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124 Challenging Concepts in Urological Surgery
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Table 12.2 ERAS® components for RC used at a high- volume single centre
Domain Item Elements
Clinic Preoperative counselling
and education
Prehabilitation exercise Walking for 1 hour per day
Preoperative medical
optimization
Correction of anaemia Oral iron supplements or intravenous iron
Prior to
admission
Admission Preoperative oral intake Clear fluid until 2 hours preoperatively, solid food until
Anaesthesia Standard anaesthetic
Surgery Minimally invasive
Postoperative Postoperative diet Chewing gum to start at 4 hours after surgery, oral
Bowel preparation Omitted. Normal diet until preoperative fasting
Self- administered
thromboprophylaxis
Preoperative carbohydrate
loading
Pre- anaesthesia medication Avoidance of long- acting sedatives
protocol
Antimicrobial prophylaxis 24 hours intravenous Augmentin
Skin preparation Two- stage preparation: spray alcoholic 2% chlorhexidine
Thromboembolic
prophylaxis
Regional analgesia Epidural anaesthesia omitted, rectus sheath catheters
Perioperative fluid
management
Nasogastric intubation No nasogastric tube or it is removed at the end of surgery
Preventing intraoperative
hypothermia
approach
Resection site drainage Consider omitting pelvic drain
Urinary drainage Ureteral stents or transurethral neobladder catheter should
Wound closure 2/ 0 polydioxanone suture (Ethicon®) to rectus sheath.
Prevention of postoperative
nausea and vomiting
Postoperative analgesia Rectus sheath catheters, patient- controlled opiates,
Early mobilization 6 hours out of bed on postoperative day (POD) 1, walk
Audit Audit compliance. Understand problems. Keep
Advice about maintaining activity levels, dietary and
alcohol advice, details of admission and recovery,
written material detailing postoperative recovery plan
Optimization of comorbidities, smoking cessation
advice, plan social aspects of discharge
LMWH injection 12 hours prior to surgery administered
at home
Preoperative carbohydrate loading (careful use in
diabetic patients)
6 hours preoperatively
®
gluconate and paint aqueous 10% povidone- iodine
Thromboembolic compression stockings, 28 days of
pharmacological prophylaxis with LMWH starting
day before surgery, intraoperative pneumatic
compression stockings
(0.125% bupivacaine) for first 48 hours
Avoid overhydration (<1 L crystalloid until bladder
removed). Vasopressors to maintain arterial
hypotension
Use of a warming blanket
Mini- open cystectomy incision or robotic approaches
be used. Stents removed as an outpatient or catheter
removed after cystogram for neobladder patients
3/ 0 subcuticular Monocryl® (poliglecaprone) suture
(Ethicon®) to skin
fluids to start evening of surgery— 30 mL/ hour of
clear non- fizzy fluids. Resume diet when passing
flatus, mobile, and pain controlled
Antiemetics as needed, early resumption of oral fluids
intravenous paracetamol/ acetaminophen 1 g four
times daily until diet resumed
10 m on POD 1, 50 m on POD 2, >100 m on POD 3+
resource within team
● Significant improvement in physical and emotional functioning scores after surgery between days 3
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and 7 and on discharge.
● Significant reduction in wound healing problems, deep vein thrombosis, and postoperative fever.
● Significantly lower demand for postoperative analgesia.
● Increased oral intake postoperatively (as early as day 3).
A final word from the expert
RC with lymphadenectomy remains the best chance of cure in those with muscle- invasive
disease. The preparation for curative treatment is twofold; firstly, providing the patient with
an accurate diagnosis at the earliest opportunity. Once the diagnosis of MIBC has been
made, the patient can be adequately counselled about the best possible modalities of
treatment— whether this be radical curative approaches or palliative treatments. This will
almost certainly involve a multidisciplinary approach and, in the majority of patients, RC
should be considered.
Secondly, if the patient opts for RC, they must be adequately prepared for the procedure. Not
only should this involve the provision of NAC, to improve oncological outcomes in those who
are eligible, but also surgical optimization with a thorough preoperative assessment. RC with
lymphadenectomy is a huge physiological undertaking, so consideration of extent of disease,
age, comorbidities, medication, preoperative function, and nutritional status will aid the
decision about whether radical treatment is feasible and appropriate.
Occasionally, ensuring that a patient is optimized for surgery may involve delaying RC, as
performing major surgery in a suboptimized patient may lead to poorer outcomes. In the
case described, protecting, and optimizing renal function was imperative; neoadjuvant
insertion of a PCN both ensured that the solitary right kidney was protected from malignant
ureteric obstruction, and also facilitated the delivery of NAC that would have otherwise been
inappropriate with declining renal function.
Therefore, thorough optimization and meticulous preparation of patients prior to RC not only
facilitates the delivery of multimodal therapy to improve oncological outcomes, but helps to
limit the associated morbidity from RC.
125Case 12 Muscle-invasive bladder cancer
References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185
countries. CA Cancer J Clin. 2018;68(6):394– 424.
2. Noon AP, Albertsen PC, Thomas F, Rosario DJ, Catto JWF. Competing mortality in patients
diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients. Br J Cancer. 2013;108(7):1534– 1540.
3. Cumberbatch MGK, Jubber I, Black PC, et al. Epidemiology of bladder cancer: a systematic
review and contemporary update of risk factors in 2018. Eur Urol. 2018;74(6):784– 795.
4. Cumberbatch MG, Rota M, Catto JWF, La Vecchia C. The role of tobacco smoke in bladder
and kidney carcinogenesis: a comparison of exposures and meta- analysis of incidence and
mortality risks. Eur Urol. 2016;70(3):458– 466.
5. Cumberbatch MGK, Cox A, Teare D, Catto JWF. Contemporary occupational carcinogen
exposure and bladder cancer. JAMA Oncol. 2015;1(9):1282– 1290.
6. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and Genetics of Tumours of the Urinary
System and Male Genital Organs. Lyon: International Agency for Research on Cancer; 2004.
126 Challenging Concepts in Urological Surgery
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7. Compérat E, Gontero P, Mostafid AH, et al. EAU guidelines on non- muscle- invasive bladder
cancer (TaT1 and CIS). European Association of Urology. 2017. https:// uroweb.org/ wpcontent/ uploads/ EAU- Guidelines- on- Non- muscle- Invasive- Bladder- Cancer- 2020.pdf
8. Kamoun A, de Reyniès A, Allory Y, et al. A consensus molecular classification of muscleinvasive bladder cancer. Eur Urol. 2020;77(4):420– 433.
9. Gordon PC, Thomas F, Noon AP, Rosario DJ, Catto JWF. Long- term outcomes from reresection for high- risk non– muscle- invasive bladder cancer: a potential to rationalize Use.
Eur Urol Focus. 2019;5(4):650– 657.
10. Van Den Bosch S, Witjes JA. Long- term cancer- specific survival in patients with high- risk,
non- muscle- invasive bladder cancer and tumour progression: a systematic review. Eur Urol.
2011;60(3):493– 500.
11. Catto JWF, Gordon K, Collinson M, et al. Radical cystectomy against intravesical BCG for
high- risk high- grade nonmuscle invasive bladder cancer: results from the randomized controlled BRAVO- feasibility study. J Clin Oncol. 2021;39(3):202– 214.
12. Oughton JB, Poad H, Twiddy M, et al. Radical cystectomy (bladder removal) against
intravesical BCG immunotherapy for high- risk non- muscle invasive bladder cancer (BRAVO):
a protocol for a randomised controlled feasibility study. BMJ Open. 2017;7(8):e017913.
13. Witjes JA, Compérat E, Cowan NC, et al. EAU guidelines on muscle- invasive and metastatic
bladder cancer. European Association of Urology. 2016. https:// uroweb.org/ wp- content/ uploads/
EAU- Guidelines- Muscle- invasive- and- Metastatic- Bladder- Cancer- Guidelines- 2016.pdf
14. Magers MJ, Lopez- Beltran A, Montironi R, et al. Staging of bladder cancer. Histopathology.
2019;74(1):112– 134.
15. Kiss B, Furrer MA, Wuethrich PY, Burkhard FC, Thalmann GN, Roth B. Stenting prior
to cystectomy is an independent risk factor for upper urinary tract recurrence. J Urol.
2017;198(6):1263– 1268.
16. International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer
Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies
Group); European Organisation for Research and Treatment of Cancer Genito- Urinary Tract
Cancer Group; et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle- invasive bladder cancer: long- term results
of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171– 2177.
17. von der Maase H, Sengelov L, Roberts JT, et al. Long- term survival results of a randomized
trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin,
plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602– 4608.
18. Astolfi L, Ghiselli S, Guaran V, et al. Correlation of adverse effects of cisplatin administration in patients affected by solid tumours: a retrospective evaluation. Oncol Rep.
2013;29(4):1285– 1292.
19. Nielsen ME, Palapattu GS, Karakiewicz PI, et al. A delay in radical cystectomy of >3 months
is not associated with a worse clinical outcome. BJU Int. 2007;100(5):1015– 1020.
20. Bruins HM, Veskimae E, Hernandez V, et al. The impact of the extent of lymphadenectomy
on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer: a systematic review. Eur Urol. 2014;66(6):1065– 1077.
21. Karl A, Carroll PR, Gschwend JE, et al. The impact of lymphadenectomy and lymph
node metastasis on the outcomes of radical cystectomy for bladder cancer. Eur Urol.
2009;55(4):826– 835.
22. Gschwend JE, Heck MM, Lehmann J, et al. Extended versus limited lymph node dissection
in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial. Eur Urol. 2019;75(4):604– 611.
23. Karl A, Buchner A, Becker A, et al. A new concept for early recovery after surgery for patients undergoing radical cystectomy for bladder cancer: results of a prospective randomized study. J Urol. 2014;191(2):335– 340.
24. Pang KH, Groves R, Venugopal S, Noon AP, Catto JWF. Prospective implementation of enhanced recovery after surgery protocols to radical cystectomy. Eur Urol. 2018;73(3):363– 371.
13
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CASE
Progression of high- grade
non- muscle- invasive
bladder cancer
Naomi L. Neal
Expert commentary Richard J. Bryant and Andrew Protheroe
Case history
A 73- year- old gentleman was referred urgently to the urology department following
an episode of painless visible haematuria, without any other lower urinary tract
symptoms. He had a background history of hypertension, cardiomyopathy, type 2
diabetes, and a previous ventricular fibrillation cardiac arrest with subsequent insertion of a pacemaker. Clinical examination was unremarkable, and flexible cystoscopy
revealed a 2– 3 cm papillary bladder tumour on the left side of the bladder lateral
to the ureteric orifice. A computed tomography (CT) urogram revealed a left- sided
bladder tumour but was otherwise unremarkable, with normal upper urinary tracts
(Figure 13.1).
Figure 13.1 The initial CT urogram demonstrates a left- sided bladder filling defect and normal upper
urinary tracts, with no lymphadenopathy.
128 Challenging Concepts in Urological Surgery
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A transurethral resection of bladder tumour (TURBT) was undertaken. This confirmed the presence of a 2– 3 cm papillary lesion lateral to the left ureteric orifice, with
no macroscopic solid component. The remainder of the bladder appeared normal on
cystoscopic inspection. A complete resection of the lesion was undertaken, followed
by a single instillation of postoperative mitomycin C. Histological examination of the
surgical specimen confirmed the presence of G3pT1 transitional cell carcinoma (TCC);
however, there was no muscularis propria in the specimen, and therefore a re- resection
TURBT was performed 6 weeks later. The re- resection of the previous bladder tumour
site, which did visibly detect overt tumour at cystoscopy, again revealed G3pT1 TCC of
the bladder upon histological examination of the specimen; however, the muscularis
propria was free of tumour. At outpatient clinic follow- up, the treatment options were
discussed with the patient, with these comprising bladder conservation therapy using
intravesical bacillus Calmette– Guérin (BCG) instillation therapy, or radical cystectomy
(RC) and ileal conduit urinary diversion. The patient elected to receive a bladder preservation approach strategy using BCG.
Clinical tip Re- resection TURBT
Re- resection TURBT is advised within 2– 6 weeks if there is an incomplete primary tumour resection,
or if there is no muscularis propria in the surgical specimen (unless there is a Ta low- grade cancer or
primary carcinoma in situ (CIS)), or in cases of T1 tumours. The re- resection specimen may contain
residual cancer in around a third of primary Ta, and half of all T1, cases.1 Twenty- five to forty- five per
cent of initial high- grade non- muscle- invasive bladder cancer (HGNMIBC) cases are upstaged to
muscle- invasive bladder cancer (MIBC) at early re- resection. Early re- resection of initial HGNMIBC
is associated with an increased recurrence- free survival, and improved outcomes (recurrence- free
survival, progression- free survival, and overall survival) after BCG treatment.
2
Expert comment
Treatment discussions
Treatment discussions should
include a balance of the risk of
progression to MIBC and death
(50% and 30%, respectively, by
15 years after BCG treatment)
versus the side effects of RC.
Learning point Early RC versus bladder preservation therapy with BCG
Patients with HGNMIC can be offered bladder preservation therapy with BCG, or RC. Aggressive
treatment is required due to the high risk of disease progression, which occurs in 30% of T1G3 and
80% of HGNMIBC cases with concomitant CIS.
Patients who experience HGNMIBC disease progression to MIBC following bladder preservation
therapy have a worse prognosis than those who initially present with MIBC.3 RC is recommended
over BCG for the highest risk category patients, including those with HGNIMBC T1 tumours with
concurrent CIS, multiple or large or recurrent T1 high- grade tumours, and some forms of variant
histology of urothelial carcinoma.
The patient commenced induction BCG; however, at this stage a worldwide shortage
of BCG became apparent, and this resulted in the patient receiving an incomplete full
induction course. A subsequent check cystoscopy under general anaesthetic revealed an
apparent solid lesion on the left side wall of the bladder, resulting in the left ureteric orifice being non- visible during cystoscopic inspection, while the remainder of the bladder
including the right ureteric orifice was unremarkable. The recurrent bladder tumour was
re- resected, with subsequent histology confirming recurrent G3pT1 urothelial carcinoma
with concomitant CIS, with uninvolved muscularis propria. A repeat CT urogram at
that stage revealed a left hydronephrosis and hydroureter to the vesicoureteric junction (Figure 13.2), and a normal contralateral right kidney, while the renal function
remained normal. The option of a RC and ileal conduit formation was considered at
this stage; however, given the patient’s high risk for radical surgery owing to his cardiac
Figure 13.2 A follow- up CT urogram revealed a left hydronephrosis and hydroureter to the
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vesicoureteric junction.
129Case 13 Progression of high-grade non-muscle-invasive bladder cancer
comorbidity, a further re- do TURBT was performed, and on this occasion the relatively
small amount of residual disease on the left side wall of the bladder was resected macroscopically clear, including the scar tissue around the left ureteric orifice, which resulted
in drainage of the left ureter. Subsequent histology revealed T1 TCC of the bladder along
with chronic inflammation, and the patient elected to receive a full course of induction
BCG given that this was now available following resolution of the worldwide shortage.
Learning point Morbidity of RC, and outcomes for RC following BCG failure
RC includes the surgical removal of the bladder, distal ureters, and lymph nodes, together with the
prostate and seminal vesicles in men, and adjacent vagina and uterus in women. The morbidity for this
surgery is between 30% and 60%, with many of the risks being associated with the urinary diversion,
including stoma complications, ureteroileal strictures, metabolic disturbances, and subsequent urinary
stone formation.4 Other risks include paralytic ileus, anastomotic leak, venous thromboembolism,
myocardial infarction, pulmonary complications, cerebrovascular events, and wound dehiscence or
hernia development. The mortality after RC is approximately 5%.
The presence of CIS, tumour size >3 cm, and multiple tumours at diagnosis are predictors of pathological
upstaging to T3/ 4 and/ or N+ disease after RC following BCG failure.5 Patients with recognized progression
prior to RC have a shorter time to cancer death compared to those upstaged on RC histology. It is possible
that younger patients benefit from upfront RC rather than bladder- preserving BCG treatment.
Three subsequent check cystoscopies over the next year revealed various erythematous
areas in the bladder; these were each confirmed to be benign with chronic inflammation
on histological examination of biopsy specimens, and the patient continued on maintenance BCG instillation therapy. A surveillance CT scan revealed the improvement of the previous hydronephrosis and hydroureter, and the patient’s renal function remained normal.
A further subsequent check cystoscopy under general anaesthetic showed no apparent
Expert comment
Approaches to RC
Clinical trials comparing open and
minimally invasive approaches
(including robotic cystectomy in
the Intracorporeal Robot Assisted
Radical Cystectomy (iROC) trial) are
ongoing, but currently appear to
show no significant difference other
than perhaps a small reduction
in blood transfusion rates and
length of hospital stay.6 Even in
the modern era with great surgical
advances and techniques, RC
remains a morbid operation.
130 Challenging Concepts in Urological Surgery
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active intravesical disease; however, the left ureteric orifice was re- resected as this had appeared to have re- stenosed, the subsequent histology from this procedure confirming the
presence of inflammation only, with no active TCC of the bladder on histology.
Learning point Outcomes for BCG intravesical therapy
Fifteen- year follow- up studies of patients receiving BCG for NMIBC show progression in around 50%.
Around 30% of patients die from disease progression, and only 27% survive with an intact bladder.
Around 25% of patients develop upper urinary tract cancer.
The Spanish Oncology Group (CUETO) has identified risk factors for disease recurrence, including
being female, having had a previous recurrence, multiplicity of tumours, and presence of CIS.7
Predictors of progression include age, previous recurrence, high- grade disease, T1 stage, and recurrent
disease at the first check cystoscopy at 3 months.
The patient underwent a further surveillance CT scan, which revealed the presence
of a 16 mm apparent tumour nodule in the region of the left vesicoureteric junction,
which was not visible intravesically at cystoscopy, and enlarged pelvic lymph nodes
(Figure 13.3) and an enlarged aortocaval lymph node, suspicious for metastatic disease recurrence based on radiological criteria. The patient was reviewed in the medical oncology clinic, and was informed of the concern regarding possible metastatic
TCC recurrence. The options of upfront chemotherapy in the form of gemcitabine and
carboplatin, or surveillance, were discussed, and the patient elected to receive a period
of surveillance in the first instance, as he was asymptomatic. His radiological imaging
remained stable at the next surveillance CT scan; however, a few months later a check
flexible cystoscopy under local anaesthetic revealed tumour recurrence at the bladder
base along with an area of erythema over the left lateral wall of the bladder.
Expert comment Metastatic
TCC of the bladder
The concern with the patient
at this point is that he now has
metastatic disease, albeit with a
limited burden of lymph nodal
disease, despite the histology still
demonstrating HGNMIBC. It is
appropriate in this situation to
offer systemic chemotherapy, if
the multidisciplinary team were in
agreement that this was in keeping
with radiographic development
of metastatic disease, given the
known risk that this may occur with
HGNMIBC.
Figure 13.3 A surveillance CT scan revealed the presence of enlarged pelvic lymph nodes.
Learning point Chemotherapy and immunotherapy for metastatic TCC of the bladder
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The standard first- line chemotherapy combination for metastatic BC is gemcitabine and
cisplatin,8 which has an overall response rate of approximately 50%, and a median survival of
around 14 months. MVAC (methotrexate, vinblastine, Adriamycin® (doxorubicin), and cisplatin)
would be an acceptable alternative first- line chemotherapy regimen.
cisplatin- based combination has been reported to be between 36% and 71%.11 The preference for
treating BC patients is always to give a cisplatin- based combination of chemotherapeutic agents,
as this has demonstrated better outcomes.
been developed and published.14 If the toxicity of cisplatin is a concern then a combination of
gemcitabine and carboplatin could be offered, although this has a lower response rate (28– 56%)11
and poorer overall survival.
If patients are ineligible to receive cisplatin, immunotherapy in the form of a checkpoint inhibitor
can now be offered. This is based on two phase II studies investigating atezolizumab (from the
IMvigor 210 study group) or pembrolizumab (from the KEYNOTE- 052 study group).
KEYNOTE- 052 study, investigating ‘upfront’ single- agent pembrolizumab, demonstrated a 24%
overall response following the use of this agent.16 However, the European Medicines Agency
has restricted the use of pembrolizumab for untreated urothelial carcinoma, such that it should
now only be used in adults with high levels of programmed death- ligand 1 (PD- L1) expression
in their tumours. This recommendation is based on unpublished findings in the KEYNOTE- 361
and IMvigor- 130 studies, where decreased survival in individuals with tumours with low PD- L1
expression was demonstrated in patients receiving pembrolizumab, compared with those who
received cisplatin or carboplatin- based chemotherapy.
11– 13
Criteria to determine cisplatin ineligibility have
9,10
The response rate to a
15,16
The
A further TURBT was therefore performed, where an anterior bladder neck tumour was resected, and histology of this specimen revealed recurrent G3pT1 TCC.
The scarred left ureteric orifice was re- resected in order to ‘uncap’ the left ureter,
and a retrograde ureterogram was performed which showed no ureteric tumour,
and a left- sided ureteric stent was inserted in order to maintain drainage of the left
upper urinary tract and maintain normal renal function ahead of further treatment.
Unfortunately, the patient subsequently developed intractable stent symptoms, and
so the stent was removed at a check flexible cystoscopy 4 months later.
Due to concerns regarding cardiac comorbidity and the presence of limited lymph
nodal metastatic disease, the patient was still not a candidate for RC at this point,
and further cross- sectional imaging in the form of a repeat CT scan revealed the presence of enlarging pelvic and retroperitoneal lymph nodes (Figure 13.4) suggestive of
progressive metastatic TCC. The management options at this point comprised either
chemotherapy, or bladder and pelvis radiotherapy, with the option of possible subsequent chemotherapy. A further staging CT scan confirmed progression of the paraaortic and left iliac lymphadenopathy, and in light of this, the preferred management
option was chemotherapy, with possible consolidation radiotherapy if the patient was
suitable for this in due course.
The patient commenced first- line chemotherapy in the form of gemcitabine and
carboplatin, and this was well tolerated, with a subsequent CT scan showing a
good response to chemotherapy. His condition remained under active review with
serial cross- sectional imaging. Future options, should imaging reveal further lymph
node metastatic progression, could include possible immunotherapy, or second- line
chemotherapy.
131Case 13 Progression of high-grade non-muscle-invasive bladder cancer
132 Challenging Concepts in Urological Surgery
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Figure 13.4 A repeat CT scan revealed the presence of enlarging pelvic and retroperitoneal lymph
nodes, suggestive of progressive metastatic urothelial carcinoma.
Future directions New
combinations of immunotherapy
After a prolonged period of
time where there were limited
available options for patients
with metastatic BC, suddenly and
excitingly the doors are now being
opened for new and improved
therapies. Multiple new potential
combinations of immunotherapy
and other targeted agents are being
investigated in clinical studies, with
the potential to improve patient
treatment outcomes in the future.
Learning point Second- line chemotherapy options
Up until recently, the treatment options for patients with metastatic TCC were limited, with
chemotherapy being the only available systemic treatment. Invariably, when patients developed
disease recurrence following first- line chemotherapy for metastatic disease, that disease was
aggressive, with rapid progression and only limited options for further treatment.
Second- line chemotherapy was usually offered to those patients who were fit enough to receive
it. A number of chemotherapy drugs have single- agent activity, but the US Food and Drug
Administration has approved none of these in the second- line setting. In Europe, single- agent
vinflunine is approved following a study that demonstrated a 2.6- month survival advantage over best
supportive care in patients fit enough to receive chemotherapy.17 However, taxanes are probably
the most commonly used second- line chemotherapy single agents. Paclitaxel and docetaxel are
associated with a modest overall risk reduction of 10– 30% and an overall survival improvement of
6– 9 months.
Immunotherapy with checkpoint inhibitor agents has become available and is now licensed for
metastatic urothelial cancer, and this has increased the treatment options for patients. Checkpoint
inhibitors, which either block programmed cell death- 1 (PD- 1) or PD- L1, are now licensed and
available as treatment options for patients with metastatic BC. Initial reports of the use of these agents
suggested encouraging activity and safety.21 This led to the acquisition of phase III data, in particular
from the KEYNOTE- 45 study,22 which compared pembrolizumab (a PD- 1 inhibitor) to standard- dose
chemotherapy (investigator’s choice of paclitaxel, docetaxel, or vinflunine). This study demonstrated
a significantly longer survival (3 months) with pembrolizumab, and a higher response rate (21.1% vs
11.4% in the whole group). As a result, immunotherapy is now licensed and funded as a second- line
treatment option following post- chemotherapy disease recurrence. Several immune checkpoint
inhibitors are now licensed for advanced urothelial cancer, including pembrolizumab and nivolumab
(PD- 1 inhibitors), and atezolizumab, avelumab, and durvalumab (PD- L1 inhibitors).
18– 20
Evidence base Immunotherapy
A final word from the expert
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Bladder cancer is a malignancy that is moderately sensitive to chemotherapy treatment options,
and this has therefore been the mainstay of systemic therapy until very recently. The historical
chemotherapy regimens used have been MVAC; cisplatin, methotrexate, and vinblastine; and
a combination of gemcitabine and cisplatin. Over the last 20 years, combined gemcitabine
and cisplatin has emerged to be the preferred global first- line chemotherapy combination, in
view of better toxicity and equivalent response rates and overall survival compared to MVAC.
Gemcitabine and cisplatin response rates are around 50%, with an approximately 14- month
median survival in this population of patients. Metastatic BC is a particularly aggressive form of
malignancy, and a significant proportion of patients are not eligible to receive cisplatin due to
their comorbidities and poor performance status, particularly in the form of concomitant renal
function impairment. It is estimated that up to around 50% of these patients are not eligible for
cisplatin treatment. Where necessary, cisplatin has traditionally been substituted with carboplatin
in this group of patients; however, carboplatin has slightly lower outcomes in terms of response
rates and overall survival compared against cisplatin.
The treatment options for patients with subsequent disease relapse following initial
chemotherapy have been very limited, in part because of the aggressive nature of the disease,
and further because of the poor fitness of many patients. There has also been a general lack
of good evidence that further chemotherapy is beneficial in this disease relapse situation.
Vinflunine is licensed as a second- line chemotherapy treatment option; however, there have
been concerns regarding the design of clinical trials using this agent. Taxanes, particularly singleagent paclitaxel, have also been used globally as second- line chemotherapy agents.
133Case 13 Progression of high-grade non-muscle-invasive bladder cancer
The treatment landscape for patients with BC has recently changed significantly with the
development of immune checkpoint inhibitor drugs. Indeed, PD- 1 and PDL- 1 inhibitors have
been licensed. These agents are now funded and available mainly as second- line treatments in
the metastatic disease setting, although they can be used ‘upfront’ for patients who are ineligible
for cisplatin, though only if their tumour expresses PD- 1.
References
1. Grimm MO, Steinhoff C, Simon X, Spiegelhalder P, Ackermann R, Vogeli TA. Effect of rou-
tine repeat transurethral resection for superficial bladder cancer: a long- term observational
study. J Urol. 2003;170(2 Pt 1):433– 437.
2. Sfakianos JP, Kim PH, Hakimi AA, Herr HW. The effect of restaging transurethral resection
on recurrence and progression rates in patients with nonmuscle invasive bladder cancer
treated with intravesical bacillus Calmette- Guérin. J Urol. 2014;191(2):341– 345.
3. Moschini M, Sharma V, Dell’oglio P, et al. Comparing long- term outcomes of primary
and progressive carcinoma invading bladder muscle after radical cystectomy. BJU Int.
2016;117(4):604– 610.
4. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients
with bladder cancer using a standardized reporting methodology. Eur Urol. 2009;55(1):164– 176.
5. Soria F, Pisano F, Gontero P, et al. Predictors of oncological outcomes in T1G3 patients
treated with BCG who undergo radical cystectomy. World J Urol. 2018;36(11):1775– 1781.
6. Catto JWF, Khetrapal P, Ambler G, et al. Robot- assisted radical cystectomy with
intracorporeal urinary diversion versus open radical cystectomy (iROC): protocol for a randomised controlled trial with internal feasibility study. BMJ Open. 2018;8(8):e020500.
7. Fernandez- Gomez J, Solsona E, Unda M, et al. Prognostic factors in patients with non-
muscle- invasive bladder cancer treated with bacillus Calmette- Guérin: multivariate analysis
of data from four randomized CUETO trials. Eur Urol. 2008;53(5):992– 1001.
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