Tr i m o d a l i t y Th e r a p y i n

B l a d d e r Ca n c e r
Who, What, and When?
Christopher Premo, MDa, Andrea B. Apolo, MDb,
Piyush K. Agarwal, MDc, Deborah E. Citrin, MDa,*

KEYWORDS
 Radiation  Bladder preservation  Muscle-invasive bladder cancer  Chemoradiation
 Urothelial carcinoma of the bladder

KEY POINTS
 Bladder preservation with maximal transurethral resection of the bladder tumor (TURBT), concur-
rent chemotherapy, and irradiation can result in approximately 75% of long-term survivors main-
taining a functional bladder.
 The ideal patient for bladder preservation has a clinical T2 unifocal tumor, a visibly complete
TURBT, no carcinoma in situ (CIS), and no tumor-related hydronephrosis, with good pretreatment
bladder function.
 Participation in a bladder preservation approach requires a highly motivated patient who is a good
candidate for irradiation and chemotherapy and is committed to long-term cystoscopic
surveillance.

INTRODUCTION of these modalities; however, the best outcomes

have consistently been seen with trimodality ther-
An estimated 74,690 cases of urinary bladder can- apy (TMT) including maximal TURBT followed by
cer were diagnosed in the United States in 2014,1 concurrent chemoradiation. This review focuses
of which 30% will be muscle invasive. The current on TMT for bladder preservation and does not
standard of care for the treatment of muscle- detail other therapeutic combinations for bladder
invasive bladder cancer (MIBC) is neoadjuvant preservation.
cisplatin-based chemotherapy followed by radical Several prospective trials have been completed
cystectomy (RC) with pelvic lymph node dissec- evaluating TMT as a means of bladder preserva-
tion.2 In appropriately selected patients, bladder tion. The purpose of these studies has been to
preservation can be an effective alternative to define the rate of bladder preservation and survival
RC. The term bladder preservation can include with this approach and to improve the tolerability
TURBT, limited surgery, chemotherapy, radiation and efficacy of TMT regimens. This review
therapy, or various combinations of one or more

This research was supported by the Intramural Research Program of the National Institutes of Health, National
Cancer Institute.
Disclosures and conflicts of interests: The authors have no conflicts of interests or relationships to disclose.
urologic.theclinics.com

a
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 CRC, B2-3500,
Bethesda, MD 20892, USA; b Bladder Cancer Section, Genitourinary Malignancies Branch, Center for Cancer
Research, National Cancer Institute, National Institutes of Health, 10 Center Drive 12N226, MSC 1906,
Bethesda, MD 20892, USA; c Bladder Cancer Section, Urologic Oncology Branch, National Cancer Institute,
National Institutes of Health, Building 10, Room 2W-5940, Bethesda, MD 20892-1210, USA
* Corresponding author.
E-mail address: citrind@mail.nih.gov

Urol Clin N Am 42 (2015) 169–180

http://dx.doi.org/10.1016/j.ucl.2015.02.002
0094-0143/15/$ – see front matter Published by Elsevier Inc.
170 Premo et al

provides an overview of modern TMT bladder- radiotherapy (RT) dose is delivered before
preservation strategies, focusing on important response to therapy is assessed.
criteria for patient selection, the integration of
novel radiation techniques, commonly used and Completeness of transurethral resection of the
new chemotherapies for TMT, and the role of che- bladder tumor
moradiation for T1 disease. A pooled analysis of 314 patients treated on 6
RTOG trials found that a visibly complete TURBT
DISCUSSION was associated with a significantly higher rate of
Trimodality Therapy Treatment Approach CR to TMT on multivariate analaysis.3 Similarly,
the Erlangen series showed that completeness of
TMT includes the combination of maximal tumor resection after initial TURBT was an independent
debulking and concurrent chemoradiotherapy. predictor of CR.4 Likewise, a series of 348 patients
The optimal radiation target volume, radiation frac- from Massachusetts General Hospital found that
tionation, chemotherapy, and sequencing remain visibly complete TURBT was associated with
areas of active study. In general, the patient un- higher CR rates (79% with visibly complete TURBT
dergoes a maximal, preferably visually complete, vs 57% without).5 Thus, a visibly complete TURBT
TURBT, ideally with bladder mapping (Fig. 1), fol- is ideal. A less-than-complete TURBT is not an ab-
lowed by the delivery of cisplatin-based chemora- solute contraindication to bladder preservation, as
diotherapy to a dose of approximately 40 to 45 Gy. several trials have demonstrated acceptable CR
If no evidence of disease or minimal residual dis- rates without a visibly complete TURBT.
ease is noted at cystoscopic reassessment, the
final consolidative phase of chemoradiotherapy is Tumor stage
initiated. If progressive or unresponsive disease Most TMT trials include patients with clinical T2-
is found, therapy proceeds to RC. After comple- T4a disease. In RTOG 85-12, RTOG 88-02,
tion of therapy, patients are closely surveilled RTOG 97-06, and the Erlangen series, tumor stage
with cystoscopy and urine cytology. was not significantly associated with the rate of CR
to TMT on multivariate analysis.4,6–8 A pooled
Patient Selection analysis of 361 patients treated on RTOG trials
confirmed that T stage did not predict for the likeli-
Patient selection is a key component of bladder hood of CR to TMT on multivariate analysis.3 In
preservation (Table 1). Most criteria used to select contrast, increasing T stage is reproducibly asso-
appropriate patients for TMT predict for a high rate ciated with reduced long-term survival after
of response or the ability to safely tolerate therapy. TMT.4,5,9
Factors predicting for increased rates of distant In surgical series, the presence of prostate inva-
metastases are important for predicting overall sion by urothelial carcinoma is associated with a
survival (OS) after TMT. higher risk of lymph node metastases and reduced
A complete response (CR) to induction therapy 5-year survival.10 The decrement in survival is
with concurrent chemoradiation has typically greatest for patients with prostatic stromal inva-
been defined as negative results on urine cytologic sion or extraprostatic invasion compared with pa-
analysis, as well as no visible tumor and negative tients with more limited mucosal involvement.
results on biopsies at cystoscopy. Achieving a CR Patients with prostatic stromal invasion are
to induction therapy is required to avoid salvage excluded from many trials of TMT for bladder pres-
cystectomy and has been associated with ervation; however, prostatic urethral invasion is
improved disease-free and overall survival after not generally an exclusion criterion if it is amenable
TMT. The CR rate for patients with T2-T4a disease to visibly complete resection.
treated with TMT is approximately 70%.3 Factors Few data exist regarding the treatment of pa-
that may affect the likelihood of achieving a CR after tients with involved lymph nodes with TMT. These
TMT and should be considered when selecting pa- patients have in some cases been included in
tients include completeness of TURBT, tumor RTOG trials of TMT if the lymph nodes are located
stage, hydronephrosis, multifocality and CIS, and below the bifurcation of the iliac vessels. The pres-
baseline bladder function. It is important to ence of lymph node involvement is a poor prog-
consider that the rate of response to induction ther- nostic indicator in regards to OS, and in general,
apy may not always be known, as many recent tri- these patients are counseled to undergo neoadju-
als, such as bladder cancer 2001 (BC2001) and vant chemotherapy and RC.
Radiation Therapy Oncology Group (RTOG) 0926,
do not include cystoscopic reassessment after in- Hydronephrosis
duction. For these studies, careful patient selection Tumor-related hydronephrosis has been an exclu-
becomes increasingly important as a full sion criterion for several trials of TMT. RTOG 89-03
 Trimodality Therapy in Bladder Cancer 171

Fig. 1. Sequencing of trimodality therapy for bladder preservation. Patients undergoing TMT for bladder preser-
vation undergo a maximal TURBT followed by induction chemoradiation. Patients with a CR to induction therapy
proceed to consolidative chemoradiation, whereas evidence of progression results in immediate cystectomy.
Following therapy, a strict schedule of surveillance is undertaken. Evidence of invasive recurrence is treated
with cystectomy. Noninvasive recurrences are managed with TURBT and intravesicle therapy.

found CR rates with and without hydronephrosis to significantly associated with probability of distant
be 38% and 64%, respectively. A series from the metastases and death.7 Patients with tumor-
Massachusetts General Hospital found a CR rate related hydronephrosis are poor candidates for
of 52% in those with hydronephrosis and 77% in bladder preservation and are usually excluded
those without.11 Hydronephrosis not only predicts from trials of TMT.
for a reduced likelihood of CR but also is a predic-
tor for advanced stage and decreased survival. In Multifocality and carcinoma in situ
RTOG 89-03, the 5-year OS for patients with Multiple tumors or multifocal disease has been
and without hydronephrosis was 33% and suggested as a predictive factor for decreased
54%, respectively.12 Likewise, in RTOG 88-02, hy- response rates to TMT, and patients with these
dronephrosis was the only analyzed factor to be conditions are excluded from most trials of
172 Premo et al

Table 1
Patient selection for bladder preservation

Relative Absolute
Preferred or Ideal Less than Ideal Contraindications Contraindications
T2 T3a T3b-T4a T4b
No hydronephrosis Incomplete TURBT Diffuse CIS Tumor-Related
No CIS Multifocal tumor Lymph node positive Hydronephrosis
Visibly complete TURBT Poor bladder function disease Prior pelvic radiation
Unifocal tumor or capacity therapy
Good bladder function Not a candidate for
and capacity chemotherapy
Prostatic stromal
invasion

bladder preservation. Multifocality may not predict cisplatin (RTOG 9906).22,23 The RTOG 0233 trial
for lower rates of CR but is associated with a compared paclitaxel with cisplatin with 5-FU with
higher risk for local relapse.4 In general, TMT is cisplatin with concurrent radiation in patients
not advocated in those with diffuse multifocal with mostly T2 disease (95%).24 Following TMT,
disease. patients received adjuvant gemcitabine, cisplatin,
Similarly, the presence of extensive CIS before and paclitaxel. Both regimens showed similar
therapy has been associated with lower rates of rates of CR (62%–72%), 5-year OS (71%–75%),
CR to TMT and RT alone and higher rates of and 5-year survival with an intact bladder with
recurrence after TMT.13–16 A panel convened by moderate toxicity.
the Société Internationale d’Urologie suggested Candidates for TMT may have comorbidities that
that the presence of extensive CIS should be preclude the delivery of concurrent cisplatin, and
considered a relative and not absolute contraindi- several studies have evaluated alternative regi-
cation to TMT because the presence of CIS af- mens. The BC2001 trial tested the use of 5-FU
fects only the risk of recurrence after TMT and with mitomycin-C (MMC) concurrently with RT
not survival.17 with excellent response rates and impressive toler-
ability.19 This regimen is particularly useful in those
Baseline bladder function with renal dysfunction prohibiting the use of
The rationale of bladder preservation therapy is to cisplatin. Gemcitabine is a potent radiation sensi-
preserve a functional bladder. A subset of patients tizer and has shown activity in the setting of meta-
whose bladders are preserved with TMT may static urothelial cancers. The use of 100 mg/m2
develop symptoms such as urgency and control weekly gemcitabine during RT as a component of
problems.18 Therefore, baseline dysfunction in TMT was tested in a recently completed phase II
these areas should be considered when deter- trial.25 The regimen resulted in an 88% cystoscopic
mining if a patient is a candidate for TMT. response rate and a 3-year OS of 75%. Bowel
toxicity resulted in 4 of 50 patients stopping chemo-
Chemotherapy for Trimodality Therapy
therapy and in 1 late bowel resection. There were 2
Concurrent chemotherapy has been shown in ran- treatment-related deaths.
domized trials to improve local and regional con- Single-institution phase I data supporting twice-
trol compared with RT alone.19,20 Although these weekly gemcitabine concurrent with RT as part of
trials did not demonstrate an OS advantage with TMT are available. A study from the University of
the addition of concurrent chemotherapy, several Michigan of TMT with RT delivered to a total dose
large retrospective series have found concurrent of 60 Gy found the maximum tolerated dose of
chemotherapy to be associated with improved twice-weekly gemcitabine to be 27 mg/m2.26 Of
survival.9,21 Most bladder preservation trials using the 23 patients treated in this trial, 21 obtained a
concurrent chemoradiation have used cisplatin- CR. At a median follow-up of 43 months, 65% of
based chemotherapy regimens. Cisplatin-based patients were alive with no evidence of recurrence
combination regimens have been tested with and intact bladders. Twice-weekly low-dose gem-
the aim of improving response rates. The RTOG citabine (27 mg/m2) was compared with a regimen
has evaluated cisplatin-based chemotherapy of twice-daily irradiation with 5-FU and cisplatin in
combinations including cisplatin with 5-fluoro- the recently closed RTOG 0712 trial. Results for
uracil (5-FU) (RTOG 9506) and paclitaxel with this trial are pending.
 Trimodality Therapy in Bladder Cancer 173

The target volume of radiation is an important Radiation Techniques

consideration when comparing chemotherapy
RT is a critical component of TMT. A range of
regimens for bladder cancer. Some trials testing
doses of irradiation, fractionation schedules,
alternative regimens have evaluated bladder only
sequences of treatment, and treatment volumes
irradiation and have not included an initial pelvic
have been applied in the treatment of bladder can-
irradiation field.19 Thus, toxicity for these chemo-
cer. Attempts to improve RT have been geared
therapy regimens may be greater if extrapolated
toward enhancing bladder preservation rates while
to a setting in which a pelvic field is included.
minimizing the toxicity of therapy. Newer technol-
The use of neoadjuvant cisplatin-based chemo-
ogies, such as intensity-modulated radiotherapy
therapy in the setting of cystectomy has shown im-
(IMRT) and image-guided radiotherapy (IGRT),
provements in survival compared with cystectomy
are being integrated into the clinic. The authors
alone, likely through early treatment of micrometa-
outline general concepts regarding RT field design
static disease.27,28 As distant failure remains a
and discuss current areas of research in RT
concern after bladder preservation, this approach
technique.
has been tested in several trials of TMT. Unfortu-
The optimal volume of irradiation is one area of
nately, neoadjuvant or adjuvant chemotherapy
controversy. In most North American trials, treat-
with TMT has not improved survival or bladder
ment includes an initial course of RT to a total
preservation rates. However, the data available
dose of 39.6 to 45 Gy directed at the pelvic lymph
are limited to older regimens, with only 2 cycles
nodes below the bifurcation of the common iliac
of chemotherapy delivered instead of the standard
vessels, the prostate in men, and the whole
3 to 4, and many of these studies were underpow-
bladder (Figs. 2 and 3). A margin surrounding the
ered. As more effective chemotherapeutic regi-
bladder is included to account for daily variation
mens are developed, this strategy is likely to be
in bladder filling, visceral organ motion, and setup
further explored.29
error. To minimize the field size and to increase the
Targeted agents have been an area of interest in
reproducibility of daily treatment, patients are
efforts to improve TMT outcomes. The epidermal
simulated and treated with an empty bladder
growth factor receptor family of receptors has
(immediately postvoid) with a small amount of
been of particular interest in this regard. HER2/
bladder contrast.
Neu is overexpressed in bladder cancers, particu-
The rationale for including pelvic lymph nodes in
larly in metastatic or lymph node–positive tu-
the initial portion of the radiation treatment field re-
mors,30 and overexpression may be correlated to
lates to the high rate of occult lymph node involve-
worse outcomes after chemoradiotherapy.31
ment in regions typically targeted with pelvic RT33
These findings suggest that targeting HER2/Neu
and the finding that extensive lymphadenectomy
in the context of TMT may provide a therapeutic
at the time of RC improves survival, suggesting
opportunity. RTOG 0524 evaluated the addition
that treatment of these lymph nodes has therapeu-
of trastuzumab to paclitaxel and daily irradiation
tic efficacy.34 The rationale for not specifically tar-
following TURBT in the treatment of noncystec-
geting pelvic lymph nodes includes improving
tomy candidates with MIBC.32 The study has
tolerability of therapy by excluding more normal
been reported as an abstract and showed a favor-
tissue from the treatment volume and the low
able response rate but with an increase in hemato-
rate of nodal failure when not specifically targeted.
logic toxicity and other adverse events.

Fig. 2. Pelvic radiation field for bladder preservation. (A) Anterior-to-posterior and (B) left lateral field. The fields
extend from the top of the bifurcation of the iliac vessels to the bottom of the pelvis. The bladder (yellow) and
prostate (green) with margin are included in the target volume. Field edges are noted in yellow.
174 Premo et al

Fig. 3. IMRT for bladder preservation. A comparison of IMRT (left panels) and standard 4-field plan (right panels)
for treatment of the pelvis as a component of bladder preservation. The bladder and prostate (shaded yellow)
and lower pelvic lymph nodes (shaded green) are targeted. Radiation isodose levels are noted in the top left
and are represented by the corresponding colored line. Note the superior sparing of the rectum and nontarget
tissues with the IMRT approach.

A small, single-institution trial including patients volume of bladder receiving the higher doses of ra-
with T2-T4N0 disease treated with maximal diation, thus potentially reducing long-term urinary
TURBT followed by chemoradiation with weekly and gastrointestinal toxicity. Although the most
cisplatin randomized patients between whole- common approach is to treat only the residual tu-
pelvis RT versus bladder-only RT.35 At a median mor/tumor bed to the high dose of radiation
follow-up of 5 years, no difference in 5-year (w64 Gy) with partial bladder irradiation after deliv-
disease-free survival, bladder preservation rates, ery of approximately 54 Gy to the whole bladder,
regional nodal failure rates, or 5-year OS was this can be challenging for several reasons. For
observed. In the randomized BC2001 trial one, after complete TURBT, it can be difficult to
comparing irradiation alone with irradiation with know exactly where the pre-TURBT tumor was
chemotherapy, pelvic lymph nodes were not spe- located despite using the operative report and
cifically targeted, and pelvic relapses were seen in bladder mapping. In addition, targeting the region
only 5.8% of patients, suggesting that treatment of accurately can be difficult on a day-to-day basis,
the pelvic lymph nodes may not be necessary.19 as the bladder can have significant interfraction
Although the authors concluded that bladder- and intrafraction movement due to differences in
alone RT was as effective as whole-pelvis RT bladder filling, rectal volume changes, and other
with less toxicity in their trial, a randomized trial variations in organ motion.36,37 If a tumor bed
comparing these techniques directly is warranted. boost technique is used, accurate tumor delinea-
If the pelvic lymph nodes are irradiated, 1 or 2 tion and accurate treatment delivery are critical.
reductions in the size of the fields are performed Data supporting a more limited boost include
after the pelvic nodal portion of the treatment. A the BC2001 trial, in which 219 patients were ran-
further area of controversy and ongoing evolution domized to receive full-dose radiation to the
in treatment practices is the volume included in bladder alone versus 80% of the dose to the
the reduced treatment field, which may include bladder with full dose to the bladder tumor/tumor
the entire bladder for all or part of the treatment bed.19 There was no significant difference in
or only the tumor with margin. The rationale for us- toxicity or local control; however, the investigators
ing a tumor-only boost is the ability to reduce the concluded noninferiority of locoregional control
 Trimodality Therapy in Bladder Cancer 175

could not be concluded formally. Additional trials by allowing a reduction in the additional margin of
have demonstrated comparable control rates normal tissues that must be included to account
with RT directed at the tumor as opposed to the for setup error. The use of frequent 2-dimensional
whole bladder, suggesting that this approach or 3-dimensional imaging to align patients for daily
does not compromise tumor control.38,39 treatment is known as IGRT. IGRT can be accom-
plished with daily in-room computed tomographic
(CT) scanning (on-board imaging with cone beam
New Radiation Techniques
CT, Fig. 4) or daily imaging of fiducial markers im-
Recent advances in RT delivery have included the planted within or near the target volume (see
development of IMRT, in which the beam is modu- Fig. 3). Although fiducial markers have not been
lated over the course of the treatment, resulting in widely used in the treatment of bladder cancer,
improved conformality and a reduction in the Garcia and colleagues42 published their experi-
amount of normal tissues exposed to higher ence with fiducial marker placement in the bladder
doses. This technique has been adopted in a wall for daily localization. In this small series, fidu-
wide range of tumor types as a method to improve cial marker placement was feasible and associated
the conformality of treatment and reduce toxicity, with excellent retention and no complications.
and there have been some reports of the use of Alternatives to fiducial markers, such as lipiodol
IMRT for the treatment of bladder cancer.40,41 injections in the bladder wall, have also been
Although a reduction in toxicity that may be af- used to assist with accurate daily alignment.43
forded by IMRT is welcome, one of the concerns
using IMRT is the possibility of marginal misses
Outcomes of Trimodality Therapy
in regions where there can be considerable or-
gan/target motion. Thus, inclusion of advanced Although no randomized trials compare RC with
imaging techniques for daily radiation treatment bladder preservation in patients with MIBC, many
setup is encouraged if IMRT is used. trials, prospective and retrospective, show out-
The ability to accurately define the high-risk re- comes similar to those obtained after RC in regards
gion for a whole bladder and partial bladder boost to OS (Table 2). Following maximal TURBT, defini-
on a daily basis may improve normal tissue sparing tive treatment with concurrent chemoradiation

Fig. 4. Cone beam CT fused with a treatment planning image. A cone beam CT was obtained on a patient
receiving TMT to verify alignment before radiation treatment. In each panel, the cone beam CT image is in
the upper left and bottom right portion of the image and the planning CT image is in the upper right and lower
left portion. Note that image quality of cone beam CT is inferior to that of the diagnostic image. Overlay of the
images allows comparison of the anatomy between scans to verify alignment of bony and soft-tissue structures.
Transverse, sagittal, and coronal reconstructions are presented.
 176
Table 2

Premo et al
Prospective trails of bladder preservation

Bladder
Phase/ Radiation Neoadjuvant Concurrent Adjuvant Complete intact 5-y Overall
Trial Design Stage Number (Gy) Chemotherapy Chemotherapy Chemotherapy Response survival Survival Reference
BC2001 III T2- 360 55 of 64 5FU and 48% James
T4a Mitomycin et al,19 2012
RTOG Randomized T2-4a 93 40.3 1 24 Paclitaxel/ Cisplatin 72% Pac 67% 71% Mitin
02-33 phase II Cisplatin gemcitabine 62% 5FU paclitaxel paclitaxel et al,24 2013
5FU/Cisplatin paclitaxel  71% 5FU 75% 5FU
4
RTOG I/II T2- 80 40.3 1 24 Cisplatin 1 GC x 4 81 47% 56% Kaufman
99-06 T4a Paclitaxel et al,23 2009
RTOG I/II T2- 46 40.8 1 24 Cisplatin MCV x 3 74 47 (3 y) 61 (3 y) Hagan
97-06 T4a et al,6 2003
RTOG I/II T2- 34 24 1 40 Cisplatin 1 5-FU 67 66 (3 y) 83 (3 y) Kaufman
95-06 T4a et al,22 2000
RTOG III T2- 123 39.6 1 25.2 MCV  2 Cisplatin 61 36 49 Shipley
89-03 T4a None 51 40 48 et al,12 1998
RTOG II T2- 91 39.6 1 25.2 MCV  2 Cisplatin 75 44 (4 y) 62 (4 y) Tester
88-02 T4a et al,7 1996
RTOG II T2-T4 42 40 1 24 Cisplatin 66 52 Tester
85-12 et al (25)
Erlangan N/A T1-T4 415 Median 54 Various: 72 42 51% Rodel
(89 T1) (45-69.4) cisplatin, et al,4 2002
carboplatin,
cisplatin 1
5-FU
MGH N/A T2- 106 39.6 1 25.2 MCV  2 Cisplatin 66 43 52 Kachnic
T4a et al,11 1997
Paris N/A T2-T4 54 24 120 Cisplatin 1 5-FU 74 59 (3 y) Housset
et al (53)
Italy N/A T2-T4 121 Median 65 MCV  2 Cisplatin or 86 51 68 Perdona
(34-57) carboplatin et al,9 2008
Data from Refs.4,6,7,9,11,12,22–25,53
 Trimodality Therapy in Bladder Cancer 177

leads to a CR in approximately 70% of patients.3 CR. There are data to support that less than a
The 5-year OS and disease-specific survival with CR to a complete course of TMT is associated
TMT in a series of prospective RTOG trials were with worse outcomes despite immediate RC, sug-
57% and 71%, respectively.3 An intact bladder is gesting that reassessment after about 40 Gy is
preserved in approximately 80% of patients alive important to detect nonresponders.4,29
at 5 years after TMT.3 Both RTOG 99-06 and RTOG 02-33 allowed pa-
An important consideration is the ability of TMT tients with a near-CR, including Tis and Ta, at the
to preserve a functional bladder. Although data are time of assessment following induction therapy to
limited, single-institution studies suggest normal continue with definitive chemoradiation.23,24
bladder function in 75% of conserved bladders Among 119 patients in these trials, 85% achieved
as assessed by questionnaire and urodynamic a T0 CR and 15% achieved a Ta or Tis (near-CR).
studies.18 A series of 112 patients treated with This study was presented as an abstract49 and
TMT-based bladder preservation reported that showed that with a median follow-up of 5.9 years,
79% of survivors with an intact bladder were 36% of patients with T0 tumor versus 28% of pa-
delighted or pleased with urinary function.44 The tients with Ta or Tis tumor experienced a bladder
need for cystectomy to deal with complications tumor recurrence (noninvasive and muscle inva-
of RT is uncommon and ranges from 0% to 2% sive). Among 101 complete responders, 14 patients
in several series,3,4,44,45 although bladder contrac- eventually required RC for salvage, in comparison
ture not requiring cystectomy is reported in a sub- with 1 patient among 18 near-complete responders
set of patients. (P 5 .47). There was no difference in disease-
Other possible complications of TMT include specific, bladder-intact, or overall survival. The in-
gastrointestinal complaints and sexual dysfunc- vestigators concluded that it is appropriate to
tion. The rate of these complications varies recommend that patients with Ta or Tis tumor after
greatly by study, largely because of the method induction TMT continue with bladder preservation.
of collection of data. A review of late toxicity in The numbers of patients included in this series are
157 patients treated on RTOG trials who survived small, and confirmation will be useful.
at least 2 years from the initiation of treatment
found RTOG/EORTC (European Organisation for Trimodality therapy for refractory/recurrent T1
the Research and Treatment of Cancer) grade 3 disease
late genitourinary toxicity in 5.7% and RTOG/ Bladder-preservation trials have focused on pa-
EORTC grade 3 late gastrointestinal toxicity in tients with MIBC; thus, data supporting TMT for
1.9%.46 No grade 4 or 5 toxicities were reported T1 disease (lamina propria invasion) are limited.
in this series. Single-institution series using pa- Treatment of T1 tumors typically involves conser-
tient questionnaires have reported gastrointes- vative therapy with TURBT followed by intravesical
tinal complaints of any severity (10%–32% of bacillus Calmette-Guerin (BCG), with RC reserved
patients) and sexual dysfunction (8%–38%) in a for recurrent or refractory disease. Recent data
greater number of patients.18,47,48 indicate that concurrent chemoradiation may be
Posttherapy surveillance remains a critical an effective alternative to RC in patients with
component of bladder preservation with TMT. recurrent high-grade T1 tumors after failure of
Approximately 60% of recurrences after TMT are BCG treatment.50,51
CIS and arise at the site of the original invasive tu- One argument supporting the use of TMT for pa-
mor.16 The risk of noninvasive failure is higher in tients with refractory or recurrent high-grade T1
patients with a component of CIS in the original tu- bladder tumors is the high rate of clinical-
mor. Conservative management of these patients, pathologic stage discrepancy. As many as 46%
with TURBT and intravesicle therapy, is recom- of patients with T1 disease who undergo RC are
mended. Invasive recurrence is managed with upstaged pathologically at surgery.34 Given the
salvage cystectomy. high risk of occult MIBC in these patients, it has
been suggested that more aggressive treatment
with TMT may be warranted to avoid possible
Special Considerations
undertreatment.
Response after induction The University of Erlangen reported their experi-
The presence of a CR to induction TMT is associ- ence in 141 patients with high-risk T1 disease
ated with an excellent long-term likelihood of treated with bladder preservation as the initial
bladder preservation. Obtaining less than a CR af- treatment (80% received concurrent chemoradia-
ter induction therapy and undergoing immediate tion).50 About 60% had T1 grade 3 (T1G3) disease;
RC does not affect OS compared with those who the others were high risk because of multifocal dis-
require RC for late recurrences after achieving a ease or CIS. Overall, there was an 88% CR rate
178 Premo et al

and a progression rate of 19%. Of the patients with studies are most predictive of distant metastases
T1G3 tumors, the 10-year progression-free rate of and cause-specific survival, suggesting that they
the bladder tumor was 71% and 10-year disease- may have prognostic, not predictive, efficacy.31,53
specific survival was 70%. This result compares One notable exception is expression of Mre11,
favorably to most contemporary series of patients which is predictive for cause-specific survival after
with T1G3 treated with TURBT and BCG. radical RT.54 The identification of such markers
A multicenter trial conducted in the United may allow selection of therapy most appropriate
Kingdom evaluated whole-bladder radiation based on rates of expected control with each
versus conservative therapy (observation or BCG treatment option.
depending on risk factors) after visibly complete
TURBT in patients with previously untreated T1G3
bladder cancer to determine the efficacy of radia- REFERENCES
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vival, or OS. A complete TURBT was not required cer. J Natl Compr Canc Netw 2013;11:446–75.
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