Review Article

Dening Progression in Nonmuscle Invasive Bladder Cancer:

It is Time for a New, Standard Denition
Donald Lamm,*, Raj Persad, Maurizio Brausi, Roger Buckley,
J. Alfred Witjes, Joan Palou, Andreas B ohle, Ashish M. Kamat,jj
Marc Colombel and Mark Soloway{
From the Department of Surgery, University of Arizona and BCG Oncology, Phoenix, Arizona (DL), Department of Urology/Surgery,
Bristol Royal Inrmary & Bristol Urological Institute, Bristol, United Kingdom (RP), Department of Urology, AUSL Modena, Modena,
Italy (MB), Department of Urology, North York General Hospital, Toronto, Ontario, Canada (RB), Department of Urology,
Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (JAW), Department of Urology, Fundaci o Puigvert,
Universitat Aut onoma de Barcelona, Barcelona, Spain (JP), Department of Urology, HELIOS Agnes Karll Hospital, Bad Schwartau,
Germany (AB), Department of Urology, MD Anderson Cancer Center, Houston, Texas (AMK), Department of Urology,
Claude Bernard University, H^ opital Edouard Herriot, Lyon, France (MC), and Department of Urology, University of Miami
School of Medicine, Miami, Florida (MS)
Purpose: Despite being one of the most important clinical outcomes in nonmuscle
invasive bladder cancer, there is currently no standard denition of disease pro-
gression. Major clinical trials and meta-analyses have used varying denitions or
have failed to dene this end point altogether. A standard denition of nonmuscle
invasive bladder cancer progression as determined by reproducible and reliable
procedures is needed. We examine current denitions of nonmuscle invasive
bladder cancer progression, and propose a new denition that will be more clini-
cally useful in determining patient prognosis and comparing treatment options.
Materials and Methods: The IBCG (International Bladder Cancer Group)
analyzed published clinical trials and meta-analyses that examined nonmuscle
invasive bladder cancer progression as of December 2012. The limitations of the
denitions of progression used in these trials were considered, as were additional
parameters associated with the advancement of nonmuscle invasive bladder
cancer.
Results: The most commonly used denition of nonmuscle invasive bladder
cancer progression is an increase in stage from nonmuscle invasive to muscle
invasive disease. Although this denition is clinically important, it fails to
include other important parameters of advancing disease such as progression to
lamina propria invasion and increase in grade.
Conclusions: The IBCG proposes the denition of nonmuscle invasive bladder
cancer progression as an increase in T stage from CIS or Ta to T1 (lamina propria
invasion), development of T2 or greater or lymph node (N) disease or distant
metastasis (M1), or an increase in grade from low to high. Investigators should
consider the use of this new denition to help standardize protocols and improve
the reporting of progression.
Key Words: urinary bladder neoplasms; disease progression;
BCG vaccine; drug therapy; administration, intravesical
DISEASE progression is recognized
as one of the most relevant clinical
outcomes in patients with NMIBC
(Ta/T1/CIS) and the prevention of
progression is a key goal in the
treatment of these patients. Despite
Abbreviations
and Acronyms
BCG bacillus Calmette-Guerin
CIS carcinoma in situ
MMC mitomycin C
NMIBC nonmuscle invasive
bladder cancer
TURBT transurethral resection
of the bladder tumor
Accepted for publication July 22, 2013.
* Correspondence: BCG Oncology, P.C., 3815
E. Bell Rd., Suite 1210, Phoenix, Arizona 85032
(telephone: 602-493-6626; FAX: 602-996-1383;
e-mail: dlamm@bcgoncology.com).
Financial interest and/or other relationship
with Sanofi Pasteur.
Nothing to disclose.
Financial interest and/or other relationship
with Ipsen, Sanofi Pasteur, Allergan, Telormedix,
Photocure, GE Healthcare, MEL Amsterdam and
TheraCoat.
jj Financial interest and/or other relationship
with Archimedes Inc., FKD, Photocure, Sanofi,
Cubist and Allergan.
{ Financial interest and/or other relationship
with GE Medical, Sanofi Pasteur, Dendreon and
Astellas.
For another article on a related
topic see page 261.
Editors Note: This article is the
rst of 5 published in this issue
for which category 1 CME credits
can be earned. Instructions for
obtaining credits are given with
the questions on pages 276 and
277.
20 j www.jurology.com
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THE JOURNAL OF UROLOGY

2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2013.07.102
Vol. 191, 20-27, January 2014
Printed in U.S.A.
the universally recognized importance of disease
progression, there is currently no standard deni-
tion of this outcome in NMIBC. Major clinical trials,
systematic reviews and meta-analyses have used
varying denitions (Appendix 1)
113
or have failed
to dene this important end point altogether. For
example, Cochrane investigators recently per-
formed a comprehensive review of gemcitabine tri-
als (including marker studies) and concluded that
progression in NMIBC ranges from 0% to 38%.
14
However, the investigators failed to dene what
qualied as disease progression in this analysis.
Similarly a randomized, placebo controlled study
on the diagnostic efcacy of 5-aminolevulinic acid
cystoscopy for tumor recurrence in NMIBC (370)
reported progression outcomes but also failed to
dene this end point.
15
Lack of a standard denition of progression makes
it difcult to determine whether an intervention
indeed prevents the advancement of NMIBC, and
may also lead to incongruous and perhaps even
inaccurate management recommendations. There-
fore, we examine some of the most commonly used
denitions of NMIBC progression, discuss the limi-
tations of these denitions, and propose a standard
denition of bladder cancer progression that will be
more relevant and clinically useful in determining
patient prognosis, selecting appropriate interven-
tions and assessing treatment response.
MATERIALS AND METHODS
A comprehensive MEDLINE search was conducted to
identify published clinical trials, systematic reviews and
meta-analyses on progression in NMIBC as of December
2012. Key words included bladder cancer, nonmuscle
invasive, disease progression, BCG, intravesical chemo-
therapy and TURBT. Reference lists of meta-analyses and
original papers were also reviewed to identify additional
applicable literature.
The members of the IBCG (the authors) met on 2
occasions (June 23, 2012 and April 6, 2013) to critically
review the identied literature and form consensus on a
new, standard denition of disease progression in NMIBC
that would improve the consistency and precision of
reports of therapeutic trials, potentially improve our
ability to compare and select treatments, and better esti-
mate the prognosis of patients with NMIBC. Recommen-
dations provided are based on group consensus.
RESULTS
Current Denitions of Progression
Lay dictionaries dene progression as the action or
process of advancing, and medical dictionaries dene
this term as increasing in extent or severity, or an
advancing or moving forward (Appendix 2).
1619
Unfortunately these denitions are too vague to be
useful as trial end points or prognostic indicators of
progression in NMIBC. Even the National Cancer
Institute denition of progression (ie the course of
a disease.as it becomes worse or spreads in the
body) is of little use in dening bladder cancer
progression.
One of the most commonly (yet inconsistently)
used denitions of progression in NMIBC is an
increase in stage from nonmuscle invasive disease
(ie stage Ta, T1 or CIS) to muscle invasive disease
(ie stage T2 or greater [stage T3, T4, lymph node
positive (N) or metastatic (M)]) (Appendix 1).
This denition of stage progression is accepted
because of the major difference in prognosis and
treatment between nonmuscle invasive and muscle
invasive disease. Once a urothelial cancer invades
the muscle or enters vascular spaces, the likelihood
of metastasis increases dramatically and the chan-
ces of curing the cancer are signicantly reduced.
While dening progression as advancing from non-
muscle invasive to muscle invasive (or higher) dis-
ease has clear clinical importance, should the term
progression be limited to this denition? Are there
other criteria of advancing disease that would pro-
vide important prognostic information or improve
the measurement of success in therapeutic clin-
ical trials?
Limitations of Current Denitions
The commonly used denition of progression as
local progression from Ta, T1 or CIS to muscle in-
vasion is likely inadequate. Clearly, death from
metastasis in a case of high grade T1 disease is
evidence of advancing disease, as is an increase in
stage from Ta noninvasive disease to T1, lamina
propria invasion. The ability of a cancer to invade
the basement membrane signals the capability to
enter small vessels and, thus, metastasize. Meta-
static urothelial cancer has a low cure rate despite
the use of systemic chemotherapy.
Lack of a proper denition of progression makes
it difcult to compare the antitumor efcacy of
therapeutic interventions, and may also lead to
inconsistent recommendations and conclusions. For
example, the landmark EORTC (European Organi-
zation for the Research and Treatment of Cancer)
trial 30911 comparing 3-week, 3-year maintenance
BCG with 3-week, 3-year maintenance epirubicin
limited the denition of progression to the develop-
ment of muscle invasive disease (ie metastases and
cancer specic mortality were excluded from this
denition).
12
Although a signicant reduction in
metastases and death from bladder cancer was
noted with maintenance BCG, the progression end
point, as dened by the authors, did not reach sta-
tistical signicance. This has led some experts to
conclude that BCG maintenance therapy does not
DEFINING PROGRESSION IN NONMUSCLE INVASIVE BLADDER CANCER 21
reduce disease progression, despite the fact that it
has been shown to signicantly reduce metastases
and bladder cancer mortality, both of which provide
important evidence of advancing disease and are the
outcomes about which patients truly care.
Randomized trials and meta-analyses that have
used broader denitions of progression encompass-
ing local stage progression, development of meta-
static disease, disease worsening and mortality
have concluded that BCG maintenance therapy
signicantly reduces the progression of NMIBC.
68
For example, in the SWOG (Southwest Oncology
Group) 8507 trial comparing maintenance vs in-
duction only BCG progression was dened as dis-
ease worsening, that is an increase in stage to T2 or
greater, or evidence of advancing disease as indi-
cated by a change in treatment strategy implying
impending progression (ie use of cystectomy, radi-
ation therapy or systemic chemotherapy).
6
After a
median followup of 90 months, maintenance BCG
signicantly improved median worsening-free
survival (p <0.04).
A meta-analysis of 9 clinical trials comparing
BCG and MMC in 2,410 patients with NMIBC
dened progression as an increase in tumor stage,
development of metastatic disease or disease wors-
ening (as dened in SWOG 8507).
8
Although the
overall analysis showed no signicant difference in
progression between BCG and MMC, a signicant
34% reduction in tumor progression was noted in
the 5 trials in which BCG maintenance therapy
was used.
A large EORTC meta-analysis of 24 trials
involving 4,863 patients dened progression as the
development of muscle invasive disease (T2 or
higher), lymph node and/or distant metastases, ev-
idence of disease worsening (as dened in SWOG
8507) or death from any cause.
7
Compared to the
control arm (TURBT alone, TURBT plus intra-
vesical chemotherapy or TURBT plus another
immunotherapy), treatment with maintenance BCG
was associated with a 37% reduction in the risk of
tumor progression (p 0.00004). Using the more
standard denition of advancement of NMIBC to
stage T2 or higher, or development of metastatic
disease, Di Stasi et al found that electromotive
MMC, alternating with BCG on a monthly treat-
ment schedule, signicantly reduced disease pro-
gression compared with monthly maintenance
BCG.
20
Given the discrepancies in progression outcomes
in therapeutic trials, a standard denition of pro-
gression is required to improve the consistency
of these reports and help better select appropriate
interventions for patients with NMIBC. In devel-
oping a new, standard denition for progression
in NMIBC, ideal criteria for the selection of
progression categories were considered, as were
other parameters of advancing disease beyond local
stage progression.
Considerations for Progression Category Selection
and Other Parameters of Advancing Disease
Progression categories should be simple and prac-
tical, and should reect true advancement of dis-
ease as determined by reproducible and reliable
procedures that are widely available. The IBCG
considered these principles when assessing the
usefulness of several parameters for dening the
progression of NMIBC.
Increase from nonmuscle invasive to muscle invasive
bladder cancer or metastatic disease. As previously
discussed, an increase in stage from nonmuscle
invasive to muscle invasive disease is the most
commonly used denition of NMIBC progression.
Once detrusor muscle is invaded, more aggressive
therapy (ie systemic combination chemotherapy fol-
lowed by radical cystectomy or pelvic irradiation
therapy) is required. Evenwithaggressivetreatment,
survival is signicantly decreased in muscle invasive
disease. The 5-year survival rates for patients
without muscle invasion have been estimated at
more than 90%, compared with 50% for patients
with muscle invasive or higher stage disease.
21,22
Therefore, the IBCG agreed that an increase from
nonmuscle invasive to muscle invasive bladder
cancer or metastatic disease should be included
in a standard denition of disease progression
(Appendix 3). Given the clinical signicance of the
development of T2 or greater, or lymph node (N)
disease, or distant metastasis (M1), the group also
suggests that this level of disease progression be
explicitly reported in clinical trials.
Increase from stage Ta to T1 disease (lamina propria
invasion). Because Ta tumors are, by denition,
conned to the basement membrane without access
to lymphatics and vessels, these lesions tend to
remain localized and, therefore, are at lower risk for
metastasis. Nonetheless, the invasive potential of
these tumors should not be ignored. A National
Bladder Cancer Study Group trial of 178 patients
with TaG1 tumors followed for up to 10 years (me-
dian 58 months) found that 3% of these patients had
progression to stage T1 disease and 2% to muscle
invasive (T2 or greater) disease.
23
An increase in
grade was also noted in 16% of subjects. Another
long-term followup study of 152 patients with
initial TaG1 tumors (mean followup 76 months)
noted stage progression in 5.3% of subjects and
grade progression in 15%.
24
High grade Ta lesions carry a high risk of inva-
sion into the lamina propria and beyond. Long-term
followup studies of patients with high grade Ta
22 DEFINING PROGRESSION IN NONMUSCLE INVASIVE BLADDER CANCER
tumors suggest that lamina propria invasion occurs
in as many as 40% of these subjects and progression
to muscle invasive disease occurs in up to 25%.
2528
Current estimates suggest that when using the
2004 WHO grading system, between 4% and 25% of
Ta lesions are classied as high grade.
29
Most T1 tumors are high grade and appear to
grow rapidly, with the potential for recurrence and
progression to invasion, metastases and death.
30
When treated with TURBT alone, between 35%
and 48% of patients with T1 tumors have progres-
sion to muscle invasive disease within 3 years.
31
Overall survival is signicantly worse in patients
with high grade T1 disease vs those with high grade
Ta disease.
32
Clearly, progression to T1 disease
indicates advancement of NMIBC that requires
more aggressive management than Ta disease.
Therefore, the IBCG agreed that progression to
lamina propria invasion (ie Ta to T1 disease) should
be included in the denition of NMIBC progression
(Appendix 3).
Increase in stage from CIS to T1 (lamina propria
invasion). Anatomically an increase in stage from
CIS (urothelium) to T1 (lamina propria invasion) is
clear evidence of disease progression, and the IBCG
recommends that this also be included in the de-
nition of stage progression (Appendix 3). However,
the group acknowledges that in the absence of
standard terminology for progression, there are no
data to compare the prognosis of patients with CIS
in whom T1 disease develops, in part because it is
often standard practice to proceed with cystectomy
in these patients.
Since the prognosis of a Ta tumor is better than
that of a T1 tumor, there is little hesitancy in
dening Ta to T1 progression. However, the prog-
nosis of diffuse symptomatic CIS may be worse than
that of a T1 tumor. Therefore, some experts may be
reluctant to dene a lesser malignancy as progres-
sion. Nonetheless, the development of invasion in
a patient with CIS clearly represents disease
progression.
Grade. Grade is a better prognostic indicator of
progression and mortality than recurrence.
28,33
A
retrospective review of 200 cases of newly diagnosed
pTa disease found the rates of tumor progression
(dened as tumor recurrence with histologically
conrmed invasion of the lamina propria [T1] or
muscularis propria [T2] and/or the presence of CIS)
were 5%, 10% and 33% in subjects with grade 1,
2 and 3 disease, respectively.
34
A cohort analysis
of 1,529 Spanish patients with NMIBC showed
the presence of grade 3 disease was the main
predictor of progression and mortality.
33
The
analysis also found no correlation between grade
and tumor recurrence. In another study of 269 cases
of pTa or pT1 bladder cancer, overall survival was
signicantly lower in cases of high grade disease.
32
Median expected overall survival was 12.4, 8.8 and
7.6 years for grade 1, 2 and 3 disease, respectively.
Based on this evidence the IBCG agreed that
increase in grade is evidence of advancing disease
that has prognostic importance, and recommends
that grade progression be included in a standard
denition of NMIBC progression (Appendix 3).
CIS is also considered an aggressive high grade
disease. The presence of CIS is a strong predictor of
progression and poor patient outcomes. Approxi-
mately 50% of patients with CIS will have pro-
gression to muscle invasion and 20% will die of
metastatic disease if treated conservatively, without
BCG or cystectomy.
35,36
A recent retrospective
review of patients with secondary CIS (ie detected
during the followup of patients with a previous
papillary tumor) treated with TURBT and BCG
showed the 5-year cumulative incidence of pro-
gression to T1 disease or higher was 32% (95% CI
27e39).
37
These subjects were also signicantly
less likely to respond within 6 months of BCG
therapy than those with primary CIS (39% vs
65%, p <0.001). Given these outcomes, the IBCG
concluded that the development of CIS in a patient
with low grade disease is a clear indication of grade
progression. Thus, it was included in the denition
of grade progression in Appendix 3. However, the
group also acknowledges that the detection rate of
CIS at initial cystoscopy is low, with up to 50% of
cases being missed with classic white light cystos-
copy (although improved detection has been noted
with photodynamic diagnosis).
38
The presence or
absence of CIS must be properly determined at
baseline for progression outcomes to be assessed
accurately. Cytology and bladder biopsies are
essential for the accurate diagnosis of CIS.
Staging and grading considerations. Although the
IBCG recommends the inclusion of stage and grade
progression in a standard denition of NMIBC
progression, the group acknowledges that evidence
of progression under this new denition relies
heavily on accurate and reproducible diagnoses
rendered by adequate TURBT and expert patho-
logical interpretation. Unfortunately there exists
inherent subjectivity in the interpretation of histo-
pathological material, with interobserver variability
in staging and grading ranging between 50% and
60%.
39
Therefore, the IBCG and current clinical
practice guidelines for NMIBC recommend close
cooperation between urologists and pathologists,
and suggest that slides be reviewed directly with
the pathologist, particularly in cases of T1, CIS
and high grade lesions,
39
or whenever stage or
grade progression is suggested. Current guidelines
DEFINING PROGRESSION IN NONMUSCLE INVASIVE BLADDER CANCER 23
further emphasize the importance of complete and
correct TURBT for accurate pathological assessment
and improved patient prognosis. The presence of
sufcient muscle in the TURBT specimen is
necessary for correct assignment of T category. In
addition, the absence of detrusor muscle in the
specimen is associated with a signicantly higher
risk of residual disease and early recurrence.
Comprehensive guidelines for the handling of
specimens and pathology reporting have recently
been published by the Pathology of Bladder Cancer
Work Group.
29
While staging and grading systems are designed
to remove subjectivity from histopathological diag-
nostic interpretation, sampling, slide preparation,
tumor heterogeneity and failure of a tumor to fall
neatly into a diagnostic category can preclude
reproducible assignment of stage and grade in
bladder tumors. This variability can have strong
implications for the patient and can impact the
determination of progression, especially in cases
where prior pathology cannot be accessed for re-
view. Furthermore, grade progression from low to
high may be subject to more interobserver vari-
ability than stage progression, and has a less clear
and solid baseline.
With stage there is a logical and anatomical
progression that increases if the tumor is not
treated effectively. In an individual patient the
cancer cells begin in the urothelium and typically
progress to invade the lamina propria and then the
muscularis propria. Stage of disease is dened as
the maximal depth of invasion regardless of the
volume of tumor in different layers. On the other
hand, urothelial carcinoma may originate as high
grade disease, with CIS being the primary example.
Papillary tumors are often heterogenic, composed of
high and low grade cells. Although the relative
distribution of high and low grade cancer in a
bladder tumor may be important, it is often not
reported. Also, the recurrence of heterogenic tumors
may be high or low grade. Despite these issues, the
development of high grade carcinoma is an impor-
tant, noteworthy prognostic feature that should
be included in the assessment of disease progres-
sion. The 2004 WHO/ISUP (International Society of
Urologic Pathology) grading system, which now
categorizes tumors as low or high grade, has been
shown to reduce interobserver variability in grading
interpretation compared to the WHO 1973 G1-G3
classication system.
34,40
Predictive factors or other parameters of advancing
disease. Several other predictive factors of progres-
sion or poor prognosis in NMIBC have been identi-
ed such as depth of lamina propria invasion,
multifocality, tumor size greater than 3 cm, early
recurrence, evidence of T1 disease on repeat TURBT,
prostate mucosa or duct involvement, and persis-
tent disease after an initial course of BCG.
33,41e44
There are several reasons for the poor prognosis
associated with these factors. Large tumor size,
for example, increases the risk of undetected
invasion of the lamina propria, especially in cases
in which no second resection has been performed.
45
In addition, multifocal tumors tend to be
underestimated in terms of pathological stage, and
the chance of complete resection decreases with the
number of tumors. Multifocality also indicates the
susceptibility of the entire urothelium to the
development of tumors (eld effect).
45
While increasing depth of invasion into the lam-
ina propria has been associated with worsening
prognosis,
42
the substages of T1a and T1b are
frequently not reported and, therefore, not available
for determining stage progression. Investigators
have further argued that it is often difcult to
consistently and accurately assess TURBT tissue
for the actual depth of invasion because of orienta-
tion and artifactual changes.
31
In a retrospective
analysis of 146 patients with primary stage T1G3
NMIBC, Palou et al found that it was not possible to
assess substage in almost 40% of the patients.
44
Similarly while T2a and T2b stages may have
prognostic importance, depth of invasion into the
detrusor muscle cannot be reliably determined
on the basis of TURBT or biopsy specimens.
46,47
Currently the Pathology of Bladder Cancer Work
Group and the WHO/ISUP do not recommend
substaging of pT1 due to the lack of widely accepted
and reproducible criteria.
29
However, they do
recommend that pathologists provide some form
of estimate of lamina propria invasion in pT1
tumors with respect to depth and/or quantity of in-
vasion (eg focal, multifocal, extensive etc). Recently
van Rhijn et al proposed a new substaging system
that discerns T1 microinvasive (T1m) and T1
extensive invasive (T1e) tumors.
48
Although pre-
liminary evidence suggests that this new system is
practical and highly predictive of T1 bladder cancer
behavior, it requires further validation in clin-
ical trials.
Although factors such as depth of lamina propria
invasion, multifocality etc may all be important
prognostic indicators for progression, the IBCG
agreed that using these parameters to dene pro-
gression would complicate the denition, rendering
it impractical and unusable by the majority of
investigators and clinicians. Thus, they were not
recommended for inclusion in the new denition
of progression. The IBCG did consider including
disease worsening (dened as cystectomy or change
in therapy indicative of more advanced disease,
including systemic chemotherapy or radiation
24 DEFINING PROGRESSION IN NONMUSCLE INVASIVE BLADDER CANCER
therapy) in the denition of NMIBC progression, as
was done by the SWOG investigators,
6
Sylvester
et al
7
and Bohle and Bock.
8
Disease worsening improves the sensitivity of
detecting disease progression in studies that do not
have access to complete primary data. More impor-
tantly, urologists know that recurrence of high
grade T1 disease after complete resection and
effective intravesical therapy is associated with an
increased risk of progression and cancer death that
can be reduced by radical cystectomy. Therefore, it
is common practice to perform cystectomy before
progression to muscle invasion occurs. While the
morbidity of cystectomy and other aggressive
treatments may make a patient feel as though his/
her disease has advanced, disease worsening does
not meet the anatomical or biological criteria of true
progression. Furthermore, the indications for cys-
tectomy in T1 disease among urologists vary so
widely, from invariably recommending cystectomy
to never recommending it as primary treatment,
that disease worsening cannot be trusted as a reli-
able, objective measure of progression. Therefore,
the IBCG agreed not to include it in the current
denition of NMIBC progression, but suggested
that it be reported as a separate outcome in future
clinical trials.
Mortality in bladder cancer typically results
from the progressive growth of metastatic tumor
that is unresponsive to therapy. While death from
disease is the ultimate stage of progression, cancer
related death can occur without biological disease
progression in some cases or may also result as a
complication of treatment. Therefore, the IBCG
recommends that mortality outcomes be recorded
and reported separately from disease progression.
CONCLUSIONS
Upon review of the available literature, the IBCG
concluded that a more inclusive and consistent
denition of progression in NMIBC is needed that
can increase sensitivity in detecting a benecial
antitumor effect, and that can be used to stan-
dardize protocols to improve reporting and com-
parison of agents. The group proposes that this new
denition encompass grade and stage progression,
including progression from low to high grade dis-
ease (including CIS), and from stage Ta or CIS to
lamina propria invasion (Appendix 3). The IBCG
also recommends that investigators examining dis-
ease progression in NMIBC consider the use of this
new denition in future trials or, at a minimum,
ensure that progression is clearly dened in publi-
cations and protocols. The group also acknowledges
that the proposed denition as shown in Appendix 3
has yet to be validated and anticipates that use
of this denition in upcoming NMIBC studies will
help provide the data required for its validation.
The IBCG further acknowledges that tumors are
often under staged on initial resection due to
incomplete resection and, therefore, emphasizes
the importance of thorough TURBT with adequate
deep and lateral margins, as well as repeat resec-
tion for high grade, T1 tumors. Given the interob-
server variability in tumor grading and staging,
and the fact that clinical decisions associated
with progression are critical, often involving a
change in treatment from bladder preservation to
cystectomy, the clinician should review the histo-
logical material directly with the pathologist
whenever possible.
ACKNOWLEDGMENTS
Julie Tasso and Sandra Steele from Complete
Medical Communications provided administrative
and editorial support through an unrestricted
educational grant from Sano Pasteur.
APPENDIX 1
Denitions of progression used in major clinical trials,
systematic reviews and meta-analyses in NMIBC
Study/Meta-Analysis Definition of Progression
Herr et al (1986)
1
Muscle infiltration, uncontrollable CIS or
superficially invasive disease requiring
change in treatment (cystectomy)
Martnez-Pi~neiro et al
(1990)
2
Development of muscle invasive (T2) disease
Herr et al (1995)
3
Development of muscle invasive (T2) disease
or metastases
Pawinski et al (1996)
4
Development of muscle invasive (T2 or higher)
disease
Cookson et al (1997)
5
Development of stage T2 or higher disease,
lymph node or distant metastasis
Lamm et al (2000)
6
[SWOG 8507]
Progression termed disease worsening
to include increase in stage to T2 or greater,
or evidence of advancing disease by major
treatment change: use of cystectomy, radiation
therapy or systemic chemotherapy
Sylvester et al (2002)
7
Development of muscle invasive disease
(T2 or higher), lymph node and/or distant
metastases, evidence of disease worsening
(cystectomy, systemic chemotherapy
and radiotherapy), death due to any cause
Bohle and Bock (2004)
8
Increase in tumor stage, development of
metastatic disease, or disease worsening
(cystectomy, systemic chemotherapy
and radiotherapy)
Malmstrom et al (2009)
9
Development of muscle invasive disease
(T2 or higher)
Divrik et al (2010)
10
Development of T2 disease
Di Lorenzo et al (2010)
11
Increase in tumor stage and grade
Sylvester et al: EORTC
30911 (2010)
12
Development of T2 disease
Oddens et al: EORTC
30962 (2013)
13
Development of T2 disease or greater
DEFINING PROGRESSION IN NONMUSCLE INVASIVE BLADDER CANCER 25
APPENDIX 2
Lay and general medical denitions of progression
Merriam-Webster
16
The action or process of progressing: advance
MedlinePlus
17
Progressive: increasing in extent
or severity; a progressive disease
Tabers Online
18
An advancing or moving forward
(Latin: progressus)
National Cancer Institute
19
In medicine, the course of a disease,
such as cancer, as it becomes worse
or spreads in the body
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APPENDIX 3
IBCG consensus denition for progression in NMIBC
Presence or development of any of the following:*
Stage progression: Development of or increase in stage to:
Lamina propria invasion:
e eg increase from Ta to T1, or CIS to T1
Muscle invasive disease (stage T2 or greater)
Lymph node (N) or distant metastasis (M1) disease
(patient must have previously been diagnosed with
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Grade progression:
Increase in grade from low to high (including CIS)
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WHO 2004 classification.
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DEFINING PROGRESSION IN NONMUSCLE INVASIVE BLADDER CANCER 27