Expert Review of Anticancer Therapy

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Trimodal therapy for muscle-invasive bladder

cancer

Joachim Mathes, Steffen Rausch, Tilman Todenhöfer & Arnulf Stenzl

To cite this article: Joachim Mathes, Steffen Rausch, Tilman Todenhöfer & Arnulf Stenzl (2018)
Trimodal therapy for muscle-invasive bladder cancer, Expert Review of Anticancer Therapy, 18:12,
1219-1229, DOI: 10.1080/14737140.2018.1535314

To link to this article: https://doi.org/10.1080/14737140.2018.1535314

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EXPERT REVIEW OF ANTICANCER THERAPY
2018, VOL. 18, NO. 12, 1219–1229
https://doi.org/10.1080/14737140.2018.1535314

REVIEW

Trimodal therapy for muscle-invasive bladder cancer

Joachim Mathes, Steffen Rausch, Tilman Todenhöfer and Arnulf Stenzl
Department of Urology, University of Tübingen, Tübingen, Germany

ABSTRACT ARTICLE HISTORY

Introduction: Radical cystectomy is the standard therapy for patients with muscle-invasive bladder Received 3 May 2018
cancer. Organ-preserving surgical procedures have been established as alternatives to radical surgery Accepted 9 October 2018
for localized malignancies in other anatomic sites. Trimodal therapy consisting of radiation therapy, KEYWORDS
chemotherapy, and either transurethral resection of the bladder or partial cystectomy is an effective Chemotherapy; cystectomy;
treatment for selected patients with muscle-invasive bladder cancer that allows for preservation of the muscle-invasive bladder
urinary bladder. cancer; radiation; trimodal
Areas covered: This review provides an overview of the value of trimodal therapy in the treatment of therapy; TURB
muscle-invasive bladder cancer.
Expert commentary: Prerequisites for trimodal therapy for bladder cancer include: good bladder
function, unifocal cT2 urothelial carcinoma of the bladder, and absence of hydronephrosis. Careful
selection of patients and accurate assessment of the anatomic extent of the tumor is important for
patient safety. The basis for successful trimodal therapy is complete transurethral resection of the
tumor, followed by radiation therapy with concurrent radiosensitizing chemotherapy. Cystoscopic
controls and follow-up biopsies should be performed at completion of adjuvant therapy or shortly
after induction of trimodal therapy to identify nonresponders for whom salvage radical cystectomy may
be indicated.

1. Introduction
Urothelial carcinoma of the bladder is the ninth most
common cancer worldwide [1] and the fourth most com-
mon among men in the United States. In 2016, the esti-
mated incidence was 76,960 cases, with a cancer-specific
death-rate of 16,390 cases [2]. Approximately 75% of
patients with urothelial carcinoma of the bladder present
with nonmuscle invasive disease (NMIBC) confined to the
mucosa (Ta, CIS) or submucosa (T1) [3]; the remainder
present with muscle-invasive bladder cancer (MIBC) [4,5].
Radical cystectomy with urinary diversion and pelvic lymph
node dissection is the standard therapy for patients with
MIBC, recommended in both, the National Comprehensive
Cancer Network guidelines (2017) and European
Association of Urology (EAU) guidelines [6]. Advances in
surgical therapy of localized malignancies in other ana-
tomic sites have focused on organ preservation as alter-
natives to radical, organ-ablative surgical procedures.
These conservative surgeries typically achieve respectable
oncological results and increased quality of life while
avoiding the potential morbidity or mortality of more radi-
cal operations. Trimodal therapy for urothelial carcinoma,
which includes the combination of radical transurethral
resection of the bladder (TURB) or partial cystectomy,
ionizing radiation, and chemotherapy, is an effective blad-
der-preserving treatment protocol for selected patients
with MIBC. The aim of this article was to review the cur-
rently available literature on trimodal therapy.
2. Methods
A non-systematic literature review was conducted to identify
articles and studies reporting on trimodal therapy of MIBC
between 1980 and 2018. A search was performed using the
PubMed database and a free-text hand search using single or
different combinations of the following keywords:
trimodal therapy, trimodal therapy for bladder cancer, blad-
der preservation, bladder preserving therapy, bladder sparing
therapy.
Initially, articles were screened by title and abstract to
identify publications suitable for full-text review. A manual
search of publications in journals not listed in PubMed was
also performed. Articles not available in the English language,
editorials, and case reports were excluded.
3. Patient selection for trimodal therapy
Radical cystectomy with urinary diversion and pelvic lymph
node dissection is the standard therapy for patients with
MIBC. It is also a therapeutic option for patients with high-
risk NMIBC or can be used in a palliative setting. The utiliza-
tion of this treatment protocol is supported by a high level
of evidence [7,8]. It allows for local tumor control, including
removal of micrometastases with the aims of preventing
local recurrence and increasing chances for cure [9,10].
However, despite all these advantages, radical cystectomy
is associated with a complication rate of 31–51% and a 30-
day postoperative mortality rate of 1.5–2.7% [11–13].

CONTACT Arnulf Stenzl arnulf.stenzl@med.uni-tuebingen.de Department of Urology, University of Tübingen, Tübingen, Germany
© 2018 Informa UK Limited, trading as Taylor & Francis Group
1220 J. MATHES ET AL.
Moreover, elderly patients (the median age at diagnosis for
patient with MIBC is 70 years) and those with multiple
comorbidities may not meet the minimal physical require-
ments to safely undergo such a radical surgical procedure
[14]. In addition to these patients, who are potential candi-
dates for a bladder-preserving approach, another subset of
patients with (1) good bladder function, (2) nonextensive
carcinoma in situ or unifocal cT2 urothelial carcinoma of
the bladder, (3) complete transurethral resection without
visible tumor remaining and (4) an absence of hydronephro-
sis has been proposed for an organ-sparing approach to
surgical therapy [7,15]. Based on these recommended criteria
approximately 6–19% of patients with MIBC are potential
candidates for trimodal therapy. Careful selection of patients,
including accurate assessment of the anatomic extent of
bladder cancer is of utmost importance for safe and success-
ful application of this therapeutic option [1,16–19]. Studies
have shown impressive outcomes for selected patients with
MIBC treated with trimodal therapy [1,20–24]. Rates of com-
plete tumor response and survival achieved with trimodal
therapy were similar to cohorts undergoing radical cystect-
omy [25–27]. Complete response rates of 60–80%, 5-year
disease-specific survival rates of 60–70% [28,29], 10- and
15-year disease-specific survival rates of 42–59% and 57%,
and 10- and 15-year overall survival rates of 35% and 22%
have been reported [1,21,29,30]. However, patients treated
with immediate radical cystectomy have a 20–40% higher 5-
year cancer-specific survival rate compared to non-respon-
ders treated with trimodal therapy [21,28,31–35].
Kim et al. [14] compared the clinical outcomes of 79
patients treated with radical cystectomy or trimodal therapy
using propensity score matching. With respective median fol-
low-up intervals of 23 for the radical cystectomy group and 32
months for the trimodal therapy group, 5-year distant metas-
tasis-free survival (58% vs. 67%), overall survival (56% vs. 57%),
and cancer-specific survival (69% vs. 63%) rates were similar in
both treatment groups. However, the 5-year local recurrence-
free survival was significantly better in the radical cystectomy
group than in the trimodal therapy group (74% vs. 35%) [14].
4. Exclusion criteria for trimodal therapy
Different exclusion criteria for trimodal therapy for MIBC have
been defined and include: metastatic tumors, multifocal
lesions, concomitant carcinoma in situ, incomplete or nonfea-
sible transurethral resection, aggressive histology, and hydro-
nephrosis [7,36]. The presence of high-risk NMIBC (T1/Tis, with
high grade/G3, or CIS) is associated with a higher risk of local
relapse with decreased overall therapeutic success rates fol-
lowing radical cystectomy [37]. Furthermore patients with
locally advanced urothelial carcinoma (T4) or carcinoma in
situ benefits of radiotherapy as monotherapy have not been
observed [38]. Hydronephrosis has been an exclusion criterion
for Radiation Therapy Oncology Group (RTOG) protocols since
1993 because the response rate of patients without evidence
of ureteral obstruction is ≥1.5 times higher than patients with
hydronephrosis [29,39]. Bladder-preserving therapy cannot be
recommended when one or more of these exclusion criteria
are present [28,35].
5. Trimodal therapy: split or continuous course?
Trimodal therapy of MIBC can be performed in two ways referred
to as split or continuous course (Figure 1). The basis of both
approaches is maximal transurethral resection of the bladder
tumor followed by induction radiotherapy of the whole bladder
and pelvic lymph nodes (40–45 Gy), which is then followed by
consolidation radiation therapy of the bladder (55 Gy) and tumor
bed to a total dose of 65 Gy finally. Concurrent chemotherapy
with cisplatin or mitomycin C plus 5-fluorouracil (Table 1) is also
administered for radiosensitization. Depending on the regimen,
controls via urine cytology and cystoscopy with biopsy are per-
formed either after induction (split-course) or completion (con-
tinuous course) of trimodal therapy [7,16,40]. If recurrent MIBC is
detected during surveillance, radical cystectomy is indicated. If
recurrent NMIBC is instead detected at restaging, TURB must be
repeated in combination with intravesical chemotherapy. Both
the split- and continuous course regimens have been assessed
only in retrospective series and prospective studies [21,22,28,41].
No randomized controlled clinical trials have directly compared
these different regimens. Thus, whether a split or continuous
course is recommended is typically based on the experience of
the treating clinicians [42].
6. Transurethral resection of the bladder (TURB)
Patients undergoing complete transurethral resection show
improved disease-specific and overall survival compared to
those undergoing radical cystectomy [44,45]. TURB for
NIMBC is also associated with lower rates of disease recurrence
and with improved long-term oncologic outcomes for patients
treated with trimodal therapy. Nevertheless, 30–70% of
patients develop tumor recurrence after primary TURB
[42,46,47]. Important factors that have a decisive influence
on the outcome of the TURB procedure include the experience
of the surgeon, surgical technique used, tumor location and
size, and documentation of complete tumor resection [48,49].
The results of a long-term follow-up study of 133 patients
treated with TURB monotherapy and achieving complete radi-
cal transurethral resection of cT2 bladder cancer showed a 5-
year overall survival of 73.3%, disease-specific survival of
81.9% and progression-free survival of 75.5% [45]. In a study
of survival outcomes of 900 patients after cystectomy with
pelvic lymph node dissection (without neoadjuvant che-
motherapy), 20.1% of patients who had complete transure-
thral resection (pT0 pN0 at completion cystectomy), reached
10-year tumor-specific survival rates of up to 91.0% [50]. In an-
other study, patients with an initial cT2-cT3 urothelial carcino-
mas of the bladder restaged as cT0-cT1 after TURB had a 10-
year disease-specific survival of 76% and were able to avoid
radical cystectomy in 57% of cases [44]. Consequently, com-
plete TURB of all visible tumors, including the detrusor muscle,
is essential for bladder-preservation therapy. It is the most
important factor for oncologic control and success of trimodal
therapy especially for those cases who would be considered
overtreated by radical surgery [21]. The use of intravesical
therapies, such as Mitomycin C, Valrubicin, and bacillus
Calmette Guerin (BCG) together with TURB has not yet been
investigated [42].
 EXPERT REVIEW OF ANTICANCER THERAPY 1221

Radical TURB

Radiotherapy

Split-course Continuous-course
chemoradiotherapy chemoradiotherapy
(40 to 45 Gy) (55 to 65 Gy)
(induction)

Cystoscopy Cystoscopy
+/-Re-TURB +/-Re-TURB
(after 3-4 weeks) (after 8-10 weeks)

Complete
Response Residual Residual Complete
muscle- muscle- Response
invasive invasive
Chemoradio-
disease disease
therapy
(consolidation,
20-25 Gy: total
radiation therapy
dose 55-65 Gy) Cystoscopy

Cystoscopy
+/-Re-TURB
(after 8-10 weeks)

Cysto- Recurrence Recurrence

scopy (muscle invasive) (muscle invasive)

Salvage radical cystectomy

Figure 1. Pictographic Algorithm of trimodal therapy, modified after [43].

patients treated with carboplatin [56]. Replacement of cisplatin

7. Chemotherapy
If possible, systemic first-line therapy for advanced or metastatic
disease should be cisplatin based. For almost 30 years, the
combination of methotrexate, vinblastine, doxorubicin, and cis-
platin (MVAC) has been used successfully, either in normal dose
intensity [51,52] or as dose compressed with granulocyte-colony
stimulating factor (G-CSF) support (dose-dense MVAC) [53]. The
combination of gemcitabine and cisplatin (GC) has been shown
to be less toxic, with similar response rates and median long-
term overall survival [54,55]. Patients treated with MVAC were
also found to have more severe grade 3–4 toxicities compared to
by carboplatin exhibits inferior efficacy, but also a lower inci-
dence of nephrotoxicity (which is particularly beneficial in elderly
and comorbid patients) [56,57]. Radiosensitizing chemotherapy
prior to external beam radiotherapy is associated with better
oncologic outcomes for patients treated with trimodal therapy
compared to radiation therapy alone [58–60]. Kaufman et al. [59]
followed 34 patients with clinical T2-T4a, NX, M0 bladder cancer
treated with complete TURB followed by induction chemoradia-
tion (cisplatin 15 mg/m2 i.v. and 5-fluorouracil (5-FU) 400 mg/m2
i.v. on days 1, 2, 3, 15, 16, and 17. On day 1, 3, 15, and 17, radiation
was performed immediately following chemotherapy using
1222 J. MATHES ET AL.

Table 1. Studies of trimodal therapy for muscle-invasive bladder cancer (2006–2012).

Follow-up
Study N (months) CT-R RT-Dose OS CSS CRR Course
[21] 348 92.4 Various Various 52% (5y) 64% (5y) 78% Split
[34] 39 72 Cisplatin 64.8 Gy 73% (5y) 82% (5y) 80% Split
[114] 51 96 Cisplatin and 3× 5-FU 63 36% (8y) - - Split
[41] 473 71.5 Various Various 49% (5y) - 70.4% Split
[32] 104 71 2× Cisplatin 60–65 Gy 68% (5y) 76% (5y) 78.8% Split
[63] 80 49.4 Cisplatin (weekly) and 5× Paclitaxel 64.3 56% (5y) 71% (5y) 81% Split
[adjuvant cisplatin and 4× Gemcitabine]
[115] 50 18 Cisplatin (weekly) 66 Gy 100% (1.5y) 84% (1.5y) 60% Split
[116] 29 69.4 2× Cisplatin (neoadjuvant 2× CMV or Gemcitabine/Cisplatin 64.8 Gy 72% (6y) - 86% Split
[23] 230 60 Cisplatin 65 Gy 52% (5y) - 93% Continuous
(weekly)
[22] 360 69.9 5-FU and 55/64 Gy 48% (5y) - - Continuous
2× Mitomycin
[117] 50 36 Gemcitabine (weekly) 52.5 Gy 75% (3y) 82% (3y) 82% Continuous
[33] 78 66 Cisplatin 65 Gy 68% (5y) 74% (5y) 85.7% Continuous
(neoadjuvant 2× CMV)
[118] 112 27 Cisplatin and 55.8–59.4 Gy 74% (5y) 82% (5y) 88% Continuous
2× FU
[119] 113 23 Cisplatin (weekly) 63–64 Gy 50% (5y) 86% Continuous
[CT-R: Chemotherapy Regimen; RT: Radiotherapy; OS: Overall Survival; CSS: Cancer Specific Survival; CRR: Complete Response Rate; FU: Fluorouracil; CMV: Cisplatin,
Methotrexate, Vinblastine, y: year, Gy: Gray].

twice-a-day 3 Gy per fraction cores to the pelvis for a total
radiation dose of 24 Gy. Tumor response was evaluated by
cystoscopy, cytology, and rebiopsy 4 weeks later. The complete
response rate to induction therapy of 67% and 3-year survival
with an intact bladder was 66%. A prospective randomized trial
of 99 patients examined the effect of concurrent cisplatin on
local control and survival in patients with MIBC. Patients were
randomly allocated to receive pelvic radiation with concurrent
intravenous cisplatin 100 mg/m2 at 2-week intervals for three
cycles or radiation without concurrent chemotherapy.
Occurrence rates of distant metastases were the same in both
study arms. However, 25 of 48 control patients developed a first
recurrence in the pelvis, compared to 15 of 51 cisplatin-treated
patients (P = 0.036). The pelvic relapse rate in the two groups was
significantly reduced by concurrent cisplatin (log-rank test,
P = 0.038) and this effect was preserved in a stepwise Cox
proportional hazard regression model controlling for other
important prognostic factors (hazard ratio, 0.50; 90% confidence
interval [CI], 0.29 to 0.86; P = 0.036). The authors concluded that
concurrent cisplatin may improve pelvic control of locally
advanced bladder cancer with preoperative or definitive radia-
tion but did not affect development of distant metastases or
overall survival [60].
Phase 3 clinical trials have provided support for use of
radiosensitizing chemotherapy with cisplatin and mitomycin
C plus 5-fluorouracil [61]. However the most commonly
used chemotherapeutic regimens are cisplatin-based
[31,62–64]. According to the results of RTOG 89–03, neoad-
juvant cisplatin-based chemotherapy, normal dose intensity
or dose-dense MVAC or gemcitabine with cisplatin regimens
have shown 5–6% improvement in overall survival in clinical
trials [58,65].
Chemotherapy in a neoadjuvant setting allows to evaluate
the tumor in vivo for response and assessment whether it is
sensitive to the chosen regimen. Also, the tolerability of the
patient is better before than after surgery [66]. Moreover it
allows a downstaging of the tumor mass, which may increase
the chances of complete resectability [67,68].
Chemotherapy alone is not an appropriate therapy for
MIBC being treated for cure [69]. The RTOG investigated the
efficacy of induction chemotherapy in TMT in serial phase II
studies. About 123 patients with T2-4a, Nx MIBC were rando-
mized to receive two cycles of neoadjuvant cisplatin, metho-
trexate, and vinblastine chemotherapy followed by 39,6 Gy
pelvic irradiation with concurrent cisplatin (100 mg/m2) for
two courses 3 weeks apart. In the other arm of the trial
patients did not receive MCV before concurrent cisplatin and
radiation therapy. In result 5-year overall survival rate was
49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of
the patients had evidence of distant metastases at 5 years;
33% in arm 1 and 39% in arm 2. The 5-year survival rate with a
functioning bladder was 38%, 36% in arm 1 and 40% in arm 2.
None of these differences were statistically significant [31], so
that induction chemotherapy has not been established [69].
8. Radiotherapy and chemoradiotherapy
Radiotherapy is an alternative to cystectomy for the treatment
of MIBC, especially in patients for whom radical surgery is
contraindicated (due to advanced age or poor medical condi-
tion) or who refuse radical cystectomy [70]. There are two
protocols for the implementation of radiotherapy in TMT.
Standard radiation therapy regimen includes external-beam
radiotherapy to the bladder and limited pelvic lymph nodes
to a starting dose of 40–45 Gy, followed by cystoscopy (if
necessary rebiopsy of residual tumor tissue) and consolidation
chemoradiotherapy with additional 25 Gy or radiation in case
of negative biopsy. The alternative radiation protocol includes
full-dose chemoradiation to the whole bladder to 55–65 Gy
followed by rebiopsy and surveillance in case of negative
rebiopsy [7,61,71,72]. The standard fractionation used of
both radiotherapy protocols is of 1.8–2 Gy/fraction with the
total radiation dose to the bladder of 55–70 Gy and 45–50 Gy
to the pelvic lymph nodes [73].
Intravesical Lipiodol Injection Technique for Image-guided
Radiation therapy is a supportive option to refine the

treatment of MIBC. Lipiodol is an iodinated contrast agent that
improves visualization on daily kilovoltage cone beam CT,
when injected into the submucosa of the bladder along the
tumor periphery [74] (95%, 20–30 injections) before external
beam radiation (6–7 weeks) in a bladder sparing approach. In
addition to the good visualization of the tumor, Lipiodol is
well tolerated [74,75]. Most series have a low number of cases.
Tumor imaging rates of up to 88% and 3-year OS and disease-
free survival rates of up to 71.1% are reported [76].
Compared to solitary radiotherapy, synchronous radioche-
motherapy is associated with increased rates of local control
and improved survival [59,77–79]. Since the publication of two
studies demonstrating significant improvements in complete
response, overall survival, and local tumor control with cispla-
tin-based radiosensitizing chemotherapy followed by external
beam radiotherapy [60,80], a combined cisplatin-based
approach is recommended for patients with MIBC. The RTOG
showed a complete response rate of 67% when patients with
MIBC were treated with induction chemotherapy [81].
Radiosensitizing therapy consisting of a combination of
cisplatin and paclitaxel and adjuvant chemotherapy of gemci-
tabine and cisplatin achieved complete response of 81% and a
2-year overall survival of 73% [54]. The effects of two different
radiosensitizing chemotherapy regimens (5-fluorouracil and
cisplatin versus paclitaxel and cisplatin) were compared in a
study of 93 patients. Both study arms received twice-daily
radiation and adjuvant chemotherapy (cisplatin, gemcitabine,
paclitaxel). Overall survival, 5-year complete response rates
and bladder preservation rate in the paclitaxel/cisplatin arm
was 71%, 72%, and 71%, respectively, compared to 75%, 62%,
and 67% in the 5-fluorouracil/cisplatin arm. These results were
considered comparable [82]. Whole bladder radiation and
reduced high-dose volume using a tumor boost, with or with-
out chemotherapy (mitomycin C and 5-fluorouracil) was com-
pared in the BC2001 trial [22,83]. Compared to solitary
radiotherapy, 5-fluorouracil and mitomycin C resulted in a
statistically significant improvement in locoregional disease-
free 2-year survival (54% vs. 67%) and 5-year overall survival
(35% vs. 48%) [22]. In a retrospective study of 30 bladder
cancer patients treated with bladder-preservation surgery
with concurrent chemoradiotherapy (CCRT) and 20 patients
treated with radiotherapy alone, 60% of patients treated with
combined therapy showed complete response and 26%
showed a partial response. The 5-year overall survival rate
was 37.2%, and the 5-year disease-free survival rate was
30.2%. Urinary bladders were preserved in all patients. In
multivariate analysis, tumor grade and CCRT were significant
predictors of overall survival [70]. Tunio et al. [23] compared
outcomes after treatment with bladder-only (BO-CCRT) and
whole-pelvis concurrent chemoradiation therapy (WP-CCRT)
in 230 patients with MIBC and negative lymph nodes. With a
median follow-up interval of 5 years, WP-CCRT was associated
with a 5-year disease-free survival of 47.1% compared to
46.9% for patients treated with BO-CCRT. Bladder preservation
rates and 5-year overall survival rates were 58.9% and 52.9%
for patients treated with WP-CCRT and 57.1% and 51.0% for
patients treated with BO-CCRT. Thus, both treatments showed
similar rates of bladder preservation, disease-free survival and
overall survival [23]. For the treatment of elderly patients with
EXPERT REVIEW OF ANTICANCER THERAPY 1223
MIBC an approach using hypofractionated intensity-modu-
lated radiation therapy has been reported [84].
Ritch et al. [85] performed a propensity matched compara-
tive analysis of survival in a total number of 8379 patients
following chemoradiation or radical cystectomy for muscle-
invasive bladder cancer using the National Cancer Database
(2004–2013). In result chemoradiation therapy was associated
with decreased mortality at year 1 (hazard ratio [HR] 0.84, 95%
confidence interval [CI] 0.74–0.96; P = 0.01), but at 2 years (HR
1.4, 95% CI 1.2–1.6; P < 0.001) and 3 years onward (HR 1.5, 95%
CI 1.2–1.8; P < 0.001) CRT was associated with increased
mortality. The 5-year OS was higher for radical cystectomy
than for chemoradiation therapy (38% vs. 30%, P = 0.004).
The authors of the study concluded from these results, that
patients who are suitable surgical candidates, with a low risk
of morbidity, may be better served by radical cystectomy.
Cahn et al. [86] examined the OS in a total number of
32,300 patients undergoing radical cystectomy or bladder-
preservation therapy for muscle-invasive urothelial carcinoma
of the bladder between 2004 and 2013. Patients receiving
bladder-preservation therapy were stratified as having
received any external-beam radiotherapy (any XRT), definitive
XRT (50–80 grays), and definitive XRT with chemotherapy
(CRT). The statistically determined magnitude of the OS ben-
efit became attenuated on multivariate (any XRT: hazard ratio
[HR], 2.115 [95% confidence interval [95% CI], 2.045–2.188];
definitive XRT: HR, 1.870 [95% CI, 1.773–1.972]; and CRT: HR,
1.578 [95% CI, 1.474–1.691]) and propensity score (any XRT:
HR, 2.008 [95% CI, 1.871–2.154]; definitive XRT: HR, 1.606 [95%
CI, 1.453–1.776]; and CRT: HR, 1.406 [95% CI, 1.235–1.601])
analyses. In result improved OS was observed for radical
cystectomy in all groups.
9. Partial cystectomy
While radical cystectomy continues to be the gold standard
for surgical management of MIBC, there is renewed interest in
partial cystectomy [87]. Partial cystectomy is another bladder-
sparing alternative to radical cystectomy that avoids interposi-
tion of bowel into the urinary tract and preserves urinary
bladder continence and sexual function. Selection criteria for
partial cystectomy include absence of carcinoma in situ and
unifocal bladder disease. Currently, partial cystectomies repre-
sent approximately 10% of all cystectomy procedures [5,88].
The role of partial cystectomy has been controversial ever
since three publications questioned the effectiveness of the
procedure (resulting in poor oncologic outcomes and high
recurrence rates) in the presence of in situ carcinoma [89–
91]. Nevertheless, 5-year recurrence-free survival rates of
39–67% have been reported in more recent series [92,93]. In
2009, a matched cohort study showed similar overall and
cancer-specific survival rates for radical and partial cystectomy
[94]. These results were subsequently confirmed 2012 [95].
These investigators reported 10-year metastasis-free survival
rates of 61% versus 66% (P = 0.63) and cancer-specific survival
rates of 58% versus 63% (P = 0.67), and the authors concluded
that partial cystectomy (for selected patients) does not com-
promise oncologic outcomes. Based on a retrospective analy-
sis of 101 patients with pelvic lymph node-negative MIBC,
1224 J. MATHES ET AL.
lymphovascular invasion was predictive of poor outcomes,
while a prior history of urothelial carcinoma and ureteral
reimplantation were discussed as contraindications for partial
cystectomy. Innovative approaches such as cystoscopic tattoo-
ing of tumors [96] or the use of free near-infrared fluorescence
contrast agents to improve the localization of pathologic
lesions [97] aim to increase the odds of an oncologically
satisfactory complete resection and improve surgical out-
comes. In a series of selective bladder-sparing therapy consist-
ing of induction low-dose chemotherapy and radiation
followed by a partial cystectomy, the 5-year cancer-specific
survival was 71% among the total patient population.
Among 46 patients who underwent partial cystectomy after
chemoradiation, 5-year cancer-specific survival and survival
free from recurrent MIBC was 100% [98]. Partial cystectomy
therefore represents an acceptable alternative to radical
cystectomy for a very select group of patients [87].
10. Surveillance after trimodal therapy
The aim of bladder-preserving therapy using the trimodal
therapeutic approach for MIBC is to offer a quality of life
advantage and avoid the potential morbidity or mortality of
radical cystectomy without compromising oncologic out-
comes [61]. Taking the strict selection criteria for bladder-
preserving therapy into account, the primary goal is complete
tumor control. It is absolutely necessary that patients under-
going trimodal therapy agree to commit to lifelong surveil-
lance with the option for radical cystectomy in the case of
treatment failure. Regular surveillance consists of physical and
cystoscopic examinations including bladder biopsies, abdom-
inal imaging by computed tomography or magnetic reso-
nance imaging and cytopathologic examination of urine
samples [16,61]. One should also consider that the incidence
of developing a urothelial malignancy of the upper urinary
tract after primary urothelial carcinoma of the bladder is
between 1 and 7%. Therefore, surveillance imaging of the
upper tract is recommended every 1–2 years [99].
11. Reasons for choosing a bladder-sparing
treatment
An important reason for choosing a bladder-sparing therapy
such as the trimodal therapeutic approach is preservation of
urinary bladder and sexual function. In urodynamic series and
quality of life questionnaires nearly 75% of patients showed
normal bladder function after bladder-sparing surgery. Distress
from urinary symptoms was reported in <50% of patients
(increased urinary urge 15%; urinary incontinence 19%) [100].
Efstathiou et al. [21] examined the prevalence of genitourinary or
gastrointestinal pelvic toxicity in 157 patients 2 years after blad-
der-preserving therapy and found no incidences of grade 4
toxicity in their cohort; 7% of patients showed grade 3 toxicity
(urinary urgency and hematuria was reported by 5–7% of
patients; sigmoid obstruction or proctitis was reported in 1.9%).
Also, there was no indication for salvage cystectomy secondary
to pelvic toxicity. A small, nonadjusted, case-controlled series of
33 patients with biopsy-proven T2-T4a, N0, M0 urothelial bladder
cancer showed similar overall and disease-free survival rates with
low toxicity when treated by chemoradiation compared to radi-
cal cystectomy alone. The 2- and 5-year overall survival rates after
surgery alone (74.4% and 54.8%, respectively) were not signifi-
cantly different than after chemoradiation (70.2% and 56.6%;
P = 0.8). Similarly, 2- and 5-year disease-free survival rates after
surgery alone were 67.8% and 63.2%, compared to 63% and
54.3% after chemoradiation (P = 0.89). Side effects were mild in
both groups, with grade 3 toxicity seen in only two surgical and
four irradiated patients [101]. A propensity score matched-ana-
lysis of 112 patients comparing trimodal therapy and radical
cystectomy for patients with MIBC showed a 5-year disease
specific survival rate of 73.2% for radical cystectomy and 76.6%
for trimodal therapy [102]. In summary, no significant differences
between these therapeutic options were observed in these
studies.
12. Conclusion
Prerequisites for trimodal approach to therapy of MIBC include
good bladder function, unifocal cT2 urothelial carcinoma,
complete transurethral resection without visible tumor
remaining and an absence of hydronephrosis [7,15]. The effec-
tiveness of trimodal therapy depends mainly on locoregional
tumor control [103]. This bladder-sparing treatment regimen
has been shown to produce comparable oncological results to
radical cystectomy alone. The basis for successful trimodal
therapy of MIBC is radical and complete [42] followed by
radiation therapy with concurrent radiosensitizing chemother-
apy. Cystoscopic controls with biopsies should be performed
at completion or shortly after induction of trimodal therapy to
identify nonresponders. These patients can then be offered
salvage radical cystectomy [61]. Partial cystectomy can sel-
domly be integrated into the trimodal regimen as an alterna-
tive to TURB. Patients who receive trimodal therapy seem to
be older and have more medical comorbidities and poorer
performance status than patients who undergo radical cystect-
omy [14]. Correct and careful selection of patients is of highest
importance for safe and successful trimodal therapy.
Nevertheless, radical cystectomy with urinary diversion and
pelvic lymph node dissection, as recommended by the
National Comprehensive Cancer Network (2017) the
European Association of Urology [6] remains the gold standard
therapy for patients with MIBC.
13. Expert commentary
Radical cystectomy with urinary diversion and pelvic lymph
node dissection is the standard therapy for patients with MIBC.
The utilization of this treatment protocol is supported by a
high level of evidence [7,8]. However, despite all advantages
demonstrated in studies [9,10], radical cystectomy is asso-
ciated with a complication rate of 31–51% and a 30-day post-
operative mortality rate of 1.5–2.7% [11–13]. Especially elderly
patients and those with multiple comorbidities may not meet
the minimal physical requirements to safely undergo radical
cystectomy [14]. While advances in surgical therapy of loca-
lized malignancies in other anatomic sites have focused on
organ preservation as alternatives to radical, organ-ablative
procedures, its standing in treatment of muscle-invasive

tumors is low. There is just a manageable amount of publica-
tions dealing with trimodal therapy and partial cystectomy
[95] for patients with MIBC. Although, these therapeutic
options typically achieve respectable oncologic results [1,20–
24], only 6%–19% of patients with MIBC are potential candi-
dates for trimodal therapy [1,16–19]. Nevertheless, the data
summarized thus far suggest that trimodal therapy is a poten-
tial alternative to radical cystectomy for a selected group of
patients with MIBC. It is confirmed by the work of a group that
examined a total number of 57 studies involving 30,293
patients. The mean 10-year overall survival was 30.9% for
trimodal therapy and 35.1% for radical cystectomy (P = 0.32).
The mean 10-year disease-specific survival was 50.9% for tri-
modal therapy and 57.8% for radical cystectomy (P = 0.26).
Neoadjuvant chemotherapy significantly increased the rate of
pT0 from 20.2% to 34.3% (P = 0.007) in cT2 and from 3.8% to
23.9% (P < 0.001) in cT3-4. A 5-year overall survival, disease-
specific survival, and recurrence free survival in downstaged
patients (≤ pT1) at radical cystectomy were 75.7%, 88.3%, and
75.8%, respectively. Patients who experienced downstaging
after neoadjuvant chemotherapy and radical cystectomy
exhibited improved survival compared to patients treated
with radical cystectomy only [104].
A comparable effect is also evident with the use of radio-
therapy in other studies. Compared to solitary radiotherapy,
synchronous radiochemotherapy is associated with increased
rates of local control and improved survival [58,66–68]. Since
the publication of two studies demonstrating significant
improvements in complete response, overall survival, and
local tumor control with cisplatin-based radiosensitizing che-
motherapy followed by external beam radiotherapy [59,69], a
combined cisplatin-based approach is recommended for
patients with MIBC.
In particular, the use of combined methods shows an
improvement in the patient’s outcome in terms of disease
control.
A constant challenge is the combination of new and exist-
ing therapies to optimize the outcome for patients in the
context of tumor therapy.
After a period of perceived stagnation, the approval of
vinflunine in the second-line treatment of locally advanced
and metastatic urothelial carcinomas provided a discrete
improvement compared to best supportive care. The estab-
lishment of gemcitabine and cisplatin as an alternative to
MVAC was another step. The introduction of checkpoint inhi-
bitors raised the therapeutic potential of treating tumors to a
higher level. Recently, PD-L1 inhibitors, atezolizumab, durva-
lumab, and avelumab, and PD-1 inhibitors, pembrolizumab
and nivolumab, have been approved by the US Food and
Drug Administration (FDA) for the treatment of patients with
advanced or metastatic urothelial carcinoma of the bladder
[105–108]. The clinical studies for the FDA approval showed
overall objective response rate (regardless of PD-L1 expres-
sion) of 13–24% [108].
Therefore, the next challenge will be to use the new thera-
pies for the trimodal approach.
The effect of combination of radiotherapy and checkpoint
inhibitors is investigated by studies. In a series of 10 patients
(2014 and 2016) Levy et al. analyzed the combination of
EXPERT REVIEW OF ANTICANCER THERAPY 1225
durvalumab, an antiprogrammed cell death ligand-1, and
radiotherapy in terms of safety, efficacy, and tumor growth
rate. In result, there was no unexpected adverse event. On 10/
15 in-field evaluable lesions, the objective response rate was
60%. All evaluated in-field lesions had a tumor growth rate
decrease resulting in a significant decrease in the tumor
growth rate between the two periods (before versus after RT;
P < 0.01). Overall, the combination therapy was well toler-
ated [109].
The NCT03150836 study, a Phase II multicenter study,
investigates the effect of a combination of radiation therapy
and anti-PD-L1 checkpoint inhibitor (durvalumab) with or
without anti-CTLA-4 inhibition (tremelimumab) in patients
with unresectable, muscular invasive or metastatic urothelial
carcinoma of the bladder that are ineligible or refusing
chemotherapy.
Another phase II study, that examines radiation therapy in
combination with pembrolizumab in patients with localized
urothelial carcinoma of the bladder cancer will start in May
2018 (NCT number NCT03419130).
The promising results of the new therapies suggest that
they will soon become part of trimodal therapy.
However, the challenge is to identify patients who are most
likely to benefit of these therapies. Toward this goal, validation
of clinical, molecular, and imaging biomarkers that serve for
prediction and monitoring of treatment response are of cen-
tral interest [110].
A promising approach is provided by molecular subtyp-
ing in muscle invasive bladder cancer. Seiler et al. [111]
investigated the ability of molecular subtypes to predict
pathological downstaging and survival after neoadjuvant
chemotherapy in a series of 343 patients. By using a single-
sample genomic subtyping classifier (GSC), it was shown
that luminal tumors had the best overall survival with and
without neoadjuvant chemotherapy. Claudin-low tumors
were associated with poor overall survival irrespective of
treatment regimen. Basal tumors showed the most
improvement in overall survival with neoadjuvant che-
motherapy compared with surgery alone. The authors of
the study concluded, that molecular subtyping may have
an impact on patient benefit to neoadjuvant chemother-
apy and if validated in additional studies, patients with
basal tumors should be prioritized for neoadjuvant che-
motherapy [111].
In addition to the possibility of highly efficient therapy, a
biomarker-based approach to identify patients with MIBC who
should undergo neoadjuvant chemotherapy, was shown to be
more cost-effective than unselected use of neoadjuvant che-
motherapy or radical cystectomy alone [112].
In addition to the exploration of molecular relationships,
the use of imaging techniques is indispensable for diagnosis
and treatment planning. Recently, the feasibility of noninva-
sively imaging the PD-L1 status of tumors by small-animal PET
studies was shown [113]. The early initiation of a specific
therapy should be possible by that approach.
Further studies are necessary to examine the molecular
structures of urothelial tumors and their targeted drug manip-
ulation in combination with improved imaging with the aim to
use their benefits in trimodal therapy.
1226 J. MATHES ET AL.
14. Five-year view
Advances in imaging, use of biomarkers, pharmaceutic and
radiotherapeutic enhancements enable the treatment of an
expanding spectrum of metastatic tumor diseases.
Therapeutic options for treatment of advanced or metastatic
carcinoma have been significantly improved by the introduc-
tion of check-point inhibitors. The use of checkpoint inhibitors
alone and in combination with other therapeutic methods in
the treatment of urothelial carcinoma is subject of ongoing
studies. A phase II trial that investigates the effect of neutron
radiotherapy with concurrent checkpoint inhibitor immu-
notherapy (Pembrolizumab) in patients with advanced urothe-
lial carcinoma started in June 2018 (NCT number:
NCT03486197). Based on promising data of targeted therapy
in treatment of other tumor entities, an increasing use in
combination with organ-preserving approaches is to be
expected. Consequently, the role of bladder-preserving ther-
apy in the treatment of metastatic urothelial carcinoma will
probably change and represent an alternative to radical,
organ-ablative surgical procedures in the future.
Key issues
● Radical cystectomy is the standard of care for patients with
muscle-invasive bladder cancer.
● Trimodal therapy is a combination of radical transurethral
resection of the bladder, radiation and (radiosensitizing)
chemotherapy using cisplatin or mitomycin C plus 5-
fluorouracil.
● Trimodal therapy is the most effective bladder-preserving
treatment regimen for selected patients with muscle-inva-
sive urothelial cancer of the bladder.
● Partial cystectomy can be used in very selected cases as an
alternative surgical method to transurethral resection of the
bladder.
● Trimodal therapy can be performed in split and continuous
courses. The basis of both approaches is maximal transure-
thral resection, followed by induction radiotherapy of the
whole bladder and pelvic lymph nodes with 40 Gy, followed
by consolidation radiation therapy of the bladder to 54 Gy
and the tumor bed to a total dose of 64 Gy.
● Controls via urine cytology and cystoscopic examination
with biopsy are performed after induction (split course) or
completion (continuous course) of trimodal therapy.
● In case of recurrence of noninvasive bladder cancer TURB
must be repeated in combination with intravesical therapy.
● In case of recurrence of a muscle-invasive bladder cancer,
radical cystectomy is indicated.
Funding
This paper was not funded.
Declaration of interest
A Stenzl reports acting as a consultant or member of the advisory board
for Ipsen Pharma, Roche, Janssen, Alere and Bristol-Myers Squibb. They
also report being a speaker on behalf of Janssen, Ipsen Pharma, Sanofi
Aventis, CureVac, and Astellas. A Stenzl also reports receiving institutional
funding from Johnson & Johnson, Roche, Cepheid, Amgen Inc, Bayer AG,
CureVac, Immatics Biotechnologies GmbH, Novartis AG and Karl Storz AG.
T Todenhoefer reports acting as a consultant for Ipsen Pharma and Roche
Pharma. The authors have no other relevant affiliations or financial invol-
vement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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