The Role of Neoadjuvant Chemotherapy in
Bladder Preservation Approaches in
Muscle-Invasive Bladder Cancer
Carlos Stecca,* Timur Mitin,y and Srikala S. Sridhar*
Neoadjuvant chemotherapy (NAC), which aims to eliminate micrometastatic disease, has
been established as the standard of care for patients with muscle-invasive bladder cancer
(MIBC) undergoing radical cystectomy (RC). This is based on randomized controlled trials
showing a survival benefit of NAC prior to RC compared to RC alone. It was anticipated
that a similar survival benefit would also be seen when NAC was given prior to bladder
preserving approaches, but the e phase III RTOG 8903 study which explored this concept
was reported to be a negative study. However, there are a number of important caveats
to be considered. First, the profile of patients opting for bladder preservation has
changed from the older, frailer non-surgical candidates, to now also include younger, fitter
patients opting for bladder preservation and who are also more likely to tolerate NAC. In
recent years, there have also been important advances in systemic chemotherapy, immunotherapy, radiation techniques, and supportive care. As such revisitng the role of NAC
prior to bladder preserving approaches in MIBC appears warranted.
Semin Radiat Oncol 33:51−55 Ó 2022 Elsevier Inc. All rights reserved.
Introduction
A
t diagnosis, although most patients will present with
non-muscle-invasive bladder cancer (NMIBC), approximately 25% will have muscle-invasive bladder cancer
(MIBC).1 MIBC is a highly aggressive chemo-sensitive disease with nearly 50% of patients developing metastatic disease, likely owing to the presence of micrometastases at
diagnosis.1 For this reason, a multidisciplinary approach
to MIBC consisting of chemotherapy combined with local
therapies is the key to optimizing outcomes and improving
overall survival.
Abbreviations: MIBC, Muscle-Invasive Bladder Cancer; NAC, Neoadjuvant
Chemotherapy; RC, Radical Cystectomy; BP, Bladder Preservation;
MVAC, Methotrexate Vinblastine Adriamycin Cisplatin; GC, Gemcitabine Cisplatin; RT, Radiotherapy; CR, Complete Response; HR, Hazard
Ratio
*
Division of Medical Oncology and Hematology, Princess Margaret Cancer
Centre, Toronto, ON, Canada
y
Department of Radiation Medicine, Knight Cancer Institute, Oregon Health
and Science University, Portland, Oregon
No conflict of interest was reported by the authors.
Address reprint requests to Srikala S. Sridhar, Division of Medical Oncology
and Hematology, University of Toronto, Princess Margaret Cancer Centre, 700 University Ave, Toronto, ON M5G 1Z5, Canada. E-mail:
srikala.sridhar@uhn.ca
https://doi.org/10.1016/j.semradonc.2022.10.006
1053-4296/© 2022 Elsevier Inc. All rights reserved.
Neodjuvant Chemotherapy in MIBC
The mainstay of systemic treatment for patients with MIBC
has traditionally been neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy (RC) with
bilateral pelvic lymph node dissection.2 This is based on the
randomized Phase III study by Grossman et al, showing a
survival advantage for patients treated with neoadjuvant
MVAC (methotrexate, vinblastine, adriamycin, cisplatin) followed by RC, compared with RC alone (77 vs 46 months,
p = 0.06 by a 2-sided stratified log-rank test). In both groups,
a complete pathological response was associated with
improved overall survival, and this occurred more frequently
in the neoadjuvant arm (38 percent vs 15 percent, p <
0.001).3 Similarly, the long-term results of the BA06 30894
trial, which will be discussed in more detail below, also
documented a significant 16% reduction in the risk of death
with neoadjuvant chemotherapy given either prior to surgery
or radiation (HR, 0.84; 95% CI, 0.72-0.99; p=0.037).4
Dose dense MVAC (ddMVAC), which is similar to MVAC,
but administered every 2 weeks with growth factor support,
has also been studied in phase II clinical trials in the neoadjuvant setting, and has shown comparable efficacy, shorter duration of administration and better tolerance when indirectly
compared with classic MVAC.5,6 Extrapolating from the metastatic setting, another commonly used neoadjuvant regimen is
gemcitabine and cisplatin (GC). GC showed similar efficacy but
51
52
better tolerability compared to classic MVAC. In the neoadjuvant setting, a retrospective multicenter study has shown that
neoadjuvant GC and MVAC achieved comparable pCR rates
providing further evidence to support its use in this setting.7
The first and only prospective randomized Phase 3 study
in the perioperative setting to directly compare ddMVAC (6
cycles) and GC (4 cycles) is the GETUG/AFU V05 VESPER
study. This study showed a statistically significant overall
survival benefit for ddMVAC compared to GC, in the subset
of patients treated in the neoadjuvant setting (HR 0.66, 95%
CI 0.47-0.92).8 Despite these encouraging results, ddMVAC
was associated with a higher toxicity and may not be the
ideal choice for older patients or those with significant
comorbidities, where GC would still be preferred. Currently
all guidelines on the management of MIBC recommend neoadjuvant cisplatin-based combination chemotherapy for
patients undergoing RC.
Trimodality Treatment in MIBC
Despite being widely recommended, RC can be associated
with significant perioperative risk as well as diminished quality of life due to urinary, gastrointestinal, and sexual
dysfunction.9,10 Combined modality approaches using maximal transurethral resection of the bladder tumor (TURBT)
followed by chemoradiation commonly referred to as bladder preservation (BP), is an established treatment option for
patients who are medically unfit for RC or for patients that
would otherwise be candidates for RC but are seeking nonsurgical alternatives. For carefully selected patients who are
otherwise surgical candidates, Kulkarni et al have shown that
BP appears to result in similar oncologic outcomes compared
to RC. Recently, the NCCN 2020 guidelines were updated to
incorporate BP as a category 1 recommendation for the primary treatment of MIBC.11
Neoadjuvant Chemotherapy Prior to Bladder
Sparing Approaches
Until recently, most patients undergoing BP tended to
be elderly and frail with multiple comorbidities that
precluded both RC and cisplatin-based NAC. However,
it is very important to recognize that the demographics
of patients receiving BP in 2022 is rapidly changing with more and more patients who are fit, healthy and
potentially eligible for cisplatin-based NAC opting for
BP. Also, with modern anti-emetics and growth factor
support, cisplatin-based NAC chemotherapy in the
modern era is much better tolerated than it used to be,
significantly lowering the threshold of patients who can
potentially receive it. NAC works primarily by eliminating micrometastases and preventing distant recurrences
and has shown an overall survival benefit in the context of RC12-14 and especially in patients achieving a
complete pathological response. Since distant recurrences after BP approaches are similar to that seen with
RC (in the range of 22-39%),15-17 the rationale for
using NAC prior to BP is also applicable.
C. Stecca et al.
Studies of NAC Prior to Bladder Sparing
RTOG 8802
One of the first studies to address the question of NAC prior
to bladder sparing approaches was the nonrandomized
phase II RTOG 8802 study.18 This study enrolled 91 T24N0M0 patients from 1988 to 1990, who received 2 cycles
of neoadjuvant MCV (methotrexate (30 mg/m2), cisplatin
(70 mg/m2), and vinblastine (3 mg/m2)) followed by oncedaily RT to 39.6 Gy with concurrent cisplatin (70 mg/m2
every 3 weeks). RTOG 8802 showed that NAC followed by
BP was feasible and effective yielding similar survival outcomes to RC, forming the basis of the RTOG 8903 phase III
randomized study.
RTOG 8903
RTOG 8903 assigned 123 patients, from 37 centers, between
1990 and 1992, with T2-4 NX M0 MIBC to 2 cycles of neoadjuvant MCV versus no MCV, followed by once-daily pelvic
RT to 39.6 Gy and 2 cycles of concurrent cisplatin (100 mg/
m2 given 3 weeks apart).15 Tumor response was scored as a
clinical complete response (CR) when the cystoscopic
tumor-site biopsy and urine cytology results were negative.
The CR patients were treated with an additional 25.2 Gy to a
total of 64.8 Gy and 1 additional dose of cisplatin. Those
with less than a CR underwent cystectomy. After a median
follow-up of 60 months there were no significant differences
in pCR rate, or OS between the arms.
However, there are a number of important caveats related
to the interpretation of these results. First, this study was
stopped early, reaching only 71% of its expected accrual target
(123/174), and was likely underpowered to show a difference
between arms. By comparison, the Grossman study3 which
showed an overall survival benefit of NAC prior to RC,
accrued 317 patients; and the ABC meta-analysis which also
showed a 5% absolute OS benefit from NAC, was based on
patient-level data from 3005 trial patients.12 In RTOG 8903,
only 67% of patients in the NAC arm actually completed treatment (due to high rates of neutropenia and sepsis), compared
to 81% completing treatment in the arm without NAC.15 This
led to a protocol amendment where better baseline renal function was required at study entry, which led to reduced rates of
sepsis, and serves to highlight the critical importance of careful
patient selection and supportive strategies when evaluating
chemotherapy-based approaches in MIBC.
It should also be mentioned that MCV is not currently a
standard regimen in MIBC and that typically patients receive
4 cycles of NAC with modern anti-emetics and growth factors. The latter has made contemporary NAC regimens
much more tolerable with less severe hematological toxicities
and raises the question of whether repeating this study with
more patients, contemporary NAC regimens and enhanced
supportive measures may have a different result.
BA06894
Another phase III study, the BA06894, randomized 976 MIBC
patients from 1989 to 1995, to receive 3 cycles of MCV or no
MCV prior to their choice of surgery or radiotherapy (without
Seminars in Radiation Oncology
53
Table 1 Studies Assessing Neoadjuvant Chemotherapy Prior to Chemoradiation
Study
RTOG 88-02
RTOG 89-03
BA06 30894
Jiang et al.
Design
Phase II
Phase III
Arm 1: NAC followed by CRT
Arm 2: CRT alone
Phase III
Arm 1: NAC followed by CRT or surgery
Arm 2: CRT or surgery alone
Retrospective
n
NAC Regimen
Main Results
91
123
MCV x2
MCV x2
4y-survival with intact bladder of 44%
5-year survival of 48% (arm 1) vs 49% (arm 2)
976
MCV x3
Significant Increase in the 10-y OS from 30%
to 36% with NAC
57
GC x4
2-year OS of 74% and 2-year DSS of 88%
MVC, methotrexate, cisplatin and vinblastine; GC, cisplatin and gemcitabine.
radiosensitizing chemotherapy).4 After a median follow up of
8 years there was a statistically significant increase in the OS
favoring the NAC arm (HR 0.84; 95% CI, 0.72-0.99;
P = 0.037), translating into an increase in 10-year survival
from 30% to 36%.18 NAC reduced the risk of death by 26%
for patients who received RC and by 20% for patients who
received radiotherapy alone. Based on a pre-planned interaction analysis, there was no evidence to suggest that the effect
of NAC was impacted by the local definitive management.
There was however an imbalance in baseline patient characteristics between arms, where patients in the radiotherapy arm
were older and frailer, but despite this still benefited from
NAC. It is unclear if the benefit of NAC would change if
patients had received concurrent chemoradiotherapy, which is
currently the standard of care for BP approaches4 (Table 1).
Safety, Tolerability, and Efficacy of NAC
Followed by BP
More recent retrospective reports have evaluated and confirmed both the safety and efficacy of NAC followed by concurrent chemoradiation, with CR, OS, and cancer-specific
survival (CSS) rates ranging from 73% to 86%, 68% to 72%,
and 76% to 79%, respectively.19-22 In the BC2001 prospective trial 117 patients received NAC (mostly platinum-based
regimens) and then were randomized to radiotherapy (48%)
or concurrent chemoradiation with MMC-5FU (52%).23
NAC did not compromise the delivery of radical curative
treatment; and despite the use of NAC, concurrent chemoradiation still showed a non-significant trend to improved
locoregional disease control over radiation alone. Taken
together, this data suggests that NAC and concurrent chemotherapy may improve outcomes independently in MIBC, by
targeting micrometastases and local disease respectively.
Similar results were also seen in a prospective cohort
study by Thompson and colleagues.24 In this study, patients
were selected for NAC on the basis of performance status,
comorbidities and renal function; all patients received 3-6
cycles of platinum-based therapy followed by concurrent
chemoradiation with gemcitabine as the radiosensitizer. Of
the 78 patients, 38 received NAC and 40 did not. There was
no additional toxicity seen in the NAC arm, treatment completion rates were acceptable and DFS and OS were similar.
The performance-status-based patient selection for NAC is
used in many UK cancer centers today, similar to selection
criteria for NAC prior to RC. The use of NAC followed by BP
is supported by UK national guidelines, published in 2015
based on the results of BA06 30894, in which NAC is recommended regardless of the local therapy of choice − RC or BP.
This is in stark contrast to the NCCN guidelines which do
not discuss NAC prior to concurrent chemoradiation.11
Since contemporary NAC in appropriately selected
patients, using standard platinum-based regimens is well tolerated, some leading North American institutions have also
started to incorporate this strategy into their standard clinic
protocols. A retrospective analysis from the Princess Margaret Cancer Center, reported on 57 MIBC patients who
were treated initially with 2-4 cycles of GC, then evaluated
by a multidisciplinary team to determine tumor response
using imaging and cystoscopy.16 Patients with stable disease
or clinical response received concurrent chemoradiation
with weekly cisplatin 40 mg/m2 for 6 weeks. Most patients
(95%) completed planned NAC though about half required
dose reductions or delays, but still suggesting better tolerance than CMV or MVAC. All patients completed radiation
therapy, and 84% completed at least 60% of the planned
concurrent weekly cisplatin doses. Despite the fact that
patients were elderly, a quarter had hydronephrosis and
mean tumor size was 4cm, bladder-intact and OS curves
were remarkably similar to both surgical series and RTOG
bladder preservation series. Of note, presence of hydronephrosis was a significant factor affecting OS but not bladder
preservation rates, whereas presence of residual disease in
the bladder after NAC was associated with an almost 5-fold
higher risk of in-bladder recurrence. Most relapses were
locoregional and distant relapse rates were lower than what
was observed in other series, occurring in only 11% of
patients,16 which underscores the possible benefit of NAC in
treating occult micrometastases.
Patient Selection for NAC Followed by BP
In selecting patients for NAC followed by BP, it is important to
ensure adequate renal function so patients can receive cisplatin-based treatment, which is superior to carboplatin-based
approaches.25 A recently published algorithm provides important guidance in assessing cisplatin- eligibility specifically in
MIBC, and can be applied regardless of local definitive
management.26,27 Since many patients do respond to NAC,
with a proportion even having a CR, some patients who
would initially not be considered suitable for BP, may become
eligible after NAC, and be spared from having a RC.12 In the
Jiang study, a number of patients had higher risk disease
54
C. Stecca et al.
Table 2 Studies on NAC Followed by Surveillance Alone
Study
Phase
Enrollment (n)
Chemotherapy
Primary Endpoint
Retain NCT02710734
Retain 2 NCT04506554
HCRN NCT03558087
Alliance NCT03609216
II
II
II
II
78
74
76
271
AMVAC
AMVAC + Nivolumab
GC + Nivolumab
GC
MFS at 2 years
MFS at 2 years
cCR
EFS at 3 years
AMVAC, accelerated MVAC; GC, gemcitabine/cisplatin; MFS, metastasis-free survival; cCR, Clinical complete response; EVS, event-free
survival.
Figure 1 The role of neoadjuvant chemotherapy (NAC) prior to local therapy of MIBC in US and UK, based on interpretation of results of published clinical trials SWOG 8710,4 RTOG 890315 and MRC/EORTC BA06.5 (Color version
of figure is available online.)
features prior to NAC, including 25% with hydronephrosis,
28% with CIS and 11% with nodal metastasis, and yet the
study still described encouraging results, comparable with RC
series.16 Finally, there is likely no better way to select patients
for BP than based on tumor biology, and response after NAC.
Since absence of response negatively impacts outcomes with
BP,28-30 the use of both imaging and cystoscopic evaluation is
important to accurately determine response post NAC.16
independent classification systems, with broad similarities
between them and 2 major subtypes in common, luminal,
and basal. Prognosis and response to chemotherapy have
varied among subtypes,39 therefore future prospective studies taking molecular classification into consideration are
important and may help further selecting patients for the
most appropriate treatment strategy.
Conclusion
Future Directions and the Role of
Immunotherapy
There have been significant advances in the field of bladder cancer over the last 5 years. In particular, the immune checkpoint
inhibitors (ICI), antibody drug conjugates and FGFR inhibitors
have revolutionized treatment in advanced disease. These drugs
are now being evaluated in earlier disease settings.31,32 For
example, in cisplatin-ineligible MIBC patients, neoadjuvant ICI
monotherapy has shown pCR rates ranging from 31% to 38%,
in patients undergoing RC.33-35 This response rate is similar to
the overall response rates but superior to the pCR rates
observed with carboplatin-based regimens.25,36 Despite an
unpredictability of late immune-related side effects, in general
neoadjuvant ICIs were well tolerated. These results have in part
paved the way for other neoadjuvant trials in cisplatin-eligible
and ineligible MIBC patients combining chemotherapy and
ICIs, or combining antibody drug conjugates and ICIs.37,38
Although these trials initially focused only on patients undergoing RC, newer trials are beginning to incorporate patients
undergoing BP approaches as well. If these novel strategies do
increase response rates and specifically pCR rates, some MIBC
patients may not require any local therapy at all, and a number
of ongoing studies are underway addressing this important
question (Table 2).
There have also been recent advances in our understanding of bladder cancer at the molecular level. There are now 4
NAC has shown significant survival benefit in large trials when
given prior to RC, especially in patients with a complete pathological response. NAC prior to BP makes logical and clinical
sense in properly selected patients, using contemporary chemotherapy regimens, antiemetics, growth factor support and
modern radiation techniques. The use of NAC is not only feasible and safe, but also an effective option for patients considering a BP approach Figure 1. The role of ICIs, ADC and
targeted therapies in this setting remains under investigation
and will hopefully improve outcomes in MIBC in the near
future. Until that time, the use of NAC in MIBC requires a
multi-disciplinary approach, in which medical oncologists,
urologists and radiation oncologists can agree on starting with
systemic therapy and then allowing tumor biology and
patients’ preferences to guide the selection of local treatment
options.
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