Original Article

Optimizing Bladder Cancer Locoregional Failure Risk

Stratification After Radical Cystectomy Using SWOG 8710
John P. Christodouleas, MD, MPH1; Brian C. Baumann, MD1; Jiwei He, MS2; Wei-Ting Hwang, PhD2; Kai N. Tucker, BA1;
Justin E. Bekelman, MD1; Catherine M. Tangen, MS, PhD3; Seth P. Lerner, MD4; Thomas J. Guzzo, MD, MPH5; and
S. Bruce Malkowicz, MD5

BACKGROUND: Clinical trials of radiation after radical cystectomy (RC) and chemotherapy for bladder cancer are in development,
but inclusion and stratification factors have not been clearly established. In this study, the authors evaluated and refined a published
risk stratification for locoregional failure (LF) by applying it to a multicenter patient cohort. METHODS: The original stratification,
which was developed using a single-institution series, produced 3 subgroups with significantly different LF risk based on pathologic
tumor (pT) classification and the number of lymph nodes identified. This model was then applied to patients in Southwest Oncology
Group (SWOG) 8710, a randomized trial of RC with or without chemotherapy. LF was defined as any pelvic failure before or within 3
months of distant failure. RESULTS: Patients in the development cohort and the SWOG cohort had significantly different baseline
characteristics. The original risk model was not fully validated in the SWOG cohort, because lymph node yield was not as strongly
associated with LF as in the development cohort. Regression analysis indicated that margin status could improve the model. A re-
vised stratification using pT classification, margin status, and the number of lymph nodes identified produced 3 subgroups with signif-
icantly different LF risk in both cohorts: low risk (pT2), intermediate risk (pT3 with negative margins AND 10 lymph nodes
identified), and high risk (pT3 with positive margins OR <10 lymph nodes identified) with 5-year LF rates of 8%, 20%, and 41%,
respectively, in the SWOG cohort and 8%, 19%, and 41%, respectively, in the development cohort. CONCLUSIONS: A model incorporat-
ing pT classification, margin status, and the number of lymph nodes identified stratified LF risk in 2 different RC populations and may
inform the design of future trials. Cancer 2014;120:1272–80. V C 2014 American Cancer Society.

KEYWORDS: bladder cancer, urothelial cancer, local failure, adjuvant radiation.

INTRODUCTION
Patients with muscle-invasive bladder cancer who undergo radical cystectomy plus bilateral pelvic lymphadenopathy (RC)
with or without the receipt of perioperative chemotherapy have an estimated 5-year overall survival rate of approximately
50%.1 Although considerable attention has been given to the problem of distant relapse after RC, approximately 33% of
patients with pT3 tumors develop a recurrence within the pelvis, either as isolated locoregional failures (LF) or cosyn-
chronous with distant metastases.2 Several organizations are now considering clinical trials to assess the impact of radiation
therapy (RT) after RC. However, criteria for the selection and stratification of patients most likely to benefit from adju-
vant RT in these trials have not been clearly defined. A LF risk-stratification model derived from a single-institution expe-
rience has recently been published but not externally validated.3 The purpose of this study was to assess the validity of this
LF stratification model within the Southwest Oncology Group (SWOG) 8710 database, a heterogeneous, multi-
institutional cohort of patients who were randomized to undergo RC with or without neoadjuvant chemotherapy.1,2

MATERIALS AND METHODS

Original Risk Stratification
The original LF risk-stratification model divided patients in the development cohort into 3 statistically distinct risk groups
based on 2 variables: pathologic tumor classification at cystectomy (pT2 or pT3) and the total number of benign or
malignant lymph nodes identified in the RC pathology specimen (<10 or 10 benign or malignant lymph nodes). The
model indicated that patients with pT2 tumors were at low risk of LF, those with pT3 tumors who had 10 lymph

Corresponding author: John P. Christodouleas, MD, MPH, Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania,
3400 Civic Center Blvd, TRC-2 West, Philadelphia, PA 19104; Fax: (215) 349-5445; christojo@uphs.upenn.edu
1
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; 2Department of Biostatistics and Epidemiology, University of Pennsyl-
vania, Philadelphia, Pennsylvania; 3Fred Hutchinson Cancer Research Center, Seattle, Washington; 4Department of Urology, Baylor College of Medicine, Houston,
Texas; 5Department of Urology, University of Pennsylvania, Philadelphia, Pennsylvania

DOI: 10.1002/cncr.28544, Received: September 17, 2013; Revised: November 21, 2013; Accepted: November 22, 2013, Published online January 3, 2014 in
Wiley Online Library (wileyonlinelibrary.com)

1272 Cancer April 15, 2014


nodes identified were at intermediate risk of LF, and those
with pT3 tumors who had <10 lymph nodes identified
were at high risk of LF.3
Development Cohort
The development cohort included 486 consecutive patients
who underwent RC with or without perioperative chemo-
therapy at the Hospital of the University of Pennsylvania
between 1990 and 2008. Of these, 44 patients were
excluded because they lacked elements of urothelial carci-
noma (37 patients) or had received radiation (7 patients),
leaving 442 patients (91%) for analysis. Details of the eval-
uation, surgery, and pathologic review of these patients
have been previously described.3 After surgery, patients
were evaluated every 4 months for 2 years, every 6 months
until year 5, and then annually with routine chest x-rays
and biannual computed tomography (CT) scans or mag-
netic resonance imaging (MRI) of the abdomen and pelvis.
SWOG Cohort
SWOG 8710 was a randomized trial that compared RC
alone versus 3 cycles of neoadjuvant methotrexate, vin-
blastine, doxorubicin, and cisplatin (MVAC) followed by
RC for patients with clinical T2 through T4a transitional
cell carcinoma with or without squamous differentiation.
In total, 317 patients were accrued between 1987 and
1998. Of these, 53 were excluded because they did not
undergo RC (35 patients) or their records were not avail-
able for review (18 patients), leaving 264 patients (85%)
for analysis. Study patients were operated on by 106 dif-
ferent surgeons at 109 different institutions. The workup,
surgery, and pathologic review have been described previ-
ously in detail.1,2 The recommended evaluation after sur-
gery was every 3 months for the first year, every 6 months
for the second year, and yearly thereafter with chest x-rays.
Abdominal or pelvic imaging was not required according
to the protocol.
Endpoints and Statistical Analyses
he primary endpoint of this analysis was LF, but overall
survival (OS) and isolated distant metastasis (DM) also
were recorded. These endpoints were scored based on a
review of original medical records at the Hospital of the
University of Pennsylvania and case report forms and
source documentation in the SWOG 8710 database. LF
was defined as imaging evidence of recurrence in the pel-
vic soft tissues or lymph nodes below the aortic bifurca-
tion before or within 3 months after DM. Recurrence
within the inguinal lymph nodes was classified as DM.
The time to LF, OS, and isolated DM were calculated
Cancer April 15, 2014
Bladder Cancer Risk Stratification/Christodouleas et al
from the date of surgery with censoring at the date of last
follow-up. LF was analyzed using a cumulative incidence
function in which isolated DM, death, and second pri-
mary malignancies (including ureteral or urethral malig-
nancies) other than prostate or skin cancers were
considered competing events. Chi-square tests were used
to compare baseline patient characteristics between the de-
velopment cohort and the SWOG cohort. Log-rank tests
were used to compare OS. The goal of the external valida-
tion was to demonstrate that the original LF stratification
produced significantly different subgroups when applied
to the SWOG cohort. Fine and Gray regression was used
to compare the cumulative incidences of LF or isolated
DM between subgroups and to determine whether the ex-
planatory power of the original risk stratification could be
improved with additional covariates. Alternative risk-
stratification rubrics were compared using Harrell c-
indices and log likelihoods after excluding patients with
unknown model parameters. The number of patients in
each model was fixed by excluding those with unknown
margin status and an unknown number of lymph nodes
identified to ensure a fair comparison between models.
RESULTS
Differences Between the Development and
SWOG Cohorts
The cohorts differed significantly with respect to age,
pathologic tumor classification, lymph node positivity,
surgical soft-tissue margins, the number of lymph nodes
identified, and receipt of neoadjuvant and adjuvant
chemotherapy (P < .01 for all comparisons) but not sex
or histology (Table 1). There was a borderline signifi-
cant difference with respect to OS (log-rank P 5 0.05)
with 5-year OS estimates of 42% (95% confidence
interval [CI], 37%-47%) and 49% (95% CI, 43%-
55%) for the development and SWOG cohorts, respec-
tively. There were 80 and 40 LF events in the develop-
ment and SWOG cohorts, respectively. There were no
significant differences with respect to overall LF (Gray
P 5 .13) or overall isolated DM (Gray P 5 .22). In the
development and SWOG cohorts, the overall 5-year LF
estimates were 18% (95% CI, 14%-22%) and 15%
(95% CI, 11%-20%), respectively, and the 5-year iso-
lated DM estimates were 17% (95% CI, 14%-21%)
and 20% (95% CI, 16%-26%), respectively.
Evaluating the Original Risk Stratification
Within the SWOG Cohort
Applying the original risk stratification to the SWOG
cohort, the 5-year LF estimates were 8%, 29%, and 36%
1273
Original Article

TABLE 1. Differences in Patient Characteristics

Between the Development Cohort and the South-
west Oncology Group Cohort

No. of Patients (%)

SWOG Cohort, Development

Characteristic N 5 264 Cohort. N 5 442 Pa

Age, y
<65 147 (56) 192 (43) < .01
65 117 (44) 250 (57)
Sex
Men 210 (80) 348 (79)
Women 54 (20) 94 (21) .87
Histology
Pure TCC 214 (81) 369 (83)
TCC mixed histology 50(19) 73 (17) .47
Pathologic tumor classification
pT2 183 (69) 232 (52)
pT3 81 (31) 210 (48) < .01
Lymph node status
Negative 212 (80) 308 (70)
Positive 52 (20) 131 (30)
Unknown 0 (0) 3 (<1) < .01
Margin status
Negative 215 (81) 375 (85)
Positive 23 (9) 59 (13) Figure 1. Cumulative incidence of locoregional failure (LF)
Unknown 26 (10) 8 (2) < .01 within the Southwest Oncology Group (SWOG) cohort, sepa-
No. of lymph nodes identifiedb rated according to the original risk stratification, is illustrated
10 136 (52) 336 (76) according to the number of years of follow-up after cystec-
<10 128 (48) 101 (23) tomy as follows: low-risk (pathologic T2 classification or less
Unknown 0 (0) 5 (1) < .01 [pT2]), intermediate-risk (pT3 with 10 benign or malig-
Neoadjuvant chemotherapy nant lymph nodes identified), and high-risk (pT3 with <10
No 134 (51) 371 (84) benign or malignant lymph nodes identified).
Yes 130 (49) 36 (8)
Missing 0 (0) 35 (8) < .01
Adjuvant chemotherapy
No 264 (100) 310 (70)
Yes 0 (0) 98 (22) with LF when controlling for the original risk stratifica-
Unknown 0 (0) 34 (8) <.01 tion (Table 2).
Abbreviations: SWOG, Southwest Oncology Group; TCC, transitional cell
carcinoma. Revising the LF Risk Stratification to Include
a
P values were calculated using the chi-squared test. Margin Status
b
Values indicate the number of benign or malignant lymph nodes. Because margin status appeared to have a stronger associa-
tion with LF than the number of lymph nodes identified
for the low-risk, intermediate-risk, and high-risk groups, in the SWOG cohort, we considered 2 modifications to
respectively (Fig. 1). The risk of LF differed significantly the original risk-stratification model. The first alternative
between the low-risk and intermediate-risk groups (sub- included 2 variables, pT classification and margin status,
hazard ratio [SHR], 3.93; 95% CI, 1.87-8.26; P < .01) as follows: low risk, pT2 tumor; intermediate risk,
and between the low-risk and high-risk groups (SHR, pT3 tumor AND negative margins; and high risk,
5.63; 95% CI, 2.64-11.98; P < .01). However, the origi- pT3 tumor AND positive margins. The second alterna-
nal risk stratification was not fully validated in the SWOG tive included 3 variables, pT classification, the number of
cohort, because the risk of LF was not significantly differ- lymph nodes identified, and margin status, as follows: low
ent between the intermediate-risk and high-risk groups risk, pT2 tumor; intermediate risk, pT3 tumor with
(SHR, 1.43; 95% CI, 0.64-3.17; P 5 .38) (Fig. 1). Fine 10 lymph nodes identified AND negative margins; and
and Gray regression was used to determine whether LF high risk, pT3 tumor with <10 lymph nodes identified
risk stratification in the SWOG cohort could be improved OR positive margins). The second alternative was selected
by the addition of 1 or more patient characteristics within for further evaluation because it was associated with the
the model. All characteristics that were significantly differ- highest Harrell c-index (0.709) and log-likelihood
ent between the 2 cohorts were tested (Table 1). Of these (2649) in a data set that combined the SWOG and devel-
variables, only margin status was associated significantly opment cohorts (Table 3).

1274 Cancer April 15, 2014

 Bladder Cancer Risk Stratification/Christodouleas et al

TABLE 2. The Association of Characteristics in the Southwest Oncology Group Cohort With Locoregional
Failure Controlling for the Original Risk Stratification

Univariate Analysis Adjusted Analysis

No. of 5-Year
a
Characteristic Patients (%) LF Rate, % SHR [95% CI] P SHR [95% CI] Pb

Age, y
<65 147 (56) 15 Ref Ref Ref Ref
65 117 (44) 17 1.25 [0.673-2.31] .48 1.087 [0.58-2.04] .80
Pathologic tumor classification
pT2 183 (69) 8 Ref Ref NA NA
pT3 81 (31) 32 4.66 [2.48-8.77] <.01
Lymph node status
Negative 212 (80) 13 Ref Ref Ref Ref
Positive 52 (20) 27 2.27 [1.17-4.39] .02 1.22 [0.62-2.41] .56
Margin status
Negative 215 (81) 10 Ref Ref Ref Ref
Positive 23 (9) NR 7.04 [3.39-14.62] <.01 3.43 [1.46-8.10] <.01
Unknown 26 (10) 31 4.36 [1.97-9.65] <.01 3.52 [1.44-8.63] <.01
No. of lymph nodes identifiedc
>10 136 (52) 12 Ref Ref NA NA
10 128 (48) 19 1.69 [0.90-3.17] .10
Neoadjuvant chemotherapy
No 134 (51) 17 Ref Ref Ref Ref
Yes 130 (49) 14 0.73 [0.39-1.36] .32 1.01 [0.53-1.92] .99

Abbreviations: CI, confidence interval; LF, locoregional failure; NA, not applicable (because the variable was included in the original risk stratification); NR, 5-
year endpoint not reached; Ref, reference variable; SHR, subhazard ratio.
a
Univariate P values.
b
Adjusted P values.
c
Values indicate the number of benign or malignant lymph nodes identified.

TABLE 3. C-Indices for the Fine and Gray Regressions of 3 Risk Stratifications in the Southwest Oncology
Group Cohort, the Development Cohort, and Both Cohorts

SWOG Cohort, Development Cohort, Combined Cohort,

N 5 238a N 5 429a N 5 667a

Risk Risk Group Log Log Log

Stratification Definitions C-Index Likelihood C-Index Likelihood C-Index Likelihood

Original Low, pT2; intermediate, 0.726 2154 0.688 2430 0.702 2652
pT3 and 10 lymph nodesb;
high, pT3 and <10 lymph nodesb
Alternative 1 Low, pT2; intermediate, 0.739 2151 0.679 2432 0.703 2652
pT3 and NM; high,
pT3 and PM
Alternative 2 Low, pT2; intermediate, 0.734 2152 0.693 2429 0.709 2649
pT3 with NM and 10 lymph
nodesb; high, pT3 with
PM or <10 lymph nodesb

Abbreviations: NM, negative margins; PM, positive margins; pT, pathologic tumor classification; SWOG, Southwest Oncology Group.
a
The number of patients in each model was fixed by excluding those with unknown margin status and those who had an unknown number of lymph nodes.
b
Values indicate the number of benign or malignant lymph nodes identified.

Evaluating the Revised LF Risk Stratification
By using the revised risk stratification, the 5-year LF esti-
mates were 8%, 20%, and 41% for the low-risk, interme-
diate-risk, and high-risk groups, respectively, in the
SWOG cohort (Fig. 2A) and 8%, 19%, and 41% for the
low-risk, intermediate-risk, and high-risk groups, respec-
tively, in the development cohort (Fig. 2B). Within the
SWOG cohort, the risk of LF was significantly different
between the low-risk and intermediate-risk groups (SHR,
2.60; 95% CI, 1.01-6.65; P 5 .04) and between the low-
risk and high-risk groups (SHR, 6.32; 95% CI, 3.20-
12.49; P < .01). The risk of LF differed with borderline
significance between the intermediate-risk and high-risk
groups (SHR, 2.44; 95% CI, 0.96-6.17; P 5 .06). Within

Cancer April 15, 2014 1275

Original Article

Figure 2. Risk stratification of locoregional failure (LF) is illustrated after radical cystectomy in (A) the Southwest Oncology
Group (SWOG) cohort and (B) the development cohort as follows: low risk (pathologic T2 classification or less [pT2]), interme-
diate risk (pT3 with 10 benign or malignant lymph nodes identified and negative margins [NM]), and high risk (pT3 with <10
benign or malignant lymph nodes identified or positive margins [PM]).

the development cohort, the risk of LF was significantly
different between the low-risk and intermediate-risk
groups (SHR, 2.13; 95% CI, 1.18-3.83; P 5 .01) and
between the low-risk and high risk groups (SHR, 5.70;
95% CI, 3.38-9.62; P < .01). The risk of LF also differed
significantly between the intermediate-risk and high-risk
groups (SHR, 2.68; 95% CI, 1.55-4.63; P < .01).
To better characterize the behavior of the revised
risk stratification, we evaluated the secondary endpoints
of OS and isolated DM. Within each cohort, the OS of
each risk group was significantly different from the OS for
the other risk groups (log-rank P < .01 for all pair-wise
comparisons). The 5-year OS estimates were 62%, 39%,
and 7% for the low-risk, intermediate-risk, and high-risk
groups, respectively, in the SWOG cohort (Fig. 3A) and
60%, 31%, and 10% for the low-risk, intermediate-risk,
and high-risk groups, respectively, in the development
cohort (Fig. 3B). In contrast, the 3 risk groups were not
consistently stratified with respect to the risk of isolated
DM in either the SWOG cohort or the development
cohort. The 5-year isolated DM estimates were 15%,
30%, and 38% for the low-risk, intermediate-risk, and
high-risk groups, respectively, in the SWOG cohort (Fig.
3C) and 14%, 22%, and 17% for the low-risk, intermedi-
ate-risk, and high-risk groups, respectively, in the devel-
opment cohort (Fig. 3D).
DISCUSSION
A revised risk model that included surgical margin status,
pathologic tumor classification, and the number of lymph
nodes identified stratified LF outcomes in 2 different RC
cohorts. The revised model identified subgroups that also
had significantly different OS rates but not significantly
different isolated DM rates.
LF Is an Emerging Target for Clinical Trials
Patients with medically operable, muscle-invasive urothe-
lial carcinoma of the bladder have a poor prognosis, with a
5-year OS rate of approximately 50%.1 Because of the
high rate of distant metastatic disease, much of the feder-
ally funded clinical research over the past several decades
has focused on the use of systemic chemotherapy, and
small but important gains have been confirmed with neo-
adjuvant chemotherapy.
The problem of LF has received less attention,
largely because LF rates reported in large cystectomy series

1276 Cancer April 15, 2014

 Bladder Cancer Risk Stratification/Christodouleas et al

Figure 3. (A,B) Overall survival (OS) and (C,D) isolated distant metastases (DM) are stratified according to the revised risk strati-
fication for both the Southwest Oncology Group (SWOG) cohort and the development cohort as follows: low risk (pathologic T2
classification or less [pT2]), intermediate risk (pT3 with negative margins [NM] and 10 benign or malignant lymph nodes
identified), and high risk (pT3 with positive margins [PM] and <10 benign or malignant lymph nodes identified).

have underestimated the risk. Few series used routine only site of recurrence.4-8 More recently, LF after RC has
postoperative surveillance imaging of the pelvis to detect been recognized increasingly as a significant problem in
LF, and most series reported LF only if it was the first and patients who present with locally advanced disease. LF as

Cancer April 15, 2014 1277

Original Article
the first evidence of recurrent disease for patients who
have extravesical disease or positive lymph nodes in the
University of Ulm series, in which surveillance pelvic CT
scanning was used, can be estimated from data in the arti-
cle at approximately 31%.9 The University of Texas MD
Anderson Cancer Center experience in clinically staged
patients, most of whom received chemotherapy, revealed
5-year LF rates after RC of 29% and 44%, respectively for
patients with clinical T3b (cT3b) and cT4 disease.10,11 In
an international trial of neoadjuvant chemotherapy for
muscle-invasive bladder cancer, the subset of patients who
had RC had a locoregional recurrence rate of approxi-
mately 40%.12
The hypothesis that reducing locoregional recur-
rences may improve disease-free survival by eliminating
a potential source of DM is supported by several studies.
In the report from The University of Texas MD Ander-
son Cancer Center, pelvic failures typically preceded the
emergence of DM and very uncommonly occurred after
the development of metastases, suggesting that reseeding
of the pelvis from distant disease is unusual and that
some distant sites may be seeded from locally recurrent
disease.11 That same study indicated that locoregional
recurrence was an independent variable predicting DM,
a finding replicated by others.13 The observation that
survival is enhanced with more extensive lymph node
dissections, even in the absence of lymph node metasta-
sis,14 suggests that the eradication of unrecognized mi-
croscopic lymph node disease in the pelvis may improve
survival by decreasing distant as well as local failure. The
study of adjuvant locoregional therapy is also encour-
aged by results from an older randomized trial of adju-
vant radiation from the National Cancer Institute of
Egypt.15 Although that trial mainly involved squamous
cell carcinoma, urothelial carcinoma represented 20% of
cases, and there appeared to be similar benefits to adju-
vant RT regardless of histology.15 Postoperative radia-
tion also was identified as an independent predictor of
improved cancer-free survival in a small Italian study.16
Consequently, several institutions, including the Univer-
sity of Pennsylvania,17,18 Emory University (Ashesh Jani
and Joseph Shelton, personal communication, June 22,
2013), and the Radiation Therapy Oncology Group
(RTOG) (Libni Eapen, personal communication, March
9, 2013), are developing or have developed clinical trials
of adjuvant RT for subsets of higher risk patients with
urothelial carcinoma. These efforts would be improved
by a rigorous understanding of which subsets of patients
are most likely to benefit and how these patients should
be stratified.
1278
Margin Status Improves LF Risk Stratification
To our knowledge, this is the first study attempting to
externally validate a model of LF risk after RC. The original
model, which was developed in a large and heterogeneous
single-institution database, included 2 variables: pT classifi-
cation at cystectomy and the number of lymph nodes iden-
tified. This risk stratification was not fully validated in the
SWOG 8710 cohort, because LF in the intermediate-risk
and high-risk groups was not significantly different (Fig.
2). Regression analysis suggested that the inclusion of surgi-
cal margin status along with the original stratification varia-
bles could significantly improve LF risk modeling within
the SWOG patient population. Within the SWOG cohort,
margin status was a stronger independent predictor of LF
than the number of lymph nodes identified. However,
when margin status was initially considered as a risk factor
in the development cohort, it was not an independent pre-
dictor of outcome in models that included the number of
lymph nodes identified.3
There are at least 2 reasons why the relative impor-
tance of margin status and the number of lymph nodes
identified may have differed between the 2 groups. First,
in the development cohort, in which a majority of patients
had 10 lymph nodes identified (76%), a more limited
lymph node dissection may have been used for patients
whose operative goals were palliative. In these patients,
achieving a negative margin also may have been less of a
surgical priority. The co-occurrence of these 2 outcomes
in a small subset of palliative patients may have exacer-
bated the problem of collinearity in the regression analysis
and obscured the independent association of margin sta-
tus and LF in the development cohort. Information on
surgical intent was not available in the development data-
base, but it likely included some palliative patients,
because the database contained all of the RCs performed
on nonmetastatic patients at a single institution over an
18-year period. In contrast, the SWOG cohort explicitly
did not include patients who were treated with palliative
intent, thus minimizing the potential of a confounded
relation between margin status and the number of lymph
nodes identified.
Second, variability in the anatomic extent of lymph-
adenectomy and the way lymph nodes were pathologically
assessed also may have influenced the relative importance
of lymph node yield and margin status. There were >100
institutions represented in the SWOG data set. Variability
in the pelvic lymph node dissection and the approach to
counting lymph nodes across these institutions would
tend to decrease this outcome’s explanatory power. In the
development data set, however, all patients were treated
Cancer April 15, 2014

and evaluated at a single institution by subspecialized
urologists and pathologists according to standardized pro-
tocols, which perhaps better preserved a correlation
between the number of lymph nodes identified and LF.
The revised LF model identifies subgroups that have
significantly different OS, confirming its clinical rele-
vance. It is noteworthy that these subgroups do not have
significantly different rates of isolated DM, which sug-
gests that the stratification is not simply a marker of meta-
static potential and provides information complementary
to existing models that predict any recurrence risk or
disease-free survival.19
Notably absent from the risk-stratification model is
an association between receipt of chemotherapy and LF.
In the SWOG data set, in which patients were random-
ized to receive neoadjuvant MVAC, chemotherapy was
not significantly associated with LF on univariate analysis,
and adjusting for other predictors of LF decreased the
likelihood of any potential correlation (Table 2). It is pos-
sible that patients who are at risk for LF may simply have
too great a burden of disease within the pelvis to be mean-
ingfully impacted by the chemotherapy regimens used for
these patients.
Another interesting finding is the absence of patho-
logic lymph node status as a predictor of LF. This variable
has been used to select patients for adjuvant RT in the
past,15,20 but the inclusion of pathologic lymph node sta-
tus failed to improve our model in either the development
cohort or the SWOG cohort, suggesting that positive
lymph node status as a predictor of pelvic failure is less sig-
nificant than pathologic tumor classification, margin sta-
tus, and the extent of lymph node dissection, probably
because the competing risk of early DM in lymph node-
positive patients is so high.
Limitations
This study has several important limitations. First,
because the revised LF risk rubric was developed using
both cohorts, external validation in additional data sets is
warranted. Moreover, both data sets used in this study
included only patients who received treatment in the
United States, so it is important to validate the model in
a regionally distinct cohort in which surgical techniques
and pathologic assessment protocols may differ. Second,
although this study was completed in part to inform the
design of clinical trials, the LF estimates reported here,
and in any retrospective cohort study, may be higher
than the LF estimates in the observation arm of a pro-
spective study of adjuvant therapy. A proportion of these
patients (especially those in the high-risk group) develop
Cancer April 15, 2014
Bladder Cancer Risk Stratification/Christodouleas et al
LF rapidly after RC (Fig. 1) and are unlikely to be eligi-
ble long enough to be enrolled in a prospective protocol.
This effect should be accounted for when powering
trials.
Conclusion
A revised risk model that included surgical margin status,
pathologic tumor classification, and the number of lymph
nodes identified stratified LF outcomes in 2 significantly
different RC cohorts. This model may represent an im-
portant step toward developing rigorous clinical trials of
adjuvant locoregional therapy for bladder cancer.
FUNDING SUPPORT
Mr. Tucker reports grants from Howard Hughes Medical Institute
via Swarthmore College during the conduct of the study.
CONFLICT OF INTEREST DISCLOSURES
Dr. Christodouleas reports employee status at Elekta, AB.
REFERENCES
1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemo-
therapy plus cystectomy compared with cystectomy alone for locally
advanced bladder cancer. N Engl J Med. 2003;349:859-866
2. Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influ-
ence bladder cancer outcomes: a cooperative group report. J Clin
Oncol. 2004;22:2781-2789.
3. Baumann BC, Guzzo TJ, He J, et al. A novel risk stratification to pre-
dict local-regional failures in urothelial carcinoma of the bladder after
radical cystectomy. Int J Radiat Oncol Biol Phys. 2013;85:81-88.
4. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the
treatment of invasive bladder cancer: long-term results in 1,054
patients. J Clin Oncol. 2001;19:666-675.
5. Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystec-
tomy for bladder cancer today—a homogeneous series without neo-
adjuvant therapy. J Clin Oncol. 2003;21:690-696.
6. Millikan R, Dinney C, Swanson D, et al. Integrated therapy for
locally advanced bladder cancer: final report of a randomized trial of
cystectomy plus adjuvant M-VAC versus cystectomy with both pre-
operative and postoperative M-VAC. J Clin Oncol. 2001;19:4005-
4013.
7. Hassan JM, Cookson MS, Smith JA Jr, Chang SS. Patterns of initial
transitional cell recurrence in patients after cystectomy. J Urol. 2006;
175:2054-2057.
8. Advanced Bladder Cancer Overview Collaboration. Neoadjuvant
chemotherapy for invasive bladder cancer [serial online]. Cochrane
Database Syst Rev. 2005;(2):CD005246.
9. Volkmer BG, Kuefer R, Bartsch GC Jr, Gust K, Hautmann RE.
Oncological follow-up after radical cystectomy for bladder cancer-is
there any benefit? J Urol. 2009;181:1587-1593.
10. Cole CJ, Pollack A, Zagars GK, Dinney CP, Swanson DA, von
Eschenbach AC. Local control of muscle-invasive bladder cancer:
preoperative radiotherapy and cystectomy versus cystectomy alone.
Int J Radiat Oncol Biol Phys. 1995;32:331-340.
11. Pollack A, Zagars GK, Cole CJ, Dinney CP, Swanson DA,
Grossman HB. The relationship of local control to distant metastasis
in muscle invasive bladder cancer. J Urol. 1995;154:2059-2063.
12. International Collaboration of Trialists, Medical Research Council
Advanced Bladder Cancer Working Party (now the National Cancer
Res. Institute Bladder Cancer Clinical Studies Group), European
Organisation for Research and Treatment of Cancer Genito-Urinary
Tract Cancer Group, et al. International phase III trial assessing neo-
adjuvant cisplatin, methotrexate, and vinblastine chemotherapy for
1279
Original Article
muscle-invasive bladder cancer: long-term results of the BA06 30894
trial. J Clin Oncol. 2011;29:2171-2177.
13. Ide H, Kikuchi E, Miyajima A, et al. The predictors of local recur-
rence after radical cystectomy in patients with invasive bladder can-
cer. Jpn J Clin Oncol. 2008;38:360-264.
14. Skinner EC, Stein JP, Skinner DG. Surgical benchmarks for the
treatment of invasive bladder cancer. Urol Oncol. 2007;25:66-71.
15. Zaghloul MS, Awwad HK, Akoush HH, Omar S, Soliman O, el
Attar I. Postoperative radiotherapy of carcinoma in bilharzial blad-
der: improved disease free survival through improving local control.
Int J Radiat Oncol Biol Phys. 1992;23:511-517.
16. Cozzarini C, Pellegrini D, Fallini M, et al. Reappraisal of the role of
adjuvant radiotherapy in muscle-invasive transitional cell carcinoma
1280
of the bladder [abstract]. Int J Radiat Oncol Biol Phys. 1999;45:221-
222.
17. Baumann BC, Guzzo TJ, He J, et al. Bladder cancer patterns of pel-
vic failure: implications for adjuvant radiation therapy. Int J Radiat
Oncol Biol Phys. 2013;85:363-369.
18. Noa K, Dolney D, Baumann BC, Bekelman JE, Christodouleas JP.
Adjuvant radiation for bladder cancer: a dosimetry study [abstract].
Int J Radiat Oncol Biol Phys. 2012;84:S420.
19. Shariat SF, Margulis V, Lotan Y, Montorsi F, Karakiewicz PI.
Nomograms for bladder cancer. Eur Urol. 2008;54:41-53.
20. Reisinger SA, Mohiuddin M, Mulholland SG. Combined pre- and
postoperative adjuvant radiation therapy for bladder cancer—a ten
year experience. Int J Radiat Oncol Biol Phys. 1992;24:463-468.
Cancer April 15, 2014