- Email: [email protected]
Bladder cancer
COMMON CANCERS
Bladder cancer
Key points
Marcelino Yazbek-Hanna
C
Haematuria is the most common symptom of bladder cancer and is present in almost 75% of patients
C
Primary treatment of bladder cancer is endoscopic transurethral resection of the bladder tumour (TURBT)
C
‘Superficial’ non-muscle-invasive bladder cancers are stratified after TURBT by their risk of recurrence and progression, and can require adjuvant intravesical therapy
C
Muscle-invasive bladder cancer has a 50% 5-year survival and is treated with neoadjuvant chemotherapy and surgery or radiotherapy
C
Metastatic disease is often responsive to chemotherapy or immunotherapy
Sunjay Jain
Abstract Bladder cancer is the most frequently occurring tumour of the urinary tract and the eighth most common cause of cancer death in the UK. It is characterized by a high recurrence rate, pathological progression and poor survival in advanced metastatic disease. Owing to the long follow-up period and associated costs of disease monitoring, it is one of the most expensive cancers to manage. Local therapy and surveillance are the mainstays of management of early disease, which comprises 75% of cases. Radical surgery and radiotherapy are the main curative options in advanced non-metastatic disease. Chemotherapy can be used in a neoadjuvant, adjuvant or palliative setting. There remains a great need for effective tumour markers to aid diagnosis, staging, monitoring and predicting prognosis.
Keywords Bladder cancer; chemotherapy; intravesical therapy; MRCP; radical cystectomy; radical radiotherapy; urinary markers
squamous cell carcinoma, adenocarcinoma and neuroendocrine tumours. Squamous cell carcinoma accounts for only for 5% of bladder cancers in industrialized countries but >50% of tumours in Africa and the Middle East, where bilharzia (Schistosoma haematobium) is endemic.
Epidemiology
Grading and staging
Bladder cancer is 2.5 times more prevalent in men than women, with a peak incidence in the sixth and seventh decades of life. In the UK, it accounts for >10,000 new diagnoses and 5000 deaths annually. Its incidence peaked in the 1990s and has since gradually declined by approximately 40%, possibly because of reductions in smoking and occupational carcinogens, and alterations in disease coding. It remains, however, a significant economic burden to the NHS.
Histological grading is based on a combination of the World Health Organization 1973 and 2004 criteria. Papillary tumours are graded from 1 to 3, low grade and high grade (Figure 1). Higher grade lesions carry a greater risk of tumour recurrence and progression. Staging is with the tumour, nodes, metastasis (TNM) classification (Figure 2).
Aetiology
Haematuria is present in almost 75% of patients. Other symptoms include urinary urgency and/or frequency and bladder pain. Weight loss, abdominal pain and renal impairment secondary to ureteric obstruction are usually signs of advanced disease. Urgent urological referral is mandated for: (1) patients aged 45 years and over with unexplained visible haematuria without urinary tract infection, or visible haematuria that persists or recurs after successful treatment of urinary tract infection; and (2) patients aged 60 or over who have unexplained non-visible haematuria and either dysuria or a raised white cell count on a blood test. All patients in whom bladder cancer is suspected are appropriately investigated with diagnostic cystoscopy and upper urinary tract imaging with ultrasonography or computed tomography urography (CTU) (to identify lesions within the ureter, renal pelvis and renal parenchyma). Urine cytology can be a useful test in diagnosing high-grade disease.
Diagnosis
Risk factors include cigarette smoking, which accounts for approximately 50% of cases, occupational exposure to chemicals such as aniline dyes and aromatic amines,1 consumption of analgesics containing phenacetin, chronic infection or irritation of the bladder (e.g. indwelling catheters, calculi), chemotherapeutic agents such as cyclophosphamide and pelvic irradiation. Smokers have a 4-fold increased risk compared with those who have never smoked.
Pathology Over 90% of malignant tumours of the bladder are ‘urothelial’ transitional cell carcinoma (TCC). Less common forms include
Marcelino Yazbek-Hanna MRCS FRCS MD is a Urology Fellow at St James’ University Hospital, Leeds, UK. Competing interests: none declared.
Initial management and staging Primary treatment of bladder cancer is endoscopic transurethral resection of bladder tumour (TURBT). Muscle should be included
Sunjay Jain MD FRCS is a Consultant Urological Surgeon at St James’ University Hospital, Leeds, UK. Competing interests: none declared.
MEDICINE xxx:xxx
1
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
Grading of papillary tumours Grade 1 (PUNLMP) , Grade 1 (LG) / Grade 2 (LG) , Grade 2 (HG) / Grade 3 (HG)
HG, high-grade carcinoma; LG, low-grade carcinoma; PUNLMP, papillary urothelial neoplasm of low malignant potential. Figure 1
European Organization for Research and Treatment of gico Espanol de TrataCancer (EORTC) and Club Urolo gico (CUETO) scores are risk calculators miento Oncolo that can predict risk of recurrence and progression in individual patients.
in the resection specimen to stage the disease accurately and reduce recurrence. If the tumour is palpable after resection, the tumour is staged as cT3, or as cT4 if the bladder is fixed. Around 75% of patients present with ‘superficial’ non-muscleinvasive bladder cancer (NMIBC). Carcinoma-in-situ (CIS) is superficial disease that has a high rate of recurrence and progression (60% progress if left untreated and 20% progress despite Bacillus CalmetteeGuerin (BCG) treatment) so is stratified into the high-risk category of NMIBC. More than 50% of patients with NMIBC experience recurrence and 10e15% progress to muscle-invasive bladder cancer (MIBC). Increasing tumour grade, stage, size, multifocality and recurrence rate are associated with increased risk of progression. These are used to guide further management (Figure 3): Low-risk patients generally need only surveillance Intermediate-risk patients are recommended to have intravesical chemotherapy or immunotherapy. High-risk patients require a second cystoscopy and reresection to avoid understaging and remove residual disease.2 Intravesical therapy is an option but patients should be offered early curative radical surgery (cystectomy). The
Intravesical chemotherapy and immunotherapy It has been shown that a single installation of intravesical chemotherapy (mitomycin, epirubicin) within 6 h of TURBT reduces the recurrence rate of NMIBC by 50%. Maintenance therapy with mitomycin or BCG is used for intermediate- and highrisk tumours.3 BCG is thought to initiate an extensive local inflammatory reaction in the bladder wall and trigger a complex immunological cascade, which can cause marked irritative voiding symptoms. Disease surveillance Patients should be subject to a period of endoscopic surveillance with check flexible cystoscopy under local anaesthetic 3 months after initial TURBT. Frequency of further follow-up depends on the risk group.
T-stages of transitional cell carcinoma bladder cancer (TNM classification)
T
T
2a
1
T
2b
T
3
Ta Tis
T
4
Mucosa Submucosa
T4-contiguous organs
Deep muscularis propria Perivesical fat Figure 2
MEDICINE xxx:xxx
2
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
Mangement of bladder cancer Investigations • Urine bacteriology, exclude infection – Urine cytology • Upper urinary tract imaging: – Diagnostic flexible cystoscopy – USS for non-visible haematuria – CTU for visible haematuria
Presenting symptoms Haematuria, urinary frequency, urgency, pelvic pain, weight loss
Diagnosis of bladder cancer TURBT + postoperative intravesical chemotherapy when appropriate
Non-muscle invasive bladder cancer Low-risk disease • Solitary G1/G2 (LG) pTa <3 cm • PUNLMP
Intermediate-risk disease • Solitary G1/G2 (LG) pTa >3 cm or multifocal • G2pTa (HG) • Any low-risk disease recurring within 12 months of last tumour occurrence
Muscle invasive bladder cancer High-risk disease • Any G3 or T1 disease • CIS • G1G2Ta, multiple and recurrent & large (>3 cm) (all features must be present) Highest risk disease • G3T1 + CIS • Multiple G3T1 • Large G3T1 >3cm • Recurrent G3T1 • Variant histology
Non-metastatic
Metastatic
Early re-resection to exclude understaging for T1 disease and in the absence of muscle in the initial resection in intermediate- and high-risk disease Treatment • One course of at least 6 doses of intravesical (MMC). Refer to MDT in case of recurrence or • 1-year full course of BCG or 1 year on MMC
• Intravesical full-dose BCG for 1–3 years or • Radical cystectomy in highest risk tumours • (G3pT1 + CIS, multiple and/or large and/or recurrent G3pT1, urethral CIS, LVI, variant histology)
Neoadjuvant chemotheapy unless contraindicated
Consider primary chemo-radiotherapy in case of low-volume metastasis
Radical cystectomy or radiotherapy with a radiosensitizer
Palliative care
Follow-up NICE: cystoscopy at 3 and 9 months, discharge
NICE: cystoscopy at 3, 9 and 18 months, then yearly for 5 years
EAU: cystoscopy at 3, 9 and 12 months, then yearly for 5 years
EAU: instruction on frequency of cystoscopy
NICE: cystoscopy 3-monthly for 2 years, then 6-monthly for 2 years, then yearly for life EAU: as per NICE + cytology
Cystectomy: • Annual renal function blood test, folate and vitamin B12 • Imaging: annual renogram + GFR yearly for 5 years CTU at 6,12 and 24 months • Urethral wash for cytology for 5 years
Radiotherapy: • Rigid cystoscopy at 3 months • Flexycystoscopy 3-monthly for 2 years, 6-monthly for 2 years, yearly thereafter • CTU at 6, 12 and 24 months
pho vascular invasion; MDT, multidisciplinary team; MMC, mitomycin C; NICE, National Institute for Health and Care Excellence, pTa, Pathologically Ta (papillary disease involving the bladder mucosa only); PUNLMP, papillary urothelial neoplasm of low malignant potential. G1, G2, G3, pathological grading of cancer cells from least to most aggressive, Figure 3
MEDICINE xxx:xxx
3
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
Management of T2D muscle-invasive bladder cancer
Chemotherapy Gemcitabine/cisplatin is the standard regimen, with carboplatin used as an alternative to cisplatin for individuals with poor renal function. Second-line chemotherapy can be considered for fit patients. Rechallenge with gemcitabine/cisplatin can be considered if patients relapse >12 months from initial therapy. Other agents have not been shown to have a proven survival advantage.
MIBCs have a high rate of metastatic disease and poor long-term survival. They require staging with CT of the chest and abdomen, and CT and/or magnetic resonance imaging of the pelvis. Fluorodeoxyglucose positron emission tomography-CT has a role with equivocal lesions. The standard approach for MIBC in UK is radical cystectomy or radical radiotherapy. These have similar 5-year overall survival of approximately 50%, although this is increased by 5% for TCCs given neoadjuvant chemotherapy.4
Immunotherapy Immunotherapy with checkpoint inhibitors has shown to have significant anti-tumour activity, tolerability, safety profile, and durable responses in these patients.5 Active agents include PD-1 (programmed death 1) inhibitors (pembrolizumab, nivolumab) and PD-L1 (programmed death-ligand 1) inhibitors (atezolizumab, avelumab, durvalumab); have similar efficacy in patients progressing during, or after, standard platinum-based chemotherapy and have good activity levels in patients ineligible for cisplatin-based therapy: a 29% overall response rate and 7% complete response rate for pembrolizumab, and a 29% overall response rate, 9% complete response rate and median overall survival (OS) of 15.9 months for atezolizumab. In a Phase III trial and as a second-line treatment during or after platinum-based first-line chemotherapy, atezolizumab and pembrolizumab showed an improved OS benefit of 3 months compared with chemotherapy with paclitaxel, docetaxel or vinflunine (10.3 versus 7.4 months). Treatment stratification is thought to be possible by immunohistochemical staining that can detect patients with negative PD-L1 status who might have an impaired response to PD-L1 inhibitors, as shown in a Phase II trial. A
Cisplatin-based chemotherapy such as gemcitabine/cisplatin is now the standard combination for TCC but some centres use dose-dense MVAC (methotrexate, vinblastine, doxorubucin cisplatin), which has a better pathological response rate and downstaging ability in Phase II trials. Cisplatin has many adverse effects including nephrotoxicity as it is renally excreted; it cannot be used safely in patients with renal impairment, which is very common in MIBC. Other multivariable histology, including squamous cell carcinoma, neuroendocrine and sarcomatoid differentiation, are less responsive to chemotherapy. Adjuvant chemotherapy after radical cystectomy is under debate and infrequently used. Surgery and radiotherapy The choice of radiotherapy or surgery is made on the basis of patient choice and co-morbidity as there is no high-level evidence comparing the two modalities. Cystectomy is a highly morbid operation but outcomes have improved in recent years; this is partly because of centralization of surgery in specialist centres and partly because of the use of minimal access surgery using a da Vinci robotic system. Urinary diversion is required, and although most patients have a stoma (ileal conduit), a neobladder is an option that allows normal voiding in selected well-motivated individuals. Radiotherapy techniques have evolved to reduce morbidity, particularly bowel toxicity. Current protocols use radiosensitizers to improve outcomes. The followup protocol for patients after radical treatment is detailed in Figure 3.
KEY REFERENCES 1 Delclos GL, Lerner SP. Occupational risk factors. Scand J Urol Nephrol Suppl 2008; 218: 58e63. 2 Naselli A, Hurle R, Paparella S, et al. Role of restaging transurethral resection for T1 non-muscle invasive bladder cancer: a systematic review and meta-analysis. Eur Urol Focus 2018; 4: 558e67. 3 European Association of Urology. Non-muscle-invasive bladder cancer, 2018. 4 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005; 48: 202e5. 5 Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase ii study. J Clin Oncol 2018; 36: 3353e60.
Management of metastatic disease Chemotherapy remains the mainstay of treatment for patients with metastatic disease, with a response rate of up to 49% depending on the agent used. However, prognosis remain poor, with a survival rate of 5e10% at 5 years and an overall survival of 12e14 months. Several factors has been shown to negatively affect prognosis, for example a Karnofsky performance status <80% and the presence of visceral metastases.
MEDICINE xxx:xxx
4
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. propria) disease in a single lesion <2 cm in size, with muscle present in the biopsy
Question 1 A 69-year-old man presented with history of asymptomatic visible haematuria. His past medical history includes hypertension, Atrial fibrilation on warfarin and chronic obstructive pulmonary disease. He is a lifetime non-smoker and had worked in an office. An ultrasound scan organized by the GP showed a suspicious bladder abnormality at the bladder neck.
What is the next step in his management A. Bacillus CalmetteeGuerin (BCG) B. Mitomycin C. Conservative with surveillance cystoscopy D. Cystectomy E. Re-resection TURBT þ BCG if no pathological upgrade
How would be the next step in his investigation? A. Diagnostic flexible cystoscopy B. General anaesthetic cystoscopy and proceed to transurethral resection of bladder tumour (TURBT) C. CT urogram D. Urine cytology E. Urine culture
Question 3 A 76-year-old man presented with haematuria. He was found to have a T3 N1 M0 transitional cell carcinoma of the bladder. He had a history of chronic renal failure (CKD stage 3), type 2 diabetes mellitus and hypertension.
Question 2 A 70-year-old man presented with asymptomatic visible haematuria. He is otherwise a fit and well men. ex-smoker with a 40 packeyear history. A TURBT was performed.
What is the next management step? A. Palliative treatment B. Methotrexate, vinblastine, cisplatin, doxorubicin (MVAC) þ cystesctomy C. Gemcitabine þ cisplatin þ cystectomy D. Carboplatin þ paclitaxel þ cystectomy E. Primary cystectomy
Investigation Histology of the completely resected specimen showed G3pT1 (Grade 3 pathologically T1; invading the lamina
MEDICINE xxx:xxx
5
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
Bladder cancer
Key points
Marcelino Yazbek-Hanna
C
Haematuria is the most common symptom of bladder cancer and is present in almost 75% of patients
C
Primary treatment of bladder cancer is endoscopic transurethral resection of the bladder tumour (TURBT)
C
‘Superficial’ non-muscle-invasive bladder cancers are stratified after TURBT by their risk of recurrence and progression, and can require adjuvant intravesical therapy
C
Muscle-invasive bladder cancer has a 50% 5-year survival and is treated with neoadjuvant chemotherapy and surgery or radiotherapy
C
Metastatic disease is often responsive to chemotherapy or immunotherapy
Sunjay Jain
Abstract Bladder cancer is the most frequently occurring tumour of the urinary tract and the eighth most common cause of cancer death in the UK. It is characterized by a high recurrence rate, pathological progression and poor survival in advanced metastatic disease. Owing to the long follow-up period and associated costs of disease monitoring, it is one of the most expensive cancers to manage. Local therapy and surveillance are the mainstays of management of early disease, which comprises 75% of cases. Radical surgery and radiotherapy are the main curative options in advanced non-metastatic disease. Chemotherapy can be used in a neoadjuvant, adjuvant or palliative setting. There remains a great need for effective tumour markers to aid diagnosis, staging, monitoring and predicting prognosis.
Keywords Bladder cancer; chemotherapy; intravesical therapy; MRCP; radical cystectomy; radical radiotherapy; urinary markers
squamous cell carcinoma, adenocarcinoma and neuroendocrine tumours. Squamous cell carcinoma accounts for only for 5% of bladder cancers in industrialized countries but >50% of tumours in Africa and the Middle East, where bilharzia (Schistosoma haematobium) is endemic.
Epidemiology
Grading and staging
Bladder cancer is 2.5 times more prevalent in men than women, with a peak incidence in the sixth and seventh decades of life. In the UK, it accounts for >10,000 new diagnoses and 5000 deaths annually. Its incidence peaked in the 1990s and has since gradually declined by approximately 40%, possibly because of reductions in smoking and occupational carcinogens, and alterations in disease coding. It remains, however, a significant economic burden to the NHS.
Histological grading is based on a combination of the World Health Organization 1973 and 2004 criteria. Papillary tumours are graded from 1 to 3, low grade and high grade (Figure 1). Higher grade lesions carry a greater risk of tumour recurrence and progression. Staging is with the tumour, nodes, metastasis (TNM) classification (Figure 2).
Aetiology
Haematuria is present in almost 75% of patients. Other symptoms include urinary urgency and/or frequency and bladder pain. Weight loss, abdominal pain and renal impairment secondary to ureteric obstruction are usually signs of advanced disease. Urgent urological referral is mandated for: (1) patients aged 45 years and over with unexplained visible haematuria without urinary tract infection, or visible haematuria that persists or recurs after successful treatment of urinary tract infection; and (2) patients aged 60 or over who have unexplained non-visible haematuria and either dysuria or a raised white cell count on a blood test. All patients in whom bladder cancer is suspected are appropriately investigated with diagnostic cystoscopy and upper urinary tract imaging with ultrasonography or computed tomography urography (CTU) (to identify lesions within the ureter, renal pelvis and renal parenchyma). Urine cytology can be a useful test in diagnosing high-grade disease.
Diagnosis
Risk factors include cigarette smoking, which accounts for approximately 50% of cases, occupational exposure to chemicals such as aniline dyes and aromatic amines,1 consumption of analgesics containing phenacetin, chronic infection or irritation of the bladder (e.g. indwelling catheters, calculi), chemotherapeutic agents such as cyclophosphamide and pelvic irradiation. Smokers have a 4-fold increased risk compared with those who have never smoked.
Pathology Over 90% of malignant tumours of the bladder are ‘urothelial’ transitional cell carcinoma (TCC). Less common forms include
Marcelino Yazbek-Hanna MRCS FRCS MD is a Urology Fellow at St James’ University Hospital, Leeds, UK. Competing interests: none declared.
Initial management and staging Primary treatment of bladder cancer is endoscopic transurethral resection of bladder tumour (TURBT). Muscle should be included
Sunjay Jain MD FRCS is a Consultant Urological Surgeon at St James’ University Hospital, Leeds, UK. Competing interests: none declared.
MEDICINE xxx:xxx
1
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
Grading of papillary tumours Grade 1 (PUNLMP) , Grade 1 (LG) / Grade 2 (LG) , Grade 2 (HG) / Grade 3 (HG)
HG, high-grade carcinoma; LG, low-grade carcinoma; PUNLMP, papillary urothelial neoplasm of low malignant potential. Figure 1
European Organization for Research and Treatment of gico Espanol de TrataCancer (EORTC) and Club Urolo gico (CUETO) scores are risk calculators miento Oncolo that can predict risk of recurrence and progression in individual patients.
in the resection specimen to stage the disease accurately and reduce recurrence. If the tumour is palpable after resection, the tumour is staged as cT3, or as cT4 if the bladder is fixed. Around 75% of patients present with ‘superficial’ non-muscleinvasive bladder cancer (NMIBC). Carcinoma-in-situ (CIS) is superficial disease that has a high rate of recurrence and progression (60% progress if left untreated and 20% progress despite Bacillus CalmetteeGuerin (BCG) treatment) so is stratified into the high-risk category of NMIBC. More than 50% of patients with NMIBC experience recurrence and 10e15% progress to muscle-invasive bladder cancer (MIBC). Increasing tumour grade, stage, size, multifocality and recurrence rate are associated with increased risk of progression. These are used to guide further management (Figure 3): Low-risk patients generally need only surveillance Intermediate-risk patients are recommended to have intravesical chemotherapy or immunotherapy. High-risk patients require a second cystoscopy and reresection to avoid understaging and remove residual disease.2 Intravesical therapy is an option but patients should be offered early curative radical surgery (cystectomy). The
Intravesical chemotherapy and immunotherapy It has been shown that a single installation of intravesical chemotherapy (mitomycin, epirubicin) within 6 h of TURBT reduces the recurrence rate of NMIBC by 50%. Maintenance therapy with mitomycin or BCG is used for intermediate- and highrisk tumours.3 BCG is thought to initiate an extensive local inflammatory reaction in the bladder wall and trigger a complex immunological cascade, which can cause marked irritative voiding symptoms. Disease surveillance Patients should be subject to a period of endoscopic surveillance with check flexible cystoscopy under local anaesthetic 3 months after initial TURBT. Frequency of further follow-up depends on the risk group.
T-stages of transitional cell carcinoma bladder cancer (TNM classification)
T
T
2a
1
T
2b
T
3
Ta Tis
T
4
Mucosa Submucosa
T4-contiguous organs
Deep muscularis propria Perivesical fat Figure 2
MEDICINE xxx:xxx
2
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
Mangement of bladder cancer Investigations • Urine bacteriology, exclude infection – Urine cytology • Upper urinary tract imaging: – Diagnostic flexible cystoscopy – USS for non-visible haematuria – CTU for visible haematuria
Presenting symptoms Haematuria, urinary frequency, urgency, pelvic pain, weight loss
Diagnosis of bladder cancer TURBT + postoperative intravesical chemotherapy when appropriate
Non-muscle invasive bladder cancer Low-risk disease • Solitary G1/G2 (LG) pTa <3 cm • PUNLMP
Intermediate-risk disease • Solitary G1/G2 (LG) pTa >3 cm or multifocal • G2pTa (HG) • Any low-risk disease recurring within 12 months of last tumour occurrence
Muscle invasive bladder cancer High-risk disease • Any G3 or T1 disease • CIS • G1G2Ta, multiple and recurrent & large (>3 cm) (all features must be present) Highest risk disease • G3T1 + CIS • Multiple G3T1 • Large G3T1 >3cm • Recurrent G3T1 • Variant histology
Non-metastatic
Metastatic
Early re-resection to exclude understaging for T1 disease and in the absence of muscle in the initial resection in intermediate- and high-risk disease Treatment • One course of at least 6 doses of intravesical (MMC). Refer to MDT in case of recurrence or • 1-year full course of BCG or 1 year on MMC
• Intravesical full-dose BCG for 1–3 years or • Radical cystectomy in highest risk tumours • (G3pT1 + CIS, multiple and/or large and/or recurrent G3pT1, urethral CIS, LVI, variant histology)
Neoadjuvant chemotheapy unless contraindicated
Consider primary chemo-radiotherapy in case of low-volume metastasis
Radical cystectomy or radiotherapy with a radiosensitizer
Palliative care
Follow-up NICE: cystoscopy at 3 and 9 months, discharge
NICE: cystoscopy at 3, 9 and 18 months, then yearly for 5 years
EAU: cystoscopy at 3, 9 and 12 months, then yearly for 5 years
EAU: instruction on frequency of cystoscopy
NICE: cystoscopy 3-monthly for 2 years, then 6-monthly for 2 years, then yearly for life EAU: as per NICE + cytology
Cystectomy: • Annual renal function blood test, folate and vitamin B12 • Imaging: annual renogram + GFR yearly for 5 years CTU at 6,12 and 24 months • Urethral wash for cytology for 5 years
Radiotherapy: • Rigid cystoscopy at 3 months • Flexycystoscopy 3-monthly for 2 years, 6-monthly for 2 years, yearly thereafter • CTU at 6, 12 and 24 months
pho vascular invasion; MDT, multidisciplinary team; MMC, mitomycin C; NICE, National Institute for Health and Care Excellence, pTa, Pathologically Ta (papillary disease involving the bladder mucosa only); PUNLMP, papillary urothelial neoplasm of low malignant potential. G1, G2, G3, pathological grading of cancer cells from least to most aggressive, Figure 3
MEDICINE xxx:xxx
3
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
Management of T2D muscle-invasive bladder cancer
Chemotherapy Gemcitabine/cisplatin is the standard regimen, with carboplatin used as an alternative to cisplatin for individuals with poor renal function. Second-line chemotherapy can be considered for fit patients. Rechallenge with gemcitabine/cisplatin can be considered if patients relapse >12 months from initial therapy. Other agents have not been shown to have a proven survival advantage.
MIBCs have a high rate of metastatic disease and poor long-term survival. They require staging with CT of the chest and abdomen, and CT and/or magnetic resonance imaging of the pelvis. Fluorodeoxyglucose positron emission tomography-CT has a role with equivocal lesions. The standard approach for MIBC in UK is radical cystectomy or radical radiotherapy. These have similar 5-year overall survival of approximately 50%, although this is increased by 5% for TCCs given neoadjuvant chemotherapy.4
Immunotherapy Immunotherapy with checkpoint inhibitors has shown to have significant anti-tumour activity, tolerability, safety profile, and durable responses in these patients.5 Active agents include PD-1 (programmed death 1) inhibitors (pembrolizumab, nivolumab) and PD-L1 (programmed death-ligand 1) inhibitors (atezolizumab, avelumab, durvalumab); have similar efficacy in patients progressing during, or after, standard platinum-based chemotherapy and have good activity levels in patients ineligible for cisplatin-based therapy: a 29% overall response rate and 7% complete response rate for pembrolizumab, and a 29% overall response rate, 9% complete response rate and median overall survival (OS) of 15.9 months for atezolizumab. In a Phase III trial and as a second-line treatment during or after platinum-based first-line chemotherapy, atezolizumab and pembrolizumab showed an improved OS benefit of 3 months compared with chemotherapy with paclitaxel, docetaxel or vinflunine (10.3 versus 7.4 months). Treatment stratification is thought to be possible by immunohistochemical staining that can detect patients with negative PD-L1 status who might have an impaired response to PD-L1 inhibitors, as shown in a Phase II trial. A
Cisplatin-based chemotherapy such as gemcitabine/cisplatin is now the standard combination for TCC but some centres use dose-dense MVAC (methotrexate, vinblastine, doxorubucin cisplatin), which has a better pathological response rate and downstaging ability in Phase II trials. Cisplatin has many adverse effects including nephrotoxicity as it is renally excreted; it cannot be used safely in patients with renal impairment, which is very common in MIBC. Other multivariable histology, including squamous cell carcinoma, neuroendocrine and sarcomatoid differentiation, are less responsive to chemotherapy. Adjuvant chemotherapy after radical cystectomy is under debate and infrequently used. Surgery and radiotherapy The choice of radiotherapy or surgery is made on the basis of patient choice and co-morbidity as there is no high-level evidence comparing the two modalities. Cystectomy is a highly morbid operation but outcomes have improved in recent years; this is partly because of centralization of surgery in specialist centres and partly because of the use of minimal access surgery using a da Vinci robotic system. Urinary diversion is required, and although most patients have a stoma (ileal conduit), a neobladder is an option that allows normal voiding in selected well-motivated individuals. Radiotherapy techniques have evolved to reduce morbidity, particularly bowel toxicity. Current protocols use radiosensitizers to improve outcomes. The followup protocol for patients after radical treatment is detailed in Figure 3.
KEY REFERENCES 1 Delclos GL, Lerner SP. Occupational risk factors. Scand J Urol Nephrol Suppl 2008; 218: 58e63. 2 Naselli A, Hurle R, Paparella S, et al. Role of restaging transurethral resection for T1 non-muscle invasive bladder cancer: a systematic review and meta-analysis. Eur Urol Focus 2018; 4: 558e67. 3 European Association of Urology. Non-muscle-invasive bladder cancer, 2018. 4 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005; 48: 202e5. 5 Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase ii study. J Clin Oncol 2018; 36: 3353e60.
Management of metastatic disease Chemotherapy remains the mainstay of treatment for patients with metastatic disease, with a response rate of up to 49% depending on the agent used. However, prognosis remain poor, with a survival rate of 5e10% at 5 years and an overall survival of 12e14 months. Several factors has been shown to negatively affect prognosis, for example a Karnofsky performance status <80% and the presence of visceral metastases.
MEDICINE xxx:xxx
4
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011
COMMON CANCERS
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. propria) disease in a single lesion <2 cm in size, with muscle present in the biopsy
Question 1 A 69-year-old man presented with history of asymptomatic visible haematuria. His past medical history includes hypertension, Atrial fibrilation on warfarin and chronic obstructive pulmonary disease. He is a lifetime non-smoker and had worked in an office. An ultrasound scan organized by the GP showed a suspicious bladder abnormality at the bladder neck.
What is the next step in his management A. Bacillus CalmetteeGuerin (BCG) B. Mitomycin C. Conservative with surveillance cystoscopy D. Cystectomy E. Re-resection TURBT þ BCG if no pathological upgrade
How would be the next step in his investigation? A. Diagnostic flexible cystoscopy B. General anaesthetic cystoscopy and proceed to transurethral resection of bladder tumour (TURBT) C. CT urogram D. Urine cytology E. Urine culture
Question 3 A 76-year-old man presented with haematuria. He was found to have a T3 N1 M0 transitional cell carcinoma of the bladder. He had a history of chronic renal failure (CKD stage 3), type 2 diabetes mellitus and hypertension.
Question 2 A 70-year-old man presented with asymptomatic visible haematuria. He is otherwise a fit and well men. ex-smoker with a 40 packeyear history. A TURBT was performed.
What is the next management step? A. Palliative treatment B. Methotrexate, vinblastine, cisplatin, doxorubicin (MVAC) þ cystesctomy C. Gemcitabine þ cisplatin þ cystectomy D. Carboplatin þ paclitaxel þ cystectomy E. Primary cystectomy
Investigation Histology of the completely resected specimen showed G3pT1 (Grade 3 pathologically T1; invading the lamina
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Please cite this article as: Yazbek-Hanna M, Jain S, Bladder cancer, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.011