Defining the Clinical Target Volume for Bladder Cancer Radiotherapy Treatment Planning

Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 5, pp. 1379–1384, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2009.01.063

CLINICAL INVESTIGATION

Bladder

DEFINING THE CLINICAL TARGET VOLUME FOR BLADDER CANCER RADIOTHERAPY TREATMENT PLANNING PETER JENKINS, PH.D., F.R.C.R.,* SALIM ANJARWALLA, F.R.C.PATH.,y HUGH GILBERT, F.R.C.S.,z z AND RICHARD KINDER, F.R.C.S. * Gloucestershire Oncology Centre, y Department of Pathology, and z Department 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 on the planning scan. While this appearance may reflect extravesical extension (EVE), it may also be an artifact of previous transurethral resection (TUR). Methods and Materials: Eighty patients with muscle-invasive bladder cancer who had undergone radical cystectomy were studied. All patients underwent preoperative TUR and staging computed tomography (CT) scans. The presence and extent of tumor growth beyond the outer bladder wall was measured radiologically and histopathologically. Results: Forty one (51%) patients had histologically confirmed tumor extension into perivesical fat. The median and mean extensions beyond the outer bladder wall were 1.7 and 3.1 mm, respectively. Thirty five (44%) patients had 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 lymphovascular invasion or squamoid differentiation predict a greater extent of EVE. Conclusions: In patients with radiological evidence of extravesical disease, the CTV should comprise the outer bladder wall plus a 10-mm margin. In patients with no evidence of extravesical disease on CT scans, the CTV should be restricted to the outer bladder wall plus a 6-mm margin. These recommendations would encompass microscopic disease extension in 90% of cases. Ó 2009 Elsevier Inc. Bladder cancer, Radiation therapy, Clinical target volume.

patient position. As far as we are aware, there are no published data about the appropriate margin to be applied around the tumor 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 tumor infiltration into the perivesical adipose tissue. However, it may also reflect local inflammation or edema following transurethral resection (TUR), particularly when macroscopic tumor clearance and deep muscle biopsies have been performed (3). The inability of computed tomography (CT) scans to accurately define the boundary between the tumor and perivesical 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

INTRODUCTION Radiotherapy, as a component of multimodality, organ-preserving 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 radiation 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 accurately define and target the tumor. Attempts to improve the accuracy of radiotherapy for bladder cancer have, to date, focused on the planning target volume (PTV) expansion required to account for the variability in bladder filling and the uncertainty surrounding day-to-day

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.

Reprint requests to: Peter Jenkins, Ph.D., Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, United Kingdom GL53 7AN. Tel: (44) 8454-22-4019; Fax: (44) 845422-3506; E-mail: [email protected] Presented at the Genitourinary Cancer Symposium, San Fran1379

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Table 1. Tumor characteristics* Parameter

Characteristic

Histology

TCC TCC (squamoid differentiation) TCC (sarcomatoid differentiation) TCC (squamoid and sarcomatoid differentiation) SCC CISy No tumor identifiedy Pathological stage pT0y pTis pTay pT1 pT2 pT3 pT4 Grade CIS Grade 2 Grade 3 No tumor seeny Radiological stage Txy T2 T3 T4 Anatomical position Lateral wall Posterior wall Anterior wall Base Fundus

No. of patients 46 16 3 2 7 2 4 4 2 1 5 16 41 11 2 6 68 4 2 39 35 4 46 34 24 29 17

Abbreviations: CIS = carcinoma in situ; SCC = squamous cell carcinoma; TCC = transitional cell carcinoma. * Data are from 61 male and 19 female patients with a median age of 69 years (range, 40-83 years). The median tumor size was 35 mm (range, 0–120 mm). Tumor histology, grade, and size refer to the analysis of the cystectomy specimen. A tumor could involve multiple sites within the bladder. y Muscle-invasive disease was previously confirmed on TUR.

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 accurate definition of microscopic extension will assume greater relative importance in the future. The primary purpose of this study was to quantify the magnitude of extravesical 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 undergone 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 radiological investigations could not be retrieved. We also excluded

Fig. 1. Pathological assessment of extravesical extension. (Top) Tumor is destroying muscle and extending through the bladder wall into perivesical fat. The bar illustrates the measurement of extravesical spread. Original magnification x20. (Middle) A higher magnification view of the top panel shows tumor eroding through into 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.

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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 carcinoma, 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 anesthesia, 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 between TUR and the scan was 27 days (range, 1–216 days). CT scans were performed with the bladder comfortably full. In 46 patients, intravenous contrast was also given. Images were reviewed by using soft tissue windows (window level, 40; window width, 400 Hounsfield 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) nomenclature. We modified this staging system to create four radiological 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 hematoxylin and eosin and examined by two reporting pathologists. For the purpose this report, slides were further reviewed by a third pathologist, 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 account 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 parameters with EVE was analyzed using Fisher’s exact test for categorical variables and Student’s t test for continuous variables (equal variances 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, specificity, 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 overall 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.

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

Sixty-five patients had a TUR performed prior to the staging scan. For the 6 patients in this group with false-positive CT scans, we tested for the possible influence of a TUR biopsy 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

Fig. 3. The distribution of extravesical extension as measure histopathologically (top panel) or radiologically on CT scans (bottom panel).

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 disease 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 predict 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.

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 compared with similar cystectomy series, 5-year disease-specific survival is almost identical (1, 8). The addition of either induction (9) or concurrent (10) cisplatin-based chemotherapy further 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 local relapse in the bladder (2). It is noteworthy that up to 95% of recurrences occur at the original site of disease (11). The International 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 radiologically 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 quantitative determination of these expansions relies on clinical measurement. In the case of the CTV, current imaging technology 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 cancer, the pragmatic solution adopted by many radiation oncologists is to add a composite safety margin of 1.5 to 2 cm around

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Table 2. Factors that predict extravesical extension No. with EVE

Extent of EVE (mm)*

Tumor characteristics

No. of tumors found

No. with EVE/no. with characteristic

No. with EVE/no. without characteristic

p value

No. with characteristic

No. without characteristic

p value

Squamoid differentiationy LVI Necrosis CIS Tumor size >35mm Grade 3

25 44 17 17 41 68

15/25 24/44 12/17 19/36 23/39 37/68

26/55 17/36 29/63 22/44 18/41 4/12

0.29 0.51 0.07 0.81 0.18 0.18

5.1 4.0 3.4 2.7 3.0 3.2

2.2 2.0 3.0 3.4 2.3 2.9

<0.01 0.02 0.68 0.36 0.04 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 3DCRT 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 patients (15). Finally, a comprehensive Dutch study found similar movements and concluded that anisotropic margins of 1 cm laterally/anteriorly, 1.4 cm posteriorly, and 2 cm for the bladder 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 treatment 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 accuracy 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 postbiopsy 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 accuracy of CT scans in determining perivesical extension improves if the scanning is performed 7 days after the TUR (19). We do not think that the correlation between EVE as measured 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 overestimate the true extent of EVE. As a result, we would recommend that in the absence of radiologically overt T3 disease, an expansion 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 emphasized that these recommendations apply to patients in whom the CT scan demonstrates the ‘‘stranding’’ or ‘‘misting’’ pattern of perivesical shadowing (Fig. 2). Magnetic resonance imaging (MRI) is being used increasingly 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 imaging modalities. However, we note that even with gadolinium 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 lymphadenectomy (24). Similarly, squamoid differentiation in bladder 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.

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Several limitations of our study methodology must be acknowledged. 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 intravenous 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 influenced by the interval postbiopsy (19). Finally our methodology for measuring EVE was not sufficiently sophisticated to account for fixation artifacts or the problem of tangential sectioning.

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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 recommendations and the accuracy of staging MRI in predicting EVE.

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