The Role of Neoadjuvant and
Adjuvant Chemotherapy in
Muscle Invasive Bladder TCC
Scott North, MD, FRCPC, MHPE
Associate Professor, Dept. of Oncology, University of Alberta
Medical Oncologist, Cross Cancer Institute
Edmonton, AB
ACOG
June 24, 2011
Disclosure
• Honoraria received from Amgen, Pfizer,
Novartis, Janssen-Ortho
Objectives
• Discuss the scope of the problem
• Discuss potential advantages and
disadvantages of perioperative chemotherapy
approaches
• Review the pertinent literature of perioperative
chemotherapy use
• Discuss ongoing projects to optimally select
patients for treatment
• Review one center’s “real world” experience
Transitional Cell Carcinoma (TCC)
in Canada
• Canadian Cancer Society 2010 statistics
– 7,100 new cases
– 1,850 deaths
• 75% of new cases will be superficial TCC
• 25% of cases will be muscle invasive or
extravesical
• Patients with superficial disease can
progress to muscle invasive disease over
time
Peri-operative chemotherapy
Rationale
• TCC is really two separate disease entities
– Superficial versus muscle invasive
• Patients often perceive superficial disease as an
“annoyance” and not a serious threat
– 75% 5 y OS1
• Once disease is muscle invasive, the stakes are
much higher and mortality is significant
– 30-70% 5 y OS1 depending on depth of invasion (T2
versus higher)
1. US NCI, cancer.gov
Peri-operative chemotherapy
Rationale
• Deaths from TCC are generally not local
events
• Patients die as a result of metastatic
disease
• Local interventions will not deal with micrometastatic disease
• Systemic therapy must be given to
eradicate micrometastatic disease in order
to improve cure rates
Peri-operative chemotherapy
Rationale
• For many malignancies, there is clear cut
evidence for the order of therapies
– colon cancer: surgery first then
chemotherapy later
– Inflammatory breast cancer: chemo first then
local therapy
• For a long time, there was little evidence
to guide us in TCC as to optimal
sequencing
Rationale for Adjuvant Therapy
• If the bladder is the problem, deal with it
immediately
• Chemotherapy decisions can be based on
true pathology
• If perioperative treatment benefit is
modest, complete the most important
modality of therapy first
• Surgery is a “stress test” that gives you
info about tolerance for chemo
Rationale for Neoadjuvant Therapy
• Give systemic therapy when the pelvic
blood supply is intact
• in vivo chemo-sensitivity trial
• Deal with micrometastatic disease
immediately
• Patient is fitter and more able to tolerate
chemotherapy
Adjuvant Chemotherapy
• Multiple trials
– Small patient numbers ranging from 49-102
– Two trials suggest survival benefit
– Skinner et al. J Urol 1991
• 91 patients
• Included T3-4 or node positive patients
• Randomized to 4 cycles of cis/doxo/cyclo or
observation
• Median survival
– 4.3 yrs chemo
p=0.006
– 2.4 yrs observation
• Criticized - ? selection bias:
– 91 of 498 patients screened were eligible
Skinner DG et al, J Urol. 1991 Mar;145(3):459-64
Adjuvant Chemotherapy
• Stockle et al. J Urol 19951, BJU 20062
– High risk patients randomized to:
• Cystectomy
• Cystectomy + MVAC (or MVEC)
– Terminated early - only 49 patients as interim
analysis showed significant improved 3 yrs survival
• 63% vs 13%
p=0.002
– 10 yr survival data still favours chemo group
• Progression free survival 44 vs13%
• Tumour specific survival 42 vs17%
• OS 27% vs 17%
1. Stockle M et al, J Urol. 1995 Jan;153(1):47-52
2. Lehmann J, et al, BJU Int. 2006 Jan;97(1):42-7
p=0.002
p=0.007
p=0.07 trend
Adjuvant Chemotherapy
• 4 other trials – negative
However….
– All small trials
– Two trials only included bladder confined
disease
– Inferior chemotherapy - single agent cisplatin
Adjuvant chemotherapy
• Meta analysis» Cochrane Collaboration 2006
– 491 pts. from 6 trials
– Power limited
•
•
•
•
Small numbers
Impact of trials stopped early
Patients not receiving allocated rx
Patients not receiving salvage chemotherapy
– Showed a relative decrease in death of 25% in favour
of adjuvant chemotherapy (p=0.02)
– Absolute survival benefit: 9%
Cochrane Database Syst Rev. 2006 Apr 19;(2):CD006018
Neoadjuvant chemotherapy
• MRC trial (European)
– 967 patients randomized to CMV vs no
chemotherapy
– Definitive management of primary either
cystectomy or RT
– 7 yr follow shows statistically significant
benefit with neoadjuvant chemotherapy
– No subgroup analysis done to compare
cystectomy and RT groups
Lancet 354 (9178): 533-40, 1999
Neoadjuvant Chemotherapy
• INT-0800(American) study
» Confirmed results of MRC study
– 317 patients with T2 to T4a disease
– Randomized to 3 cycles of neoadjuvant
MVAC prior to cystectomy or cystectomy
alone
– Improved median survival by almost 3
years (77 months vs 46 months)
– Decreased risk of bladder cancer specific
death by 25%
– Improved OS by 5% (p=0.06)
Grossman et al, N Engl J Med 349 (9): 859-66, 2003
Neoadjuvant Chemotherapy
• INT-0080 continued
– Of long term survivors 85% had a
complete pathologic response at the time
of cystectomy
– cPR rates
• 38% in MVAC group
• 15% in surgery alone group (post TURBT)
• p=0.001
– Patients with T3 and T4 disease achieved
the greatest survival benefit
Neoadjuvant Chemotherapy
• Meta-analyses (3)
– Advanced Cancer Meta-analysis
Collaboration
• Included 2688 patients from 10 randomized
trials (did not include INT-0080)
• Showed increased overall survival benefit of
5% at 5 yrs p=0.016 when neoadjuvant
platinum based combination chemotherapy
used
• Not significant if only single agent cisplatin
trials were included
Advanced Bladder Cancer Meta-analysis Collaboration.: Neoadjuvant chemotherapy in
invasive bladder cancer: a systematic review and meta-analysis. Lancet 361 (9373):
1927-34, 2003
Neoadjuvant Chemotherapy
• Canadian Meta-analysis
• Winquist et al
– 2605 patients in 11 trials with stage II or stage
III disease
– 2-4 cycles of neoadjuvant chemo
– Improved OS by 6.5% p=0.006
– Mortality due to chemotherapy 1.1%
Winquist E, et al, J Urol. 2004 Feb;171(2 Pt 1):561-9
Neoadjuvant Chemotherapy
• Advanced Bladder Cancer Meta-analysis
collaboration
– Now included 11 trials with 3005 patients
– Included 98% of all known patients in
randomized trials using cisplatin based
combination chemotherapy
– Improved OS by 5%; p=0.003
– Decreased risk of death by 14%
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.
Eur Urol. 2005 Aug;48(2):202-5
Compare and Contrast
•
•
•
•
•
Neoadjuvant
Deals with micromets
sooner
Best evidence of
benefit
Concern re: delay in
surgery
? Increased surgical
complications
Is benefit worth it?
•
•
•
•
•
Adjuvant
Treats only the
highest risk pts.
No delay in local Rx
Evidence of benefit is
weaker
Delays in healing may
preclude giving
therapy
Is benefit worth it?
Neoadjuvant chemotherapy
• Reasons for lack of wide acceptance:
– Inaccuracies in staging—needless
chemotherapy
– Delay in definitive surgery in patients that are
non-responders to chemotherapy
– Is the 5% absolutely survival improvement
worth it?
• Patient not referred or treated
CPG’s
Do they make a difference?
• Data was presented at the 2009 GU
ASCO meeting regarding uptake of
neoadjuvant consult requests in Alberta
based on our guidelines
– B. Miles, B. Eigl and others
• Two cohorts of muscle invasive TCC
patients
– Diagnosed within 18 mos. pre or post
publication of our guidelines recommending
neoadjuvant treatment
CPG impact
• Pre-Guidelines era
– 2/107 (1.5%) of patients with presumptive >T2
TCC undergoing cystectomy were referred
– No patient was offered any therapy preoperatively
• Post-Guidelines era
– 23/129 (21.5%) were referred
– 18/23 were offered treatment (cis/gem)
2009 Genitourinary Cancers Symposium, Feb 26-8, 2009,
Orlando, FL, abstract #270
CPG impact
• While referral rates have improved, there is still
significant room for improvement
• In Edmonton, our referral rate has picked up
recently
– Approximately 2-3 patients/mo referred
• Patient selection and discussion with Urology is
critical
– Not all patients are appropriate for neoadjuvant
treatment
• Urology comfort level with pre-op treatment is
higher due to good results and lack of major
perioperative complications
Can we improve patient selection
for neoadjuvant therapy?
• If global benefit is 5% improvement in
survival, can we better target the
population to treat?
• Should we only treat patients with
extravesical disease on CT
– Patients with pure T2 metastasize too
– CT/MRI isn’t wonderful at clinical staging
Who to treat?
• Pathological features
– LVI?
• Genetic markers
– p53 status?
• Other biomarkers
– Area of research
• Novel markers
• SNP’s
• Nucleoside transporters
What’s happening in the “real world”
Neoadjuvant MO survey
• 30 Canadian medical oncologists were surveyed
– 25 responded
– 90% were academic based, 50% in practice >10
years
– Half of respondents see 5-10 muscle invasive
patients/yr
– 25% see >20 cases/yr
• Sample is skewed towards those who see lots of
TCC patients
Neoadjuvant bladder cancer
survey
• All but one physician offered neoadjuvant
therapy
• Patients who are offered neoadjuvant
treatment:
– Tend to be younger (<65)
– Better PS (ECOG 0-1)
– Good renal function (GFR >40)
• Most used GC, although 20% used HDMVAC
Neoadjuvant bladder cancer
survey
• Despite MO willingness to treat, referrals
nationally remain low
• Plan is to survey Urologists to see if they
are referring or not
• Explore barriers to referral
• Highlights the ever increasing multidisciplinary nature of disease
management and need for good
communication
CCI Neoadjuvant Project
• All cases sent for neoadjuvant treatment
who were treated and have cystectomy
path available were reviewed
• 2007 to present day
• TURBT info on 62 patients; cystectomy
path on 61 currently available
• Clinical staging info based on Urology and
CT assessment available at baseline
CCI Neoadjuvant Project
• Baseline TURBT (n=62):
– T2: 30
– T3: 29
– T4: 3
• 46 men; 16 women
• No age cutoff; oldest patient is 84
• All received cisplatin based regimens
CCI Neoadjuvant Project
• Cystectomy Pathology (n=61)
– pT0:
– pTis
– pT1
– pT2 or higher
17
7
3
34
• 28% are free of all cancer after Rx
• 45% have no residual invasive disease
CCI Neoadjuvant Project
• No patient who was deemed operable out
the outset became inoperable due to time
for chemo delivery
• No perioperative mortality
• No anecdotal reporting of increased
perioperative morbidity
• DFS and OS data still being collected
CCI Neoadjuvant Project
• Significant pT0 rates can be achieved with GC
– ?comparable to MVAC
– This study is observational and not randomized
• “real life” experience in giving chemotherapy
shows it is doable if patients are properly
selected
• Once a good experience has occurred with one
patient, it begets further referrals
Neoadjuvant chemotherapy
Lessons learned
• Urologists and Med Oncs need to case
conference invasive TCC patients
• Recognition that not all patients are good
neoadjuvant chemo candidates is key
• We can’t presume to know what
magnitude of benefit a patient thinks is
“worth it” to proceed
• Having a case go smoothly dramatically
increases referrals
Conclusions
• Muscle invasive bladder cancer carries a
significant risk of mortality
• Most deaths are due to systemic disease
• Strength of evidence for perioperative
chemotherapy lies with neoadjuvant
therapy
• Treatment should be a cisplatin-based
combination therapy for a 12 week period
Conclusions
• Magnitude of benefit is similar to many other
oncology situations
– Node negative breast cancer, high risk stage II colon
cancer
• Despite evidence, referrals nationally are still
low
• Multidisciplinary care models are critical for good
outcomes
• Hopefully in the future we will be able to better
select patients for therapy