GENITOURINARY CANCERS - ESMO POCKET GUIDELINE - 2024

Genitourinary
Cancers
Pocket Guideline 2024
Distributed with support from Novartis Pharma AG.
Novartis Pharma AG has not influenced the content of this publication.
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ESMO POCKET GUIDELINES
GUIDELINES COMMITTEE
Chair: Elizabeth Smyth; Deputy Chair: Emanuela Romano; Subject Editors: Teresa Amaral, Paolo Ascierto, Kjetil
Boye, Michel Ducreux, Caroline Even, Karim Fizazi, Nadia Harbeck, Mats Jerkeman, Angela Lamarca, Natasha
Leighl, Ana Oaknin, Sanjay Popat, Christina Ruhlmann; International Coordinator of Guidelines Adaptation in
Asia Pacific: Takayuki Yoshino; Staff: Tiziana Aske, Claire Bramley, Sammi Cham, Sarah Edwards, Lisa Farrar,
Svetlana Jezdic, Lone Kristoffersen, Valérie Laforest, Keith McGregor, Ioanna Ntai, George Pentheroudakis, Kiley
Pitsos, Hayley Redston, Francesco Rho. Medical writing support: Kstorfin Medical Communications (KMC) Ltd.
ESMO CLINICAL PRACTICE GUIDELINES

Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Powles T, Albiges L, Bex A, Comperat E, Grünwald V, Kanesvaran R, Kitamura H, McKay R, Porta C, Procopio G,
Schmidinger M, Suarez C, Teoh J, de Velasco G, Young M and Gillessen S, on behalf of the ESMO Guidelines
Committee
Ann Oncol 2024;35(8):692-706
https://www.annalsofoncology.org/article/S0923-7534(24)00676-8/fulltext
Penile cancer: ESMO–EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up
Muneer A, Bandini M, Compérat E, De Meerleer G, Fizazi K, Gietema J, Gillessen S, Kirkham A, Sangar V,
Alifrangis C and Powles T, on behalf of the ESMO Guidelines Committee
ESMO Open 2024;9(7):103481
https://www.esmoopen.com/article/S2059-7029(24)01250-X/fulltext
Testicular seminoma and non-seminoma: ESMO–EURACAN Clinical Practice Guideline for
diagnosis, treatment and follow-up
Oldenburg J, Berney DM, Bokemeyer C, Climent MA, Daugaard G, Gietema JA, De Giorgi U, Haugnes HS,
Huddart RA, Leão R, Sohaib A, Gillessen S and Powles T, on behalf of the ESMO Guidelines Committee and
EURACAN
Ann Oncol 2022;33(4):362-75
Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, Necchi A, Valderrama BP, Ravaud A,
Shariat SF, Szabados B, van der Heijden MS and Gillessen S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2022;33(3):244-58
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ESMO POCKET GUIDELINES (CONT’D)
ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial
carcinoma
Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, Necchi A, Valderrama BP, Ravaud A,
Shariat SF, Szabados B, van der Heijden MS and Gillessen S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2024;35(6):485-90
Prostate cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, Tombal B and Gillessen S, on behalf of the ESMO
Guidelines Committee
Ann Oncol 2020;31(9):1119-34
Updated treatment recommendations for prostate cancer from the ESMO Clinical Practice
Guideline considering treatment intensification and use of novel systemic agents
Fizazi K and Gillessen S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2023;34(6):557-63
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ESMO GUIDE TO EVALUATION OF DATA
ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE

FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN
EASILY ACCESSIBLE FORMAT.
This quick reference booklet provides you with the most important content of the
ESMO Clinical Practice Guidelines (CPGs) on the management of genitourinary (GU)
cancers (including renal cell carcinoma, penile cancer, testicular seminoma and
non-seminoma, bladder cancer and prostate cancer). Key content includes diagnostic
criteria, staging of disease, treatment plans and follow-up. The ESMO CPGs on GU
cancers are intended to provide you with a set of recommendations for the best
standards of care for GU cancers, using evidence-based medicine. Implementation
of ESMO CPGs facilitates knowledge uptake and helps you to deliver an appropriate
quality of focused care to your patients.
The approval and licensed indication of drugs mentioned in this pocket guideline may
vary in different countries. Please consult your local prescribing information. This
booklet can be used as a quick reference guide to access key content on evidence-
based management of GU cancers.
Please visit http://www.esmo.org to view the full guidelines.
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TABLE OF CONTENTS
11-22
RENAL CELL CARCINOMA (RCC)

DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY................................................... 11
STAGING AND RISK ASSESSMENT............................................................................... 12
TREATMENT................................................................................................................. 14
Management of local and locoregional RCC................................................................ 14
Management of advanced and metastatic RCC........................................................... 16
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP..................................... 22
23-37
PENILE CANCER
DIAGNOSIS AND PATHOLOGY....................................................................................... 23
Diagnosis..................................................................................................................... 23
Pathology..................................................................................................................... 24
STAGING....................................................................................................................... 26
TREATMENT................................................................................................................. 28
Management of local and locoregional penile cancer................................................. 28
Management of advanced and metastatic penile cancer............................................ 35
38-50
TESTICULAR CANCER
DIAGNOSIS................................................................................................................... 38
Pathology..................................................................................................................... 39
TREATMENT................................................................................................................. 42
Management of locoregional testicular cancer........................................................... 42
Management of metastatic testicular cancer.............................................................. 46
PERSONALISED MEDICINE........................................................................................... 48
Survivorship care plan................................................................................................. 50
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TABLE OF CONTENTS (CONT’D)
51-63
BLADDER CANCER
DIAGNOSIS................................................................................................................... 51
Pathology/molecular biology....................................................................................... 52
TREATMENT................................................................................................................. 56
Management of local/locoregional bladder cancer..................................................... 56
Management of advanced/metastatic bladder cancer................................................ 60
FOLLOW-UP AND LONG-TERM IMPLICATIONS.............................................................. 62
Non-muscle-invasive bladder cancer.......................................................................... 62
Muscle-invasive bladder cancer.................................................................................. 62
Advanced/metastatic bladder cancer.......................................................................... 63
64-76
PROSTATE CANCER
SCREENING.................................................................................................................. 64
DIAGNOSIS AND PATHOLOGY....................................................................................... 64
MANAGEMENT OF LOCAL/LOCOREGIONAL PROSTATE CANCER................................... 68
Neoadjuvant and adjuvant hormone treatment........................................................... 68
Postoperative radiotherapy.......................................................................................... 71
Treatment of relapse after radical local treatment...................................................... 72
METASTATIC HORMONE-NAIVE PROSTATE CANCER..................................................... 72
NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER................................ 74
METASTATIC CASTRATION-RESISTANT PROSTATE CANCER......................................... 74
PRECISION MEDICINE................................................................................................... 75
PALLIATIVE CARE......................................................................................................... 76
FOLLOW-UP AND LONG-TERM IMPLICATIONS.............................................................. 76
77-79
GLOSSARY
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RENAL CELL CARCINOMA
DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

• The initial presentation of renal cell carcinoma (RCC), based on the classic triad of flank
pain, gross haematuria and palpable abdominal mass, has been largely replaced by
incidental detection
• Patients with suspected RCC should have appropriate investigations with cross-sectional
imaging, histopathology analysis and laboratory tests
• A suggested diagnostic work-up of suspected RCC is shown in the figure below
DIAGNOSTIC WORK-UP OF RCC
Investigations for suspected RCC
Detection of renal mass (incidental finding

or on imaging carried out for suspicion)
Contrast-enhanced CT of the chest, abdomen and pelvis for staging

Consider neuroimaging and bone scan
Localised disease Advanced disease
PN or RN (or percutaneous
Percutaneous biopsy of renal
biopsy of renal mass if
mass or metastatic site for
non-surgical management)
histopathological confirmation
for histopathological confirmation
CT, computed tomography; PN, partial nephrectomy; RCC, renal cell carcinoma; RN, radical nephrectomy
• Neuroimaging [computed tomography (CT) or magnetic resonance imaging] and a

bone scan are desirable before starting systemic therapy for advanced disease
° Positron emission tomography (PET) is not recommended for routine staging or
assessment of RCC
9
• Laboratory assessment of serum creatinine, haemoglobin, leukocyte and platelet counts,
lymphocyte-to-neutrophil ratio and serum-corrected calcium should be carried out
° These tests are used in prognostic scoring systems and treatment selection for
advanced disease, including the International Metastatic RCC Database Consortium
(IMDC) score
• Histopathology analysis should be carried out to determine tumour subtype and results
should be available before starting systemic treatment
• The recent molecular-driven renal tumour classification from the World Health
Organization, based on molecular analysis techniques that are not currently widely
available, is not routinely required
° Instead, attention should be given to established subtypes with well-defined
treatment algorithms, such as clear-cell RCC (ccRCC) and papillary RCC (pRCC)
• Genetic assessment is recommended for younger patients, those with multiple or
bilateral lesions, those with first- or second-degree relatives who have had RCC, those
with related disorders associated with known predisposing conditions and those who
have exhausted standard therapeutic options
STAGING AND RISK ASSESSMENT

• Staging should follow the Union for International Cancer Control (UICC)
tumour–node–metastasis (TNM) eighth edition, as shown in the tables below and
opposite
STAGING OF RCC ACCORDING TO THE UICC TNM EIGHTH EDITION

PRIMARY TUMOUR (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour ≤ 7 cm in greatest dimension, limited to the kidney
T1a Tumour ≤ 4 cm
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 Tumour > 10 cm, limited to the kidney
Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal
T3
gland and not beyond the Gerota fascia
Tumour grossly extends into the renal vein or its segmental (muscle containing) branches,
T3a or tumour invades the perirenal and/or renal sinus fat (peripelvic) fat but not beyond the
Gerota fascia
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T3b Tumour extends into the vena cava below the diaphragm
T3c Tumour extends into the vena cava above the diaphragm or invades the wall of the vena cava
Tumour invades beyond the Gerota fascia (including contiguous extension into the ipsilateral
T4
adrenal gland)
REGIONAL LYMPH NODES (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in regional lymph node(s)
DISTANT METASTASIS (M)
M0 No distant metastasis
M1 Distant metastasis
M, metastasis; N, node; RCC, renal cell carcinoma; T, tumour; TNM, tumour–node–metastasis; UICC, Union for International
Cancer Control
Brierley J et al. TNM classification of malignant tumours, 8th edition. John Wiley & Sons, Ltd, Oxford, UK; 2017. Reprinted with
permission
STAGE GROUPING FOR RCC ACCORDING TO THE UICC TNM EIGHTH EDITION
STAGE GROUPING T STAGE N STAGE M STAGE
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage III
T1, T2, T3 N1 M0
T4 Any N M0
Stage IV
Any T Any N M1
M, metastasis; N, node; RCC, renal cell carcinoma; T, tumour; TNM, tumour–node–metastasis; UICC, Union for International
Cancer Control
Brierley J et al. TNM classification of malignant tumours, 8th edition. John Wiley & Sons, Ltd, Oxford, UK; 2017. Reprinted with
permission
• Prognostic scoring systems should be used to assess risk both in operable and
advanced disease
• For operable disease, the TNM prognostic classification used in the KEYNOTE-564
study is the preferred risk classification
° Intermediate–high-risk disease is defined as:
– Pathological (p)T2, grade 4 or sarcomatoid, N0, M0; or
– pT3, any grade, N0, M0
° High-risk disease is defined as:
– pT4, any grade, N0, M0; or
– any pT, any grade, lymph node positive, M0
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• For advanced disease, the IMDC score is a useful tool for predicting prognosis
° This system uses six clinical and laboratory risk factors to produce three risk
categories: Favourable, intermediate and poor
° The risk category can be used to estimate prognosis and guide treatment decisions
for first-line therapy and beyond
• Gene expression panels can identify high-risk disease in operable cases and can
potentially identify angiogenic versus immunogenic tumours in advanced disease;
however, these are not applicable for routine use
• Programmed death-ligand 1 (PD-L1) has been unreliable as a biomarker in RCC, and
serum and urine biomarkers are experimental
TREATMENT
Management of local and locoregional renal cell carcinoma
• Treatment options for local and locoregional RCC are shown in the figure opposite
• Surgical resection remains the standard of care (SoC) for localised RCC
° Preference for minimally invasive or open approaches depends on tumour size and
complexity of the required surgery
• Partial nephrectomy (PN) is the preferred option in organ-confined tumours measuring
≤ 7 cm
° PN can be carried out via open, laparoscopic or robot-assisted laparoscopic approaches
° If PN is not technically feasible, conventional or robot-assisted laparoscopic radical
nephrectomy (RN) is recommended
° A nephron-sparing strategy, including PN, is the SoC in patients with compromised
renal function, solitary kidney or bilateral tumours
° Several nephron-sparing options, ranging from surveillance to PN, are recommended
for small renal masses (T1 ≤ 4 cm)
° Radiofrequency ablation, stereotactic body radiotherapy (SBRT), microwave ablation
and cryoablation are non-surgical options, particularly for patients with small cortical
tumours
• Minimally invasive RN is the preferred option for T2 tumours > 7 cm
• Open RN is the SoC for complex T3 and T4 tumours requiring surgery, although robotic
and laparoscopic approaches can be considered
• Belzutifan may avoid surgeries and can be considered for patients with germline von
Hippel–Lindau (VHL) variants and localised renal cancer [Food and Drug Administration
(FDA) approved, not European Medicines Agency (EMA) approved]
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MANAGEMENT OF LOCAL AND LOCOREGIONAL RCC
Local and locoregional RCC
Non-surgical options
T1 (≤ 7 cm) T2 (> 7 cm) T3 and T4 for small renal VHL-associated RCC
masses (≤ 4 cm)*
PN (preferred) RN (minimally invasive Open RN (laparoscopic RFA Nephron-sparing

RN preferred) can be considered) SBRT Belzutifan‡ surgery
MWA
CA
Active surveillance
Consider adjuvant
pembrolizumab†
*For example, in cases of high surgical risk, patient frailty, solitary kidney, compromised renal function, hereditary RCC or bilateral tumours
†
If appropriate at final histology (e.g. T2 with nuclear grade 4 or sarcomatoid differentiation, ≥ T3 or regional lymph node metastasis)
‡
FDA approved, not EMA approved
CA, cryoablation; EMA, European Medicines Agency; FDA, Food and Drug Administration; MWA, microwave ablation; PN, partial nephrectomy; RCC, renal cell carcinoma; RFA, radiofrequency
ablation; RN, radical nephrectomy; SBRT, stereotactic body radiotherapy; T, tumour; VHL, von Hippel–Lindau syndrome
13
• Adjuvant pembrolizumab should be considered for patients with intermediate–high- or
high-risk operable ccRCC (as defined by KEYNOTE-564 criteria) after careful patient
counselling regarding potential long-term adverse events
° Treatment should start within 12 weeks of surgery and continue for up to 1 year
• Adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapies are
not recommended
Management of advanced and metastatic renal cell carcinoma
Management of advanced and metastatic ccRCC
Role of surgery and local therapy
• Cytoreductive nephrectomy (CN) should usually be avoided in advanced RCC and
should only be considered for selected patients with favourable- or intermediate-risk
disease after multidisciplinary team (MDT) review
° Deferred CN is an option for patients with durable and near complete response at
metastatic sites following systemic therapy after MDT review
• Metastasectomy, thermal ablation, stereotactic radiosurgery, SBRT, CyberKnife
radiotherapy (RT) and hypofractionated RT can be considered for selected patients
with low metastatic burden after MDT review
° These treatments typically focus on a single site of disease
• Patient selection for local therapies or surveillance in the metastatic setting should be
discussed by an MDT
° Both strategies should be avoided in patients with a high burden of metastases,
short interval to recurrence or aggressive disease
• Adjuvant pembrolizumab can be offered to patients with oligometastatic disease who
have undergone complete resection (M1 and no evidence of disease)
Systemic treatment of advanced and metastatic ccRCC
• Systemic treatment options for advanced and metastatic ccRCC are shown in the
figure opposite
First-line treatment of advanced and metastatic ccRCC
• Lenvatinib–pembrolizumab, axitinib–pembrolizumab or cabozantinib–nivolumab is
recommended for first-line treatment of advanced ccRCC, irrespective of IMDC risk group
° There is no preferred VEGFR tyrosine kinase inhibitor (TKI)–anti-programmed cell
death protein 1 (PD-1) combination
• Ipilimumab–nivolumab is recommended as first-line treatment for IMDC intermediate-
and poor-risk disease and is an option for favourable-risk disease
14
SYSTEMIC TREATMENT OF ADVANCED AND METASTATIC ccRCC
Advanced and metastatic ccRCC
Favourable-risk disease Intermediate- or poor-risk disease
Lenvatinib–pembrolizumab
Axitinib–pembrolizumab Lenvatinib–pembrolizumab
Cabozantinib–nivolumab Axitinib–pembrolizumab
Ipilimumab–nivolumab Cabozantinib–nivolumab
Sunitinib Ipilimumab–nivolumab
Pazopanib Axitinib–toripalimab*
Tivozanib
A VEGFR TKI that has not been given previously

Cabozantinib
Axitinib
Lenvatinib–everolimus
Pazopanib
Sunitinib
Tivozanib
Belzutifan†
A VEGFR TKI that has not been given previously

Belzutifan†
Everolimus
*Not EMA or FDA approved

†
FDA approved, not EMA approved
ccRCC, clear-cell renal cell carcinoma; EMA, European Medicines Agency; FDA, Food and Drug Administration; TKI, tyrosine
kinase inhibitor; VEGFR, vascular endothelial growth factor receptor
• Axitinib–toripalimab is a first-line option for patients with intermediate- or poor-risk

disease (combination not EMA or FDA approved)
• Sunitinib, pazopanib and tivozanib as first-line monotherapy are potential alternatives to
immune checkpoint inhibitor (ICI)-based combinations in IMDC favourable-risk disease
due to a lack of clear superiority for VEGFR TKI–anti-PD-1 combinations over sunitinib
15
• Axitinib–avelumab is not associated with an overall survival (OS) benefit compared
with sunitinib and is therefore not recommended over single-agent VEGFR TKI therapy
• Surveillance is an alternative approach in a small, undefined subset of patients with
favourable-risk disease, but this approach requires careful consideration
• Cessation of ICIs should be considered after 2 years
• Treatment breaks from VEGFR TKI therapy do not appear to have any detrimental effect
on efficacy
Second-line treatment of advanced and metastatic ccRCC
• Sequencing VEGFR TKI therapy after first-line ICI-based combination therapy is the SoC
° VEGFR TKIs that have not been previously used should be considered
° Cabozantinib is the preferred agent for second-line treatment
° Axitinib, lenvatinib–everolimus, pazopanib, sunitinib and tivozanib are also options
• Further ICI therapy after first-line ICI-based combination therapy is not recommended
and is potentially harmful
• Belzutifan is an alternative option for patients who have progressed on ICI-based
combination therapy (FDA approved, not EMA approved)
Third-line treatment of advanced and metastatic ccRCC
• Sequencing VEGFR TKI therapy or belzutifan (FDA approved, not EMA approved) can be
recommended
• Belzutifan should be considered instead of everolimus in heavily pretreated patients
(after first-line ICI-based combination therapy and second-line VEGFR TKI therapy)
(FDA approved, not EMA approved)
• Everolimus remains an option for patients who have received first-line ICI-based
combination therapy and second-line VEGFR TKI therapy, but other approaches are
preferable
° Everolimus should be considered when other approaches, such as belzutifan or other
VEGFR TKIs, are not available
• The use of further anti-PD-1 or anti-PD-L1-targeted therapy after progression on
first-line ICI-based combination therapy is not recommended
Treatment of advanced and metastatic ccRCC when ICIs are unsuitable
• Treatment options for advanced and metastatic ccRCC when ICIs are unsuitable or not
available are shown in the figure opposite
16
SYSTEMIC TREATMENT OF ADVANCED AND METASTATIC ccRCC WHEN ICIS ARE
CONTRAINDICATED OR NOT AVAILABLE
Advanced and metastatic ccRCC
ICIs contraindicated or not available
Sunitinib
Pazopanib
Tivozanib
Cabozantinib (intermediate- or poor-risk disease)
Nivolumab (if available and ICIs not contraindicated)

Cabozantinib
Axitinib
Everolimus
Lenvatinib–everolimus
ccRCC, clear-cell renal cell carcinoma; ICI, immune checkpoint inhibitor
• Sunitinib, pazopanib and tivozanib are alternatives to first-line ICI-based combination

therapy when ICI therapy is contraindicated or not available
° Cabozantinib is also an alternative in IMDC intermediate- and poor-risk disease for
those patients who cannot receive first-line ICI-based combination therapy
• For patients who received first-line VEGFR TKI monotherapy, nivolumab (if available
and not contraindicated) and cabozantinib are both associated with an OS benefit
° Axitinib, everolimus and lenvatinib–everolimus are also options
Management of advanced and metastatic pRCC
• The role of CN and other surgical techniques is not clearly defined in metastatic pRCC
° Surgery may be appropriate for intermediate-risk disease
° Patients with poor-risk disease are unlikely to derive benefit and surgery should be
avoided
° There is no consensus on the definition of patients who should be considered for
surgery
• Systemic treatment options for advanced and metastatic pRCC are shown in the figure
on the next page
17
SYSTEMIC TREATMENT OF ADVANCED AND METASTATIC pRCC
Advanced and metastatic pRCC
Preferred:
Cabozantinib
Alternative single-agent options:
Sunitinib
Pembrolizumab*
Alternatives to single-agent therapy:
Cabozantinib–nivolumab
A systemic therapy that has not been given previously

Cabozantinib
Sunitinib
Everolimus
Pembrolizumab*
*Not EMA or FDA approved for use as single-agent therapy

EMA, European Medicines Agency; FDA, Food and Drug Administration; pRCC, papillary renal cell carcinoma
• Cabozantinib is the preferred first-line monotherapy for advanced pRCC without

additional molecular testing
° Alternative single-agent options include sunitinib and pembrolizumab (not EMA or
FDA approved for use as single-agent therapy)
• Lenvatinib–pembrolizumab and cabozantinib–nivolumab have impressive response
rates but are not proven to be superior to single-agent therapy
° These may be considered as alternatives to single-agent therapy
• Data from small, randomised studies have suggested that the MET inhibitor savolitinib
is active in the first-line treatment of MET-altered pRCC; however, further randomised
data are needed and savolitinib cannot currently be recommended in this setting (not
EMA or FDA approved)
• Second-line therapy may focus on agents that have not been used previously
° Options include cabozantinib, sunitinib, everolimus and pembrolizumab (not EMA or
FDA approved for use as single-agent therapy)
° Best supportive care alone can be considered in selected patients due to the lack of
data for systemic therapy
18
Management of advanced and metastatic non-clear-cell and non-papillary RCC
• There is a lack of data to guide management of non-clear-cell, non-papillary RCC
histologies; therefore, enrolment into clinical trials is strongly recommended
• Surgery is used in intermediate-risk advanced disease; however, there is no available
evidence to support this approach as a recommendation
• Systemic treatment options for advanced and metastatic non-clear-cell and non-
papillary RCC are shown in the figure below
SYSTEMIC TREATMENT OF ADVANCED AND METASTATIC NON-CLEAR-CELL AND

NON-PAPILLARY RCC
Advanced and metastatic

non-clear-cell and non-papillary RCC
Clinical trial if available
Chromophobe Collecting duct and medullary Sarcomatoid (predominant)
Ipilimumab–nivolumab
Sunitinib
Cisplatin-based ChT regimen Axitinib–pembrolizumab
Pazopanib
Sunitinib Cabozantinib–nivolumab
Lenvatinib–everolimus*
Pazopanib Lenvatinib–pembrolizumab
Everolimus*
Cabozantinib Sunitinib
Pazopanib
*Not EMA or FDA approved for first-line treatment

ChT, chemotherapy; EMA, European Medicines Agency; FDA, Food and Drug Administration; RCC, renal cell carcinoma
• Sunitinib, pazopanib, lenvatinib–everolimus (not EMA or FDA approved for first-

line treatment), everolimus (not EMA or FDA approved for first-line treatment) and
lenvatinib–pembrolizumab may be used for advanced chromophobe RCC
• Cisplatin-based chemotherapy is recommended for collecting duct carcinomas and
switch/sucrose non-fermentable-related matrix-associated actin-dependent regulator
of chromatin subfamily B member 1 (SMARCB1)-deficient RCC
° Sunitinib, pazopanib and cabozantinib are alternative options
19
• ICI-based therapies including ipilimumab–nivolumab, axitinib–pembrolizumab,
cabozantinib–nivolumab and lenvatinib–pembrolizumab are preferred for advanced
RCC with sarcomatoid (predominant) histology
° Sunitinib and pazopanib are alternative options for patients with contraindications to
ICI-based therapy
• Bevacizumab–erlotinib may be used in advanced fumarate hydratase-deficient RCC
(not EMA or FDA approved)
• After first-line therapy, no recommendations are possible for subsequent lines of
therapy due to a lack of robust data
Role of RT and bisphosphonates
• RT can provide symptom palliation and local control of disease, including in cases of
oligometastatic disease or mixed response to ICIs and/or targeted therapies
• RT is also an effective treatment for palliation and prevention of disease progression in
critical sites such as the bones or brain
° Stereotactic RT is recommended for patients with brain metastases
° Whole-brain RT is associated with cognitive dysfunction and should be avoided
• Zoledronic acid or denosumab can be considered in patients with bone metastases
after assessment of individualised risk
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

• There is no robust evidence to guide recommendations for the frequency of follow-up
imaging in early- or advanced-stage RCC
• After nephrectomy, a risk-based follow-up approach should be considered, with
imaging for ≥ 2 years
° For patients with high-risk disease, CT scans of the thorax and abdomen should be
carried out every 3-6 months for the first 2 years regardless of whether adjuvant
pembrolizumab is used
° For patients with low-risk disease, annual CT scans are likely sufficient
° Continuation of imaging for up to 5 years can be considered, although the benefits
after 2 years are unclear
• In advanced disease, CT scans should be considered every 2-4 months to assess
response to therapy
° Radiological response may be evaluated in conjunction with clinical assessment
20
PENILE CANCER
DIAGNOSIS AND PATHOLOGY

Diagnosis
• The most common tumour affecting the penis is squamous cell carcinoma (SCC)
• A suggested diagnostic work-up of penile cancer is shown in the figure below
DIAGNOSTIC WORK-UP OF PENILE CANCER
Diagnostic work-up of penile cancer
Assessment of the primary tumour:

Clinical assessment, including size, morphology, relationship with adjacent structures
In cases of uncertainty, MRI or US combined with an intracavernosal injection of
prostaglandin E1 can be useful
Assessment of regional LNs:

Impalpable inguinal LNs: US and FNAC
Palpable inguinal LNs: US and percutaneous FNAC or biopsy, with repeat FNAC or excisional
biopsy of the node advised in cases of a negative biopsy and clinically suspicious nodes
Assessment of distant metastasis:

CT of the chest, abdomen and pelvis
MRI or CT fusion PET can be used in patients with high-risk disease
Staging, pathology and risk group classification:

Staging should be according to WHO 2022, UICC eighth edition or AJCC eighth edition
Pathological assessment, including HPV status and histological grade and tumour type
Grading should be according to the WHO system
AJCC, American Joint Committee on Cancer; CT, computed tomography; FNAC, fine-needle aspiration cytology; HPV, human
papillomavirus; LN, lymph node; MRI, magnetic resonance imaging; PET, positron emission tomography; UICC, Union for
International Cancer Control; US, ultrasound; WHO, World Health Organization
21
• Clinical assessment of the primary tumour should record the size, morphology and
relationship to adjacent structures
• Magnetic resonance imaging (MRI) or ultrasound (US) combined with an
intracavernosal injection of prostaglandin E1 is useful to assess the primary lesion
• Fine-needle aspiration cytology (FNAC) should be used for clinically impalpable
inguinal nodes when they are detected as morphologically abnormal on US
• Percutaneous FNAC should be used for palpable inguinal nodes
° In case of negative findings for clinically suspicious nodes, the FNAC should be
repeated or an excisional biopsy should be carried out
• Computed tomography (CT) is advised in all cases for the assessment of distant
metastases
° MRI or CT fusion positron emission tomography (PET) can be used in patients with
high-risk disease
Pathology
• Pathological assessment should include human papillomavirus (HPV) status,
histological grade and tumour type
• The World Health Organization (WHO) system is recommended for disease grading
• A summary of information to include in the pathology report is shown in the table below
and opposite
MANDATORY AND RECOMMENDED INFORMATION TO INCLUDE IN THE

PATHOLOGY REPORT
INFORMATION TO BE INCLUDED
ACCORDING TO THE ICCR DATA SET RECOMMENDED MANDATORY
Clinical information X
Prior treatments (topical, RT, ChT)
Non-palpable LNs X
Tumour focality X
Macroscopic maximum tumour dimension, including:

• Depth of invasion
• Distance (in mm) from basement membrane to
X
deepest point of invasion
• Maximum thickness
• Size of tumour
Block identification X
Histological tumour type X
22
INFORMATION TO BE INCLUDED
ACCORDING TO THE ICCR DATA SET RECOMMENDED MANDATORY
Histological grade X
Microscopic maximum dimensions (combination of

X
gross and microscopic if large tumours)
Extent of invasion X
LVI X
Perineural invasion X
Margin status (in mm) X
LN status, including:
• Size of largest nodal tumour deposit (not LN size)
• Number of positive LNs, presence of ECS,
location (pelvic, inguinal) X
• Tumour (positive or negative), size, ECS (positive
or negative) to be reported for every site
separately
Stage X
ChT, chemotherapy; ECS, extracapsular spread; ICCR, International Collaboration on Cancer Reporting; LN, lymph node; LVI,
lymphovascular invasion; RT, radiotherapy
Corbishley C et al. eds. Carcinoma of the Penis and Distal Urethra Histopathology Reporting Guide. 1st ed. Sydney, Australia:
International Collaboration on Cancer Reporting; 2017. Adapted with permission
Precursor lesions
• Penile intraepithelial neoplasia (PeIN) is a recognised precursor of invasive SCC
• Two major subgroups of PeIN can be distinguished, as shown in the table below
TYPES OF PeIN
Non-HPV-related PeIN Differentiated PeIN

Basaloid (undifferentiated) PeIN
HPV-related PeIN Warty (condylomatous) PeIN
Warty-basaloid (mixed) PeIN
Other rare patterns of PeIN Clear cell, pagetoid
HPV, human papillomavirus; PeIN, penile intraepithelial neoplasia

Chaux A et al. Hum Pathol 2012;43(7):1020-27. Adapted with permission
23
Non-HPV-related penile cancer
• The most common histological subtype of non-HPV-related penile cancer is SCC
usual type (48-65% of cases), which also includes the well differentiated pseudo-
hyperplastic form
• Other subtypes are verrucous carcinoma (which includes a low-grade entity called
carcinoma cuniculatum), papillary carcinoma, pseudoglandular carcinoma, mixed
carcinoma, the rare sarcomatoid carcinoma and the extremely rare adenosquamous
carcinoma (including mucoepidermoid carcinoma)
HPV-related penile cancer
• HPV-associated SCC is related to high-risk HPV, such as HPV 16 and 18, and
demonstrates p16 expression
• Histological subtypes include basaloid SCC, warty carcinoma, clear-cell carcinoma,
lymphoepithelioma-like carcinoma and mixed (previously termed warty-basaloid)
carcinoma
SCC not otherwise specified
• Invasive keratinising carcinoma without any special features and which cannot be
tested for HPV is designated as SCC not otherwise specified
STAGING
• Tumour staging must be carried out according to a recognised staging classification
system, such as the WHO 2022, Union for International Cancer Control (UICC) eighth
edition or American Joint Committee on Cancer (AJCC) eighth edition
• The UICC tumour–node–metastasis (TNM) eighth edition is shown in the table below
and opposite
STAGING OF PENILE CANCER ACCORDING TO THE UICC TNM EIGHTH EDITION

PRIMARY TUMOUR (T)
Tis Carcinoma in situ
Ta Non-invasive verrucous carcinoma*
T1 Tumour invades sub-epithelial connective tissue
Tumour invades sub-epithelial connective tissue without lymphovascular invasion and is not
T1a
poorly differentiated
Tumour invades sub-epithelial connective tissue with lymphovascular invasion or is poorly
T1b
differentiated
24
T2 Tumour invades corpus spongiosum with or without invasion of the urethra
T3 Tumour invades corpus cavernosum with or without invasion of the urethra
T4 Tumour invades other adjacent structures
REGIONAL LYMPH NODES (N) – CLINICAL
NX Regional LNs cannot be assessed
N0 No palpable or visibly enlarged inguinal LNs
N1 Palpable mobile unilateral inguinal LN
N2 Palpable mobile multiple or bilateral inguinal LNs
N3 Fixed inguinal nodal mass or pelvic lymphadenopathy unilateral or bilateral
M1 Distant metastasis
pTNM – PATHOLOGICAL CLASSIFICATION†
pNX Regional LNs cannot be assessed
pN0 No regional LN metastasis
pN1 Metastasis in 1 or 2 inguinal LNs
pN2 Metastasis in > 2 unilateral inguinal nodes or bilateral inguinal LNs
Metastasis in pelvic LN(s), unilateral or bilateral or extranodal extension of regional LN
pN3
metastasis
STAGE GROUPING
Stage T N M
Tis N0 M0
0
Ta N0 M0
I T1a N0 M0
IIA T1b, T2 N0 M0
IIB T3 N0 M0
IIIA T1, T2, T3 N1 M0
IIIB T1, T2, T3 N2 M0
T4 Any N M0
IV Any T N3 M0
Any T Any N M1
*Verrucous carcinoma not associated with destructive invasion
†
The pT categories correspond to the T categories. The pN categories are based on biopsy or surgical excision
LN, lymph node; M, metastasis; N, node; p, pathological; T, tumour; TNM, tumour–node–metastasis; UICC, Union for International
Cancer Control
Brierley JD et al. UICC TNM classification of malignant tumours, 8th edition. Wiley-Blackwell, Oxford, UK; 2017. Adapted with
permission
25
TREATMENT
Management of local and locoregional penile cancer
Management of local penile cancer according to stage
• Treatment of penile cancer is based on non-randomised data largely derived from
heterogeneous patient cohorts
° The rarity of the disease makes large randomised trials unfeasible
• The primary aim of surgical intervention is to remove the tumour using penile-preserving
techniques
° Preservation of aesthetic, sexual and urinary function is an important outcome to
allow penetrative sexual intercourse and voiding standing up
• Several organ-sparing surgery (OSS) options have been described to manage primary
penile cancer, but no randomised controlled trials or comparative studies are available
to define the best OSS
° Surgical options should be tailored according to the disease stage, patient
willingness for reconstruction and clear surgical margins
• Treatment options for local and locoregional penile cancer are shown in the figure
opposite
PeIN
• Circumcision is recommended as the initial treatment in any biopsy-proven PeIN
located on the glans or prepuce
• Following circumcision, any residual PeIN can be treated using topical agents, such as
5-fluorouracil (5-FU) or imiquimod
° Carbon dioxide laser ablation is an alternative option
• If topical treatment fails, wide local excision or glans resurfacing, whereby the mucosal
layer is removed and replaced with a split-thickness skin graft (SSG), should be
considered
• Vaccination against HPV in HPV-related PeIN has not been routinely used as the
long-term efficacy is unclear, but it is an option that can be discussed in high-risk
unvaccinated men
Ta-1 penile cancer
• Patients with tumour localised to the foreskin can undergo circumcision, which is often
therapeutic
• For small tumours located on the glans penis, wide local excision of lesions with
reconstruction using an SSG or penile shaft skin is preferable
26
MANAGEMENT OF LOCAL AND LOCOREGIONAL PENILE CANCER
Primary penile tumour
Clinical and radiological assessment
Tis or Ta T1 or T2 glans T2-T4 (with tunical

or cavernosal involvement)
Small lesions Large or multifocal lesions
Glansectomy with distal

Circumcision ± WLE Glansectomy with or
Circumcision and WLE corporectomy
or without grafting
or or
Topical ChT or immunotherapy or
Laser therapy Partial penectomy
or Glansectomy with distal
or or
Laser therapy urethrectomy
WLE and partial Total penectomy
or or
glans resurfacing or
Partial/total glans resurfacing Brachytherapy and/or EBRT
Brachytherapy and/or EBRT
ChT, chemotherapy; EBRT, external beam radiotherapy; T, tumour; Tis, carcinoma in situ; WLE, wide local excision
27
• Glans resurfacing is recommended for T1a lesions
• Mohs micrographic surgery can be used for small, low-grade penile lesions (T1) if the
appropriate clinical set-up, including a pathologist, is available
• Brachytherapy is an alternative to surgery in pathological (p)T1 disease
° Patients should be referred to specialist centres for multidisciplinary consideration of
the suitability of surgery or brachytherapy in this context
T2 penile cancer
• In T2 tumours of the glans penis, glansectomy (with or without distal urethrectomy)
and SSG reconstruction is recommended
° Surgical margins of > 1 mm are accepted
• Partial or total penectomy remain valid alternatives in T2 disease when:
° Adequate surgical margins cannot be guaranteed, or
° The patient is unfit for reconstruction after OSS
• In selected patients with low-volume disease, brachytherapy is an option in specialist
centres
T3 penile cancer
• Partial or total penectomy with perineal urethrostomy is recommended when the
cancer infiltrates proximally into the corpus cavernosum (T3-T4)
• Penile shaft length should be evaluated before surgery
° In case of adequate penile shaft length, partial penectomy with an SSG or urethral
advancement for neo-glans reconstruction are valid options
° For shorter penile shaft lengths or where there is a buried penis, total penectomy
with urinary diversion via a perineal urethrostomy is advised
• Total phallic reconstruction can be considered following subtotal or total penectomy
T4 penile cancer
• Total penectomy with perineal urethrostomy is the recommended option for more
extensive disease
• Toilet procedures with urinary diversion are also considered as palliative treatment in
advanced cases when negative margins cannot be achieved
Inguinal lymph node disease
• The inguinal lymph nodes (LNs) represent the initial site for metastatic disease in
patients with penile cancer
• The presence of metastatic disease in the inguinal LNs is the most important prognostic
indicator; thus, clinical and pathological assessment of the inguinal LNs is pivotal
28
• Options for the management of inguinal LNs in penile cancer are shown in the figure
on the next page
• Patients with impalpable inguinal LNs are classified as clinical (c)N0 and those with
unilateral or bilateral palpable disease are classified as cN1-3
• Cases of grossly enlarged or fungating inguinal LNs are classified as cN3
cN0 penile cancer
• No imaging technique has the desired sensitivity to detect micrometastatic disease in
patients with cN0 penile cancer
° Clinical management is often based on the disease characteristics of the primary
tumour, such as pT stage, histological grade and the presence of lymphovascular
invasion
° Patients with cN0 disease are classified into low-, intermediate- and high-risk
groups based on these characteristics
• Clinical surveillance of the inguinal nodes is recommended in patients presenting with
cN0 tumours with low-risk features [pTa/pTis and pT1 grade (G)1]
• Dynamic sentinel LN biopsy (DSLNB) should be carried out in patients with cN0
intermediate- or high-risk disease (pT1 G2, pT1-4 G3/G4 or lymphovascular invasion)
before proceeding to a radical inguinal lymphadenectomy in the presence of
metastatic nodes
° When DSLNB is not available, modified inguinal LN dissection (ILND) can be carried
out in patients with intermediate- or high-risk disease and can be combined with an
on-table frozen section
cN1-2 penile cancer
• Radical inguinal lymphadenectomy is recommended in cN1-2 disease to remove the
superficial and deep inguinal LNs, with preservation of the long saphenous vein and
the fascia lata where possible
• Myocutaneous flap reconstruction is an option to cover the groin defect when there is
extensive skin involvement
• Minimally invasive approaches (robotic or laparoscopic) have demonstrated similar
oncological outcomes to open approaches but with less intraoperative blood loss,
shorter hospital stays, reduced wound infection rates and reduced skin necrosis rates
° The number of patients studied, however, is too small to conclude if there are any
benefits in terms of oncological outcomes or lymphocele and lymphoedema rates
29
30
MANAGEMENT OF INGUINAL LNs IN PENILE CANCER
Inguinal LNs
Clinical stage assessment
Impalpable LN (cN0) Palpable LN (cN1-2) LN ulcerated or fixed (cN3)
Low risk Intermediate risk High risk Fine needle biopsy

(Tis, Ta, T1G1) (T1G2) (T1G3 or greater)
Negative Positive
T1aG2 T1bG2 Excisional

biopsy
DSLNB Superficial modified

ILND and frozen section Mobile Fixed Pelvic LN
Positive
(if DSLNB is not available) enlarged
Positive Positive Neoadjuvant ChT

Radical ILND RT with concurrent ChT
≥ 2 positive LNs, Stable or Disease
0-1 positive
Negative Negative Negative ENE, metastasis clinical progression or
LNs
diameter > 30 mm response non-resectable
PLND Consolidation ChT or RT for

surgery local control
Clinical trial
Adjuvant ChT
Postoperative RT
Surveillance
c, clinical; ChT, chemotherapy; DSLNB, dynamic sentinel lymph node biopsy; ENE, extranodal extension; G, grade; ILND, inguinal lymph node dissection; LN, lymph node; N, node; PLND, pelvic
lymph node dissection; RT, radiotherapy; T, tumour; Tis, carcinoma in situ
31
cN3 penile cancer
• For bulky or ulcerated disease, neoadjuvant chemotherapy (ChT) followed by ipsilateral
radical inguinal lymphadenectomy, with or without pelvic lymphadenectomy in
responders, should be discussed for eligible patients
• Contralateral procedures should be evaluated according to clinical and pathological
assessment
Pelvic LN dissection
• Patients with pelvic LN metastases have a poorer prognosis than those with only
inguinal LN metastases
• Unilateral pelvic LN dissection (PLND) is recommended in patients with ≥ 2 ipsilateral
inguinal metastases, metastasis with a diameter of ≥ 30 mm or extranodal extension
Salvage ILND
• Clinicians may recommend salvage inguinal lymphadenectomy with myocutaneous
flap reconstruction in recurrent inguinal disease
• Salvage ILND should be considered as part of multimodal treatment, which should also
include neoadjuvant or adjuvant ChT
Radiotherapy for primary disease
• The optimal tumour characteristics which render a penile cancer suitable for
radiotherapy (RT) are superficial or exophytic lesions measuring < 4 cm and located on
the glans or coronal sulcus
• Although external beam RT (EBRT) has the advantage of being widely available, the
use of RT to treat the primary lesion is reserved for selected cases
° Localised lesions can be treated using orthovoltage beams or electrons of 9 MeV
with a total dose in the range of 35 Gy delivered in 10 fractions over 2 weeks
• Most patients referred to the radiation oncology department present with advanced
disease requiring external megavoltage RT as a palliative option
• A typical EBRT course is 66-74 Gy in 2 Gy fractions, five times per week
• Low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy may be recommended in
specialist centres, especially if surgery is not an option
° The usual doses are 60-65 Gy delivered continuously (LDR) or in hourly pulses
(pulse-dose rate) over 5 days and 35 Gy in nine fractions over 5 days (HDR)
° Low-volume residual disease can be treated with 38.4 Gy in 12 fractions but for intact
tumours, the most frequently proposed schedule is 42-45 Gy in 12-14 fractions
32
Systemic therapy for locally advanced disease
• Neoadjuvant ChT with triplet regimens such as paclitaxel–ifosfamide–cisplatin (TIP) or
docetaxel–cisplatin–5-FU (TPF) should be considered for patients with cN3 fixed nodes
° Consolidation surgery (bilateral and deep ILND and ipsilateral PLND if possible)
should be considered for responding patients
• Additional systemic ChT, local-field RT or participation in a clinical trial may be
considered for patients with disease progression or unresectable LNs
• Adjuvant ChT should be considered for patients with pN2 and pN3 disease following
LN dissection
Adjuvant postoperative RT for regional LN metastases
• The role of adjuvant postoperative RT is controversial and there is a lack of prospective
studies to guide its use
• Adjuvant RT with ≥ 50 Gy in 2 Gy fractions (or a biological equivalent dose in 1.8 Gy
fractions) in combination with adjuvant ChT may be considered for patients with pN3
disease
° Higher doses up to 66 Gy have also been recommended
• It is currently unclear which patients benefit most from this approach; prospective
clinical trial data are needed to inform decision making
Management of advanced and metastatic penile cancer
Management of recurrent penile cancer
• Recurrent disease can develop at the site of the primary tumour or within the inguinal
areas
• When feasible, further surgery can help palliate these patients and allow easier wound
management
• For recurrences without invasion of the corpora cavernosa, salvage penile-sparing
options can be considered, including wide local excision, distal corporectomy, or in
selected cases, brachytherapy
• Invasion of the corpora cavernosa warrants partial or total penectomy
• For regional recurrences in the inguinal and pelvic LNs, systemic ChT, EBRT, surgery or
a combination of these approaches can be considered
Palliative ChT for metastatic penile cancer
• Treatment options for patients with metastatic penile cancer include systemic ChT with
platinum-based combination regimens e.g. cisplatin–5-FU, carboplatin–paclitaxel, TIP
or TPF, depending on the patient’s comorbidities, fitness and performance status
33
• Clinical trial enrolment is strongly recommended
• Second-line systemic ChT or RT for local control and/or best supportive care or a
clinical trial may be considered for patients with no response or disease progression
• Palliative RT or RT with concurrent ChT for sites requiring local control should be
considered
Molecular profiling and immunotherapy
• Preclinical studies have shown that penile SCC expresses programmed death-
ligand 1 (PD-L1) and may be amenable to therapeutic intervention with anti-PD-L1
immunotherapies that have been successful in other genitourinary (GU) cancers
• In selected patients with tumour mutational burden high (TMB-H), microsatellite
instability high (MSI-H) or mismatch repair deficient (dMMR) tumours, the use of anti-
PD-L1 immunotherapy can be considered
° Pembrolizumab is Food and Drug Administration (FDA) approved [but not European
Medicines Agency (EMA) approved] for the treatment of patients with unresectable or
metastatic TMB-H solid tumours that have progressed following prior treatment and
have no alternative treatment options
° Pembrolizumab is EMA approved for MSI-H/dMMR biliary tract cancer, gastric, small
intestine, endometrial and colorectal cancers, and is FDA approved for all MSI-H/
dMMR solid tumours
° Nivolumab is EMA approved (in combination with ipilimumab) and FDA approved (as
single agent or in combination with ipilimumab) for MSI-H/dMMR colorectal cancer
• Biomarker-selected clinical trials should be considered where available
Histopathological subtypes
• Across various GU malignancies, sarcomatoid SCC has been associated with a more
aggressive disease course and tempo, with a propensity for early metastatic disease
° This aggressive behaviour has also been reported in penile SCC
• There is currently no evidence to suggest that the earlier use of systemic therapy for the
management of these tumour subtypes provides a benefit, but given the poor outcome if
left untreated, it remains reasonable to consider ChT in this rare group of patients

• Close follow-up every 3-4 months for the first 2 years following primary surgery is
required to detect local recurrence
• Follow-up should include clinical examination as well as imaging, which may include
US of the inguinal LNs if the patient has undergone DSLNB or regular CT surveillance if
the patient has undergone radical inguinal lymphadenectomy for pN+ disease
34
• Regular follow-up can provide psychological support and address sexual and urinary
dysfunction as well as lymphoedema-related complications
35
TESTICULAR CANCER
DIAGNOSIS
• Testicular cancer is usually diagnosed as a unilateral testicular mass found by the
patient or identified incidentally during an ultrasound (US)
• Testicular US should be carried out with a high-frequency probe with colour Doppler
assessment
° The role of scrotal magnetic resonance imaging (MRI) is limited; it may be used
to distinguish between an intra- and extra-testicular mass when this cannot be
confirmed clinically or with US
• Diagnosis of a germ cell tumour (GCT) should be based on histology of the testicular
mass, except when urgent chemotherapy (ChT) is required
° If the clinical picture is clear, symptomatic patients with a high tumour burden and
elevated tumour markers should receive ChT without delaying treatment to achieve
a biopsy
• Serum tumour markers are part of the initial work-up and diagnosis, as shown in the
table below
SERUM TUMOUR MARKERS FOR NON-SEMINOMA TESTICULAR CANCER
LDH (U/L) β-hCG (U/L) AFP (ng/mL)
SX NA* NA* NA*
S0 Normal Normal Normal
S1 < 1.5 x ULN < 5000 < 1000
S2 1.5-10 x ULN 5000-50,000 1000-10,000
S3 > 10 x ULN > 50,000 > 10,000

*Marker studies not available or not carried out
AFP, α-fetoprotein; β-hCG, beta subunit of human chorionic gonadotropin; LDH, lactate dehydrogenase; NA, not applicable; S, serum
tumour marker; ULN, upper limit of normal
• Levels of α-fetoprotein (AFP), beta subunit of human chorionic gonadotropin (β-hCG)

and lactate dehydrogenase should be determined before orchiectomy, as they are
associated with GCT histology and support diagnosis
36
• Post-orchiectomy levels of serum tumour markers are important for prognostic
stratification and should be monitored in patients with initially elevated markers until
normalisation
° Persistent or increasing tumour marker levels after orchiectomy usually indicate
metastatic disease
Pathology
• > 95% of malignant testicular tumours arise from germ cells
• Testicular tumours should be categorised according to the World Health Organization
(WHO) 2016 classification [Williamson SR et al. Histopathol 2017;70(3):335-46]
• The major preneoplastic lesion of GCTs is germ cell neoplasia in situ (GCNIS)
° GCTs may be divided into those derived from GCNIS (most adult GCTs) and those not
derived from GCNIS
• Seminomas are characterised by cells analogous to the primordial germ cells or
gonocytes present during early embryonic development
• Non-seminomas show a variety of differentiation patterns from embryonic and
extra-embryonic tissues
• ~5% of patients with GCT harbour GCNIS in the contralateral testis, requiring physical
and/or US examinations during follow-up
° As radiotherapy (RT) for GCNIS prevents fatherhood by natural means, upfront versus
delayed RT should be carefully discussed with patients
• Most experts do not consider a routine biopsy of the contralateral testis necessary

• Post-orchiectomy management should only be carried out by highly experienced
clinicians
• Staging and risk group categorisation should be carried out according to the Union
for International Cancer Control (UICC) and the International Germ Cell Cancer
Collaborative Group (IGCCCG)
° At present, there is disparity between the American Joint Committee on Cancer
(AJCC) and UICC versions of the testicular GCT tumour–node–metastasis (TNM)
staging systems, such that the applied staging system should always be specified
• For stage I disease, different risk factors have been identified for seminoma and
non-seminoma, based on histological features in the primary tumour
° In stage I non-seminoma, most experts consider the presence of vascular invasion as the
single and most important predictor of micrometastases and subsequent recurrence
° In stage I seminoma, tumour size and possibly rete testis infiltration represent
weaker risk factors for identifying “higher-risk” patients
37
• Computed tomography (CT) with contrast enhancement of the thorax, abdomen and
pelvis is mandatory for all patients
• MRI of the central nervous system (CNS) is indicated in poor-prognosis patients,
particularly in patients with choriocarcinoma and high β-hCG, multiple lung
metastases or cerebral symptoms
• Routine positron emission tomography (PET) scanning is not recommended
• The IGCCCG prognostic classification is recommended for stratification of patients
with metastatic disease into three prognostic groups, as shown in the table below and
opposite
THE IGCCCG PROGNOSTIC CLASSIFICATION FOR METASTATIC GERM CELL CANCERS
PROGNOSTIC GROUP AND SURVIVAL PROGNOSTIC FACTORS
Good
Non-seminoma All of the following criteria:
Testicular/retroperitoneal primary
No non-pulmonary visceral metastases
5-year PFS 92%
AFP < 1000 ng/mL
5-year OS 96%
hCG < 5000 IU/L (1000 ng/mL)
LDH < 1.5 x ULN
Seminoma with LDH < 2.5 x ULN All of the following criteria:
Any primary site

3-year PFS 92% and 93%, in training and No non-pulmonary visceral metastases
validation set, respectively
Normal AFP
3-year OS 97% and 99%, in training and
validation set, respectively Any hCG
LDH within 2.5 x ULN
Seminoma with LDH > 2.5 x ULN All of the following criteria:
Any primary site

3-year PFS 80% and 75%, in training and No non-pulmonary visceral metastases
Normal AFP
LDH > 2.5 x ULN
38
Intermediate
Criteria for patients not belonging to good or

Non-seminoma
poor prognosis
Testicular/retroperitoneal primary
5-year PFS 78% No non-pulmonary visceral metastases
5-year OS 89% And any of the following criteria: AFP 1000-

10,000 ng/mL, hCG 5000-50,000 IU/L or
LDH 1.5-10 x ULN
Seminoma All of the following criteria:
Any primary site

3-year PFS 78% and 61%, in training and Non-pulmonary visceral metastases
Normal AFP
Any LDH
Poor
Non-seminoma Any of the following criteria:
Mediastinal primary
5-year PFS 54% Non-pulmonary visceral metastases
5-year OS 67% AFP > 10,000 ng/mL or hCG > 50,000 IU/L
(10,000 ng/mL) or LDH > 10 x ULN
Seminoma No patients classified as poor prognosis

Pre-ChT serum tumour markers should be assessed after orchiectomy and immediately before ChT administration (same day)
AFP, α-fetoprotein; ChT, chemotherapy; hCG, human chorionic gonadotropin; IGCCCG, International Germ Cell Cancer
Collaborative Group; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; ULN, upper limit of normal
Beyer J et al. J Clin Oncol 2021;39(14):1553-62 and Gillessen S et al. J Clin Oncol 2021;39(14):1563-74. Reprinted with
permission
39
TREATMENT
Management of locoregional testicular cancer
Management of the primary tumour
• Semen analysis and sperm cryopreservation should be offered to all patients,
preferably before orchiectomy
° Semen preservation is the most cost-effective strategy for fertility preservation
• Radical orchiectomy is carried out through an inguinal incision
° The tumour-bearing testis is resected with the spermatic cord at the level of the
internal inguinal ring
• Testis-sparing surgery is feasible in experienced centres for selected patients in
case of a small tumour, particularly in patients with synchronous bilateral testicular
tumours, tumour in a solitary testis or contralateral atrophic testis
• Testis-sparing surgery should only be offered together with frozen section examination
• If a GCT is diagnosed during testis-sparing surgery, completion orchiectomy or post-
resection testicular RT (if solitary testis) is mandatory due to the high risk of GCNIS in
the remaining testis
Seminoma
• Management strategies for seminoma are shown in the figure on the next page
Stage I seminoma
• Surveillance is the preferred strategy
• Adjuvant ChT with one course of carboplatin should be discussed with patients who
are not willing or not able to undergo surveillance or higher-risk patients, defined by
the presence of one or both risk factors (i.e. tumour size and rete testis invasion)
° Adjuvant carboplatin should not be offered to patients without risk factors
• Adjuvant RT should not be given as the risk of second malignancies is considered
too high
• Patient autonomy should be considered when selecting post-orchiectomy
management, following thorough discussion of the pros and cons of surveillance
versus one cycle of carboplatin
40
STANDARD MANAGEMENT STRATEGIES FOR SEMINOMA
Standard management strategies for seminoma
Stage I Stage IIA Stage IIB-III
Lower risk* Higher risk*
Carboplatin
Carboplatin BEP x 3 cycles Participation
Surveillance Surveillance RT BEP x 3-4 cycles†
x 1 cycle AUC 7 EP x 4 cycles in clinical trials
Follow-up Follow-up Consider biopsy or

resection of PET-
positive lesions > 3 cm
Follow-up
*Lower and higher risk based on size of primary tumour and infiltration of rete testis with lower risk defined as absence of both risk factors and higher risk as presence of one or both risk factors
†
In case of contradiction against bleomycin, refer to text on page 46
AUC 7, area under the curve of 7; BEP, bleomycin–etoposide–cisplatin; EP, etoposide–cisplatin; PET, positron emission tomography; RT, radiotherapy
41
Stage IIA seminoma
• The risk of overtreatment should be minimised by histological/cytological verification
of metastasis, or at a minimum, an observed radiological progression over time
• Patients should receive either RT (30 Gy in 2 Gy fractions) or cisplatin-based ChT
[three cycles of bleomycin–etoposide–cisplatin (BEP) or four cycles of etoposide–
cisplatin (EP)] according to IGCCCG recommendations
• Participation in clinical trials should be encouraged
Non-seminoma
• Management strategies for non-seminoma are shown in the figure on the next page
Stage I non-seminoma
• Surveillance is recommended for low-risk (defined as the absence of vascular
invasion) stage I non-seminoma
° For patients who are unwilling or unable to undergo surveillance, adjuvant ChT
with one cycle of BEP or open nerve-sparing retroperitoneal lymph node dissection
(RPLND) in highly experienced centres are alternative options
• Patients with high-risk (defined as the presence of vascular invasion) stage I
non-seminoma are candidates for adjuvant ChT with one cycle of BEP
• Nerve-sparing RPLND should only be considered in case of contraindications against
the strategies recommended above
• Patient autonomy should be considered when selecting post-orchiectomy
management, following thorough discussion of the pros and cons of surveillance
versus one cycle of adjuvant BEP
Marker negative, stage IIA non-seminoma
• Careful assessment is recommended to avoid overtreatment as ~15-35% of clinical
stage IIA patients do not harbour metastases in the enlarged lymph nodes
• The risk of overtreatment may be reduced by the following strategies:
° Close follow-up with abdominal imaging every 6 weeks until regression or
progression, resulting in observation only or treatment, respectively
° Lymph node biopsy or primary nerve-sparing RPLND
° Completely removed pure teratoma should not trigger ChT
Marker positive, stage IIA-IIB non-seminoma
• Patients with marker-positive, stage IIA-IIB non-seminoma should be managed
according to IGCCCG recommendations, e.g. three cycles of BEP or four cycles of EP
(in the case of contraindications against bleomycin) in good-risk patients
42
STANDARD MANAGEMENT STRATEGIES FOR NON-SEMINOMA
Standard management strategies for non-seminoma
Stage I Stage IIB-III
Low risk* High risk*
Preferred Alternative Preferred Alternative Good risk Intermediate risk Poor risk
BEP x 3 cycles BEP x 4 cycles BEP x 4 cycles

Surveillance BEP x 1 cycle BEP x 1 cycle Surveillance EP x 4 cycles VIP x 4 cycles
VIP x 4 cycles
RPLND† Dose intensification‡
Follow-up Resection in case of

lesion > 1 cm
Follow-up
*Low risk and high risk based on absence and presence of vascular invasion, respectively
†
Marker-negative stage IIA/IIB tumours
‡
In selected cases, e.g. poor marker decline
BEP, bleomycin–etoposide–cisplatin; EP, etoposide–cisplatin; RPLND, retroperitoneal lymph node dissection; VIP, etoposide–ifosfamide–cisplatin
43
Management of metastatic testicular cancer
Seminoma
Stage II-III seminoma
• The standard treatment for stage IIB-IIC and III seminoma is cisplatin-based ChT,
according to the IGCCCG classification for advanced/metastatic disease
° Three cycles of BEP is the standard therapy for patients categorised as good prognosis
° Four cycles of BEP are recommended for patients with intermediate prognosis
° If there are contraindications against bleomycin, four cycles of EP or four cycles of
etoposide–ifosfamide–cisplatin (VIP) are recommended in good- and intermediate-
prognosis patients, respectively
• Only patients unfit for cisplatin-based ChT should be treated with carboplatin-based
ChT (carboplatin–etoposide–bleomycin)
• Patients with stage IIB seminoma unsuitable for ChT should receive para-aortic and
ipsilateral iliac field RT up to 36 Gy in 2 Gy fractions
Seminoma post-ChT management
• Patients with a complete response after ChT do not require further treatment
• A [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET scan at least 6 weeks after completion
of ChT is recommended for residual tumours of > 3 cm
° Negative PET lesions require no further management and these patients can be
followed routinely by repeated imaging
° 75% of positive PET scans are falsely positive; therefore, a biopsy is recommended
before RT or resection
Non-seminoma
Metastatic stage IIA, marker-positive and stage IIB-III non-seminoma
• Good-prognosis patients should receive three cycles of BEP
° Four cycles of EP can be used if there are contraindications against bleomycin
• Intermediate- or poor-prognosis patients should receive four cycles of BEP
° Four cycles of VIP with granulocyte colony-stimulating factor (G-CSF) support can be
used if there are contraindications against bleomycin
• AFP and β-hCG decline should be assessed after the first cycle of BEP in poor-risk
patients
° Patients with poor decline should be considered for treatment intensification at high-
volume expert centres
• Patients with CNS metastases or primary mediastinal tumours should always be
treated at high-volume expert centres
44
• Poor-prognosis patients with significantly symptomatic disease, including extensive
metastatic lung and/or liver involvement, have a significant risk of toxicity with
standard BEP
° A first cycle with adapted cisplatin and etoposide doses should be considered
° The full number of cycles should be applied after this induction cycle
° Orchiectomy may be carried out after finishing first-line ChT
• Prophylactic G-CSF should be considered to maintain dose intensity in patients with
intermediate and poor prognosis, particularly when using VIP
Prevention of thromboembolic events
• Prophylaxis of thromboembolic events should be considered in patients receiving
cisplatin-based ChT, especially when presenting with one or more of the established
risk factors (retroperitoneal lymph nodes > 3.5 cm, stage III disease, central venous
access catheter, intermediate- or poor-risk features or immobilisation)
• Peripheral venous access should be used instead of an indwelling vascular
access device
Non-seminoma post-ChT management
• In case of complete response, no further treatment is necessary
• Residual lymph nodes > 1 cm in axial diameter should be surgically removed,
preferentially by open nerve-sparing RPLND
• Patients with complete resection of differentiated teratoma or fibrotic tissue require no
further treatment
• Patients with completely resected viable malignant tumour comprising < 10% of the
specimen do not benefit from adjuvant ChT
• In patients with intermediate or poor prognosis, > 10% viable tumour in the specimen
and/or incomplete resection, consolidation ChT (e.g. two cycles of VIP) may be
considered, although surveillance also appears justified
• Patients with multiple visceral metastases should always be evaluated at expert
centres for the possibility of radical resection
• Patients with rising tumour markers indicative of progressive disease usually require
salvage ChT
Salvage treatment
• Salvage can be achieved with high-dose (HD) ChT or standard-dose cisplatin-based
regimens, such as paclitaxel–ifosfamide–cisplatin (TIP), VIP or cisplatin–ifosfamide–
vinblastine
45
• HD ChT should be used for third-line therapy, if not used earlier, and can cure selected
patients in this setting
° HD ChT and the accompanying side-effects require management by highly
experienced GCT oncologists
• Surgery is an important part of the salvage strategy, particularly in patients with
localised or late relapse and with a poor response to ChT
• Multimodal approaches are important for the management of rare localisations of
metastases (e.g. in the brain)
° All ablative therapies, including stereotactic RT and radiofrequency ablation, should
be considered within a multidisciplinary approach at an expert centre
Late relapse
• A late relapse is defined as re-occurrence > 2 years after complete response to at
least three cycles of ChT
• Patients developing a late relapse should be managed in expert centres
• Radical surgical resection of all lesions, if feasible, is the recommended approach in
patients with marker-negative disease
• ChT should be individualised based on the histology of the late relapse and tumour
marker development
° If salvage ChT is the first late-relapse treatment, radical post-ChT surgery should be
carried out whenever possible
PERSONALISED MEDICINE
• Serum microRNA (miRNA) shows promising clinical applicability but cannot be
recommended yet in routine clinical care
° Ongoing multi-institutional prospective studies aim to validate miRNA as a
clinical biomarker
• Treatment-resistant testicular GCTs harbour genomic alterations of the Ras and
phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)
pathways and alterations in the tumour suppressor protein p53 (TP53)-mouse double
minute 2 (MDM2) axis
° Discovery of specific alterations may guide clinical research to identify therapeutic
targets, select patients and provide tailored therapies
46
• The main aim of initial follow-up is the timely diagnosis of recurrent disease
• Many follow-up recommendations expose survivors to unnecessary radiation
° Most guidelines have subsequently reduced the number of recommended CT scans
• Recommendations for the follow-up schedule are shown in the tables below and on the
next page
° These schedules should be adapted according to national and institutional requirements
RECOMMENDATIONS FOR FOLLOW-UP FOCUSED ON RELAPSE DETECTION
Recommended minimal follow-up for patients with clinical stage I seminoma on
active surveillance or after adjuvant treatment (carboplatin or RT)
AFTER 5
MODALITY YEAR 1 YEAR 2 YEAR 3 YEARS 4 & 5
YEARS
Tumour markers ±
2 times 2 times 2 times Once Further
doctor visit
management
Chest X-ray - - - - according to
survivorship
Abdominopelvic Once at Once at
2 times 2 times care plan
CT or MRI 36 months 60 months
CT, computed tomography; MRI, magnetic resonance imaging; RT, radiotherapy
Recommended minimal follow-up for patients with clinical stage I non-seminoma on

active surveillance
AFTER 5
YEARS
Tumour markers ±
4 times* 4 times 2 times 1-2 times
doctor visit
Further
Once at management
Once in case
Chest X-ray 2 times 2 times 60 months according to
of LVI
if LVI survivorship
care plan
Abdominopelvic Once at Once at
2 times At 24 months†
*In case of high-risk (LVI+), a minority of the consensus group members recommended six times
†
In case of high-risk (LVI+), a majority of the consensus group members recommended an additional CT at 18 months
CT, computed tomography; LVI, lymphovascular invasion; MRI, magnetic resonance imaging
47
Recommended minimal follow up after adjuvant treatment for patients with clinical
stage I non-seminoma or complete remission for metastatic seminoma or non-
seminoma (excluded: “Poor prognosis” and no remission)
AFTER 5
YEARS
Tumour markers ±
4 times* 4 times 2 times 2 times
doctor visit
Further
Once at management
Chest X-ray 2 times Once Once
60 months according to
Abdominopelvic Once at Once at survivorship
2 times At 24 months care plan†
Thorax CT * * * *
*Same time points as abdominopelvic CT/MRI in case of pulmonary metastases at diagnosis
†
In case of teratoma in resected residual disease: The patient should remain with the uro-oncologist
CT, computed tomography; MRI, magnetic resonance imaging
• GCT survivors should undergo regular hormonal assessments due to their long-term
risk of hypogonadism
° Testosterone replacement therapy should only be offered to testicular cancer
survivors with testosterone levels below the normal range and clinical symptoms of
hypogonadism
Survivorship care plan
• A healthy lifestyle should be encouraged for wellbeing and minimisation of
cardiovascular disease and secondary cancers, which are the most serious long-term
toxicities
• Every patient should have an informative end-of-treatment summary, together with a
survivorship care plan
48
BLADDER CANCER
DIAGNOSIS
• Bladder cancer is also known as urothelial carcinoma (UC) since it can occur in any
part of the urothelium, including the upper tracts and kidney
• Painless haematuria is the most common presenting symptom of bladder cancer and
should be investigated in all cases. Other common symptoms include dysuria and
increased frequency and/or urgency of urination
• A definitive diagnosis of bladder cancer is based on cystoscopic examination of the
bladder and histological evaluation of tissue via cold-cup biopsy or transurethral
resection of the bladder tumour (TURBT), as shown in the figure below
° Complete resection of all tumour tissue should be achieved when possible, and
muscle tissue should be included in biopsies, except when a non-invasive/low-grade
(LG) tumour is suspected
DIAGNOSTIC WORK-UP OF PATIENTS WITH SUSPECTED BLADDER CANCER
Presentation
1. Painless haematuria (80% of patients)
2. Irritative symptoms [e.g. dysuria, frequency, urgency (invasive or HG tumours)]
3. Bone pain (suspected bone metastasis) or flank pain (from retroperitoneal metastases or
ureteral obstruction)
Work-up
1. History and physical examination
2. Cystoscopic evaluation including biopsy or TURBT with bimanual examination
3. Urine cytology
4. Blood work (haematology and biochemistry)
5. Upper urinary tract imaging, mainly CT urogram, alternatively intravenous or retrograde pyelogram
(to exclude 2.5% of patients who have synchronous upper tract urothelial cancer)
6. Metastatic work-up in patients with high risk of metastases (CT chest, abdomen and pelvis,
liver function tests)
Staging and grading
Management of organ-confined disease Management of metastatic disease
CT, computed tomography; HG, high grade; TURBT, transurethral resection of the bladder tumour
49
• In high-grade (HG) bladder cancer, cross-sectional upper tract imaging via computed
tomography (CT) or magnetic resonance imaging (MRI) urography is recommended to
screen for synchronous urinary tract urothelial carcinoma (UTUC)
Pathology/molecular biology
• 90% of carcinomas of the upper and lower urothelial tract are UC
• Pathological diagnosis of bladder cancer should be made according to the World
Health Organization (WHO) 2016 classification, as shown in the table below
WHO CLASSIFICATION OF TUMOURS OF THE UROTHELIAL TRACT

INVASIVE UC NON-INVASIVE UC
Nested UC in situ
Microcystic Papillary UC, low grade
Micropapillary Papillary UC, high grade
Lymphoepithelioma-like PUNLMP
Plasmacytoid/signet ring cell/diffuse
Sarcomatoid
Giant cell
Poorly differentiated
Lipid rich
Clear cell
PUNLMP, papillary urothelial neoplasm of low malignant potential; UC, urothelial carcinoma; WHO, World Health Organization
Moch H et al. Eur Urol 2016;70(1):93-105. Reprinted with permission
• The presence and percentage of variant histology, lymphovascular invasion and

presence of detrusor muscle should be reported
° Variant histology includes nested carcinoma, large nested, microcystic,
micropapillary, lymphoepithelioma-like, plasmacytoid/signet ring cell/diffuse,
sarcomatoid, giant cell, poorly differentiated, lipid rich and clear cell UC
° Small cell/neuroendocrine subtypes should be specified when they are present
• Urine cytology can facilitate the diagnosis of HG UC but cannot be used as the primary
method of histological diagnosis
° The Paris system should be used for reporting urine cytology
50
• Molecular subtype analysis does not currently have a role in treatment selection
• Oncogenic alterations [e.g. fibroblast growth factor receptor (FGFR) DNA alterations]
and immune checkpoint inhibitor (ICI) biomarker testing [e.g. programmed
death-ligand 1 (PD-L1) expression] are used for patient selection
° Clinicians should follow European Medicines Agency (EMA) guidance on linking
specific biomarker methods with specific agents

• Patients with non-muscle-invasive bladder cancer (NMIBC) are classified into four risk
categories based on tumour characteristics (low risk, intermediate risk, high risk and
very high risk), as shown in the table below and on the next page
• This risk categorisation constitutes the basis for treatment and follow-up
recommendations
RISK GROUP STRATIFICATION OF PATIENTS WITH NMIBC AND TREATMENT

RECOMMENDATIONS
RISK GROUP TREATMENT

CHARACTERISTICS
STRATIFICATION RECOMMENDATIONS
One immediate instillation of

Primary, solitary, Ta G1 (PUNLMP, intravesical ChT after TURBT
Low-risk tumours
LG), < 3 cm, no Tis followed by cystoscopic
surveillance
In patients with previous low

recurrence rate (≤ 1 recurrence
per year) and expected EORTC
recurrence score < 5, one
immediate instillation of
intravesical ChT after TURBT
All tumours not defined in the two In all patients, either:
Intermediate-risk tumours adjacent categories (between the
• Instillations of ChT for a
category of low and high risk)
maximum of 1 year
Or
• 1 year full-dose BCG treatment
(induction plus 3-weekly
instillations at 3, 6 and 12
months)
51
Any of the following:
• T1 tumour
• G3, HG tumour
Full-dose BCG instillations for
High-risk tumours • Tis 1-3 years or radical cystectomy
• Multiple, recurrent and large
(> 3 cm) Ta G1-G2/LG tumours
(all features must be present)
• T1 G3/HG associated with

concurrent bladder Tis
• Multiple and/or large T1 G3/HG
and/or recurrent T1 G3/HG, T1 Radical cystectomy or BCG
Subgroup of highest-risk
G3/HG with Tis in the prostatic induction and 3 years of
tumours
urethra maintenance if achievable
• Some forms of variant histology
of urothelial carcinoma,
lymphovascular invasion
BCG, bacillus Calmette–Guerin; ChT, chemotherapy; EORTC, European Organisation for Research and Treatment of Cancer;
G, grade; HG, high grade; LG, low grade; NMIBC, non-muscle-invasive bladder cancer; PUNLMP, papillary urothelial neoplasm of
low malignant potential; T, tumour; Tis, carcinoma in situ; TURBT, transurethral resection of the bladder tumour
• Muscle-invasive bladder cancer (MIBC) should be staged according to the Union for
International Cancer Control (UICC) tumour–node–metastasis (TNM) eighth edition and
the American Joint Committee on Cancer (AJCC) TNM staging system, as shown in the
tables on the next pages
• In patients with invasive disease (≥ T1), regional and distant staging should be carried
out with further imaging studies such as contrast-enhanced CT of the chest/abdomen/
pelvis or MRI of the abdomen/pelvis combined with chest CT
° Imaging should be carried out before TURBT
• Pelvic nodes > 8 mm and abdominal nodes > 10 mm in maximum short-axis diameter
should be considered as suspicious for lymph node metastasis
• MRI is generally more accurate than CT for determining depth of invasion
• [18F]2-fluoro-deoxy-D-glucose (FDG)-positron emission tomography (PET)-CT may aid
in the detection of lymph node and distant metastases
52
UICC TNM EIGHTH EDITION CLINICAL CLASSIFICATION FOR BLADDER CANCER
PRIMARY TUMOUR (T)
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ: “Flat tumour”
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscle
T2a Tumour invades superficial muscle (inner half)
T2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue
T3a Microscopically
T3b Macroscopically (extravesical mass)
Tumour invades any of the following: Prostate stroma, seminal vesicles, uterus, vagina, pelvic
T4
wall, abdominal wall
T4a Tumour invades prostate stroma, seminal vesicles, uterus or vagina
T4b Tumour invades pelvic wall or abdominal wall
N0 No regional lymph node metastasis
Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or
N1
presacral)
Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external
N2
iliac or presacral)
N3 Metastasis in common iliac lymph node(s)
M1a Non-regional lymph nodes
M1b Other distant metastases
53
M, metastasis; N, node; T, tumour; TNM, tumour–node–metastasis; UICC, Union for International Cancer Control
Brierley JD et al, eds. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2016. Reprinted with
permission from John Wiley & Sons, Ltd
AJCC TNM STAGING SYSTEM FOR BLADDER CANCER

Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2a-T2b N0 M0
T3a-T3b, T4a N0 M0
Stage IIIA T1-4a N1 M0
T1-T4a N2 or N3 M0
T4b N0 M0
Stage IVA
Any T Any N M1a
Stage IVB Any T Any N M1b
AJCC, American Joint Committee on Cancer; M, metastasis; N, node; T, tumour; Tis, carcinoma in situ; TNM tumour–node–metastasis
Amin MB et al, eds, AJCC Cancer Staging Manual. 8th edition. Springer; 2017. Reprinted with permission
TREATMENT
Management of local/locoregional bladder cancer
NMIBC
• Optimal treatment for NMIBC is complete removal of all visible lesions in the bladder,
followed by intravesical instillations or early radical cystectomy (RC), depending on risk
stratification, as shown in the figure on the next page
• If available, improved tumour visualisation techniques such as fluorescence
cystoscopy and narrow-band imaging should be used during TURBT
• In patients with low-risk NMIBC and in those with small papillary recurrences detected
> 1 year after the previous tumour, a single, immediate, intravesical chemotherapy
(ChT) instillation (e.g. mitomycin C), is recommended in combination with continued
cystoscopic surveillance
• In patients with intermediate-risk NMIBC, additional courses of intravesical therapy are
recommended to reduce the risk of recurrence
° Either ChT instillations for a maximum of 1 year or 12 months of bacillus Calmette–
Guerin (BCG) instillation therapy (induction therapy with six BCG instillations at
weekly intervals, followed by maintenance therapy with BCG instillations at 3, 6 and
12 months after the start of the induction cycle)
54
MANAGEMENT OF HISTOPATHOLOGICALLY CONFIRMED NMIBC
NMIBC
If suspected low-risk tumour:

One immediate instillation of
intravesical ChT after TURBT
Very high risk or

Low risk Intermediate risk High risk
BCG unresponsive
Cystoscopic surveillance
Cystoscopic surveillance
Cystoscopic + intravesical
+ intravesical instillations Offer RC
surveillance instillations
(e.g. 36 months BCG)
(e.g. 12 months BCG)
BCG, bacillus Calmette–Guerin; ChT, chemotherapy; NMIBC, non-muscle-invasive bladder cancer; RC, radical cystectomy; TURBT,
transurethral resection of the bladder tumour
• In patients with high-risk NMIBC, full-dose intravesical BCG for 1-3 years is
recommended
° Maintenance therapy for 3 years is more effective than 1 year to prevent recurrences
• In high-risk NMIBC, there is a significant risk of residual disease after initial TURBT;
therefore, a second resection should be carried out 4-6 weeks after the first resection
in the following cases:
° When the initial TURBT was incomplete
° If there is no detrusor muscle in the specimen on the initial resection, except for Ta
LG and carcinoma in situ (Tis)
° In all pathological T1 tumours and all HG tumours, except for patients with primary Tis
• The second TURBT should include a resection of the previous tumour site
• Patients with very high-risk disease or HG tumours that are unresponsive to BCG
should be offered RC due to the high risk of progression
° Thermo-ChT can be offered as an alternative to patients who are unwilling or unable
to have RC
° BCG re-induction may also be considered as an alternative
55
• In patients who are BCG-unresponsive and are ineligible for or refuse RC, intravenous
pembrolizumab or intravesical nadofaragene firadenovec can be considered; however,
more robust data are required before stronger recommendations can be made
° A multidisciplinary approach is required for these patients
MIBC
• Multidisciplinary care via tumour board discussions and/or directed consultations with
a medical oncologist, radiation oncologist and urologist are recommended for patients
with MIBC
• Management options are shown in the figure below
MANAGEMENT OF HISTOPATHOLOGICALLY CONFIRMED MIBC
MIBC
Unfit for Fit for

cisplatin-based ChT cisplatin-based ChT
3-4 cycles cisplatin-based

ChT
RC with pelvic lymphadenectomy

Multimodality bladder-sparing treatments
Risk- and treatment-adapted follow-up
ChT, chemotherapy; MIBC, muscle-invasive bladder cancer; RC, radical cystectomy
56
• The standard treatment for MIBC T2-T4a N0 M0 is RC with pelvic lymph node
dissection (PLND)
° Standard PLND includes removal of all lymphatic tissues around the common iliac,
external iliac, internal iliac and obturator regions up to the crossing of the ureters
over the common iliac vessels at a minimum
• Continent orthotopic (neobladder), continent cutaneous (catheterisable pouch) or
incontinent cutaneous (conduit) reconstructions can be carried out, based on the
patient’s general health and wishes
• Patients with radiologically suspicious node-positive disease (clinical N1) can be
considered for surgery but preoperative platinum-based ChT should be discussed
Organ-preservation therapy
• Organ-preservation therapy with radiotherapy (RT) is a reasonable option for patients
with MIBC seeking an alternative to RC and for those who are medically unfit for
surgery
• The preferred protocol is a trimodal combination of TURBT plus RT and ChT
° Other protocols include aggressive TURBT alone, TURBT plus RT or TURBT plus ChT
• The ideal cases for trimodal therapy are patients with tumours that can undergo visible
complete resection, have no associated hydronephrosis, do not invade the prostatic
urethra and are not associated with diffuse Tis throughout the bladder
• A cystoscopy with bladder biopsy is mandatory for response evaluation (either midway
through treatment or 2-3 months thereafter)
• If persistent or recurrent muscle-invasive disease is observed at response evaluation
or during follow-up, prompt RC is recommended when possible
• RT can be offered for palliation (bleeding, pain)
Neoadjuvant and adjuvant therapy
• Neoadjuvant cisplatin-based ChT (three to four cycles) is recommended in patients
with MIBC
• Although there is a lack of consensus regarding the optimal regimen, cisplatin–
gemcitabine or accelerated methotrexate–vinblastine–adriamycin–cisplatin (MVAC) are
the most widely used regimens in this setting and can be recommended
• Neoadjuvant ICI therapy is not currently recommended in cisplatin-eligible or
-ineligible patients
• There is no role for adjuvant ChT or RT in patients who have received neoadjuvant ChT
• Adjuvant cisplatin-based ChT can be considered in patients who have not received
neoadjuvant therapy, but evidence to support this approach is weak and neoadjuvant
ChT is preferred
57
• Inconsistent results exist for adjuvant ICI therapy and an overall survival advantage is
needed before it can be recommended as standard therapy; inconsistent results also
exist for the PD-L1 biomarker
Management of advanced/metastatic bladder cancer
• Treatment options for advanced or metastatic bladder cancer are shown in the figure
on the next page
First-line treatment
• Enfortumab vedotin–pembrolizumab is recommended as the preferred first-line
therapy for advanced or metastatic UC, irrespective of platinum eligibility
° First-line enfortumab vedotin–pembrolizumab may also be considered for patients
who have received ICI as adjuvant therapy
• Patients not able to receive enfortumab vedotin–pembrolizumab should be treated
with either:
° Nivolumab plus up to six cycles of gemcitabine–cisplatin (if cisplatin eligible only)
° Up to six cycles of platinum-based ChT (gemcitabine–cisplatin or gemcitabine–
carboplatin) followed by maintenance avelumab (for non-progressing tumours)
• Single-agent ICIs have a limited role in the first-line treatment advanced disease and
should not be routinely recommended
Subsequent lines of treatment
Progression after enfortumab vedotin–pembrolizumab
• After progression on enfortumab vedotin–pembrolizumab, the following treatment
options can be recommended:
° Standard platinum-based ChT without maintenance avelumab (unselected patients)
° Erdafitinib in selected patients with FGFR-altered tumours
• Rechallenge with a single-agent ICI is not encouraged
• Treatments not previously given may be considered for third- and fourth-line therapy
Progression after platinum-based ChT and an ICI
• After progression on first-line platinum-based ChT and an ICI (with the ICI given
concurrently, sequentially as maintenance therapy or as second-line therapy) the
following treatment options can be recommended:
° Erdafitinib for patients with selected FGFR DNA fusions and mutations
° Sacituzumab govitecan (FDA approved, not EMA approved)
• Single-agent taxane or vinflunine can also be considered
58
MANAGEMENT OF ADVANCED OR METASTATIC BLADDER CANCER
Treatment-naive advanced or Treatment-naive advanced or metastatic UC (stage IV) when

metastatic UC (stage IV) enfortumab vedotin–pembrolizumab unavailable or contraindicated*
Cisplatin-eligible only Cisplatin- or carboplatin-eligible
Enfortumab vedotin–pembrolizumab
Nivolumab–gemcitabine– Gemcitabine–cisplatin
cisplatin Gemcitabine–carboplatin
Disease Disease No disease

progression progression progression
Disease progression
Pembrolizumab Maintenance
Erdafitinib† Atezolizumab avelumab║
Enfortumab vedotin
Sacituzumab govitecan‡
Platinum-based ChT§ Platinum-based ChT¶ Disease
Erdafitinib† Vinflunine# or taxanes# progression
*Enfortumab vedotin–pembrolizumab is preferred over platinum-based ChT irrespective of platinum eligibility

†
In tumours with selected FGFR DNA fusions and mutations
‡
FDA approved; not EMA approved
§
Rechallenge with single-agent ICI is not encouraged without further evidence
║
This should be assessed within 10 weeks of completing ChT
¶
Rechallenge with platinum-based ChT may be considered if progression occurred at least 12 months after the end of previous platinum-based ChT or previous platinum-based ChT and
maintenance avelumab
#
To be considered when other therapies are not available
59
ChT, chemotherapy; EMA, European Medicines Agency; FDA, Food and Drug Administration; FGFR, fibroblast growth factor receptor; ICI, immune checkpoint inhibitor; UC, urothelial carcinoma
UTUC
• The key investigations for UTUC are CT urography and diagnostic ureteroscopy
• During ureteroscopy, an in situ cytology sample of the upper tract should be collected,
despite the fact that cytology is less sensitive for UTUC than bladder cancer
• UTUCs are stratified into two risk categories:
° Low-risk tumours include unifocal tumours of < 2 cm, LG disease at cytology/biopsy
and no invasive features on CT urography
° High-risk tumours are ≥ 2 cm, with possible hydronephrosis, HG disease at cytology/
biopsy, multifocal disease, variant histology or previous RC for bladder cancer
• Kidney-sparing management, such as endoscopic laser ablation, should be offered to
patients with low-risk UTUC
• Open or laparoscopic radical nephroureterectomy with bladder cuff excision should be
offered to patients with high-risk UTUC
• Systemic therapy recommendations for advanced UTUC follow those for advanced
bladder cancer
• There is evidence to support the use of adjuvant cisplatin-based ChT, but adjuvant
carboplatin-based ChT is not currently recommended
FOLLOW-UP AND LONG-TERM IMPLICATIONS

Non-muscle-invasive bladder cancer
• There is no generally accepted follow-up protocol for NMIBC; the frequency and
duration of cystoscopic examination and subsequent imaging should reflect the
individual patient’s risk of recurrence and progression
• In all patients with a new diagnosis of Ta-T1 tumours and/or Tis, cystoscopy should be
carried out at 3 month intervals
• Regular cystoscopy and cytology are recommended every 3-6 months during the first
2 years of follow-up, and every 6-12 months thereafter
• Regular upper tract imaging (CT intravenous urography) is recommended for high-risk
tumours
Muscle-invasive bladder cancer
• There is no generally accepted follow-up protocol for MIBC
• Imaging of the chest, upper tract, abdomen and pelvis should be carried out every
3-4 months for 2 years, and then every 6-12 months up to 5 years to detect relapse
after potentially curative therapy
° Regular upper tract imaging is recommended as UTUC occurs in 4-10% of cases
after RC
60
° The benefits of follow-up beyond 5 years are unclear and it is reasonable to
discharge patients
• After bladder-sparing procedures with curative intent, follow-up should evaluate for
both local and systemic relapse
° Cystoscopic examination should be carried out every 3-6 months for the first 5 years
° CT of the thorax and abdomen is recommended every 3-4 months for the first 2 years,
and then every 6 months up to 5 years
° The role of surveillance beyond 5 years is uncertain
Advanced/metastatic bladder cancer
• Response evaluation is recommended every 2-3 months for patients receiving
systemic therapy for advanced disease
• Cross-sectional imaging should be carried out every 3-4 months for 2 years upon
completion of systemic therapy
• Bone scans/MRI may also be required
61
PROSTATE CANCER
SCREENING
• Population-based prostate-specific antigen (PSA) screening of men for prostate cancer
is not recommended
• Risk-adapted early PSA testing can be offered to men > 50 years, men > 45 years
with a family history of prostate cancer, African-American men > 45 years and
BRCA1/2 carriers > 40 years of age
• Prostate cancer testing in asymptomatic men with a life expectancy of < 10 years
should not be done
DIAGNOSIS AND PATHOLOGY

• The use of risk calculators, incorporating age, ethnicity, family history, PSA level, free/total
PSA ratio and findings on digital rectal examination, are encouraged
• Multiparametric magnetic resonance imaging (mpMRI) is recommended before
prostate biopsy, as shown in the figure on the next page
° Biopsy should be done when the mpMRI is positive [i.e. Prostate Imaging-Reporting
and Data System (PI-RADS) ≥ 3], but not when it is negative (i.e. PI-RADS ≤ 2) and
clinical suspicion of prostate cancer is low
• Targeted transperineal biopsies are recommended over systematic transrectal
ultrasound (US)-guided biopsies due to an increase in the detection of clinically
significant disease, a decrease in the detection of clinically insignificant disease and
fewer side-effects
• Biopsies should be reported using the International Society of Urological Pathology
(ISUP) consensus recommendations
62
DIAGNOSTIC WORK-UP AND STAGING FOR PROSTATE CANCER
Elevated PSA
Repeat test
Elevated PSA
mpMRI
Other factors*
No biopsy Biopsy
Positive
Localised disease Advanced/metastatic disease
Low risk Intermediate risk High risk

T1-T2a and GS ≤ 6 T2b and GS = 7 ≥ T2c or GS = 8-10
and PSA ≤ 10 ng/mL and/or PSA or PSA > 20 ng/mL
10-20 ng/mL
Staging:
Technetium bone scan
and thoraco-abdominal CT scan
or whole-body MRI
or PSMA PET-CT
*In addition to PSA level and MRI results, the decision to biopsy or not should be made in light of DRE findings, ethnicity, age,
comorbidities, free/total PSA, history of previous biopsy and patient values
CT, computed tomography; DRE, digital rectal examination; GS, Gleason score; mpMRI, multi-parametric magnetic resonance
imaging; MRI, magnetic resonance imaging; PET, positron emission tomography; PSA, prostate-specific antigen; PSMA,
prostate-specific membrane antigen; T, tumour
63
• Staging according to the eighth edition of the American Joint Committee on Cancer
(AJCC) staging manual and risk assessment are shown in the table below and on the
next page
PROSTATE CANCER STAGING ACCORDING TO THE AJCC EIGHTH EDITION
PRIMARY TUMOUR (T)

T1 Clinically inapparent tumour that is not palpable
T1a Tumour incidental histological finding in ≤ 5% of tissue resected
T1b Tumour incidental histological finding in > 5% of tissue resected
T1c Tumour identified by needle biopsy found in one or both sides, but not palpable
T2 Tumour is palpable and confined within prostate
T2a Tumour involves one half of one side or less
T2b Tumour involves more than one half of one side but not both sides
T2c Tumour involves both lobes
T3 Extraprostatic tumour that is not fixed or does not invade adjacent structures
T3a Extraprostatic extension (unilateral or bilateral)
T3b Tumour invades seminal vesicle(s)

Tumour is fixed or invades adjacent structures other than seminal vesicles such as external
T4
sphincter, rectum, bladder, levator muscles and/or pelvic wall

N0 No positive regional lymph nodes
N1 Metastases in regional node(s)
64
DISTANT METASTASIS (M)*
cM0 No distant metastasis
cM1 Distant metastasis
cM1a Non-regional lymph node(s)
cM1b Bone(s)
pM1 Distant metastasis, microscopically confirmed
pM1a Non-regional lymph node(s), microscopically confirmed
pM1b Bone(s), microscopically confirmed
pM1c Other site(s) with or without bone disease, microscopically confirmed
*When more than one site of metastasis is present, the most advanced category is used. M1c is most advanced
AJCC, American Joint Committee on Cancer; c, clinical; M, metastasis; N, node; p, pathological; T, tumour
Amin MB et al, eds, AJCC Cancer Staging Manual, 8th edition. Springer; 2017. Reprinted with permission
RISK GROUPS FOR LOCALISED PROSTATE CANCER

Low risk T1-T2a and GS ≤ 6 and PSA ≤ 10 ng/mL
Intermediate risk T2b and/or GS 7 and/or PSA 10-20 ng/mL
High risk T3a/T3b or GS 8-10 or PSA > 20 ng/mL

GS, Gleason score; PSA, prostate-specific antigen; T, tumour
• Magnetic resonance imaging (MRI) provides T staging and can inform surgical technique
• Patients who are not suitable for treatment with curative intent due to poor general
health do not normally require staging investigations
• Localised disease should be classified as low, intermediate or high risk
• Patients with low-risk disease [T1/T2, Gleason score (GS) ≤ 6, PSA ≤ 10 ng/mL] do not
require further imaging
• Patients with intermediate-risk disease should be staged for metastases using MRI or
computed tomography (CT) (abdomen and pelvis) and bone scan or next-generation
imaging
• Patients with high-risk disease should be staged for metastases using CT (chest,
abdomen and pelvis) and bone scan or next-generation imaging
• Whole-body MRI, choline-positron emission tomography (PET)-CT and prostate-specific
membrane antigen (PSMA)-PET-CT have better sensitivity/specificity but do not improve
clinical outcomes over CT or bone scan
65
MANAGEMENT OF LOCAL/LOCOREGIONAL PROSTATE CANCER
• There is no consensus regarding optimum management strategies for localised disease.
Stage-matched therapeutic strategies are shown in the table on the next page and in the
figures on pages 70 and 71
• Patients should be informed about the benefits and harms of the range of treatments
and the potential for sexual dysfunction, infertility, and bowel and urinary problems
• Watchful waiting with delayed androgen deprivation therapy (ADT) for symptomatic
progression is an option for men who are not suitable for, or who are unwilling to have,
radical treatment
• Active surveillance, with PSA, repeat biopsies and MRI, is recommended for low-risk
disease
• Curative options include radical prostatectomy (RP), external beam radiotherapy (EBRT)
and low dose-rate brachytherapy
• Studies to-date have not demonstrated a clear benefit of RP over watchful waiting or
active surveillance in low-risk disease
• RP or radiotherapy (RT, external beam or brachytherapy) is an option for men with low-risk
disease not suitable for active surveillance and for men with intermediate-risk disease
• Primary ADT alone is not recommended as standard initial treatment for
non-metastatic disease
• The addition of EBRT to ADT is recommended for men with high-risk or locally
advanced prostate cancer
• EBRT–ADT–abiraterone–prednisone is recommended for men with very high-risk M0
prostate cancer, defined by N1 disease or ≥ 2 risk factors among T3-T4, PSA > 40 ng/mL,
GS 8-10 [not European Medicines Agency (EMA) or Food and Drug Administration (FDA)
approved for use in M0 disease]
Neoadjuvant and adjuvant hormone treatment
• Neoadjuvant and concurrent ADT with RT in men with high-risk localised and locally
advanced disease is recommended
• Patients with unfavourable intermediate-risk disease {primary Gleason pattern 4,
≥ 50% positive biopsy cores or ≥ 2 intermediate risk factors [clinical (c)T2b-cT2c,
GS 7, PSA 10-20 ng/mL]} might be more likely to benefit from neoadjuvant ADT than
patients with favourable intermediate-risk disease
• RP plus pelvic lymphadenectomy is an option for selected men with high-risk disease
• Men receiving radical RT for intermediate-risk disease should have short-course ADT
for 4-6 months
66
STAGE-MATCHED THERAPEUTIC STRATEGIES FOR PROSTATE CANCER
Active surveillance
Brachytherapy
Low risk
RP
Radical RT
RP
Localised disease Radical RT ± neoadjuvant ADT
Intermediate risk
Brachytherapy
Active surveillance
Long-term ADT + radical RT
High risk
RP + pelvic lymphadenectomy*
Very high risk† EBRT–ADT–abiraterone–prednisone‡
Locally advanced Neoadjuvant ADT + radical RT + adjuvant ADT
–
disease RP + pelvic lymphadenectomy
ADT–apalutamide
M0 CRPC High risk ADT–darolutamide
ADT–enzalutamide
ADT–abiraterone–prednisone
ADT–docetaxel–abiraterone
ADT–docetaxel–darolutamide
ADT–enzalutamide
Metastatic disease Hormone naive ADT–apalutamide
RT for low volume
ADT alone for frail patients who cannot tolerate the above
treatments
Prevention of bone loss with bone health agents, if indicated
Abiraterone–prednisone
Docetaxel
Enzalutamide
Castration resistant 223
Ra for patients unfit for above treatments (and
(first line) bone-only metastases)
Olaparib–ARPI§
Bone health agents (denosumab or zoledronic acid) to
Metastatic disease
prevent SREs
Abiraterone–prednisone
Cabazitaxel
Second line or Enzalutamide
post-docetaxel 223
Ra
177
Lu-PSMA-617
Olaparib§
*Only in selected cases as part of a multimodality approach
†
Defined by N1 disease or ≥2 risk factors among T3-T4, PSA > 40 ng/mL, GS 8-10
‡
Not EMA or FDA approved for use in M0 disease
§
For men with mCRPC and BRCA1/2 alterations
177
Lu-PSMA-617, lutetium-177 vipivotide tetraxetan; 223Ra, radium-223; ADT, androgen deprivation therapy; ARPI, androgen
receptor pathway inhibitor; CRPC, castration-resistant prostate cancer; EBRT, external beam radiotherapy; EMA, European Medicines
Agency; FDA, Food and Drug Administration; GS, Gleason score; M0, non-metastatic; mCRPC, metastatic castration-resistant
prostate cancer; N, node; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy; SRE, skeletal-related
events; T, tumour
67
68
MANAGEMENT OF LOCALISED PROSTATE CANCER
Localised PC
Low risk Intermediate risk
Watchful waiting, Active surveillance RT (EBRT or RP Consider neoadjuvant

delayed ADT* brachytherapy) and concurrent ADT
for 4-6 months
Active surveillance RT (EBRT or

RP
brachytherapy)
Relapse after radical therapy
After RT After RP
Local salvage (HIFU, HDR brachytherapy, RP) Salvage RT to prostate bed ± pelvic nodes
or observation with delayed ADT† Consider ADT for 6-24 months
*Also suitable for localised/locally advanced disease if patient not suitable for (or unwilling to have) radical treatment
†
For men with biochemical relapse and symptomatic local disease, proven metastases or a PSA doubling time of < 3 months
ADT, androgen deprivation therapy; EBRT, external beam radiotherapy; HDR, high dose-rate; HIFU, high-intensity focused ultrasound; PC, prostate cancer; PSA, prostate-specific antigen;
RP, radical prostatectomy; RT, radiotherapy
MANAGEMENT OF HIGH-RISK LOCALISED AND LOCALLY ADVANCED PROSTATE CANCER
High-risk localised and locally advanced PC
Neoadjuvant ADT for 4-6 months RP + pelvic lymphadenectomy
EBRT + ADT
Adjuvant ADT (3 years)

(combined with 2 years of
abiraterone–prednisone* for men
with very high-risk disease)
Relapse after radical therapy
After RT After RP
Local salvage (HIFU, HDR brachytherapy, RP)

Salvage RT to prostate bed ± pelvic nodes
Observation with delayed ADT†
Consider ADT for 6-24 months
Immediate intermittent ADT‡
*Not EMA or FDA approved for use in M0 disease

†
For men with biochemical relapse and symptomatic local disease, proven metastases or a PSA doubling time of < 3 months
‡
For men with high-risk biochemical relapse
ADT, androgen deprivation therapy; EBRT, external beam radiotherapy; EMA, European Medicines Agency; FDA, Food and Drug
Administration; HDR, high-dose rate; HIFU, high-intensity focused ultrasound; M0, non-metastatic; PC, prostate cancer; PSA,
prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy
• Men receiving radical RT for high-risk disease should have long-course ADT (18-36 months)
° Given the additional toxicity of longer-term ADT, 18 months of treatment may be
preferred by some patients
• Men receiving EBRT–ADT–abiraterone–prednisone for very high-risk disease should
have long-course ADT plus abiraterone–prednisone (2-3 years in total)
Postoperative radiotherapy
• Postoperative RT following RP may be given as adjuvant RT (undetectable
postoperative PSA) or salvage RT (persistent or rising PSA)
69
• Adjuvant RT appears to offer no consistent survival benefit compared with observation
after RP and is not routinely recommended
• Observation with salvage RT in the event of serum PSA failure is the current standard
after RP, with salvage RT being started early (when PSA < 0.5 ng/mL)
• Concomitant ADT for 6 months or bicalutamide 150 mg daily for 2 years may be
offered to men receiving salvage RT
° The benefit of bicalutamide was particularly pronounced in men with pre-salvage RT
PSA > 0.7 ng/mL, GS 8-10 and positive margins
• Men receiving salvage RT to the prostate bed may be offered pelvic nodal RT
Treatment of relapse after radical local treatment
Restaging
• Men with biochemical relapse after radical RT, who may be candidates for local
salvage or metastasis-directed treatment, should undergo imaging with PET-CT
° There is no evidence that earlier detection of recurrence with more sensitive imaging
methods, such as PSMA-PET, and subsequent changes in management improve
outcomes
Local salvage therapy
• Life expectancy should be considered when choosing local treatment options
• Treatment options for biopsy-confirmed local recurrence without metastases, including
salvage RP, high-intensity focused US, cryoablation and brachytherapy, give only
temporary biochemical control in most patients and have important morbidity
Metastasis-directed therapy
• Currently, there is no conclusive evidence for the benefit of metastasis-directed therapy
Systemic therapy
• Early ADT alone is not recommended for men with biochemical relapse unless they
have a rapid PSA doubling time, symptomatic local disease or proven metastases
• Men starting ADT for biochemical relapse in the absence of metastatic disease should
be offered intermittent rather than continuous treatment
METASTATIC HORMONE-NAIVE PROSTATE CANCER

• Treatment recommendations for metastatic hormone-naive prostate cancer (mHNPC)
are shown in the figure on the next page
70
MANAGEMENT OF HORMONE-NAIVE METASTATIC PROSTATE CANCER
Metastatic PC
Hormone-naive disease
Low burden High burden
ADT–ARPI Preferred:
ADT–ARPI–docetaxel (selected cases) ADT–docetaxel–abiraterone–prednisone*,†
Consider adding prostate RT ADT–docetaxel–darolutamide‡
(de novo mHNPC only) Alternative:
ADT–ARPI
*Not EMA or FDA approved
†
For fit men with de novo mHNPC who are able to tolerate triplet therapy
‡
For fit men with de novo mHNPC and those who have progressed to metastatic disease who are able to tolerate triplet therapy
ADT, androgen deprivation therapy; ARPI, androgen receptor pathway inhibitor; EMA, European Medicines Agency; FDA, Food and
Drug Administration; mHNPC, metastatic hormone-naive prostate cancer; PC, prostate cancer; RT, radiotherapy
• ADT is recommended as first-line treatment of mHNPC in combination with docetaxel,

abiraterone–prednisone, apalutamide or enzalutamide
° The benefit of adding docetaxel to ADT appears to be independent of disease volume
in men with de novo metastatic disease. On the other hand, no benefit is observed in
men with relapsing and low-volume disease
° The benefit of adding abiraterone–prednisone to ADT in patients with relapsing M1
disease is uncertain
° The benefit of adding apalutamide to ADT appears to be independent of disease
volume but beneficial effects in patients who have received early docetaxel remain
unclear
° The benefit of adding enzalutamide to ADT appeared to be independent of disease
volume and was greater in patients who were not planned to also receive docetaxel
° Docetaxel alone is no longer a standard of care if an androgen receptor pathway
inhibitor (ARPI) is available
71
° ADT–docetaxel–abiraterone–prednisone is recommended as first-line treatment
for fit men with de novo mHNPC, especially in those with multiple bone metastases
(> 3) or visceral metastases (not EMA or FDA approved)
° ADT–docetaxel–darolutamide is also recommended as first-line treatment of
mHNPC, including patients with de novo mHNPC and those who have progressed to
metastatic disease
• Since no biomarkers have been identified to select one therapy over another, the
selection of agent should be individualised based on cost, access to treatment, toxicity
profile, duration of treatment, comorbidities and patient preference
• RT to the primary tumour combined with systemic treatment is recommended for
patients with low-volume mHNPC
• ADT alone is recommended as first-line systemic treatment of mHNPC in vulnerable
men who cannot tolerate treatment intensification
• For men starting ADT, management to prevent cancer treatment-induced bone loss
(CTIBL) is recommended
NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

• Non-metastatic castration-resistant prostate cancer (CRPC) is characterised as disease
progression during ADT, with serum testosterone at castrate levels, and the absence of
metastases on bone scintigraphy and CT scan
• Apalutamide, darolutamide and enzalutamide should be considered as options for men
with M0 CRPC and a high risk of disease progression, although overall survival (OS)
data from trials are still immature
METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

• For men with metastatic CRPC (mCRPC), both bicalutamide and low-dose
corticosteroids show a benefit in terms of PSA and symptomatic responses, but OS
benefits have not been demonstrated in clinical trials
• Abiraterone–prednisone or enzalutamide are recommended for asymptomatic/mildly
symptomatic men with ChT-naive mCRPC
• Docetaxel is recommended for men with mCRPC
• In the post-docetaxel setting, cabazitaxel, abiraterone–prednisone and enzalutamide
are recommended options when these agents have not been used earlier
• In patients with bone metastases from CRPC at risk for clinically significant skeletal-
related events (SREs), denosumab or zoledronic acid is recommended (see section on
palliative care on page 76)
72
• Radium-223 (223Ra) is recommended for men with bone-predominant, symptomatic
mCRPC without visceral metastases
° H223owever, an increased risk of fractures has been observed among patients receiving
Ra in combination with abiraterone–prednisone
° The Pharmacovigilance Risk Assessment Committee of the EMA has restricted the
use of Ra to patients who have received at least two lines of systemic treatment
223
for CRPC (abiraterone–prednisone–enzalutamide and docetaxel) or who are ineligible

to receive these therapies
° The administration of Ra in association with abiraterone is not permitted
223
• Lutetium-177 (177Lu)-PSMA-617 [lutetium (177Lu) vipivotide tetraxetan] showed

radiographic progression-free survival and OS improvements in men with PSMA-
positive mCRPC who had received at least one taxane and at least one next-generation
ARPI; therefore, it should be considered in this population
• The optimal sequence of these agents is largely unknown, although there is strong
evidence for cross-resistance between abiraterone and enzalutamide
° The use of a second ARPI (abiraterone after enzalutamide or vice versa) is not
recommended
° In daily practice, sequencing decisions will be made based on the distribution, extent
and pace of disease; comorbidities; previous treatments; patient preference and
drug availability
PRECISION MEDICINE
• Tissue-based molecular assays may be used in conjunction with clinicopathological
factors for treatment decision making in localised prostate cancer
• Androgen receptor splice variant 7 is of limited value for therapy selection and cannot be
recommended
• Actionable targets are identified in the majority of advanced prostate tumours
° Germline testing for BRCA2 and other genes involved in DNA damage and repair
associated with cancer predisposition syndromes is recommended in patients with
a family history of cancer and should be considered in all patients with metastatic
prostate cancer
• Tumour testing for homologous recombination genes and mismatch repair defects (or
microsatellite instability) in patients with mCRPC should be considered
• Patients with pathogenic mutations in cancer-risk genes identified through tumour
testing should be referred for germline testing and genetic counselling
73
• Olaparib should be considered in men with mCRPC and BRCA1/2 alterations:
° As first-line treatment in combination with an ARPI
° Who have progressed following prior treatment with an ARPI (with or without prior
taxane therapy)
PALLIATIVE CARE
• A single fraction of EBRT provides similar pain relief to fractionated doses and is
recommended for palliation of painful, uncomplicated bone metastases
° Multifraction RT is commonly used for bone metastases associated with
complications, such as nerve root compression from soft tissue extension
• In patients with bone metastases from CRPC at risk for clinically significant SREs, a
bisphosphonate or denosumab is recommended
° Abiraterone, enzalutamide, corticosteroids and Ra all increase the risk of fragility
223
fractures but reduce the risk of other SREs; if bone health recommendations are
followed, the added value of zoledronic acid or denosumab for SRE prevention is unclear
• In men with CRPC with vertebral metastases, MRI of the spine is recommended
to detect subclinical cord compression, with early detection critical for successful
management
• In men with CRPC with vertebral metastases and neurological symptoms, urgent MRI
of the spine to detect cord compression is very strongly recommended
• The use of beta-emitting, bone-seeking radionuclides has largely been superseded by
223
Ra
FOLLOW-UP AND LONG-TERM IMPLICATIONS

• Given the substantial survival improvements in mCRPC and the corresponding
increases in length of time on ADT and other treatments, bone health in men with
prostate cancer is an increasingly important issue
° Lifestyle measures to maintain bone health are recommended for men on ADT: Weight-
bearing exercise, stopping smoking, ≤ 2 units of alcohol daily, adequate calcium intake
and vitamin D status (i.e. reach and maintain reference vitamin D levels)
• Men starting long-term ADT should be either:
° Offered an oral bisphosphonate (with zoledronic acid every 12 months or denosumab
every 6 months as alternatives for those unable to tolerate oral bisphosphonates), or
° Monitored with dual-energy X-ray absorptiometry scanning and then treated
according to ESMO guidelines for CTIBL
74
GLOSSARY
5-FU, 5-fluorouracil
177
Lu, lutetium-177
223
Ra, radium-223
ADT, androgen deprivation therapy
AFP, α-fetoprotein
AJCC, American Joint Committee on Cancer
ARPI, androgen receptor pathway inhibitor
β-hCG, beta subunit of human chorionic gonadotropin
BCG, bacillus Calmette–Guerin
BEP, bleomycin–etoposide–cisplatin
c, clinical
ccRCC, clear cell renal cell carcinoma
ChT, chemotherapy
CN, cytoreductive nephrectomy
CNS, central nervous system
CPG, Clinical Practice Guideline
CRPC, castration-resistant prostate cancer
CT, computed tomography
CTIBL, cancer treatment-induced bone loss
dMMR, mismatch repair deficient
DSLNB, dynamic sentinel lymph node biopsy
EBRT, external beam radiotherapy
EMA, European Medicines Agency
EP, etoposide–cisplatin
ESMO, European Society for Medical Oncology
EURACAN, European Reference Network for Rare Adult Solid Cancers
FDA, Food and Drug Administration
FDG, [18F]2-fluoro-2-deoxy-D-glucose
FGFR, fibroblast growth factor receptor
FNAC, fine-needle aspiration cytology
G, grade
GCNIS, germ cell neoplasia in situ
G-CSF, granulocyte colony-stimulating factor
GCT, germ cell tumour
GS, Gleason score
GU, genitourinary
HD, high dose
HDR, high-dose rate
HG, high grade
HPV, human papillomavirus
ICI, immune checkpoint inhibitor
IGCCCG, International Germ Cell Cancer Collaborative Group
75
GLOSSARY (CONT’D)
ILND, inguinal lymph node dissection

IMDC, International Metastatic RCC Database Consortium
ISUP, International Society of Urological Pathology
LDR, low-dose rate
LG, low grade
LN, lymph node
mCRPC, metastatic castration-resistant prostate cancer
MDM2, mouse double minute 2
MDT, multidisciplinary team
MET, MET proto-oncogene receptor tyrosine kinase
mHNPC, metastatic hormone-naive prostate cancer
MIBC, muscle-invasive bladder cancer
miRNA, microRNA
mpMRI, multi-parametric magnetic resonance imaging
MRI, magnetic resonance imaging
MSI-H, microsatellite instability high
mTOR, mammalian target of rapamycin
MVAC, methotrexate–vinblastine–adriamycin–cisplatin
NMIBC, non-muscle-invasive bladder cancer
OS, overall survival
OSS, organ-sparing surgery
p, pathological
PD-1, programmed cell death protein 1
PD-L1, programmed death-ligand 1
PeIN, penile intraepithelial neoplasia
PET, positron emission tomography
PI3K, phosphoinositide 3-kinase
PI-RADS, prostate imaging-reporting and data system
PLND, pelvic lymph node dissection
PN, partial nephrectomy
pRCC, papillary renal cell carcinoma
PSA, prostate-specific antigen
PSMA, prostate-specific membrane antigen
RC, radical cystectomy
RCC, renal cell carcinoma
RN, radical nephrectomy
RP, radical prostatectomy
RPLND, retroperitoneal lymph node dissection
RT, radiotherapy
SBRT, stereotactic body radiotherapy
SCC, squamous cell carcinoma
SMARCB1, switch/sucrose non-fermentable-related matrix-associated actin-dependent regulator of
chromatin subfamily B member 1
76
SoC, standard of care
SRE, skeletal-related event
SSG, split-thickness skin graft
TIP, paclitaxel–ifosfamide–cisplatin
Tis, carcinoma in situ
TKI, tyrosine kinase inhibitor
TMB-H, tumour mutational burden high
TNM, tumour–node–metastasis
TP53, tumour suppressor protein p53
TPF, docetaxel–cisplatin–5-fluorouracil
TURBT, transurethral resection of the bladder tumour
UC, urothelial carcinoma
UICC, Union for International Cancer Control
US, ultrasound
UTUC, urinary tract urothelial carcinoma
VEGFR, vascular endothelial growth factor receptor
VHL, von Hippel Lindau
VIP, etoposide–ifosfamide–cisplatin
WHO, World Health Organization
77
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GENITOURINARY CANCERS - ESMO POCKET GUIDELINE - 2024

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Genitourinary

ESMO CLINICAL PRACTICE GUIDELINES

ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE

Please visit http://www.esmo.org to view the full guidelines.

RENAL CELL CARCINOMA (RCC)

DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

DIAGNOSTIC WORK-UP OF RCC

Investigations for suspected RCC

Detection of renal mass (incidental finding

Contrast-enhanced CT of the chest, abdomen and pelvis for staging

Localised disease Advanced disease

• Neuroimaging [computed tomography (CT) or magnetic resonance imaging] and a

STAGING AND RISK ASSESSMENT

STAGING OF RCC ACCORDING TO THE UICC TNM EIGHTH EDITION

Local and locoregional RCC

PN (preferred) RN (minimally invasive Open RN (laparoscopic RFA Nephron-sparing

Advanced and metastatic ccRCC

Favourable-risk disease Intermediate- or poor-risk disease

A VEGFR TKI that has not been given previously

A VEGFR TKI that has not been given previously

*Not EMA or FDA approved

• Axitinib–toripalimab is a first-line option for patients with intermediate- or poor-risk

Advanced and metastatic ccRCC

ICIs contraindicated or not available

Nivolumab (if available and ICIs not contraindicated)

ccRCC, clear-cell renal cell carcinoma; ICI, immune checkpoint inhibitor

• Sunitinib, pazopanib and tivozanib are alternatives to first-line ICI-based combination

Advanced and metastatic pRCC

A systemic therapy that has not been given previously

*Not EMA or FDA approved for use as single-agent therapy

• Cabozantinib is the preferred first-line monotherapy for advanced pRCC without

SYSTEMIC TREATMENT OF ADVANCED AND METASTATIC NON-CLEAR-CELL AND

Advanced and metastatic

Clinical trial if available

Chromophobe Collecting duct and medullary Sarcomatoid (predominant)

*Not EMA or FDA approved for first-line treatment

• Sunitinib, pazopanib, lenvatinib–everolimus (not EMA or FDA approved for first-

FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

DIAGNOSIS AND PATHOLOGY

DIAGNOSTIC WORK-UP OF PENILE CANCER

Diagnostic work-up of penile cancer

Assessment of the primary tumour:

Assessment of regional LNs:

Assessment of distant metastasis:

Staging, pathology and risk group classification:

MANDATORY AND RECOMMENDED INFORMATION TO INCLUDE IN THE

Macroscopic maximum tumour dimension, including:

Histological tumour type X

Microscopic maximum dimensions (combination of

Margin status (in mm) X

Non-HPV-related PeIN Differentiated PeIN

HPV, human papillomavirus; PeIN, penile intraepithelial neoplasia

STAGING OF PENILE CANCER ACCORDING TO THE UICC TNM EIGHTH EDITION

Primary penile tumour

Clinical and radiological assessment

Tis or Ta T1 or T2 glans T2-T4 (with tunical

Small lesions Large or multifocal lesions

Glansectomy with distal

Clinical stage assessment

Impalpable LN (cN0) Palpable LN (cN1-2) LN ulcerated or fixed (cN3)

• T1 G3/HG associated with