Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 5, pp. 1379–1384, 2009Copyright � 2009 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2009.01.063

CLINICAL INVESTIGATION Bladder

DEFINING THE CLINICAL TARGET VOLUME FOR BLADDER CANCERRADIOTHERAPY TREATMENT PLANNING

PETER JENKINS, PH.D., F.R.C.R.,* SALIM ANJARWALLA, F.R.C.PATH.,y HUGH GILBERT, F.R.C.S.,z

AND RICHARD KINDER, F.R.C.S.z

*Gloucestershire Oncology Centre, yDepartment of Pathology, and zDepartment of Urology, Cheltenham General Hospital,Cheltenham, United Kingdom

Purpose: There are currently no data for the expansion margin required to define the clinical target volume (CTV)around bladder tumors. This information is particularly relevant when perivesical soft tissue changes are seen onthe planning scan. While this appearance may reflect extravesical extension (EVE), it may also be an artifact ofprevious transurethral resection (TUR).Methods and Materials: Eighty patients with muscle-invasive bladder cancer who had undergone radical cystec-tomy were studied. All patients underwent preoperative TUR and staging computed tomography (CT) scans. Thepresence and extent of tumor growth beyond the outer bladder wall was measured radiologically and histopath-ologically.Results: Forty one (51%) patients had histologically confirmed tumor extension into perivesical fat. The medianand mean extensions beyond the outer bladder wall were 1.7 and 3.1 mm, respectively. Thirty five (44%) patientshad EVE, as seen on CT scans. The sensitivity and specificity of CT scans for EVE were 56% and 79%, respectively.False-positive results were infrequent and not affected by either the timing or the amount of tissue resected at TUR.CT scans consistently tended to overestimate the extent of EVE. Tumor size and the presence of either lymphovas-cular invasion or squamoid differentiation predict a greater extent of EVE.Conclusions: In patients with radiological evidence of extravesical disease, the CTV should comprise the outerbladder wall plus a 10-mm margin. In patients with no evidence of extravesical disease on CT scans, the CTVshould be restricted to the outer bladder wall plus a 6-mm margin. These recommendations would encompassmicroscopic disease extension in 90% of cases. � 2009 Elsevier Inc.

Bladder cancer, Radiation therapy, Clinical target volume.

INTRODUCTION

Radiotherapy, as a component of multimodality, organ-pre-

serving treatment, remains a standard of care for treating

bladder cancer in the United Kingdom, Scandinavia, and

individual centers in North America. Modern series report

complete response rates of �70% and actuarial 5-year local

control in �50% of patients with muscle-invasive disease

(1, 2). Technical developments in the planning and delivery

of radiotherapy such as three-dimensional conformal radia-

tion therapy (3D-CRT) and image-guided RT may further

improve local tumor control. However, these technologies

are predicated on the radiation oncologist being able to accu-

rately define and target the tumor.

Attempts to improve the accuracy of radiotherapy for blad-

der cancer have, to date, focused on the planning target vol-

ume (PTV) expansion required to account for the variability

in bladder filling and the uncertainty surrounding day-to-day

Reprint requests to: Peter Jenkins, Ph.D., Gloucestershire Oncol-ogy Centre, Cheltenham General Hospital, Cheltenham, UnitedKingdom GL53 7AN. Tel: (44) 8454-22-4019; Fax: (44) 8454-22-3506; E-mail: peter.jenkins@glos.nhs.uk

Presented at the Genitourinary Cancer Symposium, San Fran-

13

patient position. As far as we are aware, there are no published

data about the appropriate margin to be applied around the tu-

mor to ensure coverage of microscopic disease, a prerequisite

for defining the clinical target volume (CTV). A particular

problem arises when extravesical stranding is seen on the

planning scan. This appearance is commonly reported as tu-

mor infiltration into the perivesical adipose tissue. However,

it may also reflect local inflammation or edema following tran-

surethral resection (TUR), particularly when macroscopic tu-

mor clearance and deep muscle biopsies have been performed

(3). The inability of computed tomography (CT) scans to ac-

curately define the boundary between the tumor and perives-

ical fat may explain some of the interobserver variability

reported in target contouring (4).

Defining the CTV for bladder tumors is likely to become

increasingly important. Historically, the outer bladder wall

and any solid extravesical extension have been outlined as

cisco, CA, Feb 14th–6th 2008.Conflict of interest: none.Received Sept 5, 2008, and in revised form Jan 2, 2009. Accepted

for publication Jan 14, 2009.

79

1380 I. J. Radiation Oncology d Biology d Physics Volume 75, Number 5, 2009

the CTV. However, a recent trial has questioned the need to

treat the whole bladder (5). Such partial bladder radiotherapy,

when combined with modern image-guided techniques, will

permit a marked reduction in target volumes (6). Thus, the ac-

curate definition of microscopic extension will assume

greater relative importance in the future. The primary pur-

pose of this study was to quantify the magnitude of extraves-

ical tumor extension (EVE) in cystectomy specimens and

thereby define an appropriate CTV expansion for treatment

planning. In addition, we wished to correlate radiological

and pathological findings to determine the frequency with

which perivesical CT changes result from either previous

TUR or direct disease extension.

METHODS AND MATERIALS

We conducted a retrospective review of patients who had under-

gone radical cystectomy for bladder cancer at our institution between

1998 and 2007. A total of 232 cases were initially identified from

a departmental database. We excluded any patient who had a salvage

cystectomy for disease recurrence following primary radiotherapy,

received induction chemotherapy prior to surgery, or in whom the ra-

diological investigations could not be retrieved. We also excluded

Table 1. Tumor characteristics*

Parameter CharacteristicNo. ofpatients

Histology TCC 46TCC (squamoid differentiation) 16TCC (sarcomatoid differentiation) 3TCC (squamoid and sarcomatoid

differentiation)2

SCC 7CISy 2No tumor identifiedy 4

Pathological stage pT0y 4pTis 2pTay 1pT1 5pT2 16pT3 41pT4 11

Grade CIS 2Grade 2 6Grade 3 68No tumor seeny 4

Radiological stage Txy 2T2 39T3 35T4 4

Anatomical position Lateral wall 46Posterior wall 34Anterior wall 24Base 29Fundus 17

Abbreviations: CIS = carcinoma in situ; SCC = squamous cellcarcinoma; TCC = transitional cell carcinoma.

* Data are from 61 male and 19 female patients with a median ageof 69 years (range, 40-83 years). The median tumor size was 35 mm(range, 0–120 mm). Tumor histology, grade, and size refer to theanalysis of the cystectomy specimen. A tumor could involve multi-ple sites within the bladder.y Muscle-invasive disease was previously confirmed on TUR.

Fig. 1. Pathological assessment of extravesical extension. (Top)Tumor is destroying muscle and extending through the bladderwall into perivesical fat. The bar illustrates the measurement of ex-travesical spread. Original magnification x20. (Middle) A highermagnification view of the top panel shows tumor eroding throughinto the perivesical fat. Original magnification x40. (Bottom) A‘‘tongue’’ of tumor (arrow) protrudes from the outer bladder wall.Original magnification x20. The stain is haematoxylin and eosin.M = muscle; T = tumor; A = adventitia.

Bladder cancer CTV d P. JENKINS et al. 1381

Fig. 2. Radiological patterns of extravesical extension. (Top left) Stranding; (top right) misting; (bottom left) nodular;(bottom right) solid.

patients who did not have muscle-invasive transitional cell carci-

noma, squamous cell carcinoma, or sarcoma. In total, 80 cases

were available for further analysis. Patient demographics and tumor

characteristics are shown in Table 1.

All patients had their diagnoses confirmed by TUR biopsy and had

undergone preoperative staging comprising examination under anes-

thesia, upper-tract imaging, CT scanning of the pelvis, and chest

radiography. The median mass of tumor resected at TUR was 5 g

(range, 1–151 g). In 65 patients, the tumor biopsy was performed

prior to obtaining the staging CT scan. The median time interval be-

tween TUR and the scan was 27 days (range, 1–216 days). CT scans

were performed with the bladder comfortably full. In 46 patients, in-

travenous contrast was also given. Images were reviewed by using

soft tissue windows (window level, 40; window width, 400 Houns-

field units). EVE was considered to be present when the interface

between the bladder cancer and perivesical fat was irregular or

when the tumor showed solid growth beyond the outer wall of the

bladder. Sagittal or coronal reconstructions were reviewed for

tumors on the bladder dome wherever possible. For the purpose of

this analysis, the local tumor stage was also defined on the basis of

preoperative CT images, using the tumor-node-metastasis (1997) no-

menclature. We modified this staging system to create four radiolog-

ical T stages, namely, Tx, no tumor seen; T2, tumor confined within

the bladder; T3, possible tumor extension into perivesical fat; and T4,

possible tumor extension into adjacent organs or musculature.

The median interval from the staging scan to radical cystectomy

was 25 days. Cystectomy specimens were inked before being placed

in formalin. An important feature of this study is that the whole-mount

specimens were then serially sectioned before being stained with he-

matoxylin and eosin and examined by two reporting pathologists. For

the purpose this report, slides were further reviewed by a third pathol-

ogist, and the maximal extent of EVE was recorded with relation to

the outermost muscle fibers of the bladder wall adjacent to the tumor

(Fig. 1). In specimens with multiple tumors, the maximal distance

was recorded. All measurements of EVE were made to the nearest

0.1 mm, using an optical micrometer. No adjustment was made to ac-

count for shrinkage resulting from tissue processing.

The study was approved by the Gloucestershire Urological Audit

and Research Group. SPSS (SPSS Inc. Chicago, IL) software was

used for statistical analysis. The association of histological parame-

ters with EVE was analyzed using Fisher’s exact test for categorical

variables and Student’s t test for continuous variables (equal vari-

ances not assumed). All quoted p values are two tailed.

RESULTS

Thirty five patients had T3 disease as seen on CT scanning,

while 41 patients had tumor extension into the perivesical fat

proven by pathological assessment. The sensitivity, specific-

ity, and negative and positive predictive values of CT scans

for predicting local disease extension into perivesical fat

were 56%, 79%, 49%, and 83%, respectively. Understaging

(29%) was more common than overstaging (10%). The over-

all accuracy of CT scanning relative to determination of the

presence or absence of T3 disease was 44%.

For patients with histologically confirmed EVE, the tumor

front was classified as being infiltrative in 35 (discontinuous

strands and isolated tumor cells at edge) or pushing in 6 (solid

tumor front). In patients with radiologically confirmed T3

disease which was subsequently confirmed on histology,

the pattern of EVE seen on CT scanning was also classified

(Fig. 2). In 20 patients, this had the appearance of perivesical

stranding. Less commonly seen patterns were misting (3),

nodular deposits (2), and solid tumor (2).

The distribution of disease extension beyond the bladder

wall, as measured histologically or radiologically, is shown

in Fig. 3. Overall, the median, mean, and maximal EVE

values, as measured on histology, were 1.7, 3.1, and 16 mm.

1382 I. J. Radiation Oncology d Biology d Physics Volume 75, Number 5, 2009

For the patients with EVE seen on CT scans, there were eight

false positives. For this group as a whole (n = 35), the median,

mean, and maximal EVE values, as measured histologically,

were 4.0, 4.4, and 16 mm, respectively. The 90th percentile

was 9.6 mm. In the group of patients with organ-confined dis-

ease on CT, there were 23 false negatives. Taking this group as

a whole (n = 45), the median, mean, and maximal histological

EVE distances were 1.0, 2.1, and 12 mm, respectively. The

90th percentile in this group was 6.3 mm.

The relationships between EVE as measured histologically

and as measured by CT scan are shown in Fig. 4. There was

a reasonable correlation between these two measurements

(r = 0.51; p < 0.001). The linear correlation line is defined

by the equation EVE (histological) = 1.71 + (0.31 � EVE

[CT]). It is also evident from Fig. 4 that CT scans consistently

overestimate the extent of spread beyond the bladder for

patients with radiologically confirmed T3 disease.

A number of factors were analyzed for their ability to pre-

dict the presence and/or extent of histological EVE (Table 2).

Squamoid differentiation, lymphovascular invasion (LVI),

and tumor size were all significantly associated with more

extensive extravesical tumor spread.

Fig. 3. The distribution of extravesical extension as measure histo-pathologically (top panel) or radiologically on CT scans (bottompanel).

Sixty-five patients had a TUR performed prior to the stag-

ing scan. For the 6 patients in this group with false-positive

CT scans, we tested for the possible influence of a TUR bi-

opsy on overstaging. There were no differences in the timing

of the TUR (31 vs. 35 days; p = 0.62) or the amount of tissue

resected (10.9 g vs. 13.5 g; p = 0.63) between patients with

false-positive CT scans and the rest of the sample.

DISCUSSION

Radiotherapy remains a valuable modality in the treatment

of muscle-invasive bladder cancer. Functional outcome and

morbidity are equivalent or superior to surgery (7), and com-

pared with similar cystectomy series, 5-year disease-specific

survival is almost identical (1, 8). The addition of either induc-

tion (9) or concurrent (10) cisplatin-based chemotherapy fur-

ther improves these results. However, despite these recent

advances, there still remain the �30% of patients who either

fail to attain a complete response or subsequently develop a lo-

cal relapse in the bladder (2). It is noteworthy that up to 95% of

recurrences occur at the original site of disease (11). The Inter-

national Commission on Radiation Units and Measurements

(ICRU) Report 50 has provided a conceptual framework for

3D-CRT to ensure adequate coverage of the tumor with the

prescription dose (12). A margin is added around the radiolog-

ically visible tumor to account for possible microscopic disease

extensions, which forms the CTV. A second expansion is then

applied to account for tumor movement and the variability of

patient setup, which forms the PTV. Although the ICRU report

provided definitions of the margins to be used, actual quantita-

tive determination of these expansions relies on clinical

measurement. In the case of the CTV, current imaging technol-

ogy is incapable of accurately identifying microscopic tumor

extensions. Furthermore, for most tumors, these extensions

are not uniform and can vary according to anatomical position

or pathological characteristics (13). In the case of bladder can-

cer, the pragmatic solution adopted by many radiation oncolo-

gists is to add a composite safety margin of 1.5 to 2 cm around

Fig. 4. Correlation between extravesical extension as measured his-tologically and radiologically. The correlation line is described bythe equation EVE (histological) = 1.71 + (0.31 x EVE [CT]).

Bladder cancer CTV d P. JENKINS et al. 1383

Table 2. Factors that predict extravesical extension

No. with EVE Extent of EVE (mm)*

Tumor characteristicsNo. of tumors

foundNo. with EVE/no.with characteristic

No. with EVE/no.without characteristic p value

No. withcharacteristic

No. withoutcharacteristic p value

Squamoid differentiationy 25 15/25 26/55 0.29 5.1 2.2 <0.01LVI 44 24/44 17/36 0.51 4.0 2.0 0.02Necrosis 17 12/17 29/63 0.07 3.4 3.0 0.68CIS 17 19/36 22/44 0.81 2.7 3.4 0.36Tumor size >35mm 41 23/39 18/41 0.18 3.0 2.3 0.04Grade 3 68 37/68 4/12 0.18 3.2 2.9 0.85

Abbreviations: CIS = carcinoma in situ; TCC = transitional cell carcinoma.* Values in bold type represent statistically significant associations.y TCC with squamoid differentiation and squamous cell carcinoma.

the outer wall of the empty bladder, to account for microscopic

tumor extension, as well as factors such as daily setup error and

variation in organ position. However, better quantification of

the various components of this margin would enable the

more conformal treatment plans afforded by modern 3D-

CRT to be implemented with greater accuracy. To date, most

of the research in this area has focused on interfraction organ

motion, as this is undoubtedly the dominant source of error

in the treatment of tumors within the bladder. For example,

several studies have attempted to quantify bladder movement

on serial imaging. Turner et al. showed that outward bladder

wall movements of greater than 1.5 cm occurred at least

once in over 60% of patients with maximal displacements of

2.7 cm (14). This variation compromised treatment margins

in 33% of patients. Pos et al. reported that even when a 2-cm

margin is allowed around the bladder, part of the tumor still

fell outside the PTV on one or more occasions in 52% of pa-

tients (15). Finally, a comprehensive Dutch study found simi-

lar movements and concluded that anisotropic margins of 1 cm

laterally/anteriorly, 1.4 cm posteriorly, and 2 cm for the blad-

der dome were required to ensure adequate coverage of bladder

tumors (16). This variation in the size, shape and position of the

bladder have reinforced the traditional view that large treat-

ment margins are necessary when treating tumors in this organ.

However, the development of image-guided RT technologies,

which permit visualization of soft tissue at treatment, will result

in a significant reduction in the internal margin component of

the PTV. As a consequence, accurate definition of the CTV

will acquire greater importance in the future.

In common with many previous studies, we found that CT

scans are of limited value in the preoperative assessment of

bladder cancer (17). A recent review by Zhang et al. reported

that the overall accuracy of CT staging was only 60% (18).

However, the figures quoted for the diagnostic accuracy of

CT often amalgamate nodal staging and local tumor staging.

In contrast to these studies, our report sought to assess the ac-

curacy of modern CT scans in predicting tumor extension

into the extravesical fat. In relation to EVE, the specificity

and sensitivity of CT scans was 66% and 79%, respectively.

Despite the limited accuracy of CT, our data have confirmed

that when perivesical soft tissue changes are seen, they most

commonly reflect local tumor extension rather than post-

biopsy artifacts. This observation is important for target vol-

ume delineation and most likely reflects the long time interval

(median, 27 days) between the initial biopsy and the scan in

our series. Kim et al. have previously observed that the accu-

racy of CT scans in determining perivesical extension im-

proves if the scanning is performed 7 days after the TUR (19).

We do not think that the correlation between EVE as mea-

sured on CT scans and histologically is sufficiently strong to

permit a definition of the CTV based on radiology (Fig. 4).

Even if a linear shrinkage factor of 4% is allowed for tissue

processing (20, 21), CT scans tend to consistently overesti-

mate the true extent of EVE. As a result, we would recommend

that in the absence of radiologically overt T3 disease, an ex-

pansion margin of 6 mm beyond the outer wall of the bladder

be used. However, for patients in whom extravesical stranding

is visible on scanning, the CTV expansion should be increased

to 10 mm beyond the outer wall of the bladder. These margins

are sufficient to cover microscopic disease in 90% of cases.

Where the bladder tumor itself can be visualized, it would

seem reasonable for these margins to be added to the bladder

wall along the tumor base alone. Finally, it should be empha-

sized that these recommendations apply to patients in whom

the CT scan demonstrates the ‘‘stranding’’ or ‘‘misting’’ pat-

tern of perivesical shadowing (Fig. 2).

Magnetic resonance imaging (MRI) is being used increas-

ingly for the local staging of bladder cancer and is generally

reported to be superior to CT, particularly with regard to local

staging (22). Unfortunately, very few patients in our series

had MRI performed, so we are unable to compare the two im-

aging modalities. However, we note that even with gadoli-

nium enhancement, differentiating between residual tumor

and edema, scar, or granulation tissue on MRI is difficult after

the patient has undergone TUR (23).

We observed that EVE is more extensive in patients with

LVI, squamoid differentiation, and larger tumors. LVI has

recently been found to be an independent predictor for local

recurrence in patients with negative lymph nodes at lympha-

denectomy (24). Similarly, squamoid differentiation in blad-

der tumors has also been reported to be a predictor of local

recurrence following cystectomy (25). Taken together, these

data suggest that when squamoid cell differentiation or LVI is

noted on the TUR specimen, larger CTV expansions may be

required. The same is true for tumors with a maximum

dimension greater than 3.5 cm.

1384 I. J. Radiation Oncology d Biology d Physics Volume 75, Number 5, 2009

Several limitations of our study methodology must be ac-

knowledged. Staging CT scans were performed with the

bladder comfortably full as opposed to planning scans which

are usually undertaken with the bladder empty. Many

patients in our series had CT scans performed with intrave-

nous contrast, which has been shown to improve the accuracy

of staging (26). Furthermore, the findings we report relate to

CT scans performed at a median of 4 weeks after biopsy. The

accuracy of radiological staging has been shown to be influ-

enced by the interval postbiopsy (19). Finally our methodol-

ogy for measuring EVE was not sufficiently sophisticated to

account for fixation artifacts or the problem of tangential sec-

tioning.

CONCLUSIONS

This is the first study that has systematically evaluated the

radiological and pathological investigations of patients with

bladder tumors to determine the extent of tumor spread into

perivesical fat. There is a substantial variation in the degree

of EVE. Using these data, we have made recommendations

for the CTV margin that is required for treatment planning.

This margin must be integrated with the other components of

3D-CRT to ensure coverage of the target. Future work will

look at the effect of induction chemotherapy on these recom-

mendations and the accuracy of staging MRI in predicting

EVE.

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