Primary Bladder Preservation Treatment for Urothelial Bladder Cancer

Several approaches to muscleinvasive bladder cancer can
spare total bladder resection.
Michele R. Sassi. Traditional Fishing, Cochin, India. Photograph.
Primary Bladder Preservation Treatment for
Urothelial Bladder Cancer
Matthew C. Biagioli, MD, Daniel C. Fernandez, MD, PhD,
Philippe E. Spiess, MD, and Richard B. Wilder, MD
Background: Significant advancements have occurred in surgical procedures and chemoradiation therapy for
bladder preservation.
Methods: This review addresses primary treatment options for bladder cancer, including an overview of
bladder-sparing strategies.
Results: Surgical series demonstrate that highly selected patients with cT2N0M0 urothelial bladder cancers
can be managed with partial cystectomy and bilateral pelvic lymphadenectomy. For patients with cT2N0M0 to
cT4aN0M0 urothelial bladder cancers, neoadjuvant chemotherapy followed by radical cystectomy or maximal
transurethral resection of the bladder tumor (TURBT) followed by chemoradiation therapy results in equivalent
survival rates. However, each treatment option has a different impact on quality of life. Current chemoradiation
therapy trials are evaluating novel approaches to improve outcomes.
Conclusions: Maximal TURBT followed by chemoradiation therapy demonstrated equivalent survival with
radical cystectomy while preserving bladder function in the majority of patients. Future efforts will be directed
toward improving survival and quality of life.
Introduction
Radical cystectomy remains the mainstay of treatment
in patients with muscle-invasive urothelial bladder
cancer, with the primary goal of maximizing survival.
However, important secondary goals include minimizFrom the Radiation Oncology Program (MCB, DCF, RBW) and the
Department of Genitourinary Oncology (PES) at the H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Florida.
Submitted March 15, 2012; accepted October 2, 2012.
Address correspondence to Matthew C. Biagioli, MD, Radiation
Oncology Program, Moffitt Cancer Center, 12902 Magnolia Drive,
MCC-RAD ONC, Tampa, FL 33612. E-mail: Matthew.Biagioli@
Moffitt.org
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
188 Cancer Control
ing toxicity and maximizing quality of life (QOL). This
review article describes modern approaches to bladder
cancer, particularly bladder preservation strategies.
Epidemiology and Histology
Based on the 2012 estimates from the American Cancer Society, bladder cancer represents the fourth most
common cancer in men and the twelfth most common
cancer in women in the United States.1 The estimated
overall incidence of bladder cancer in the United States
for 2012 was 73,510 new cases involving 55,600 men
and 17,910 women.1 The median age at diagnosis is 65
years. There are 14,880 deaths per year in the United
States, of which 10,510 are men and 4,370 are women.1
The incidence and mortality rates per 100,000 persons
July 2013, Vol. 20, No. 3
are 31.1/12.1 among men and 9.5/4.5 among women.
The incidence among white men is twice that of African American men. Although bladder cancer incidence
rates are stable among men, they are increasing among
women by 0.2% per year. Alternatively, mortality rates
are stable in men, yet they have been declining in
women by 0.4% each year since 1986.1 The increasing incidence and decreasing mortality in women are
most likely due to greater early detection.2 However,
no major cancer group recommends screening the
general population for bladder cancer.
The majority of bladder cancer cases are urothelial
(transitional cell) carcinomas, representing 90% to
95% of all cases. Other histologies include squamous
cell carcinoma (1.5%), adenocarcinoma (1.2%), and
small cell carcinoma (< 1%).3 The vast majority of
nonsurgical trials have excluded patients with nonurothelial carcinoma.
patients (11%) were candidates for surveillance following TURBT.8 Of the 27 patients who opted for
surveillance, 15 developed subsequent recurrence,
with 8 undergoing radical cystectomy. Consequently,
TURBT alone is best suited to patients with noninvasive (cTa or cTis) disease. If there is an incomplete
resection or no muscle in the specimen, then a repeat
TURBT should be performed.
Staging
The seventh edition of the American Joint Committee on Cancer (AJCC) staging of bladder cancer uses
the tumor/node/metastasis (TNM) system.4 A total of
75% to 85% of bladder cancers are superficial (stages
pTa, pTis, and pT1), while 7% of patients present
with lymph node involvement, and another 4% present with distant metastases. Patients with papillary
carcinoma or in situ disease have a 5-year overall
survival (OS) rate higher than 85% compared with
14% for patients with node-positive disease.
Partial Cystectomy
Compared with radical cystectomy, removal of a
portion of the bladder may result in better retention
of sexual function. Optimal candidates for partial
(segmental) cystectomy are those who have solitary
lesions with focal muscularis propria involvement located either anteriorly or on the bladder dome where
a 1- to 2-cm resection margin is possible.9 Patients
should also have an absence of carcinoma in situ
secondary to an increased risk of recurrence.10 In
addition, Smaldone et al11 demonstrated that, in 25
highly selected patients who underwent partial cystectomy for solitary tumors, tumor size was significantly
associated with local recurrence. In appropriately
selected patients, partial cystectomy can result in longterm, bladder-intact survival rates ranging from 50%
to 75%.10-13 However, only 5% to 10% of patients with
cT1N0 to cT2N0 disease are candidates for this treatment. Bilateral pelvic lymphadenectomy should be
performed and minimally include common, internal,
and external iliac, and obturator nodes.
Transurethral Resection of Bladder Tumor
Limited research evaluates transurethral resection of
bladder tumor (TURBT) alone as curative treatment.
However, in select patients with small, solitary tumors
with focal invasion into the muscularis propria, longterm, bladder-intact survival rates of 60% to 70% have
been reported.5-8 A large retrospective series of 432
patients referred for definitive management of muscle-invasive disease evaluated 151 patients who, after
maximal TURBT, had either no residual or T1 stage disease.7 Ninety-nine patients were managed with active
surveillance and 52 underwent radical cystectomy. The
10-year disease-free survival (DFS) rate was equivalent
between the two groups, and 57% of those managed
with surveillance retained their bladders. A subsequent
phase II prospective trial of 133 patients treated with
radical TURBT alone was performed.5 The inclusion
criteria required no residual tumor after TURBT (T0),
negative repeat biopsies of the tumor bed, and absence
of hydronephrosis. In addition, the majority of patients
had unifocal disease and no evidence of carcinoma in
situ. The researchers found 10-year OS and bladderintact survival rates of 79% and 65%, respectively.
Despite these encouraging results, a separate
retrospective review of 327 patients found that 35
Neoadjuvant Chemotherapy Followed by
Partial Cystectomy or Transurethral Resection
of Bladder Tumor
The Medical Research Council (MRC) and Southwest
Oncology Group (SWOG) trials evaluating neoadjuvant cisplatin-based chemotherapy prior to cystectomy
demonstrated a survival advantage in patients with
pT2N0 to pT4aN0 urothelial bladder cancers.14,15 Some
of the patients who received neoadjuvant treatment
had complete responses at the time of cystectomy.
Consequently, it may be possible to perform partial
cystectomy on these patients with similar oncological
results as radical cystectomy but with less functional morbidity. In a prospective trial, Sternberg et al16
evaluated 104 patients with muscle-invasive disease
who underwent 3 cycles of methotrexate, vinblastine,
doxorubicin, and cisplatin (MVAC) chemotherapy followed by TURBT alone (n = 52), partial cystectomy
(n = 3), or radical cystectomy (n = 39) based on the
response to neoadjuvant chemotherapy. Of the 52
patients who underwent TURBT alone, 29 had either
a pathological complete response (pT0) or superficial
disease after chemotherapy. In addition, 44% maintained an intact bladder, with a 5-year OS rate of 67%.
In a separate study of 111 candidates for cystectomy
July 2013, Vol. 20, No. 3
Cancer Control 189
with cT2 to cT3 disease who had undergone neoadjuvant MVAC chemotherapy, 60 were found to have a
complete response (pT0) on restaging TURBT.17 Of
these 60 patients, 43 had bladder-sparing surgery and
17 underwent radical cystectomy. The 10-year OS rate
for the 43 patients who underwent partial cystectomy
was 74% compared with 65% in the radical cystectomy
group. In the bladder-sparing group, 40% of patients
ultimately underwent cystectomy, due in part to the
limitations of restaging TURBT in determining the full
extent of disease in the bladder.
In the SWOG S0219 trial, 46% of the 74 evaluable
patients who received 3 cycles of neoadjuvant paclitaxel, carboplatin, and gemcitabine chemotherapy for cT2
to cT4a bladder cancer had a pathological complete
response on restaging TURBT.18 Of these 34 patients,
10 underwent immediate cystectomy. Six of the 10
patients who underwent cystectomy had persistent
muscle-invasive disease despite a negative restaging
TURBT. Although this study did not include cisplatin
chemotherapy, neoadjuvant chemotherapy and TURBT
are typically reserved for patients with extensive comorbid disease or a poor performance status.
Radiation Therapy
Predating the use of concomitant chemoradiation
therapy, patients with muscle-invasive bladder cancers
deemed inoperable or those who were nonsurgical
candidates secondary to comorbidities were treated
with radiation therapy alone. Currently, radiation
therapy is rarely used by itself in the definitive management of bladder cancer in the United States except
in rare cases of inoperable patients with cT2N0 to
cT3N0 disease and extensive comorbid disease or a
poor performance status in which chemotherapy is
not possible. More commonly, radiation therapy alone
is used to palliate metastatic disease in cases where
chemotherapy is not possible.
Few contemporary, large prospective trials have
been conducted involving radiation therapy alone
for bladder cancer. Rather, most studies of external
beam radiation therapy are retrospective analyses
from single institutions, and they describe varying
techniques. Outcomes with radiation therapy alone
are inferior to those with surgery. Radiotherapy alone
results in 5-year OS rates of 20% to 50% and local
control rates of approximately 50% to 60%.19-22 In
the 1970s, preoperative radiation therapy appeared
to provide a benefit as demonstrated by pathological downstaging in a subset of patients with muscleinvasive bladder cancer.23,24 However, subsequent
randomized trials demonstrated no benefit in OS rates
when compared with radical surgery alone; moreover, the use of preoperative radiation complicated
the urinary diversion reconstruction.25,26 Randomized
trials have demonstrated the inferiority of radiation
190 Cancer Control
Table 1. — Selected Patients Treated With
Bladder Preservation Treatmenta
Complete
Response
(%)
5-yr
Overall Survival
(%)
Radiotherapy29
57
47
Radiotherapy + cisplatin27
85
69
Radiotherapy + carboplatin28
70
57
Treatment
a
Treatment was radiotherapy alone or a platin derivative concurrently
with radiotherapy.
therapy alone compared with chemoradiation therapy
both in tumor response and in OS rates (Table 1).27-29
In a phase III randomized trial performed by James
et al29,30 the 2-year locoregional DFS rate for those
receiving radiation therapy alone was 54% compared
with 67% for those receiving chemoradiation therapy
(P = .02). The chemoradiation therapy results were
superior, even though cisplatin-based chemotherapy
was not used. In addition, the 5-year OS rates were
48% and 35% in the chemoradiation and radiationalone arms, respectively.
For patients treated with radiation therapy alone,
radiation doses in the range of 50 to 70 Gy, given
in daily fractions of 1.8 to 2.5 Gy for 4 to 7 weeks,
were used to treat the entire bladder and draining
lymph nodes. Dose and fractionation in some of these
studies were considered inadequate by current standards and resulted in 5-year OS rates of 10% to 40%.31
Factors contributing to these disappointing survival
rates include failure to define the true extent of the
tumor because of inadequate staging techniques, the
inclusion of patients with a poor prognosis (patients
treated with radiation therapy alone tend to have extensive comorbid disease or poor performance status),
and the fact that most patients with high-grade, locally
advanced bladder cancers have already developed
occult metastases by the time of initial presentation.32
Radical Cystectomy With or Without
Neoadjuvant Chemotherapy
Radical cystectomy involves the removal of the bladder, prostate, seminal vesicles, proximal vas deferens,
and proximal urethra in men. By contrast, anterior pelvic exenteration involves removing the anterior vaginal
wall, the bladder, ovaries, fallopian tubes, and urethra
in women. Both of these surgeries are typically performed with a pelvic lymphadenectomy. Ileal conduit, orthotopic neobladder, and continent cutaneous
reservoir are all options for urinary diversion. These
operations can be performed open, laparoscopically,
or with a robotic-assisted laparoscopic approach.
Several large series have evaluated the long-term
results of radical cystectomy (Table 2).15,33-37 A series
July 2013, Vol. 20, No. 3
of 181 patients with pT2 to T4a disease demonstrated
a 5-year OS rate of 36%.33 Stein et al34 published an
evaluation of 633 patients with pT2 to T4a disease
and reported 5- and 10-year OS rates of 48% and
32%, respectively. For T2, T3a, T3b, and T4a disease,
the 10-year recurrence-free survival rates were 87%,
76%, 61%, and 45%, respectively, for node-negative
patients and 50%, 37%, 29%, and 33%, respectively,
for node-positive patients. Similarly, Madersbacher
et al38 found a 5-year recurrence-free survival rate of
73% for pT2N0M0 disease and 56% for disease stages
higher than pT2N0M0 compared with 33% for pT1 to
T4 node-positive disease. Five-year OS rates for these
three groups were 62%, 49%, and 24%, respectively.
The worst recurrence-free and OS rates in patients
with higher pathological T stage and node-positive
invasive bladder cancer have been attributed to microscopic metastases at the time of surgery. Micrometastatic disease is found in regional lymph nodes
in 25% of patients undergoing radical cystectomy.
If the tumor has invaded into the perivesicular fat
(pT3), that risk increases to 50%.39 Once metastatic
disease is identified, median survival is 6 to 9 months.
Due to this risk of microscopic disease, neoadjuvant
cisplatin-based chemotherapy prior to radical cystectomy was evaluated.
Griffiths et al14 published long-term results of
the MRC international randomized trial, BA06 30894,
and evaluated 3 cycles of neoadjuvant methotrexate,
vinblastine, and cisplatin chemotherapy or no neoadjuvant therapy prior to either surgery or radiation
therapy for muscle-invasive urothelial carcinoma. A
total of 976 patients were recruited between 1989
and 1995. At a median follow-up of 8 years, the
investigators found a statistically significant 16% reduction in the risk of death (hazard ratio [HR], 0.84;
95% confidence interval, 0.72–0.99; P = .037) in favor
Table 2. — Long-term Survival in Selected Studies of
Radical Cystectomy and Bladder Preservation
Reference
Stage
No. of
Patients
Overall Survival (%)
5-yr
10-yr
Radical Cystectomy
Stein34
pT2–pT4a
633
48
32
Dalbagni33
pT2–pT4a
181
36
27
Grossman15
cT2–cT4a
307
50
34
Bladder Preservation
Rödel35
cT2–cT4a
326
45
39
Efstathiou36
cT2–cT4a
348
52
35
Shipley37
cT2–cT4a
123
49
N/A
N/A = not applicable.
July 2013, Vol. 20, No. 3
of neoadjuvant treatment. This risk reduction corresponded to an increase in 10-year survival rates from
30% to 36%. A similar trial, SWOG 8710 (INT-0080),
was initiated in 1987.15 A total of 317 patients with
pT2N0 to T4aN0 bladder cancer were randomized to
cystectomy or 3 cycles of MVAC followed by cystectomy. The investigators observed a median survival
rate of 46 months in patients treated with surgery
alone compared with 77 months for those treated
with neoadjuvant MVAC followed by surgery, resulting
in a disease-specific HR of 1.66 (P = .002) favoring
neoadjuvant MVAC. Despite two large randomized
trials showing a significant decrease in death due
to pT2N0 to T4aN0 urothelial bladder cancer with
cisplatin-based neoadjuvant chemotherapy, this approach was not widely adopted. In an evaluation
of the Surveillance, Epidemiology, and End Result
(SEER) registry, Schrag et al40 found that 11% of the
4,664 patients with stage III disease recorded in the
SEER registry between 1991 and 1999 received perioperative chemotherapy. A multi-institutional trial
conducted from 2003 to 2008 with 15 participating
institutions found that 34% of patients received perioperative chemotherapy41; however, 11% received
neoadjuvant cisplatin-based chemotherapy as supported by the MRC and SWOG trials.
Maximal Transurethral Resection of
Bladder Tumor Followed by Concurrent
Chemotherapy and Radiotherapy
Rationale
The rationale for the addition of chemotherapy to
radiation therapy is based on four main premises.
First, clinical and autopsy data indicate that micrometastases are often present concurrently with invasive
bladder cancer. One study reviewed the autopsies of
367 individuals with invasive bladder cancer and identified distant metastases in 68% of these cases.42 The
frequencies of metastases increased with tumor stage
(pT2, 36%; pT3a, 45%; pT3b, 69%; and pT4, 79%),
supported by the high probability of subsequent distant metastasis after cystectomy or radiation therapy
alone of approximately 50% at 2 years.34 Therefore,
it is logical to assume that chemotherapy coupled
with radiation therapy may reduce the likelihood of
distant failure by eradicating occult micrometastatic
disease. Second, the optimal time to treat potential
micrometastatic cells is during radiation therapy and
before the appearance of gross metastatic disease.
Third, radiotherapy can induce vascular sclerosis over
a period of months to years, thus reducing access of
chemotherapeutic agents to tumors at later times.43
Fourth, certain conventional chemotherapy drugs
such as 5-fluorouracil (5-FU), cisplatin, gemcitabine,
and paclitaxel act as radiosensitizers that render cancer cells more sensitive to radiation therapy.44
Cancer Control 191
Early Experiences
One of the earliest experiences using a combined modality approach occurred during the 1980s. Researchers treated patients with muscle-invasive bladder cancer
with maximal TURBT followed by cisplatin and 5-FU
chemotherapy concurrently with an accelerated course
of radiation therapy.45 Patients received doses of 24
Gy twice daily in 8 treatments over 17 days. Biopsies
were performed 6 weeks later. If no residual disease
existed, then the patients continued chemoradiation
therapy with an additional 8 doses of 20 Gy twice daily.
Patients with residual carcinoma following the initial
24-Gy dose subsequently underwent cystectomy. The
first 8 patients without residual tumor on repeat cystoscopy with biopsies underwent cystectomy. The pathological complete response in these patients was 100%,
thus supporting bladder preservation. The 5-year OS
rate in patients who were complete responders with
bladder preservation was 63%.45,46 In addition, no difference existed in OS rates in complete responders to
chemoradiation therapy with or without cystectomy.
Between 1980 and 1985, Shipley et al47 used a
bladder-sparing approach to treat 70 patients with
cT2 to cT4a muscle-invasive bladder cancer who were
not surgical candidates. Patients received cisplatin
chemotherapy concurrently with split-course radiation therapy using fields based on each patient’s bony
anatomy rather than bladder plus nodal anatomy or
bladder anatomy alone. Cystoscopy, cytology, and
rebiopsy were performed 2 to 3 weeks into the treatment break to direct further therapy. Patients in
whom repeat biopsy revealed persistent tumor invasion into or beyond the lamina propria (≥ T1 disease)
underwent radical cystectomy, whereas patients who
had T0 or Ta disease underwent consolidation therapy
consisting of an additional dose of cisplatin and radiotherapy to the tumor using a 2.0- to 2.5-cm margin
to the block edge to a total dose of 64.8 Gy. Normal
areas of the bladder were excluded from the high-dose
volume for the 25.2 Gy radiotherapy boost. In the 62
patients who completed the full course of induction
and consolidation chemoradiation therapy, the complete response rate was 77%. Among the complete
responders, the 4-year OS rate was 57%.
In another study, German patients were treated
with radiation therapy and, after 1986, chemoradiation
therapy.48 A total of 415 patients were treated with a
radiation dose of 54 Gy. Those who had a cystoscopic
complete response were observed while those who
did not underwent salvage radical cystectomy. The
clinical complete response rate was approximately
85% in patients receiving chemoradiation therapy.
The 5-year OS rate in patients concurrently treated
with cisplatin-based chemotherapy and radiation
therapy was approximately 63%. The European and
American experiences helped to define the current
192 Cancer Control
multimodality approach of maximal TURBT followed
by cisplatin-based chemotherapy concurrently with
radiation therapy.47,48
Modern Approaches
Although radical cystectomy remains the standard
of care for muscle-invasive urothelial cancers, many
patients are not candidates for curative surgery due
to advanced age, poor nutrition, multiple comorbidities, or loss of cognitive function. In addition, some
patients refuse to undergo surgery and instead opt for
a bladder-sparing approach. Although bladder preservation strategies have often been perceived to result
in inferior survival compared with radical cystectomy,
no randomized trials support this bias. Five-year DFS
rates of 61% to 71% have been achieved in appropriately selected patients who retain their bladders with
modern bladder preservation approaches.
In general, patients with a solitary, clinical T2 to
T4a transitional cell carcinoma smaller than 5 cm, with
a Zubrod performance status of 0 to 1, a visibly and
microscopically complete TURBT, absence of ureteral
obstruction, and negative nodes (patients with radiographically positive nodes should have negative nodes
by needle biopsy) are eligible for bladder preservation.49 Moreover, patients should have no associated
carcinoma in situ, have a normally functioning bladder, and be amenable to lifelong bladder surveillance
with prompt salvage cystectomy if local recurrence is
present.31 The completeness of the TURBT is one of
the strongest prognostic factors for OS.50 Patients with
hydronephrosis, distant metastases, white blood cell
counts below 4,000, absolute neutrophil counts below
1,800, hemoglobin levels below 10.0, platelet counts below 100,000, creatinine clearances below 60 mL/minute,
serum creatinine levels above 1.5, serum bilirubin levels
above 2.0 mg, or a history of prior pelvic radiotherapy
are suboptimal candidates for a bladder-sparing treatment approach. Ideal candidates for bladder-sparing
chemoradiotherapy are summarized in Table 3.
Table 3. — Ideal Candidates for Trimodality Bladder Preservation
American Joint Committee on Cancer tumor stage T2–T3a, N0, M0
No hydronephrosis or disease near ureteral orifices
No involvement of bladder trigone
Unifocal disease, absence of extensive invasive tumor-associated
Tis stage
Status post visibly and microscopically complete transurethral
resection of the bladder tumor
Zubrod performance status ≤ 1
No contraindications to concurrent chemotherapy
Good pretreatment bladder capacity and function
Understanding and acceptance by the patient regarding lifelong
bladder surveillance with prompt salvage cystectomy if local
recurrence is detected
No prior pelvic radiotherapy
July 2013, Vol. 20, No. 3
To keep radiotherapy field sizes as small as possible, patients should be simulated and treated to the
whole bladder plus pelvic nodes or the whole bladder
alone to between 39.6 Gy in 22 fractions and 50.4 Gy
in 28 fractions with the bladder empty. The rectum
should also be empty during simulation to maximize
reproducibility of rectal volumes during treatment.
Chemotherapy (eg, cisplatin on weeks 1 and 4) is
given concurrently as a radiosensitizer with ≥ 10 MV
external beam radiotherapy. In patients with low
or moderate renal function, 5-FU and mitomycin C
or paclitaxel chemotherapy can be used in place of
cisplatin. In general, patients should be treated with
four, not two, radiotherapy fields if three-dimensional
conformal radiation therapy (3D-CRT) is used.51 Intensity-modulated radiation therapy (IMRT) reduces
the radiation dose delivered to adjacent normal organs
such as the rectum relative to 3D-CRT.52 With IMRT,
the bladder with or without adjacent lymph nodes
(initial clinical target volume) can be contoured on a
treatment-planning computed tomographic scan and
used instead of bony anatomy to determine radiotherapy field borders. A 2.0- to 2.5-cm margin is
created in all directions on the initial clinical target
volume for the initial planning target volume. A 0.5to 0.7-cm margin beyond the planning target volume
is added for penumbra. Patients should be treated
to a cumulative radiation dose between 63.0 Gy in
35 fractions and 66.6 Gy in 37 fractions. The more
recent use of continuous-course chemoradiation seen
in Radiation Therapy Oncology Group (RTOG) protocol 05-24, rather than the more traditional split-course
chemoradiation, may help improve outcomes by not
providing tumor cells with the time to repopulate
during a planned treatment break.53
Close coordination among all specialties is required
to achieve optimal results with bladder preservation.
Radiotherapy predominantly causes genitourinary (eg,
urinary frequency, burning) and gastrointestinal (eg,
diarrhea) acute toxicity, and cisplatin-based chemotherapy mainly causes hematological (eg, neutropenia, anemia, thrombocytopenia), gastrointestinal (eg,
nausea, vomiting), and neurological (eg, paresthesias,
sensory ataxia, loss of vibration sense) acute toxicity.54
The incidence of significant late pelvic toxicity
with a bladder-sparing approach is low. On RTOG
protocols 89-03, 95-06, 97-06, and 99-06, the incidence of late grade 3 genitourinary and gastrointestinal toxicities was 6% and 2%, respectively, based on
a median follow-up of 5 years (range, 2 to 13 years).55
Late grade 3 toxicity persisted in 1 of the 9 patients.
No patients experienced late grade 4 or 5 toxicity.
None of the clinical variables studied predicted for
late toxicity. QOL and quality of bladder function
were satisfactory in 67% of patients who underwent
bladder preservation.56
July 2013, Vol. 20, No. 3
Results
During the past two decades, bladder preservation has
been investigated in prospective series from single
centers and cooperative groups, with more than 1,000
patients with transitional cell carcinoma provided with
treatment. Complete response rates have ranged from
47% to 87%, and 5-year OS rates have ranged from
30% to 70%. Three- to 5-year survival rates with an
intact bladder have ranged from 37% to 66%.27,30,47,54,57-61
Level 2 evidence suggests that the outcomes with
chemoradiation may be better than those with external
beam radiotherapy alone, realizing that selection bias
may play a role in these findings.35,56,62 The incidence
of acute grade 3/4 toxicity with cisplatin-based chemotherapy and concurrent radiotherapy has ranged
between 20% to 25%. Selected bladder preservation
trials are presented in Table 4.27,30,47,54,57-61
There are no data from randomized trials to allow
a level 1 evidence comparison between radical cystectomy and chemoradiation.
Controversies Regarding Primary Treatment
of Muscle-Invasive Urothelial Carcinoma
of the Bladder
Radical cystectomy remains the standard of care in
the United States for the primary treatment of muscleinvasive urothelial bladder cancer in patients who are
medically operable. However, prospective results from
multi-institutional bladder preservation trials suggest
that this is also a reasonable approach. Table 3 shows
equivalent long-term survival with radical cystectomy
compared with bladder preservation.15,33-37 When comparing studies of each approach, there are two main
caveats. First, surgical series involve pathologically
staged tumors as opposed to clinically staged tumors
in the chemoradiation trials, favoring the surgical series because many cancers are upstaged at the time
of surgery. Second, retrospective radical cystectomy
series do not report an intent-to-treat analysis, which
is in contrast to prospective chemoradiation trials.
Randomized trials comparing these two treatments
are unlikely to be forthcoming in the near future and
are based, in part, on physician biases.31
Inappropriate surgical candidates include patients
who have poor nutrition, high anesthesia risk, multiple
comorbidities, and loss of cognitive function. However, age alone should not necessarily rule out surgery
because the rates of major and minor surgical complications are no different in patients with bladder cancer
who are 80 years of age compared with those who
are younger.63 Treatment decisions should be based
on patient preferences and an understanding of the
QOL issues associated with each treatment modality.
Quality of Life
For patients undergoing radical cystectomy, three surCancer Control 193
gical urinary reconstructions have been developed to
eliminate urine. Typically, the preferred method is to
construct an orthotopic neobladder. In this procedure, a neobladder is created from the small bowel
and subsequently connected to the ureters and urethra
in an attempt to maintain continence via the urethra.
Urination is performed similarly to an intact bladder,
although catheterization of the urethra is sometimes
necessary for emptying. A second approach is an ileal
conduit (urostomy) in which the bladder is removed
Table 4. — Selected Studies of Bladder Preservation
Reference
Study Phase
(No. of
Patients)
Clinical
Tumor
Stage
Shipley47
II (70)
T2–T4
64.8 Gy
45 Gy pelvis plus 19.8 Gy boost
plus cisplatin
CR: 70%
4-yr OS: 35%
4-yr OS advantage for CR: 57% vs 11%;
P < .01
73% bladder preservation
24
Tester58
II (42)
T2–T4
64 Gy (40 Gy pelvic field; if
CR: 24 Gy boost) plus cisplatin
on weeks 1 and 3
CR: 67%
3-yr OS: 64%
40% bladder preservation with CR
12% bladder preservation with
superficial recurrence treated with
TURBT + Bacillus-Calmette-Guérin
26% cystectomy rate
36
Coppin27
III (99)
T2–T4b
60 Gy (40 Gy pelvis plus 20 Gy
tumor boost) with or without
cisplatin on weeks 1, 3, and 5
CR: 47% (CRT) vs 31% (RT); P = .16
3-yr OS: 47% (CRT) vs 33% (RT); P = .34
Better pelvic PFS with CRT (P = .038)
At 5 yrs, 7/8 CRT patients with CRT had
intact bladder vs 3/7 RT patients (P = .2)
78
Chauvet59
II (109)
T2–T4
60 Gy (40 Gy pelvic field plus
20 Gy tumor boost) with or
without cisplatin on weeks
1 and 5
CR: 65%
4-yr survival: 41.9% for all patients,
51.4% for CR patients
4-yr locoregional control rate: 47.6% for
all patients, 61.2% for patients with CR
4-yr survival with intact bladder: 37%
55
Kaufman60
I/II (34)
T2–T4a
24 Gy in 3 Gy fx twice daily on
days 1, 3, 15, and 17 to pelvis
plus 5-FU/cisplatin
If CR: additional 20 Gy in 2.5 Gy fx
twice daily boost with 5-FU/cisplatin
on weeks 1 and 3; higher biologically
effective dose overall
CR: 67%
3-yr OS: 83%
3-yr survival with intact bladder: 66%
29
Hagan54
I/II (52)
T2–T4a
64.8 Gy (44 Gy to pelvis twice daily;
if CR: additional 24 Gy)
RT with cisplatin weeks 1–3,
followed by adjuvant methotrexate,
cisplatin and vinblastine for 3 cycles
CR: 74%
3-yr OS: 61%
3-yr survival with intact bladder: 48%
20% acute grade 3 and 4 toxicity with
induction CRT
26
Gogna57
II (113)
T2–T4
63–64 Gy RT and weekly cisplatin
CR: 70%
5-yr OS: 50%
Salvage cystectomy: 13%
Survival with intact bladder: 61%
60
Kaufman61
I/II (50)
T2–T4a
64.3 Gy RT (40 Gy days 1–5, 8–17
twice daily) with weekly cisplatin
plus paclitaxel
If CR: additional 24 Gy with weekly
cisplatin plus paclitaxel, followed by
adjuvant gemcitabine and cisplatin
CR: 87%
5-yr OS: 56%
5-yr disease-specific survival: 71%
26% acute grades 3 and 4 toxicity
with induction chemoradiation
49
III, 2 × 2 factorial
(360)
T2–T4
55 Gy in 20 treatments vs 64 Gy
in 32 treatments with (n = 178)
or without (n = 182) 5-FU and
mitomycin C
RT alone vs CRT: 5-yr OS: 35% vs 48%
2-yr bladder preservation: 83% vs 89%
2-year locoregional relapse-free survival:
68% vs 82%
James30
RT and CT Following
Maximal TURBT
Outcomes
Median
Follow-up
(mos)
69.9
5-FU = 5-fluorouracil, CR = complete response, CRT = conformal radiation therapy, CT = computed tomography, fx = fractions,
OS = overall survival, PFS = progression-free survival, RT = radiation therapy, TURBT = transurethral resection of the bladder tumor.
194 Cancer Control
July 2013, Vol. 20, No. 3
or bypassed and a conduit is constructed of small
bowel or colon that carries urine to an opening on the
abdominal wall. The urine is collected in a drainable
pouch secured to the abdomen. A third approach involves a continent urinary diversion. This reconstruction involves the creation of an internal pouch from
loops of the intestine connected to the abdominal
wall. There is a “one-way” passage between the opening on the abdominal wall (stoma) and the internal
pouch so that urine is contained within the pouch.
Urine is drained by passing a catheter through the
stoma and into the pouch every 3 to 4 hours.
Several QOL studies have evaluated these reconstructive methods. A study in Japan assessed 85 patients following radical cystectomy, 48 with an orthotopic neobladder (26 with an ileal neobladder and 22
with a colon neobladder) and 37 with an ileal conduit.64
QOL was evaluated using the Short Form-36 survey that
contains 36 questions assessing physical functioning,
role-physical functioning, bodily pain, general health,
vitality, social functioning, role-emotional functioning,
and mental health. No significant difference existed
in any scale scores between the neobladder and ileal
conduit groups. However, general health and social
functioning in both the neobladder and ileal conduit
groups were significantly lower than those in the United States general population. Another study evaluated
QOL in 49 neobladder and 23 ileal conduit patients.65
The researchers found on multivariate analysis that
no significant difference was present in QOL between
the two groups (P = .09). A third study evaluated 224
patients following radical cystectomy and also found
no difference regarding the type of diversion used.66
In addition to urinary function, erectile function
is a major concern following radical cystectomy. One
study evaluated 49 sexually active men who underwent radical cystectomy; 33% of those had undergone
a nerve-sparing procedure.67 With a median followup of 47 months, the mean sexual health inventory
scores decreased from 22 to 4 (P < .05), with 86% of
men unable to perform vaginal penetration. This is
supported by a Swedish cross-sectional comparison
study that found 13% of patients receiving radical
cystectomy had intercourse in the previous month
compared with 38% of patients receiving chemoradiation therapy.68 In an Italian series, 8% of patients who
underwent radical cystectomy had erectile function.69
This is in contrast to a Massachusetts QOL study of
chemoradiation therapy that revealed that 8% of men
reported dissatisfaction with their sex lives and 50%
of men had normal erectile function.70
Toxicity
A surgical series involving 1,142 patients reported
that 64% of patients had more than one complication
in the 90 days following surgery.71 Of those patients,
July 2013, Vol. 20, No. 3
13% had major complications (grades 3 to 5). In addition, the readmission rate was 26% with a 90-day
mortality of 2%. The perioperative morbidity and
mortality rates of salvage cystectomy after previous
bladder chemoradiation therapy were no different
from primary cystectomy.72
A major criticism of maximal TURBT followed by
chemoradiation therapy is that the preserved bladder ultimately becomes a poorly functioning bladder.
However, a group in Massachusetts published results
of QOL and urodynamic studies on 71 patients with
intact bladders after chemoradiation therapy.70 With a
median follow-up of 6.3 years, they found that 75% of
patients had normally functioning bladders based on
urodynamic studies, and 85% reported no urgency or
occasional urgency. In addition, 22% had a reduced
bladder capacity, with 7 of the patients reporting significant symptoms. Efstathiou et al55 published late
pelvic toxicity from 157 prospectively followed patients from an RTOG protocol after bladder preservation treatment with a median follow-up of 5.2 years.
They reported a 6% grade 3 or higher genitourinary
system toxicity. This report is consistent with findings
by Weiss et al73 who found that 4% of patients were dissatisfied with their bladder function following chemoradiation therapy. In addition, Rödel et al35 reported
that 2% of patients experienced unacceptable bladder
toxicity requiring palliative cystectomy. Ultimately,
patient preference should drive modality selection.
Future Directions of Chemoradiation Therapy
Altered Fractionation
In an effort to improve on the 67% likelihood of having a bladder free of invasive tumor that functions
well at an initial evaluation following 3 months of
treatment, the RTOG protocol 07-12 studied the use
of maximal TURBT followed by concurrent cisplatinbased chemotherapy with twice-daily radiation treatment, also known as hyperfractionation.74 Regional
lymph nodes were excluded from the radiotherapy
fields. Complete response rates were reportedly
above 85%. However, longer follow-up is necessary.
In a randomized trial comparing chemoradiation vs
radiation alone, two fractionation schemes were administered: 55 Gy in 20 fractions (39%) and the more
standard regimen of 64 Gy in 32 fractions (61%).30
The researchers found no differences in the HR for
locoregional DFS between the two groups.
Lipiodol for Image-Guided Radiation Therapy
Technological advances in radiotherapy over the
past decade lend themselves to a bladder-sparing approach. For example, image-guided radiation therapy
(IGRT) can more accurately target tumors in organs
that move, especially the bladder.75 Approximately
three to four radio-opaque gold markers can be imCancer Control 195
planted in the bladder wall surrounding the tumor
using a rigid cystoscope during TURBT and then used
for online image tracking during radiation therapy to
account for tumor movement.76 Disadvantages of this
approach are that it can be painful, and approximately
one-half of the markers can fall out during radiotherapy.77 Alternatively, 0.3 to 0.4 cc of the contrast agent
lipiodol can be injected three to five times under the
urothelium of the bladder wall around the tumor at
the time of TURBT using a flexible cystoscope. Use
of more than 0.4 cc of lipiodol per injection can result in diffusion of the contrast outward through the
bladder wall, making it difficult to precisely define the
tumor bed.77 With IGRT, the patient is prepared for
radiotherapy each day based on the location of the
fiducial markers on orthogonal radiography or conebeam computed tomography. The bladder moves
based on factors such as urine filling and bowel distention. By allowing a therapist to set up the patient
based on the location of the tumor rather than bony
anatomy, lipiodol-based IGRT significantly improves
treatment accuracy while decreasing the dose delivered to adjacent normal tissues (Fig 1). Lipiodol also
allows for the use of smaller tumor margins of 0.6 to
A
B
C
Fig 1 A-C. — (A) Axial, (B), sagittal, and (C) coronal views of a radiotherapy treatment-planning CT scan performed after lipiodol injection around the tumor
bed at the transurethral resection of the bladder tumor. The blue line represents the gross tumor volume defined by cystoscopy and a CT scan prior to
lipiodol. The black line represents the lipiodol-defined gross tumor volume. Note that lipiodol makes it easier to define the location of the tumor on the
treatment-planning CT scan for the radiation boost.
196 Cancer Control
July 2013, Vol. 20, No. 3
1.0 cm rather than 2.0 to 2.5 cm during the boost,78
and washout of lipiodol is minimal during IGRT.77
Intra-Arterial Chemotherapy, HER2/Neu,
and Epidermal Growth Factor Receptor
Several novel agents are being evaluated for use in
combination with radiation therapy. Azuma et al79
reported a prospective, nonrandomized, single-institutional study of 192 cT2 to cT4, N0 to N1 patients
who initially underwent maximal TURBT. Of these
patients, 96 then underwent radical cystectomy. If
radical cystectomy was not feasible or if patients refused radical cystectomy, they underwent balloonoccluded arterial infusion of cisplatin chemotherapy
with concomitant hemodialysis and radiation therapy
(referred to as the OMC regimen; n = 96). Arms were
unequal in that the patients receiving the OMC regimen had more high-grade tumors (P = .004), worse
performance status (P = .03), more T4 tumors (16.7%
vs 0%), and a higher prevalence of node-positive disease (10% vs 0%). Despite these selection biases,
the 5- and 15-year OS rates favored the chemoradiation therapy arm at 91% and 81% vs 60% and 40%,
respectively (P < .001). No grade 3 or higher toxicity
was reported. However, these results require further
investigation to determine whether they can be reproduced in a multi-institutional setting.
Biological agents such as trastuzumab are currently under investigation for use with radiation therapy.
Chakravarti et al80 reported on a pathological evaluation of four bladder-sparing RTOG protocols. They
described a significant correlation between HER2/
neu overexpression and decreased complete response
rates. This finding led to the development of the
ongoing RTOG trial 05-24. In this phase II study, patients who overexpressed HER2/neu were treated with
trastuzumab and concomitant paclitaxel. Nguyen et
al81 demonstrated that tumor overexpression of epidermal growth factor receptor was associated with worse
clinical outcomes. Cell culture studies have revealed
that cetuximab, an epidermal growth factor receptor
inhibitor, is limited in its ability to halt growth of bladder cancer cells.82 However, despite this in vitro data,
phase II studies of cetuximab and radiation therapy
for locally advanced disease and as monotherapy for
stage I disease are currently underway.
Conclusions
Although no randomized trials exist that compare
radical cystectomy with maximal transurethral resection of the bladder tumor followed by chemoradiation
therapy, the 5- and 10-year OS rates are comparable,
even though undergoing cystectomy and those undergoing chemoradiation therapy were pathologically
and clinically staged, respectively. Bladder-sparing
therapy helps to achieve a disease-free survival rate
July 2013, Vol. 20, No. 3
and preserves a functional bladder in approximately
two-thirds of patients. In addition, quality-of-life studies demonstrate that the bladder functions well, and
sexual function is also favorable with bladder preservation. The incidence of grade 3 or higher toxicity is
low with a bladder-sparing approach. Furthermore,
the incidence of radical cystectomy performed for
palliation of treatment-related toxicity has been low,
and the morbidity of salvage cystectomy may be comparable with primary cystectomy.
Selective bladder-sparing therapy represents an
opportunity for radiation oncologists, urological surgeons, and medical oncologists to work together to
equally contribute to the quality of life for patients
with bladder cancer. Surgical techniques continue
to evolve, and the optimal combination of systemic
therapy and radiotherapy continues to be investigated.
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