Review Articles

Invasive Bladder Cancer: The Role of Bladder Preserving

Therapy

SEYYED YOUSEF HOSSEINI*

Department of Urology, Shaheed Modarress Hospital, Shaheed Beheshti University of Medical

Sciences, Tehran, Iran

ABSTRACT

Purpose: To evaluate the reported outcomes of multimodality therapy with organ

preservation in invasive bladder cancer and assess it as an alternative for radical

cystectomy in selected cases.

Materials and Methods: All the articles on multimodality therapy with organ

preservation in invasive bladder cancer, published from 1974 to 2004, were reviewed

and the results were compared with the outcome of radical cystectomy in cases with

invasive bladder cancer.

Results: Multimodality therapy is transurethral resection of the bladder tumor

(TURBT) combined with chemoradiation therapy. It yields a 36% to 48% 5-year survival

rate, when the bladder is preserved, and an overall rate of 48% to 63%. This method

takes a long time for treatment and is accompanied by significant morbidity and

mortality. Cystectomy will be required in 34% to 45% of the patients, during the

treatment course, and in 28%, repeat TURBT will be performed due to recurrence of

superficial tumors. 

Conclusion: Organ preserving in multimodality therapy of invasive bladder cancer

can have acceptable results in some special situation, provided that a close cooperation

between urologist, radiotherapist, and oncologist exists. However, radical cystectomy

is still considered the standard treatment for invasive bladder cancer.

KEY WORDS: bladder neoplasm, bladder preservation, chemotherapy, radiation therapy, cystectomy

1

Urology Journal

UNRC/IUA

Vol. 2, No. 1, 1-7 Winter 2005

Printed in IRAN

Introduction

Since 1990s, the main aim of treatment in

patients with cancer has been organ preservation

with chemoradiation, with or without limited

local surgery. This approach has gained footage

in breast, esophageal, larynx, lung, and anal

cancers. Yet, radical cystectomy in invasive

bladder cancer has its own place as the standard

treatment. The treatment results of these tumors,

when radiotherapy, TURBT, or chemotherapy is

used alone in order to preserve bladder, have

been disappointing. But trimodality bladder-

preserving therapy, using combined transureteral

resection of the bladder tumor (TURBT),

radiotherapy, and chemotherapy, has brought

hope on the horizon in some special cases. 

In clinically staged groups of patients,

trimodality bladder-preserving therapy has had

comparable outcomes with radical cystectomy.

Eighty percent of these patients who survived for

at least five years enjoyed their own normal

bladder, while in 20% of whom, transureteral

resection (TUR) had been required again due to

superficial tumors relapses.(1) These tumors, like

the primary ones, are sensitive to intravesical
*Corresponding author: Urology and Nephrology

Research Center, No. 44, 9th Boustan, Pasdaran,

Tehran, Iran.

Tel: ++98 912 354 2496, E-mail: info@unrc.ir



Bladder Preserving Therapy for Invasive Bladder Cancer

installation of Bacillus Calmette Guerin (BCG).

Bladder function studies have shown that 70% of

these patients are able to void normally and

nearly 50% of them have normal erection.

Trimodality bladder-preserving therapy,

notwithstanding that it cannot surpass radical

cystectomy, could be offered as an alternative

approach to the patients.

The Need for Multimodality Approach

Single modality treatment of invasive bladder

tumors with TURBT, radiotherapy, or

chemotherapy has not been successful. Barnes et

al have reported 27% 5-year survival in 85

patients with well to moderately differentiated T2

bladder tumors who had undergone TURBT.(2)

Herr studied on highly-selective patients treated

with TURBT and found that survival at 5 years

was 76%.(3) Chemotherapy has also discouraging

results as a single therapy in invasive bladder

cancer. Robert and colleagues used methotrexate

and cisplatin for the treatment of T3 and T4

bladder tumors; complete response was seen in 5

patients (11%) and partial response in 15 (34%).(4)

Radiotherapy has been used in Europe and

Canada as monotherapy in invasive bladder

cancer. Duncan and Quilty performed a study in

Edinburgh to evaluate external beem

radiotherapy in 699 patients with invasive

bladder cancer. The overall 5-year survival was

30%.(5) In Toronto, Canada, Gospodarowicz et al

reported 31.6% overall 5- year survival in 121

cases treated with radiotherapy.(6)

Unfavorable outcomes of these approaches have

urged physicians to consider multimodality

approach, since its results in other cancers have

been encouraging. The usage of TURBT and

radiotherapy is to locally control the tumor and

chemotherapy is helpful mainly for systemic

therapy. Previous reports indicate that complete

response can be achieved in 45% of cases using

radiotherapy and TUR.(6-8)

A proportion of patients who undergo radical

cystectomy may have undetectable

micrometastases, which are the most common

cause of mortality within the three postoperative

years.(9) Combining TURBT and radiotherapy

with chemotherapy eliminates such

micrometastases, in addition to local therapy. In

consequence, chemotherapy with methotrexate,

cisplatin, and vinblastine (MCV) is administered

before or after radiotherapy. Also in some

protocols cisplatin and/or 5-fluorouracil is used

simultaneously with radiotherapy. Although the

therapeutic effects of this method has not been

examined yet, cisplatin and 5-fluorouracil has

proven effective as radiosensitizer in

oropharyngeal carcinomas.(10,11)

Patient Selection in Multimodality

Approach

All patients who require radical cystectomy are

eligible to undergo multimodality method, subject

to their acceptance and cooperation. However,

patients with tumors sized 6 cm or larger, and

those with hydronephrosis due to ureteral orifice

obstruction by tumor, are not appropriate

candidates. Furthermore, bladder-sparing

therapy would not be an appropriate approach in

the presence of white blood cell count <4000/µL,

platelet count <100000/µL, serum creatinine >1.7

mg/dL, creatinine clearance <60 mL/min, severe

irritative bladder symptoms, and diffused

carcinoma in situ of bladder.

Therapeutic Method in Multimodality

Approach

In this method the optimum possible TURBT is

performed and treatment is continued with

chemotherapy and radiotherapy. Afterwards,

patients receive 2400 to 4000 rad radiotherapy

and undergo 2 to 3 sessions of chemotherapy

with MCV. At the end of this stage, namely

induction therapy, re-evaluation of bladder at the

primary tumor site is done using cystoscopy,

cytology, and TUR resection. Any report of tumor

remainders is considered as failure and radical

cystectomy would be done. But if no tumor is

detected (response to treatment) patients

undergo additional chemotherapy and

radiotherapy as consolidation therapy, in order to

establish the resultant effects. At the end of the

treatment period, when complete response is

achieved, a strict follow-up consisting of

cystoscopy, biopsy of suspected areas, and

urinary cytology, is pivotal.

Follow-up is recommended to be done every

three months for the first two years, every 6

months for the subsequent 3 years, and yearly,

afterwards. A summary of the treatment schema

is shown in figure 1.

In a study by Housset et al from Paris,

induction therapy with 2400 rad radiotherapy

combined with cisplatin and 5-flurouracil was

performed in 120 cases.(12) In 18 patients with

2



Hosseini

stage T2 to T4 tumors who had responded to

induction therapy, radical cystectomy and

lymphadenectomy of pelvis were done before

consolidation therapy. Histological assessment of

bladder and lymph nodes showed no tumor. A

total of 77% of the patients had complete

response and their treatment course was

continued with 2000 rad radiotherapy, twice a

day and combination of cisplatin and 5-

fluorouracil. Patients who did not respond,

underwent cystectomy following induction

therapy and tumor recurrence. Survival at 5

years was 63%.

Fellin and colleagues reported the outcomes in

56 patients with stage T2 to T4 tumors who

underwent TURBT and two courses of MCV,

following with 4000 rad radiotherapy and

concomitant cisplatin. Complete response was

achieved in 50% of patients after induction

therapy. They were maintained on 2400 rad

radiotherapy and cisplatin as complementary

treatment. Overall 5-year survival rate was 55%

and it was 41% in cases with bladder

preservation.(13)

Paclitaxel, cisplantin, and 5-fluorouracil can

increase the sensitivity of tumoral cells to

radiotherapy, leading to better tumor removal.

The other advantage of combining radiotherapy

with chemotherapy is the potential effects on

micrometastases not visualized with the current

staging devices. To promote the effect of

radiotherapy, a twice daily bifractional plan is

recommended in some protocols.(12-14) The

rationale behind administering two sessions a

day with 12-hour intervals is that tumoral cells

will be removed more rapidly with shorter

intervals between radiotherapy sessions. In a

study by Noslund and coworkers on 168 cases of

bladder tumor, it was shown that the result of

local control at 10 years was better with

hyperfractionation with 1 Gy 3 times a day,

comparing to standard treatment.(15)

3

FIG. 1. Multimodality bladder-preserving treatment of invasive bladder cancer(1)

Biopsy-proven invasive bladder cancer 

 

 

 

Transurethral resection of the whole visible tumor (TURB-T) 

 

 

 

Induction therapy with external beam radiation and radiosensitizing chemotherapy (weeks 1 to 3) 

 

 

 

Repeat cystoscopy with transurethral biopsy (week 7) 

 

 

 

Complete pathologic response (PT0, Ta or Tcis) Residual tumor OR new site of tumor (T1 or greater)  

 

 

 

Proceed with consolidation therapy (week 8 to 9)   Radical Cystectomy (week 9) 

 

 

 

Repeat cystoscopy with transurethral biopsy (week 17)  Adjuvant Chemotherapy  

 

 

 

Complete response     Superficial Persistence     Muscle-Invasive Disease 

 

 

 

Long-term cystoscopic Intravesical therapy or Radical Cystectomy 



Bladder Preserving Therapy for Invasive Bladder Cancer

Results of Bladder Preserving

Protocols

The results of bladder saving in a series of

studies are as follows: In a study by the Radiation

Therapy Oncology Group (RTOG), they started

chemoradiation with radiotherapy combined with

5-flurouracil and cisplatin.(16) Of 34 cases, two-

third had complete response and were eligible for

commencing consolidation therapy. Kachnic et al,

from Massachusetts General Hospital (MGH),

used two courses of chemotherapy with MCV

combined with radiotherapy at a dose of 4000 rad

and cisplatin, as well as TURBT, and in those

with complete response they completed the

treatment with 2400 rad radiotherapy and

cisplatin. Sixty-six percent of the patients had

complete response after induction therapy.

Overall and bladder-saving survivals at 5 years

were 52% and 43%, respectively.(17) In MGH

group, 190 cases were followed up from 1986 to

1998; 121 of those (63%) had complete response

and entered the consolidation therapy period.(18)

In a study by Sauer and colleagues, of 181

patients, 145 (80%) had complete response,(19) and

in RTOG studies, they achieved 75%(20) and

59%(21) complete response.

One of the concerns after complete response

and ending the treatment is the tumor relapse,

either an invasive or a superficial form. Long-

term follow-up by MGH group in 121 patients had

shed light on this issue(22); of 121 cases, 73 had

no recurrence during 6.7 years follow-up. Thirty-

two of 48 recurrence cases were superficial

tumors and 16 were invasive tumors. The latter

cases were treated with radical cystectomy and

superficial ones received local therapies such as

TUR and intravesical BCG. The outcomes of

delayed cystectomy were the same as those of

primary cystectomy. Furthermore, 15% of the 72

patients in the RTOG phase III with complete

response experienced invasive tumor recurrence

within 5-year follow-up.(20) Consequently, long-

term follow-up is strongly recommended.

Neoadjuvant Chemotherapy

There exists controversy in the effects of

neoadjuvant chemotherapy, preceding radical

cystectomy and trimodality bladder preservation

therapy. In a study by the European Organization

for Research and Treatment of Cancer and the

Medical Research Council, half of 976 patients

underwent chemotherapy prior to radical

cystectomy and the other half had no

chemotherapy before cystectomy or radiotherapy.

Complete response was seen in 33% and 12% of

the patients with and without chemotherapy,

respectively.(1)

The effect of neoadjuvant chemotherapy before

the treatment protocol of trimodality bladder

preservation therapy has not been desirable. In

RTOG trial, 123 patients were divided into two

groups after TURBT, one was started on

trimodality therapy and the other received two

courses of MCV chemotherapy preceding

trimodality therapy. Five-year survival was not

different in the two groups and the possibility of

bladder preservation was 36% in the first and

40% in the second group.(20) Accordingly, it seems

that neoadjuvant therapy is not a recommendable

method in bladder preservation protocols.

Position of Bladder Preservation

Although the results of bladder preservation

have improved in the last 15 years, radical

cystectomy has reserved its place as the standard

treatment among urologists. This approach

demands a close cooperation of the specialists

team members, including oncologist,

radiotherapist, and urologist. Consequently, it is

still unclear whether we can achieve a favorable

survival in comparison with the survival rates

after radical cystectomy or not. On the other

hand, improvement in surgical methods has

provided a better outcome with low morbidity

rate for patients who undergo radical cystectomy.

This method is not associated with local and

systemic complications seen in bladder

preservation protocols.

Comparing the Effectiveness of

Multimodality Approach with Radical

Cystectomy

It has been claimed that the overall 5-year

survival of the patients with multimodality

therapy is comparable to that in primary radical

cystectomy. In 5 years, the local control is 90%

after primary radical cystectomy and survival

rate is between 40% to 60%.(23,24) However there

is no prospective randomized control trial to

compare long-term survival rates. Given et al

from Florida University have reported a better

outcome for radical cystectomy. In this study on

94 patients, 5-year survival rate was higher in

patients who had undergone radical cystectomy

4



Hosseini

during the follow-up comparing to those in whom

bladder was preserved (65% vs. 40%).(25) Some

believe that delayed cystectomy in the patients

undergone this protocol may lower the survival.

In a proportion of patients, cystectomy will be

required at the end of induction therapy, due to

incomplete response or recurrence during follow-

up period. Hautman compared 210 cases of

primary cystectomy with 88 cases of delayed

cystectomy.(26) Reasons for delay were

radiotherapy, neoadjuvant chemotherapy,

treatment of stage PT1 tumor with BCG

installation, and repeat TURBT. In primary

cystectomy group, 26% of the patients had a

tumor with stage PT3b or higher and 12% had

positive lymph nodes; while in delayed cystectomy

group, 42% had stage PT3b or higher and 26%

had positive lymph nodes. The difference was

statistically significant. Abratt et al studied on 46

patients, in whom salvage cystectomy had been

performed, following radiotherapy. Survival at 5

years was better in those with cystectomy due to

incomplete response to radiotherapy than to

recurrence in follow-up (50% vs. 32%).(27)

The above findings suggest that early

cystectomy is associated with a better 5-year

survival. However, some other researchers have

shown that delay in cystectomy does not impact

long-term outcome. Some researchers have

reported that 90-day postpone of cystectomy after

diagnosis to perform neoadjuvant chemotherapy

prior to surgery has no difference with prompt

cystectomy.(28,29) On the other hand, it has been

disputed that pathologic staging is not available

in bladder preservation. Lynch et al did

cystectomy due to irritative bladder symptoms in

5 patients with bladder preservation.

Subsequently, tumor was detected in all

pathologic samples.(30)

Quality of Life and Complications in

Bladder Preservation Protocols

Those who support bladder preservation

emphesize the better quality of life. However,

improvement in surgical methods of cystectomy

has made this advantage trivial. Continence can

be achieved in 91% of the patients during the day

time and 80% to 87.5% at night, when orthotopic

method is used as the first choice.(31,32) Clean

intermittent catheterization is required in less

that 5% of the patients. Also, potency is restored

in 64% of cases with cavernosal nerves

preservation method.(25) Cox et al and also Lynch

and colleagues reported that patients who had

undergone chemoradiation had normal bladders,

but radiotherapy could aggravate symptoms of

those who had low capacity bladder or urge

incontinence.(30,33)

Multimodality bladder preservation therapy is

an expensive and time consuming procedure.

Zietman et al, from Massachusetts General

Hospital, demonstrated that in order to complete

this procedure, cooperation of three specialist

groups during a 6 months period is required.(14)

Shiply et al believe that specific centers with the

requisite discipline are needed to perform the

protocol.(34) Radical cystectomy costs $22900,

while bladder preservation methods cost

$41268.(14)

External beam radiation therapy and systemic

chemotherapy have serious local and systemic

complications. In a RTOG's study, 38% of patients

could tolerate only one course of chemotherapy

with MCV and 4% died during induction

therapy.(20) In a report by MGH group in 1997,

20% of patients underwent changes in induction

therapy due to severe complications. Mortality

rate in this study was 4%.(17) In a study by

Skinner et al, mortality rate among patients

younger than 70 years old was reported as 2%

and it was 2.8% in those older than 70.(35) Main

complications of bladder preservation are

associated with chemotherapy. Incomplete

response or recurrence warrants cystectomy in

some patients who were candidates for bladder

preservation. During the follow-up, 45% of

patients in RTOG phase III(20) and 34% in MGH

group(17) underwent cystectomy; these patients

had undertaken complications of chemotherapy,

as well. 

Most urologists believe that chemoradiation

seriously impacts normal bladder function. In

three studies bladder function following

chemoradiation has been assessed.(36-38) In one of

those, MGH study, urodynamic tests were used as

well as a questionnaire to assess bladder function

in patients with chemoradiation and they were

compared with the results in a control group

matched for age and gender. It was shown that in

7 out of 31 patients, bladder compliance had

decreased and other parameters had been

normal. Data extracted from questionnaires were

in accordance with urodynamic findings,

corresponding to 74% satisfaction from bladder

function. Rectal symptoms in this study were not

common, but the rate of symptoms related to

5



Bladder Preserving Therapy for Invasive Bladder Cancer

small intestine was 22%. Recently, radiotherapy

has been limited to a less extensive area of lymph

nodes, so that such complications are seen less.

In MGH study, most men reported satisfaction

with their sexual activity and only 8% were

dissatisfied. Women preferred not to respond to

the questions concerning this issue.(38) The

damage to the potency of patients with

radiotherapy due to bladder cancer is less in

comparison with prostate cancer, which is

because of the lower dose needed in bladder

cancer and that the cavernous nerves are away

from the radiotherapy area.

Plans for the Future

In the recent years, remarkable results have

been reported for using molecular biomarkers

such as p53 and pRB as a prognostic factor and a

guide to select patients for chemotherapy. Several

studies have shown that p53 and pRB are the

factors indicating poor prognosis.(39-41)

Studies from Southern California demonstrated

that patients with invasive bladder cancer and

abnormal nuclear p53 accumulation benefit from

adjuvant chemotherapy.(42) It seems that in the

future, these markers will be helpful hints to

select patients eligible for chemoradiation and

bladder preservation.

Conclusion

Treatment of invasive bladder cancer with

trimodality bladder-preserving therapy method is

highly dependent on a close cooperation of the

urologists, oncologists, and radiotherapists as a

unanimous team, and the patients should be

selected carefully and be completely informed of

the procedure. This approach needs a 6 months

period to perform and a 5-year intense follow-up,

as well as complementary treatments, if needed.

Notwithstanding all the above considerations,

40% of patients will eventually undergo

cystectomy.

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