable-risk criteria, and lung metastases only. Interleukin-2 (IL-2), vaccines and targeted immunotherapy have no place in the standard treatment of advanced/mRCC.

Immune checkpoint inhibition of programmed death receptor (PD-1) and ligand (PD-L1) inhibition have been investigated in mRCC. Randomised data support the use of nivolumab

(a PD-1 inhibitor) in vascular endothelial growth factor (VEGF)-refractory disease. A combination of two immune checkpoint inhibitors ipilimumab and nivolumab versus sunitinib in a phase III study on metastatic RCC showed superior survival for a combination of ipilimumab and nivolumab in intermediate- and poor-risk patients.

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Summary of evidence	LE
Interferon-α monotherapy is inferior to VEGF-targeted	1b
therapy or mTOR inhibition in mRCC.
Interleukin (IL)-2 monotherapy may have an effect in	2a
selected cases (good PS, ccRCC, lung metastases only).
IL-2 has more side-effects than IFN-α.	2b
High-dose (HD)-IL-2 is associated with durable	1b
complete responses in a limited number of patients.
However, no clinical factors or biomarkers exist to
accurately predict a durable response in patients
treated with HD-IL-2.
Bevacizumab plus IFN-α is more effective than IFN-α	1b
in treatment-naïve, low-risk and intermediate-risk
ccRCC.
Vaccination therapy with tumour antigen 5T4 showed	1b
no survival benefit over first-line standard therapy.
Cytokine combinations, with or without additional	1b
chemotherapy, do not improve overall survival (OS)
compared with monotherapy.
Nivolumab leads to superior OS compared to	1b
everolimus in patients failing one or two lines of
VEGF-targeted therapy.
The combination of nivolumab and ipilimumab in	1b
treatment-naïve patients with clear-cell mRCC of
IMDC intermediate-and poor-risk leads to superior
survival compared to sunitinib.
The combination of nivolumab and ipilimumab in the	2b
intention to treat population of treatment-naïve
unselected patients with clear-cell mRCC leads to
superior survival compared to sunitinib.

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Due to the exploratory nature of PD-L1 tumour		2b
expression, the small sample size, the lack of OS data
and the premature results in this subpopulation,
definitive conclusions cannot be drawn.
Nivolumab plus ipilimumab was associated with 15%		1b
grade 3-5 toxicity and 1.5% treatment-related deaths.

Recommendations	Strength rating
Use ipilimumab plus nivolumab in	Strong
treatment-naïve patients with clear-cell
mRCC of IMDC intermediate and poor risk.
Offer nivolumab after one or two lines of	Strong
VEGF-targeted therapy in mRCC.
Do not offer monotherapy with interferon-α	Weak
or high-dose bolus interleukin-2 as first-line
therapy in mRCC.
Do not use bevacizumab plus INF-α in	Weak
treatment-naïve clear-cell favourable- and
intermediate-risk RCC patients.
Do not use PD-L1 tumour expression as a	Weak
predictive biomarker.
Administer nivolumab plus ipilimumab in	Weak
centres with experience of immune
combination therapy and appropriate
supportive care within the context of a
multidisciplinary team.
Do not rechallange patients who stop	Strong
nivolumab plus ipilimumab because of
toxicity with the same drugs in the future
without expert guidance and support from
a multidisciplinary team.

IMDC = The Metastatic Renal Cancer Database Consortium; VEGF = vascular endothelial growth factor.

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Targeted therapies

At present, several targeting drugs have been approved both for the treatment of mRCC.

Summary of evidence	LE
VEGF-targeted therapies increase progression-free	1b
survival (PFS) and/or OS as both first-line and second-
line treatments for patients with clear-cell mRCC.
Cabozantinib in intermediate-and poor-risk treatment-	1a
naïve clear-cell RCC leads to better response rates
and PFS but not OS when compared to sunitinib.
Tivozanib has recently been approved but the	3
evidence is still considered inferior over existing
choices.
Axitinib has proven efficacy and superiority in PFS as	1b
a second-line treatment after failure of cytokines and
VEGF-targeted therapy in comparison with sorafenib.
Sunitinib is more effective than IFN-α in treatment-	1b
naïve patients.
In treatment-naïve patients, bevacizumab in	1b
combination with INF-α has not been tested against
nivolumab plus ipilimumab and the evidence for
subsequent therapies is unclear.
Pazopanib is superior to placebo in both treatment-	1b
naïve mRCC patients and post-cytokine patients.
First-line pazopanib is not inferior to sunitinib in clear-	1b
cell mRCC patients.
Temsirolimus monotherapy prolongs OS compared to	1b
IFN-α in treatment-naïve poor-risk mRCC.
In treatment-naïve patients, temsirolimus has not	3
been tested against nivolumab plus ipilimumab and
the evidence for subsequent therapies is unclear.

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Cabozantinib is superior to everolimus in terms of		1b
PFS and OS in patients after one or more lines of
VEGF-targeted therapy.
Everolimus prolongs PFS after VEGF-targeted therapy		1b
when compared to placebo or when the patient
cannot tolerate these therapies.
Sorafenib has broad activity in a spectrum of settings		4
in ccRCC patients previously treated with cytokine or
targeted therapies. It is inferior to axitinib in both
sunitinib or cytokine pre-treated patients.
Both mTOR inhibitors (everolimus and temsirolimus)		2a
and VEGF-targeted therapies (sunitinib or sorafenib)
have limited oncological efficacy in non-clear cell RCC.
There is a non-significant trend for improved
oncological outcomes for sunitinib, over everolimus.
Lenvatinib in combination with everolimus modestly		2a
improved PFS over everolimus alone.

Recommendations	Strength rating
Use sunitinib or pazopanib in treatment-	Strong
naïve patients with clear-cell mRCC of
IMDC favourable risk.
Use cabozantinib in treatment-naïve	Weak
patients with clear-cell mRCC of IMDC
intermediate and poor risk.
Do not use bevacizumab plus INF-α in	Weak
treatment-naïve clear-cell favourable- and
intermediate-risk RCC patients.
Do not use tivozanib in treatment-naïve	Weak
clear-cell mRCC patients.
Do not use temsirolimus in treatment-naïve	Weak
clear-cell poor-risk RCC patients.

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Use VEGF-TKIs in second-line in patients	Weak
refractory to nivolumab plus ipilimumab.
Offer cabozantinib for ccRCC after one	Strong
or two lines of VEGF-targeted therapy in
mRCC.
Offer axitinib, everolimus or lenvatinib plus	Strong
everolimus to ccRCC patients who failed
VEGF-targeted therapy, and when
nivolumab or cabozantinib are not safe,
tolerable or available.
Sequence systemic therapy in treating	Strong
mRCC.
Offer sunitinib as first-line therapy for	Weak
non-clear cell mRCC.
Do not offer sorafenib as second-line	Weak
treatment to patients with mRCC.

IMDC = The Metastatic Renal Cancer Database Consortium; VEGF = vascular endothelial growth factor.

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Figure 1: Updated EAU Guidelines recommendations for the treatment of first-line clear-cell metastatic renal cancer.

	First-line therapy	Second-line therapy	Third-line therapy

IMDC favourable	suni nib or	cabozan nib or	cabozan nib or
risk disease	pazopanib	nivolumab	nivolumab


	ipilimumab/	cabozan nib or	cabozan nib or an
	ipilimumab/	VEGF-targeted	alterna ve targeted
	nivolumab	VEGF-targeted	alterna ve targeted
IMDC intermediate	nivolumab	therapy	therapy
IMDC intermediate		therapy	therapy
and poor risk
disease	cabozan nib,	VEGF targeted	An alterna ve
	cabozan nib,	VEGF targeted	An alterna ve
	suni nib or	therapy or	targeted therapy or
	pazopanib*	nivolumab	nivolumab

Boxed categories represent strong recommenda ons

IMDC = The International Metastatic Renal Cell Carcinoma Database Consortium; VEGF = vascular endothelial growth factor.

*pazopanib for intermediate-risk disease only.

Recurrent RCC

Locally recurrent disease can occur either after nephrectomy, PN, or after ablative therapy. After nephron-sparing treatment approaches the recurrence may be intra-renal or regional, e.g. venous tumour thrombi or retroperitoneal LN metastases.

Isolated local recurrence in the true renal fossa is rare. Patients can benefit from a complete surgical resection of local recurrent disease. In cases where complete surgical removal is not feasible due to advanced tumour growth and pain, palliative treatments including radiation treatment can be considered.

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Surveillance following surgery for RCC

The aim of surveillance is to detect either local recurrence or metastatic disease while the patient is still surgically curable. Surveillance after treatment for RCC allows the urologist to identify:

postoperative complications;

renal function;

local recurrence;

recurrence in the contralateral kidney;

development of metastases.

Depending on the availability of new effective treatments, more intensive follow-up schedules may be required, particularly as there is a higher local recurrence rate after cryotherapy and RFA. At present there is no evidence-based standard for the follow-up of patients with RCC, or for the optimal duration of follow-up. An example of a surveillance algorithm monitoring patients after treatment for RCC that recognises not only the patient’s risk profile but also treatment efficacy is provided in Table 2. For patients with metastatic disease, individualised follow-up is indicated.

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Table 2: Proposed surveillance schedule following treatment for RCC, taking into account patient risk profile and treatment efficacy

Risk profile				Surveillance
	6 mo	1 y	2 y	3 y	> 3 y
Low	US	CT	US	CT	CT once every 2 years;
					counsel about recurrence
					risk of ~10%
Intermediate	CT	CT	CT	CT	CT once every 2 years

CT = computed tomography of chest and abdomen, alternatively use magnetic resonance imaging for the abdomen; US = ultrasound of abdomen, kidneys and renal bed.

Summary of evidence and recommendations for surveillance following RN or PN orablative therapies in RCC

Summary of evidence	LE
Surveillance can detect local recurrence or metastatic	4
disease while the patient is still surgically curable.
After NSS, there is an increased risk of recurrence for	3
larger (> 7 cm) tumours, or when there is a positive
surgical margin.
Patients undergoing surveillance have a better overall	3
survival than patients not undergoing surveillance.
Repeated CT scans do not reduce renal function in	3
chronic kidney disease patients.

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Recommendations			Strength rating
Base follow-up after RCC on the risk of			Strong
recurrence.
Intensify follow-up in patients after NSS			Weak
for tumours > 7 cm or in patients with a
positive surgical margin.
Base risk stratification on pre-existing			Strong
classification systems such as the
University of California Los Angeles
integrated staging system integrated risk
assessment score
(http://urology.ucla.edu/body.cfm?id=443).

This short booklet text is based on the more comprehensive

EAU Guidelines (ISBN: 978-94-92671-01-1), available to all members of the European Association of Urology at their website: http://www.uroweb.org/guidelines/.

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Uro-Oncology Symposium: Moving to a New Horizon - EUA guidelines In Renal Carcinoma

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