E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 1 2 0 – 1 3 7

avai lable at www.sciencedirect .com

journal homepage: www.europeanurology.com

Collaborative Review – Bladder Cancer

Critical Analysis of Bladder Sparing with Trimodal Therapy in

Muscle-invasive Bladder Cancer: A Systematic Review

Guillaume Ploussard a,b, Siamak Daneshmand j, Jason A. Efstathiou c, Harry W. Herr d,Nicholas D. James h, Claus M. Rodel f, Shahrokh F. Shariat e, William U. Shipley c,Cora N. Sternberg g, George N. Thalmann i, Wassim Kassouf a,*

a Department of Surgery, Division of Urology, McGill University, Montreal, Quebec, Canada; b Department of Urology, Saint-Louis Hospital, Assistance

Publique Hopitaux de Paris, Paris, France; c Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;d Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; e Department of Urology, Medical University of Vienna, Vienna,

Austria; f Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; g Department of Medical Oncology, San Camillo Forlanini

Hospital, Rome, Italy; h University of Birmingham, School of Cancer Sciences, Edgbaston, Birmingham, UK; i Department of Urology, University of Berne,

Berne, Switzerland; j University of Southern California Institute of Urology, University of Southern California/Norris Comprehensive Cancer Center, Los

Angeles, CA, USA

Article info

Article history:

Accepted February 14, 2014Published online ahead ofprint on February 26, 2014

Keywords:

Urinary bladder neoplasms

Organ sparing treatments

Outcome assessment

Chemoradiotherapy

Chemotherapy

Radiotherapy

Cystectomy

Abstract

Context: Aims of bladder preservation in muscle-invasive bladder cancer (MIBC) are to offer aquality-of-life advantage and avoid potential morbidity or mortality of radical cystectomy (RC)without compromising oncologic outcomes. Because of the lack of a completed randomised con-trolled trial, oncologic equivalence of bladder preservation modality treatments compared with RCremains unknown.Objective: This systematic review sought to assess the modern bladder-preservation treatmentmodalities, focusing on trimodal therapy (TMT) in MIBC.Evidence acquisition: A systematic literature search in the PubMed and Cochrane databases wasperformed from 1980 to July 2013.Evidence synthesis: Optimal bladder-preservation treatment includes a safe transurethral resectionof the bladder tumour as complete as possible followed by radiation therapy (RT) with concurrentradiosensitising chemotherapy. A standard radiation schedule includes external-beam RT to thebladder and limited pelvic lymph nodes to an initial dose of 40 Gy, with a boost to the whole bladderto 54 Gy and a further tumour boost to a total dose of 64–65 Gy. Radiosensitising chemotherapy withphase 3 trial evidence in support exists for cisplatin and mitomycin C plus 5-fluorouracil. Acystoscopic assessment with systematic rebiopsy should be performed at TMT completion or earlyafter TMT induction. Thus, nonresponders are identified early to promptly offer salvage RC. The 5-yrcancer-specific survival and overall survival rates range from 50% to 82% and from 36% to 74%,respectively, with salvage cystectomy rates of 25–30%. There are no definitive data to support thebenefit of using of neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is properpatient selection. The best cancers eligible for bladder preservation are those with low-volume T2disease without hydronephrosis or extensive carcinoma in situ.Conclusions: A growing body of accumulated data suggests that bladder preservation with TMTleads to acceptable outcomes and therefore may be considered a reasonable treatment option inwell-selected patients.Patient summary: Treatment based on a combination of resection, chemotherapy, and radiotherapyas bladder-sparing strategies may be considered as a reasonable treatment option in properly

pean Association of Urology. Published by Elsevier B.V. All rights reserved.

selected patients.

# 2014 Euro

* Corresponding author. Department of Surgery, Division of Urology, McGill University Health Center,1650 Cedar Avenue, Room L8-315, Montreal, Quebec H3G 1A4, Canada.Tel. +1 514 934 8246; Fax: +1 514 934 8297.E-mail address: wassim.kassouf@muhc.mcgill.ca (W. Kassouf).

http://dx.doi.org/10.1016/j.eururo.2014.02.0380302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 1 2 0 – 1 3 7 121

1. Introduction

Radical cystectomy (RC) with pelvic lymph node dissection

remains widely accepted as the gold-standard treatment

for muscle-invasive bladder cancer (MIBC) supported by a

substantial body of evidence [1–3] with long-term follow-up.

Nevertheless, removal of the bladder may lead to significant

morbidity and affect patients’ comfort and quality of life

(QoL) [4,5]. Concerns about oncologic equivalence may in

part explain differences in local utilisation rates of bladder

preservation in eligible patients among different countries

[6–9].

Several bladder-preservation options exist, including

single-modality treatments such as transurethral resection

(TUR) alone, partial cystectomy, radiation therapy (RT), or

chemotherapy alone. Nevertheless, it is generally accepted

that single-modality treatments result in inferior outcomes

compared with RC. A trimodal therapy (TMT) approach,

including maximal TUR followed by concurrent radio-

sensitising chemotherapy and RT, is the most-studied

bladder-sparing strategy. The aim of this systematic review

was to assess the modern bladder-preservation treatment

modalities, focusing on TMT in MIBC.

2. Evidence acquisition

A systematic literature search in the PubMed and Cochrane

databases was performed to identify clinical and randomised

controlled trials (RCTs) published from 1980 to July 2013

[10]. Various algorithms, including the following terms,

were used: bladder cancer, bladder preservation, trimodality

treatment, radiotherapy, chemotherapy, chemoradiation, che-

moradiotherapy, organ-sparing, bladder-sparing, and salvage

cystectomy. Inclusion criteria used were published full

articles, clinical trials, retrospective series, and meta-

analyses written in English. The following exclusion criteria

were used: (1) articles reporting on bladder preservation only

in non-MIBC (NMIBC) and only in non–urothelial bladder

cancer (BCa) and (2) abstracts and congress communications.

Each identified article was analysed and classified.

Primary outcomes included oncologic results after bladder

preservation (response rates, cancer-specific survival [CSS],

overall survival [OS]). Secondary outcomes included safety

and tolerability, long-term bladder-preservation rate, QoL,

need for salvage treatment, type of TMT regimens, and

locoregional recurrence rate defined by recurrence in bladder

or pelvic nodes. Selection of articles is shown in a flow

diagram (Fig. 1). Original articles reporting clinical trials were

separated into three categories: TMT, neoadjuvant chemo-

therapy plus TMT, and TMT plus adjuvant therapy. TMT

articles were then separated between large- and small-

sample-size (<50 patients) trials. Large-sample-size TMT

trials were then separated into two categories: prospective

phase 3 trials and phase 2 or retrospective studies (Table 1).

3. Evidence analysis

Overall, five prospective TMT phase 3 trials have been

published, including two phase 3 RCTs. The remaining

articles included in this review were large retrospective

series (with heterogeneous treatment protocols) and phase

2 trials with small cohorts. Although use of conservative

management for MIBC has yielded promising results and

gained wider acceptance, most studies have small cohorts

or limited follow-up, providing few data on long-term

oncologic safety or late toxicity.

3.1. Description of optimal treatment courses

The basic strategy of TMT is to combine an aggressive but

safe TUR of the tumour followed by concurrent chemother-

apy and RT [11]. It also includes the need for prompt salvage

RC in patients who do not respond completely or who

develop invasive recurrence. Thus, the treatment is more an

attempt at bladder preservation than definitive bladder

preservation.

3.1.1. Split versus continuous course

Cystoscopic assessment with adequate biopsy of the

previous tumour site and voided urine cytology should

be performed at TMT completion (continuous course) and

may be performed early after TMT induction (split course;

Fig. 2). In case of incomplete response, patients are advised

to undergo immediate RC. To date, no prospective study has

compared both courses (continuous versus split) [12].

Induction therapy mainly consists of radiation to a dose of

40 Gy. Consolidation radiation is continued to a full dose

of approximately 65 Gy in most trials [13]. In the continuous-

course strategy, cystoscopic evaluation with biopsy is

deferred up to 1–3 mo after the end of TMT [14].

3.1.2. Radiation regimens

Several studies have assessed the impact of radiation

fractionation on oncologic outcomes in TMT trials. The

advantage of accelerated hypofractionation has been advo-

cated [15–17], but to date, radiation fractionation has not

been reported as a prognostic factor when comparing twice-

versus once-daily fractions [13,18]. The Radiation Therapy

Oncology Group (RTOG) 0712 protocol is currently under

assessment to evaluate a twice daily versus once daily

radiation regimen.

Inclusion of pelvic nodal packets in the target volume

varied among series [13,19]. One randomised trial that

included 230 patients has highlighted that targeting only

the bladder with 2-cm margins did not adversely affect

survival and could minimise side effects compared with a

whole-pelvis volume [20]. The BC2001 trial comparing RT

with or without chemotherapy by mitomycin C (MMC) and

5-fluorouracil (5-FU) had a planning target volume of

bladder plus 1.5 cm (2 cm around the visible tumour) but

nonetheless reported only a nodal recurrence rate of around

5% [14]. Nevertheless, most planned radiation regimens

included RT to a limited pelvic region (typically to the

mid-sacroiliac region, with an upper limit of the common

iliac artery bifurcation). The rationale for including a limited

pelvic field is that regional nodal involvement is not

uncommon in muscle-invasive disease; yet, by limiting the

nodal fields in size and dose (40–45 Gy), the treatments are

[(Fig._1)TD$FIG]

Records iden�fied through databasesearching(n = 1478)

Records screened(n = 973)

Records excluded(n = 542)

Full-text ar�cles assessedfor eligibility, first round

(n = 431)

Full-text ar�cles excluded, a�er rapid review, (n = 230)

Superficial cancers (n = 19)

Cystectomy series (n = 60)

Nonurothelial cancer (n = 19)

Upper urinary tract (n = 22)

Other cancers (n = 38)

Non-English (n = 43)

No link with outcomes (n = 35)

Full-text ar�cles excludeda�er complete reading*

(n = 118)

Full-text ar�cles assessed,second round

(n = 201)

Studies included insynthesis(n = 83)

* Did not meet criteria (phase 1 trials or editorials; n = 30), radia�on without concurrentchemotherapy series (n = 21), not relevant (n = 58), or duplicate data sets (n = 9).

Fig. 1 – Systematic review selection flow diagram.

E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 1 2 0 – 1 3 7122

designed to potentially conserve the small bowel for future

urinary diversions, if necessary [21]. In the BC2001 trial,

patients were also randomly assigned to undergo either

whole-bladder RT or modified-volume RT, in which the

volume of bladder receiving full-dose RT was reduced

[14,22]. The trial failed to show any side effect benefit from

reducing the dose, while the noninferiority of locoregional

control could not be concluded formally. There was,

however, a direct correlation between volume of bowel

irradiated and risk of grade 3 gastrointestinal (GI) toxicity.

Daily soft-tissue computed tomography (CT)–guided setup

for RT has been shown to be superior to traditional

kilovoltage portal positioning based on skin or bony

alignment in BCa and to decrease the treatment-related

toxicity [23]. Proton beam therapy has also been assessed,

but reports remain preliminary [24].

To date, the current radiation protocol for bladder

preservation includes external-beam RT (either once daily

or twice daily) to the bladder and limited pelvic lymph nodes

to an initial dose of 40 Gy, with a boost to the whole bladder

to 54 Gy and a further tumour boost (which incorporates all

TUR and radiographic information) to a total dose of 64–

65 Gy [3].

3.1.3. Chemotherapy regimens

3.1.3.1. Cisplatin-based chemotherapy. Cisplatin is the most active

single agent for BCa in locally advanced and metastatic

settings [25]. Its radiosensitising properties are also attractive

for combined-modality therapies [26,27]. The addition of

cisplatin to preoperative or definitive RT has been shown to

improve local control in large retrospective series and in one

phase 3 RCT [28–31]. No impact on OS was prospectively

demonstrated, but this trial closed prematurely because of

slow accrual.

Different schedules of cisplatin administration did not

demonstrate any difference in terms of response rates

[13,15,20]. Intensification of chemotherapy has been

evaluated [16,29,32–34], but no definitive benefit has yet

been demonstrated.

Concurrent use of intra-arterial cisplatin-based chemo-

therapy has also been studied, but it may be associated with

higher toxicity [33,36,37]. The addition of regional deep

Table 1 – Published series of trimodal therapy for bladder preservation: homogeneous treatment regimens

Study Design and follow-up Stage No. ofpatients

Concomitantchemotherapy

RT CRrate

Salvagecystectomy rate

CSS OS

Large sample size (>50 patients) series

PROSPECTIVE PHASE 3 STUDIES

James et al., 2012z [14] Continuous

Phase 3

(second arm: RT alone)

69.9 mo

T2–T4a

N0

182 5-FU, MMC x2

(Neoadjuvant

chemotherapy: n = 57)

55 Gy or

64 Gy

– 11.4% (at 2 yr) – 5 yr: 48

Tunio et al., 2012 [20] Continuous

Phase 3

5 yr

T2–T4 N0/Nx 200 Cisplatin weekly 65 Gy

ST

93% – – 5 yr: 52

Shipley et al., 1998z [58] Split

Phase 3 (second arm:

chemotherapy-RT with

neoadjuvant

chemotherapy)

60.0 mo

T2–T4a N0/Nx 62 Cisplatin x3 64.8 Gy

ST

60% 25.8% – 5 yr: 49

Housset et al., 1993** [16] Split

Phase 3

27 mo

T2–T4 N0/N1: n = 4 54 Cisplatin + 5-FU x4 44 Gy

BID

74% N/A** 3 yr: 62 3 yr: 59

PHASE 2 OR RETROSPECTIVE STUDIES

Lagrange et al., 2011 [51] Split

Phase 2

8 yr

T2–T4a N0/Nx 51 Cisplatin + 5-FU x3 63 Gy

ST

– 33.3% – 8 yr: 36

Gogna et al., 2006 [56] Continuous

Phase 2

23 mo

T2–T4a

N0/Nx

<10 cm

T1

113 Cisplatin weekly 63–64 Gy

ST

70% 15% 5 yr: 50 –

Kragelj et al., 2005 [57] Continuous

Phase 2

10.3 yr

T2–T4a

N0/Nx

T1

84 Vinblastine weekly 63.8–64 Gy

ST

78% 8.3%

(***)

9 yr: 51 9 yr: 25

Weiss et al., 2007 [30] Continuous

Retrospective

27 mo

T2–T4a

N0/N1: n = 58

T1: n = 54

112 Cisplatin + 5-FU x2 55.8–59.4 Gy

ST

88% 17% 5 yr: 82

(for T2–4: 73)

5 yr: 74

(for T2–4: 63)

Small size (<50 patients) series

Zapatero et al., 2012 [59] Split

Retrospective

60 mo

T2–T4a

N0

39 Cisplatin weekly

(paclitaxel: n = 5)

64.8 Gy

ST

BID: n = 24

80% 33% 5 yr: 82 5 yr: 73

Choudhury et al., 2011 [19] Continuous

Phase 2

36 mo

T2–T3

N0/Nx

50 Gemcitabine weekly 52.5 Gy in 20 82%

(88%*)

14% 3 yr: 82

5 yr: 78

3 yr: 75

5 yr: 65

EU

RO

PE

AN

UR

OL

OG

Y6

6(

20

14

)1

20

–1

37

12

3

Table 1 (Continued )

Study Design and follow-up Stage No. ofpatients

Concomitantchemotherapy

RT CRrate

Salvagecystectomy rate

CSS OS

Aboziada et al., 2009 [60] Split

Retrospective

18 mo

T2–T3b N0 50 Cisplatin weekly 66 Gy

ST

60% 28% 1.5 yr: 84 1.5 yr: 100

Peyromaure et al., 2004 [61] Split

Retrospective

36.3 mo

T2N0/Nx 43 Cisplatin + 5-FU x2 24 Gy in 8

BID

74.4% 25.6% 3 yr: 75

5 yr: 60

–

Hussain et al., 2004 [39] Continuous

Phase 1/2

50.7 mo

T2–T4a N0/Nx 41 MMC + 5-FU x2 55 Gy in 20 71% 19.5% 2 yr: 68 2 yr: 49

5 yr: 36

Kaufman et al., 2000 [15] Split

Phase 1/2

29 mo

T2–T4a N0/Nx 34 Cisplatin + 5-FU x4 44 Gy

BID

67% 29.4% 3 yr: 83 –

Varveris et al., 1997 [62] Continuous

Phase 2

32 mo

T1–T4

N0/Nx

42 Cisplatin + docetaxel 68–74 Gy

ST

54.7% – – –

Tester et al., 1993 [63] Split

Phase 2

36 mo

T2–T4a

N0–N2/Nx

48 Cisplatin x3 64 Gy

ST

66% 20.8% – 3 yr: 64

Rotman et al., 1990 [64] Continuous

Phase 2

38 mo

T1–T4 N0/N1

M0/M1

20 5-FU

(+MMC in 5 patients)

60–65 Gy

ST

74% – – 5 yr: 54

Russell et al., 1990 [65] Split

Phase 2

18 mo

T1–T4 N0/N1 34 5-FU 60 Gy

ST

81% 29.4% – 4 yr: 64

5-FU = 5-fluorouracil; MMC = mitomycin C; BID = twice daily; CR = complete response; CSS = cancer-specific survival; OS = overall survival; N/A = not applicable; RC = radical cystectomy; RCT = randomised controlled trial;

RT = radiation therapy.* Defined by pT0, pTis, or pT1 after cystoscopic assessment.** 18 patients were treated by primary RC after complete response to induction treatment; only 22 patients received full chemotherapy-RT treatment.*** 17% of patients with indication for salvage cystectomy did not undergo surgery because of locally advanced, inoperable tumour and/or poor performance status.z Phase 3 RCT. CR is evaluated after induction (split course) or completion (continuous course) of chemotherapy-RT.

EU

RO

PE

AN

UR

OL

OG

Y6

6(

20

14

)1

20

–1

37

12

4

[(Fig._2)TD$FIG]

Maximal TUR

Induc�on radia�on to about 40 GyConcurrent chemotherapy

Con�nuous course Split course

Radia�on to full doseConcurrent chemotherapy

Cystoscopic assessmentwith biopsies

Cystoscopic assessmentwith biopsies

Completeresponse

Incompleteresponse

Incompleteresponse

Completeresponse

Salvage cystectomy

Surveillance

Consolida�on radia�on to fulldose

Concurrent chemotherapy

Surveillance

Fig. 2 – The two main courses of trimodal therapy (TMT): split and continuous course. The cystoscopic assessment is performed after TMT completion(continuous course) or after TMT induction and before consolidation (split course).TUR = transurethral resection.

E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 1 2 0 – 1 3 7 125

hyperthermia to current chemotherapy-RT has been

assessed by the University of Erlangen team with encourag-

ing results [38]. Preliminary findings in 45 patients showed

an impressive response rate of 96% with acceptable toxicity

(30% grade 3–4 toxicity).

To date, in most of protocols, chemotherapy with cisplatin

is the usual radiosensitising drug in those with adequate

renal function and remains a standard of care as no published

head-to-head phase 3 trial has examined noncisplatin

regimens versus cisplatin in BCa patients treated with TMT

with regard to efficacy and the safety profile.

3.1.3.2. Alternative chemotherapy regimens. A cisplatin-based

regimen is not acceptable for all BCa patients, because many

patients have impaired renal function caused by age,

comorbidities, or prolonged hydronephrosis. Other systemic

agents have shown efficacy as alternatives to cisplatin [35].

The regimen using MMC plus 5-FU has a proven radio-

sensitising effect with acceptable toxicity in patients unfit for

a platinum-based regimen [39].

Recently, the value of a concurrent MMC/5-FU–based

regimen in addition to RT has been supported by a

randomised phase 3 trial (BC2001), with benefits in terms

of locoregional control and relapse-free survival [14]. The

addition of this drug regimen was associated with a reduction

of 33% in the risk of locoregional recurrence and of almost

50% in the risk of invasive recurrence. However, no significant

improvement in OS was reported. Interestingly, there was a

nonsignificant trend towards higher rates of salvage RC in the

RT-only arm of the trial, suggesting whether early surgical

salvage may have prevented separation of the survival

curves. A similar effect was observed in the anal cancer trials

[40].

Low-dose gemcitabine has also been shown to be an active

and potent radiosensitiser in phase 1/2 BCa trials [19,41,42].

Twice-weekly low-dose gemcitabine is currently being

assessed with daily radiation in the phase 2 randomised

trial RTOG 0712. Other agents with evidence from a

randomised trial are tumour hypoxia–reducing drugs such

as carbogen and nicotinamide [43].

3.1.4. Contribution of each treatment modality within the trimodal

approach

Contribution of each modality to outcomes in multimodal

strategies is difficult to quantify. In properly selected

patients, acceptable outcomes can be achieved with various

bladder-preservation strategies (TUR with or without

chemotherapy, TMT, partial cystectomy).

3.1.4.1. Radiation therapy alone. For several decades, RT has

been used as bladder-sparing monotherapy for MIBC,

mainly in patients unfit for surgery. When used alone, RT

offers local control rates inferior to TMT [14,28,44]. All

available data suggest that concurrent chemotherapy-RT is

more effective than RT alone (level of evidence [LoE]: 1b).

3.1.4.2. Transurethral resection alone. It is generally recognised

that TUR alone provides inadequate cancer control and leads

to a high rate of BCa recurrence and progression. To date,

limited data exist reporting long-term outcomes after TUR as

monotherapy for MIBC [45–47]. In well-selected patients

with small muscle-invasive tumours, bladder-intact survival

rates ranged from 60% to 70%. The largest published

retrospective series assessed 151 patients after restaging

TUR [46] and a minimum follow-up >10 yr. Ninety-nine

patients were managed with active surveillance and had

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E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 1 2 0 – 1 3 7126

comparable outcomes to those reported in 52 patients

undergoing RC. Solsona et al. have prospectively reported

similar results in 133 patients [47]. The 10-yr disease-specific

survival and progression-free survival rates were 80% and

65%, respectively. Nevertheless, only 11–35% of patients

were eligible for surveillance after second TUR [45,46]. In one

series, 56% of active surveillance patients developed tumour

recurrence, leading to a 30% rate of salvage cystectomy after

short-term follow-up [45].

3.1.4.3. Transurethral resection plus chemotherapy. In retrospec-

tive series with a long-term follow-up, Herr looked at

oncologic outcomes in 63 patients who were planned for

RC and declined to undergo surgery after neoadjuvant

chemotherapy [48]. All patients had a complete response

(negative TUR) to chemotherapy. Two-thirds of patients

were alive after 5 yr, and 54% of them had an intact

bladder. In a more mature study, Solsona et al. reported

results from a phase 2 nonrandomised trial comparing

TUR plus cisplatin-based chemotherapy with RC [49].

Oncologic outcomes for 75 patients who chose to keep

their bladders were compared with those achieved in 71

patients undergoing RC. Limitations are sample size, long

recruitment time, various chemotherapy regimens, and

patient selection including only highly selected invasive

tumours.

3.2. Oncologic results

3.2.1. In medically inoperable patients

Bladder preservation has been assessed in different cohorts of

inoperable patients: patients with prohibitive medical

comorbidities contraindicating radical surgery and patients

with surgically unresectable disease (Tables 1 and 2) [50–53].

In studies including only patients who had surgically

unresectable disease, OS was poor and ranged from 30%

to 42% after 4-yr follow-up [27,52,53]. It is worth noting that

these patients should not be considered to have received

TMT with curative intent and are excluded from analyses

of TMT outcomes.

In the SWOG 9312 trial, Hussain et al. classified patients

into two categories (surgical vs medical reasons) and

highlighted that this factor was predictive for OS [50]. The

criterion ‘‘unfit for surgery,’’ defined by medical comorbid-

ities contraindicating general anaesthesia or surgery, has

been associated with poorer OS [50,51].

Given these different patient profiles, most phase 2/3

trials—specifically, the RTOG protocols—included patients

who were fit for surgery (no medical contraindications) and

had resectable disease but were motivated to pursue

bladder preservation.

3.2.2. In medically operable patients

3.2.2.1. Response rate. Overall mean response rate after TMT

was 73% (Tables 1 and 2). In most series, complete response

(CR) was defined by the absence of visible tumour, the

absence of persistent pathologically proven bladder tumour

on biopsy, and the absence of tumour cells in the urine

cytology. Patients who responded completely to treatment

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induction had significantly better (by one-third) survival

rates than those who failed to achieve a CR [13,29,54]. It is

unclear what the ‘‘real’’ pathologic response after TMT

induction is. It has been assessed in a small study from

Housset et al. as 45% of complete responders having elected

to be treated by RC and not by the completion of a TMT

protocol who were found to have pT0 disease at RC [16]. In

contrast, the Memorial Sloan-Kettering Cancer Center

experience demonstrated that 30% of patients following

chemotherapy alone have residual muscle-invasive disease

on cystectomy that was not detected on the preoperative

TUR [55].

3.2.2.2. Cancer-specific survival and overall survival. CSS rates

reported in the literature are shown in Tables 1 and 2

[14–16,19,20,30,39,51,56–65]. Overall, the 5-yr CSS ranged

from 50% to 82%. In a study pooling various protocols over

time, the 5-yr CSS rate was about 60–65% [13,66].

The 5-yr OS was approximately 50%, ranging from 36% to

74% in the literature (Table 1). Discrepancies in CSS and OS

may be explained by inclusion period, patient selection,

accurate staging, duration of follow-up, differences in

chemotherapy and radiation regimens, and use of neoad-

juvant or adjuvant chemotherapy.

3.2.2.2.1. Comparison with radical cystectomy. Any direct compar-

ison between bladder-preservation modalities and RC is

difficult because of the lack of RCTs. Nevertheless, in

appropriately selected patients, the data suggest that TMT

with prompt salvage cystectomy, if necessary, can achieve

5-yr OS rates of 48–60% [13,34,67]. However, when evalua-

ting the outcomes of cystectomy series from centres of

excellence, the OS rate reached 62–68% after 5-yr follow-up

[68]. Similarly, in a 1100-patient cohort, Hautmann et al.

recently reported long-term oncologic outcomes after RC,

showing a 10-yr CSS rate of 67%, including all pT stages [69].

In a recent study from the University of Texas MD Anderson

Cancer Center and the University of Southern California that

examined patients with MIBC (cT2) without high-risk

features (hydronephrosis, palpable mass, invasion into

adjacent organs, lymphovascular invasion [LVI]) who were

treated with RC alone, the outcomes were excellent, with a

5-yr CSS rate of 83.5% [70]. This outcome in cystectomy

series appears slightly higher when compared with that of

selected TMT series (Tables 1 and 2) [71]. Furthermore,

although one has to be careful when comparing the two

approaches in subset analyses, the recent update of the

Medical Research Council neoadjuvant trial, which ran-

domised patients to neoadjuvant chemotherapy or not

followed by either RC or radiation (alone or TMT), revealed

that the OS rate of patients in the cystectomy arm was

higher than the radiation arm [72]; however, the authors

recognised that the randomisation was for the neoadjuvant

chemotherapy and that there was selection bias in

subsequent local therapy choice.

Unfortunately, clinicopathologic stage discordance and

inclusion biases limit the validity of any comparisons

between the two procedures. Patients fit for surgery and

treated by bladder preservation are rigorously selected,

with exclusion criteria such as hydronephrosis, carcinoma

in situ (CIS), or inability to perform a maximally safe

TUR, and might not be comparable with all patients

undergoing primary RC. Conversely, potential discordance

between clinical and pathologic staging has also been

suggested to introduce an outcome bias favouring cystec-

tomy series when oncologic outcomes are stratified by

pathologic stage [73]. Nevertheless, it is worth noting that

the downstaging rate between TUR and cystectomy series

ranges from 17% to 30%, and presumed cT2 tumours treated

by chemotherapy-RT may persist as pT0/1 tumours after

TUR [70,73,74].

3.2.2.2.2. Predictors of good response. BCa constitutes a hetero-

geneous group of tumours. Thus, selection criteria in

determining ideal candidates for TMT are required. It would

be relevant to identify the subgroup of BCa types that would

not respond to TMT, as the 5-yr CSS rate was lower in

nonresponders (ranging from 20% to 40%) than in responders

[13,29–75].

Historical series of RT alone have suggested that flat

lesions such as CIS, incomplete resection, locally advanced-

stage disease (T4), and the presence of ureteral obstruction

were associated with poorer response to RT [76]. The impact

of several pretreatment variables on oncologic outcomes

has been assessed [13,17,29,31,52,58,59,61,77–86].

Hydronephrosis has also been suggested as a poor

prognostic factor and was an exclusion criterion from

participation in several studies [15,35,59,87–89]. In fact,

RTOG protocols after 1993 have excluded patients with

tumour-related hydronephrosis. Hydronephrosis that occur-

red in about 10–35% of eligible patients was significantly

linked to poorer outcomes, specifically in terms of response

rates. The response rate was improved by at least 1.5-fold in

the absence of ureteral obstruction [66,89].

Although multiplicity (defined in studies as more than

one tumour) has been identified as a predictive factor for

relapse in two studies [29,36], no significant association

was found between multiplicity and CR rate or survival.

However, studies did not include patients with diffuse

multifocal disease, and TMT is not advocated in this

subgroup of patients.

Maximal TUR before bladder preservation is a strong

predictive factor of oncologic control (Table 3). This advan-

tage may be explained by the extent of the tumour and by the

completeness of the resection. Complete TUR led to a 20%

improvement in CR and bladder preservation [13]. The role of

re-TUR would be to decrease residual tumour volume and to

optimise radiation treatment. The absence of complete TUR

was also an exclusion criterion in some TMT series [59,61,88].

Most series have significantly linked incomplete TUR to

poorer response rates and survival outcomes. Its indepen-

dent predictive impact requires further evaluation, as

incomplete TUR may be considered a surrogate for pT stage

[13]. Pathologic prognostic factors such as high clinical stage,

high tumour grade, lymph node involvement, and LVI bear

witness of aggressive disease and, as in RC series, have been

associated with poorer outcomes in patients treated with

TMT [90,91].

Table 3 – Published series of neoadjuvant chemotherapy plus trimodal therapy

Study Design andfollow-up

Stage No. ofpatients

Neoadjuvantchemotherapy

Concomitantchemotherapy

RT CRrate

Salvagecystectomy rate

CSS OS

Lin et al., 2009 [88] Split

Retrospective

47 mo

T2–T4a

N0

23 Cisplatin + 5-FU +

paclitaxel

Cisplatin weekly

(or paclitaxel)

64.8 Gy

ST

73% – – 3 yr: 77

Sabaa et al., 2010 [83] Split

Retrospective

71 mo

T2–T3a N0/Nx 104 Gemcitabine +

cisplatin x3

Cisplatin x2 60–65 Gy

ST

78.8% 16.7% 5 yr: 76 5 yr: 68

Perdona et al., 2008 [82] Continuous

Retrospective

66 mo

T2–T4a N0/Nx 78 CMV x2 Cisplatin

(carboplatin: n = 25)

65 Gy

ST

85.7% 20.2% 5 yr: 79 5 yr: 72

Cobo et al., 2006 [95] Split

Retrospective

69.4 mo

T2–T3

N0/Nx

29 CMV x2 (n = 15)

Gemcitabine-

cisplatin (n = 14)

Cisplatin x2 64.8 Gy

ST

86% 24.1% – 6 yr: 72

Danesi et al., 2004 [80] Continuous

Retrospective

82.2 mo

T2–T4a N0/Nx 77 CMV x2 (n = 42) Cisplatin + 5-FU 69 Gy

ST

80.5% 22.1% 5 yr: 75

10 yr: 73

5 yr: 59

10 yr: 55

Arias et al., 2000 [81] Split

Retrospective

73 mo

T2–T4N0 50 M-VAC x2 Cisplatin x1 65 Gy

(45 Gy ST +20 Gy BID)

68% 26% – 5 yr: 48

Shipley et al., 1998z [58] Split

Phase 3 (second arm:

chemotherapy-RT

without neoadjuvant

chemotherapy)

60.0 mo

T2–T4a N0/Nx 61 CMV x2 Cisplatin x3 64.8 Gy

ST

72.5% 17% – 5 yr: 48

Kachnic et al., 1997y [89] Split

Retrospective

4.4 yr

T2–T4a N0/Nx 106 CMV x2 Cisplatin x3 64.8 Gy

ST

80% 21.7% 5 yr: 60 5 yr: 52

Fellin et al., 1997 [94] Split

Phase 2

46 mo

T2–T4

N0/Nx

56 CMV x2 Cisplatin 64 Gy

ST

50% 46.4% 5 yr: 59 5 yr: 54

Tester et al., 1996 [79] Spit

Phase 2

4.4 yr

T2–T4a

N0–N2/Nx

91 CMV x2 Cisplatin x3 64.8 Gy

ST

75% 39.5% – 4 yr: 62

RT = radiation therapy; CR = complete response; CSS = cancer-specific survival; OS = overall survival; 5-FU = fluorouracil; CMV = cisplatin, vinblastine, methotrexate; M-VAC = methotrexate, cisplatin, adriamycin,

vinblastine; BID = twice daily; RCT = randomised controlled trial.y Update of Kaufman et al., New England Journal of Medicine, 1993.z Phase 3 RCT. CR is evaluated after induction (split-course) or completion (continuous-course) of chemotherapy-RT.

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The presence of CIS has been correlated with higher local

recurrence rates in pure RT series [92], but the impact of CIS

on response rate after TMT has not been thoroughly studied.

Although CIS was often prognostic on univariable analysis,

the presence of CIS lost its significance on multivariable

analysis in other series [29,54,59]. The link between CIS and

response rate requires further evaluation.

Pooled together, all of these factors highlighted that a

limited number of patients with MIBC meet the criteria as

‘‘ideal patients for bladder preservation.’’ In a recent review of

the current literature, Smith et al. estimated that 10–15% of

medically operable patients were good candidates for

bladder preservation [93]. The recent International Consul-

tation on Urological Diseases–European Association of

Urology International Consultation on Bladder Cancer stated

that the best patients eligible for bladder preservation are

those with early-stage T2 disease and no hydronephrosis, no

extensive CIS, and no tumour invasion into the stroma of the

prostate [3]. Nevertheless, no strong LoE clearly identifies

ideal selection factors for TMT eligibility. Moreover, TMT

remains an alternative to RC in ‘‘not ideal’’ candidates if they

refuse surgery and plays a larger role in patients who are unfit

for surgery.

3.3. Role of neoadjuvant and adjuvant therapy in trimodal

therapy

3.3.1. Neoadjuvant therapy

The impact of neoadjuvant chemotherapy before RC in

MIBC is evident [71,74]. Meta-analysis of all randomised

prospective trials confirmed the 5% absolute improvement

in survival [93]. Although widely misquoted subgroup

analyses of the BA06 30894 trial suggest that neoadjuvant

chemotherapy had a greater impact on local recurrence-free

survival (RFS) before cystectomy (with a significant 26%

reduction in risk) than before RT (with a nonsignificant 9%

reduction in risk), a closer look revealed no evidence that

neoadjuvant cisplatin, methotrexate, and vinblastine (CMV)

chemotherapy had a greater or lesser effect in subgroups of

definitive treatments [72]. Hence, the benefit of neoadju-

vant chemotherapy appears mostly for distant disease,

which suggests that it may potentially have complementary

benefits for synchronous chemotherapy-RT, a conclusion

borne out by the BC2001 trial.

Efficacy of systemic neoadjuvant therapy in the context

of bladder preservation with TMT has been evaluated

(Table 3) [94,95]. The first large randomised trial (RTOG

89-03) comparing standard a TMT course with or without

two cycles of neoadjuvant CMV was prematurely closed

because of high rates of severe toxicities [57]. Only two-

thirds of included patients completed treatment as planned,

highlighting the poor tolerability. Moreover, no significant

difference in CR, metastasis-free survival, or OS was

reported between the two arms. Other teams have also

previously reported that the addition of neoadjuvant CMV

to cisplatin-based chemotherapy-RT was associated with a

greater incidence of mucositis, diarrhoea, and severe

leucopoenia [78,79,88,93]. Completion rates of neoadjuvant

chemotherapy plus TMT protocols ranged from 68% to 93%,

depending on the type of drug protocol [79,80,89,96].

In line with these series, when reviewing their institu-

tional experience, the Massachusetts General Hospital

(MGH) team did not find neoadjuvant chemotherapy to

be a predictor of better survival [13,66]. It is unclear why

neoadjuvant chemotherapy has been shown to improve

survival in patients treated with RC but not in patients

treated with TMT. Possible hypotheses include insufficient

chemotherapy having been given in some studies and

patients enrolling in clinical trials and treated with TMT

being more selected towards favourable pathology in which

neoadjuvant chemotherapy potentially has a lower survival

impact. Another possibility is that induction chemotherapy

before TMT may be associated with its own caveats, such as

selection of radioresistant clones, induction of accelerated

repopulation, and possibly reduced compliance with TMT

[97]. The lack of demonstrated benefit may be only

explained by inadequately powered studies using neoadju-

vant chemotherapy for adequate durations to answer this

question.

3.3.2. Adjuvant therapy

Series of adjuvant chemotherapy after TMT are listed in

Table 4. Completion of all adjuvant chemotherapy has

ranged from 45% to 70%, depending on the type of drug

protocol [17,35,98]. Grade 3–4 toxicity rates are higher

when adjuvant chemotherapy is used [17]. Moreover, the

completion rate for adjuvant chemotherapy was lower than

that reported for neoadjuvant treatment.

No survival outcomes from phase 3 trials evaluating

adjuvant chemotherapy following TMT have yet been

published. To date, no level 1 evidence exists to support

the use of either neoadjuvant or adjuvant chemotherapy

towards improving local control or survival in the setting of

TMT. However, in patients who can tolerate such therapy,

there may remain a clinical rationale for considering it, and

further studies are warranted.

3.4. Follow-up

Good responders with intact bladders have to be followed

closely by cystoscopy and CT or magnetic resonance

imaging (MRI) surveillance, with prompt salvage RC in

cases of invasive recurrence. Authors also suggest system-

atic tumour-site rebiopsy and bimanual examination under

general anaesthesia after completion of therapy, because on

rare occasions, patients may have a negative cystoscopy

but tumour growth underneath the TUR scar. Additional

biopsies are taken as seems appropriate. Although most

trials advocate and support rebiopsy following TMT, some

co-authors advocate a routine resection (rather than a cold-

cup biopsy) of the tumour scar at the first assessment

following TMT. Assuming that the biopsied tissue and

cytology do not show cancer (CR), the subsequent 2–3

cystoscopic evaluations over the next 9–12 mo may include

routine cold-cup biopsies. Nevertheless, no strong LoE

recommendation can be made concerning this follow-up

interval subsequent to the initial assessment. Voided urine

Table 4 – Published series of trimodal therapy plus adjuvant chemotherapy

Study Designand

follow-up

Stage No. ofpatients

Concomitantchemotherapy

RT(dose, fractionation)

Adjuvantchemotherapy

CR rate Salvagecystectomy

rate

CSS OS

Mitin et al., 2013 [34] Split

Phase 2

5 yr

T2–T4a N0/Nx 93 Arm 1: Cisplatin +

paclitaxel x3

Arm 2: Cisplatin +

5-FU x3

64.3 Gy

BID

Cisplatin +

gemcitabine +

paclitaxel

70%

85.5%**

5.4% – 5 yr: 73

Kaufman et al., 2009 [35] Split

Phase 1/2

49.4 mo

T2–T4a

N0

(biopsy or LN

dissection, if doubt)

80 Weekly cisplatin +

paclitaxel x5

64.3 Gy

BID

Cisplatin +

gemcitabine x4

81%* 12.5% 5 yr: 71 5 yr: 56

Hagan et al., 2003 [17] Split

Phase 1/2

26 mo

T2–T4a N0

(biopsy, if doubt)

47 Cisplatin weekly 64.8 Gy

BID

CMV x3 74%

(invasive: 19%)

25.5% – 3 yr: 61

Chen et al., 2003 [98] Continuous

Retrospective

36 mo

T3–T4 N0/N1 23 Cisplatin +

leucovorin +

5-FU x3

61.2 Gy

ST

Cisplatin +

leucovorin +

5-FU x3

86% – 3 yr: 69 3 yr: 65

Hussain et al., 2001 [50] Continuous

Phase 2

27.0 mo

T2–T4a N0/N1

Unresectable: 34%

56 Cisplatin +

5-FU x2

60 Gy

ST

Cisplatin +

5-FU x2

49% N/A – 5 yr: 45

Zietman et al., 1998 [87] Split

Phase 1/2

32 mo

T2–T4a N0/Nx 18 Cisplatin +

5-FU x4

55 Gy

BID

CMV x3 77.8% 14.3% – 3 yr: 83

5-FU = fluorouracil; BID = twice daily; CMV = cisplatin, methotrexate, vinblastine; CR = complete response; CSS = cancer-specific survival; LN = lymph node; N/A = not applicable; OS = overall survival; RT = radiation

therapy.* Defined by pT0, pTis, or pT1 after cystoscopic assessment.** Defined by pT0, pTis, or pTa after cystoscopic assessment. CR is evaluated after induction (split course) or completion (continuous course) of chemotherapy-RT.

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cytology is obtained before each evaluation. Ideally, the

same urologist should perform both the initial maximal TUR

of bladder tumour and the post-TMT evaluations. In

addition to the bladder, it is recommended that the

urologist perform risk-adapted surveillance for distant

metastasis and the upper tract.

Bladder-preservation studies that offer long-term follow-

up and address the risk of late metastatic or muscle-invasive

bladder failure suggested a decrease in cancer-specific events

and a flattening of the CSS curve beyond the first 5 yr after

TMT, similar to follow-up after cystectomy [13]. Other series

report that some patients may develop late recurrences

beyond the first 5 follow-up years [99–101]. Because of the

potential risk of delayed recurrences, it is recommended that

patients should be followed lifelong with cystoscopy.

3.5. Salvage therapy

Of the patients who experienced CR after induction TMT, the

rate of recurrent bladder tumours (both noninvasive and

muscle invasive) ranged from 24% to 43.1% [17,29,30,35,

56,68,89]. The median time to local recurrence was <2 yr in

general.

Of these recurrent tumours, the rate of muscle-invasive

recurrences ranged from 11% to 18.5% among patients

achieving CR [13,14,17,29,30,35,56,58,89]. RC is the

standard salvage treatment in medically operable patients

who have muscle-invasive recurrence. In their institutional

experience, Efstathiou et al. reported that cumulative 10-yr

rates of NMIBC and MIBC recurrences were 29% and 16%,

respectively [13]. James et al. reported 2-yr local RFS rates

of 67% [14]. Literature data (Table 1) suggest that the

average overall rate of salvage cystectomy, including

immediate cystectomy for nonresponders and delayed

cystectomy in cases of invasive recurrence, was approxi-

mately 25–30%, with many studies reporting data based on

<5-yr follow-up. Although difficult to determine, there

appears to be no significant diminution of survival related

to the delay in cystectomy in that setting. In the experience

from Erlangen, the CSS 5 yr after salvage RC for recurrent

muscle-invasive tumour approached 50% [29]. Better CSS

rates have been suggested in cases of delayed salvage

cystectomy for late recurrences compared with immediate

cystectomy for nonresponse [102]. Differences may be

explained by the fact that patients whose tumours did not

respond well to TMT are likely to have more aggressive

tumours than patients whose tumours respond well and

recur later.

In the past, cystectomy following radical RT has been

approached with concerns for increased morbidity. Although

the general experience among urologic surgeons is that

cystectomy following chemotherapy-RT is associated with a

higher risk of complications, contemporary series that use

conventionally fractionated regimens suggest potentially no

significant differences in perioperative mortality and major

complications rates after salvage RC compared with those

reported after primary cystectomy series [5,102,103].

Importantly, with regards to patient counselling, ortho-

topic neobladder reconstruction (although feasible) is not

advocated after pelvic radiation because of significantly

higher risk of functional complications. This risk is confirmed

within the published literature, as most patients who

underwent a cystectomy following TMT received an ileal

conduit diversion.

NMIBC recurrence can be managed conservatively with

TUR and subsequent intravesical therapies (bacillus Calm-

ette-Guerin [BCG], intravesical therapy) [99,100]. Never-

theless, these patients experiencing non–muscle-invasive

recurrence are at risk of requiring delayed cystectomy. Series

reported that 19–45% of recurrent non–muscle-invasive

tumours did not respond to conservative management and

needed to be treated by RC [19,30,58,66,80,100]. Although

non–muscle-invasive recurrence was associated with sig-

nificantly higher rates of salvage cystectomy, there was no

significant impact on CSS [30,100]. Finally, the effect of BCG

on QoL and bladder function in patients whose bladders were

treated with TMT previously requires evaluation.

3.6. Acute and late toxicity and effects on quality of life

3.6.1. Acute toxicity of trimodal therapy

Multimodal treatment for bladder preservation can be

offered to patients with an acceptable toxicity. The rates of

acute grade 3–4 toxicities and treatment completion rates

are listed in Table 5. Except in studies using neoadjuvant or

adjuvant chemotherapy, where toxicity seems higher, this

rate ranged from 10% to 36%, while the majority (80–90%) of

patients did complete the entire course of treatment. The

main toxicities are haematologic, GI, and genitourinary

(GU). Neuropathy may be reported in cases of cisplatin-

based concurrent chemotherapy. The BC2001 trial reported

neither an increase in grade 3–4 toxicity with concurrent

chemotherapy compared with RT alone nor a decrease in RT

completion rates caused by toxicity [14].

3.6.2. Late toxicity and quality of life

Bladder preservation must help to improve QoL if bladder

functions remain preserved after treatment, but systematic

assessment of toxicity beyond the 5-yr mark is presently

lacking. In the MGH experience and RTOG protocols, no

patient required cystectomy because of treatment-related

toxicity [13,66]. Overall, the rate of RC for late effects of RT

ranged from 0% to 2% [14,19]. Urodynamics studies on 32

patients reported reduced bladder compliance in about

one-quarter of patients but distressing symptoms in only

one-third of those patients [104]. Late grade 1–2 toxicity

rates ranged from 10% to 25% for GU and 5% to 6% for GI

toxicities [21,30,56]. The main low-grade toxicities were

urgency, nocturia, dysuria, diarrhoea, and proctitis. Hae-

morrhagic cystitis, ureteral or urethral strictures, proctitis,

and bladder compliance dysfunction may arise at varying

intervals after treatment. Late grade 3 urinary toxicity rates

ranged from 3% to 8% of cases [14,29,59]. Because many

toxicities were in physician-reported rather than patient-

reported assessments, it is unclear whether some were

underestimated.

Two prospective trials have confirmed good functional

results after TMT [51,105]. In the BC2001 trial, no differences

Table 5 – Reported rates of severe acute toxicity during trimodal therapy

Study Grade 3–4 toxicity Completion rate* Stop treatmentrelated to toxicity

Mitin et al., 2013 [34] 26.9% during induction

32% during consolidation

80.2% during adjuvant chemotherapy

58% 5.2% after TMT

29.8% after adjuvant chemotherapy

James et al., 2012 [14] 36%

GU: 21.3%

GI: 9.6%

80.2% –

Choudhury et al., 2011 [19] GI: 8% 92% 8%

Tunio et al., 2012 [20] 15%

Haematologic: 1%

GU: 6%

GI: 2%

Neuropathy: 2%

93.1% 7%

Lin et al., 2009 [88] Haematologic: 20%

GU: >10%

68% –

Kaufman et al., 2009 [35] 26% during induction

8% during consolidation

70% (including

adjuvant therapy)

–

Perdona et al., 2008 [82] Haematologic: 16.6%

GU: 11.5%

Diarrhoea: 14.1%

94.9% –

Weiss et al., 2007 [30] Haematologic: 14.4%

GU: 10%

Diarrhoea: 20.5%

87% 1.8%

Gogna et al., 2006 [56] 23%

Haematologic: 13.2%

GU: 3.5%

88.5% 0%

Kragelj et al., 2005 [57] 14% 64% –

Danesi et al., 2004 [80] Haematologic: 18.2%

GU: 16.9%

GI: 10.4%

93.5% 6.4%

Hussain et al., 2004 [39] Haematologic: 17%

Diarrhoea: 10%

Cystitis: 2%

85% –

Chen et al., 2003 [98] Haematologic: 4%

GI: 8%

GU: 4%

74% 0%

Rodel et al., 2002 [29] Haematologic: 22%

Diarrhoea: 5%

Cystitis: 5%

68% –

One death noted

Hussain et al., 2001 [50] 54.5%

Diarrhoea: 18.2%

Haematologic: 14.5%

Neuropathy: 7.2%

Other: 4–12%

57% 9%

Arias et al., 2000 [81] Haematologic: 20%

GU: 12%

GI: 16%

80% 0%

Kaufman et al., 2000 [15] Haematologic: 18%

GU: 9%

GI: 15%

87% 3%

Shipley et al., 1998 [58] Haematologic: 9.7%

Cystitis: 9.7%

GI disorders: 8.1%

Renal failure: 3.2%

Neuropathy: 3.2%

81% 6%

Kachnic et al., 1997 [89] – 80% 2% (one death)

Tester et al., 1996 [79] Haematologic: 15.4%

GU: 8%

GI: 3.3%

79% –

Tester et al., 1993 [63] Haematologic: 10.4%

GU: 8%

GI: 2%

– –

GI = gastrointestinal; GU = genitourinary; TMT = trimodal therapy.* Planned protocol or minor modifications because of toxicity. No grade 5 toxicity occurred.

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in late toxicity were reported with the addition of

chemotherapy to RT, where rates of grade 3–4 toxicity were

low (GI symptoms: 0.8%; GU symptoms: 7.4% in the

chemotherapy-RT arm) [14]. One small series retrospectively

compared QoL after RC with that after bladder preservation

[106]. QoL was suggested to be better after conservative

management, mainly because of better sexual activity. A

comparative cross-sectional study suggested that urinary

symptoms and sexual function may improve after RT [107],

but the retrospective design and interpretation biases

without accounting for surgical quality factors did not allow

drawing strong conclusions.

3.7. Limitations and perspectives

Although the use of conservative management for MIBC has

yielded promising results and gained wider acceptance,

most studies have limited follow-up, providing few data on

long-term oncologic safety or very late toxicity. Moreover,

several series included small cohorts. Thus, to date, most

bladder-preservation series have not reached the sample

size and follow-up of large published cystectomy series.

Although cancer control cannot be directly compared, the

similarity in survival after RC and TMT among properly

selected patients is likely in part because of a coherent

multidisciplinary effort among urologists, medical oncolo-

gists, radiation oncologists, pathologists, and motivated

patients, with prompt salvage therapy upon recurrence of

disease. TMT might induce an increased oncologic risk and

inferior survival if patients were not properly selected [108].

Large population-based studies consistently show that OS

was superior for patients who underwent RC compared with

those who underwent alternative treatments, including

chemotherapy and/or RT [109–111]. Although such compar-

ative retrospective studies are subject to significant selection

bias, with the reservation of chemotherapy and/or RT for

older patients who have significant comorbidities, they also

highlight the importance of proper patient selection and

coherent, coordinated multidisciplinary care.

Lymphadenectomy as well as the number of nodes

removed have been proven to be independent predictors of

survival after RC [112]. This therapeutic benefit may not be

fully addressed in the TMT approach, but no significant

difference in outcome has been shown between TMT series,

regardless of whether they include pelvic lymph nodes in

the targeted volume.

Many patients who have BCa have significant lower

urinary tract symptoms resulting from benign prostatic

obstruction, BCa, or repeated TURs with intravesical

therapies. In this subgroup of patients, the literature does

not adequately address whether these symptoms worsen or

improve after radiation. The use of TMT has not been

assessed in patients with nonurothelial histology.

As highlighted previously, some patients who are candi-

dates for bladder preservation may not be eligible for

concurrent cisplatin-based chemotherapy because of im-

paired renal function. Although regimens using MMC plus 5-

FU or low-dose gemcitabine have shown radiosensitising

activity, these regimens have never been compared head to

head with cisplatin. Finally, another concern that has been

discussed is that limited data exist on whether a neobladder is

feasible after TMT. Most surgeons would not offer orthotopic

diversion because of the increased complication and inconti-

nence rates [113].

As evident from the studies above, it is noteworthy to

highlight that the importance of proper patient selection

yields acceptable outcomes in any of the bladder-preserva-

tion approaches, but to date, available data support TMT as

the primary bladder-preservation strategy of choice for MIBC

because it addresses not only the index tumour itself but also

the rest of the susceptible bladder urothelium as well as

limited pelvic lymph nodes. Ideal candidates for bladder

preservation should have the following criteria: adequate

renal function to allow cisplatin-based chemotherapy

(although alternative regimens such as 5-FU or MMC or

low-dose gemcitabine have shown good activity); adequate

bladder capacity and function; motivated patient without

history of pelvic radiation who is willing to forgo an ileal

neobladder upon recurrence; organ-confined tumour (cT2)

and small tumour size in the absence of a palpable mass; the

ability to safely perform a resection of all visible tumour with

TUR; the absence of tumour-associated hydronephrosis or

adenopathy; the absence of extensive CIS; and the absence of

diffuse, multifocal disease.

Inclusion of molecular markers predicting response to

TMT may improve patient selection and management. If

predictive markers could be identified and validated in

prospective trials, patients might be selected for the

treatment most likely to benefit them. Prognostic values of

markers appear to differ between the settings of bladder

preservation and cystectomy [114]. Several studies have

investigated the predictive role of MRI and of various

biomarkers such as MRE11 [115–122]. Nevertheless, their

usefulness in clinical practice has to be proven.

4. Conclusions

A growing body of accumulated data suggests that TMT

(with prompt cystectomy reserved for tumour recurrence

or nonresponders) leads to acceptable outcomes and may

therefore be considered a reasonable treatment option in

well-selected patients. TMT can be discussed not only in

patients unfit for surgery but also for those patients who

have MIBC and are not willing to undergo surgery.

Author contributions: Wassim Kassouf had full access to all the data in

the study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Ploussard, Kassouf.

Acquisition of data: Ploussard, Daneshmand, Efstathiou, Herr, James,

Rodel, Shariat, Shipley, Sternberg, Thalmann, Kassouf.

Analysis and interpretation of data: Ploussard, Daneshmand, Efstathiou,

Herr, James, Rodel, Shariat, Shipley, Sternberg, Thalmann, Kassouf.

Drafting of the manuscript: Ploussard, Daneshmand, Efstathiou, Herr,

James, Rodel, Shariat, Shipley, Sternberg, Thalmann, Kassouf.

Critical revision of the manuscript for important intellectual content:

Daneshmand, Efstathiou, Herr, James, Rodel, Shariat, Shipley, Sternberg,

Thalmann, Kassouf.

E U R O P E A N U R O L O G Y 6 6 ( 2 0 1 4 ) 1 2 0 – 1 3 7134

Statistical analysis: Kassouf.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Kassouf.

Other (specify): None.

Financial disclosures: Wassim Kassouf certifies that all conflicts of

interest, including specific financial interests and relationships and

affiliations relevant to the subject matter or materials discussed in the

manuscript (eg, employment/affiliation, grants or funding, consultan-

cies, honoraria, stock ownership or options, expert testimony, royalties,

or patents filed, received, or pending), are the following: Dr Ploussard is

partially funded by the Association Francaise d’Urologie and Association

pour la Recherche sur le Cancer. Dr Kassouf is a recipient of a Research

Scholar Award from the Fonds de recherche Sante Quebec.

Funding/Support and role of the sponsor: None.

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