sunwa bladder cancer dr ferguson - anzuns...conflicting results across studies cisplatin-containing...
TRANSCRIPT
SUNWA
� Management of localised MIBC
� Management of recurrent and metastatic bladder ca
Tom Ferguson
Medical Oncologist – FSH
March 2015
STATISTICS: INCIDENCE
2.1% of all
new cancers
2.1% of all
new cancers
STATISTICS: MORTALITY
2.4% of all
cancer deaths
2.4% of all
cancer deaths
STATISTICS: SURVIVAL
STATISTICS: 5 YEAR SURVIVAL
MDT - MIBC new case discussion
� What is clinical stage?
� Who should have neo-adjuvant, adjuvant or no chemo?� MVAC or GC
� Who should be considered for definitive CRT?� Cisplatin or 5FU/MMC
MUSCLE INVASIVE BLADDER CANCER
Prognosis by stage
� Stage by TNM
Stage 0 – Tis N0
Stage I – T1 N0
--------------------------------
Stage II – T2 N0
Stage III – T3-4a N0
Stage IV – all T4b, N+, M1
5-year survival
Stage 0 -- 98%
Stage I -- 88%
--------------------------------
Stage II -- 63%
Stage III -- 46%
Stage IV -- 15%
NEO-ADJUVANT THERAPY
� Ideal or best regimen not known
�Cisplatin-containing....
�MVAC
�GC
�CMV
Meta-analysis1: NEO-ADJUVANT
� Platinum-based combination chemotherapy
� 2688 individual patients from RCT
� An improvement in overall survival� HR 0.87 (95% CI 0.78-0.98)
� 5-yr OS 50% vs 45%
� Single-agent cisplatin n/s
1 Advanced Bladder Cancer Meta-analysis Collaboration, Lancet 2003
MVAC: NEO-ADJUVANT
� SWOG INT – 0080 Trial1
� 307 patients
� cT2-T4a
� Median age 63
� ECOG 0-1
� MVAC x 3 vs surgery alone
� �pCR rates 38% vs 15%
� �5yr survival 57% vs 43%
� �med OS: 77 vs 46 m (p=0.06)
- med OS T2: 105 v 75 m
- med OS T3-4: 65 v 24 m
1Grossman et al NEJM 2003
CMV: NEO-ADJUVANT
� Phase III study1
� 976 patients
� 3 x neoadjuvant CMV vs no
chemotherapy
� pCR 33%
� OS at 3 years 55 v 50% (n/s)
� Extended f/up (median of 8y)2
� 10 y OS 36 v 30% (p=0.037)
Every 28 days for 3 cycles 1Lancet 1999 2 JCO 2011
GC: NEO-ADJUVANT
� Retrospective studies in
neoadjuvant setting
� Similar rates of pCR and
survival outcomes
� In metastatic studies GC
has a better toxicity
profile
Every 28 days for a
maximum of 6
cycles
Selection of patients by stage
≤cT2 cT3/T4a and/or cN+
Immediate radicalcystectomy
Immediate radicalcystectomy
Eligible for cisplatin?
2 cycles GC
Restaging:partial or complete remission?
2 cycles GC
no
no
yes
yes
Radical cystectomy
cT2 patients
� Clinical staging under estimates staging (30% T3 or N+)
� Pivotal trials included cT2 but subgroup showed less benefit
� Prognosis of pT2 not great (5-y OS 63%)
� Difficult to assess cT2a or cT2b
Limitations of clinical staging1
� Comparison of clinical and pathologic staging
� 778 consecutive patients
� Up-staging occurred in 42% of patients
� Down-staging occurred in 22%
� For patients thought to be T2N0 or less 30% up-staged to pT3 and/or N positive
1Shariat et al Eur Urol. 2007
Selection by patient factors
� Age
� PS
� Renal function
� Social factors and safety
Selection of patients using predictive biomarkers
� No conclusive evidence is yet available on their additional value over the established clinicopathological variables
� Urinary interleukins (IL-8, IL-18)
� TNF apoptosis-inducing ligand levels
� Gene polymorphisms
� IHC stains (P53, Ki-67) seem unsuitable.
ADJUVANT THERAPY
� Quality of studies poor� Poor accrual
� Small numbers
� Conflicting results across studies
� Cisplatin-containing combination regimens
Trial evidence
2013 meta-analysis1
� 945 pt from 9 RCT
� Better OS (HR 0.77, p=0.049)
� Better DFS (HR 0.66, p=0.014)
� Did not use individual patient data
EORTC Int trial 309942
� 284 pts (planned 660)
� pT3-4 or N +
� Adjuvant chemo
Vs.
Chemo at recurrence
� 5-y PFS 48 v 32% (s/s)
� 5-y OS 54 v 48% (n/s)
1Leow et at Eur Urol. 2014 2Sternberg et al Lancet Oncol. 2015
SELECTION OF PATIENTS FOR ADJUVANT
� Good performance
status
� Creatinine clearance ≥50
mL/min
� No hearing loss
� No significant peripheral
neuropathy
� Absence of cardiac
failure
Adjuvant vs. Neoadjuvant
� 30% patients experience complications/delayed recovery after surgery precluding adjuvant chemo1
� Trial data more conclusive for neoadjuvant chemo therefore this is the preferred strategy
� Adjuvant chemo should be considered for patients not receiving neoadjuvant treatment
1Donat et al Eur Urol. 2009
OPTIMUM trial – ANZUP
MVACNeoadjuvant chemo
GCMIBC
MVACAdjuvant chemo
GC
On-hold due to funding
Bladder sparing approach
� No RCT vs. cystectomy
� 50% long-term disease free survival with CRT (appropriate selection required)
� Bladder preservation usually for:� Elderly patients with comorbidities who can’t tolerate a
cystectomy
� Patient preference
� A salvage cystectomy has to factored in for those who have not had a complete response
Definitive CRT
Good candidates for bladder sparing approach
�Tumours <5cm
�No surrounding CIS
�Early tumour stage
�Solitary tumours
�A complete TURBT
�No hydronephrosis
General schema for primary CRT
�Maximal TURBT
�64Gy combined chemotherapy
�Check cystoscopy 6 weeks post treatment to assess if salvage cystectomyrequired
Choice of concurrent chemo
Cisplatin
� Multiple RTOG trials
� All phase I/II with differing designs and use of additional chemo
� RTOG pooled analysis
� CR rate 69%
� 5-y OS 57% (24% of deaths due to bladder cancer)
� 20% cystectomy rate for those alive at 5-y
5FU + Mitomycin C
� BC2001 phase III RCT
� 360 pts
� CRT v RT alone
� 2-y locoregional control 67 v 54% (s/s)
� 5-y OS 48 v 35% (n/s)
� A good option for elderly frail patients and/or poor renal function
3D conformal radiotherapy
Metastatic disease
� 25% of patients with MIBC have or develop metastatic disease
� Median OS with combination chemo about 15 months
� Median OS prior to modern chemo about 6 months
� Patients with poor prognostic factors (liver, bone, lung mets, poor PS) have mOS around 4 months
Chemotherapy for metastatic or recurrent disease
� Platinum-sensitive � MVAC
� Cis-Gem +/- paclitaxel
� Carbo-Gem
� Platinum-resistant / second-line chemo� Response rates low (10% ORR)
� No standard option – limited value
� Options include
� Taxane
� Vinflunine
� Clinical trial
MVAC: METASTATIC
� Loehrer et al. 1992
� 269 patients
� MVAC vs cisplatin
� �pCR rates 38% vs 15%
� �ORR rates 39% vs 12%
� �median PFS 10 vs 4
months
� �OS (13 vs 8 months)
� ���� Toxicity
Every 28 days for 3 cycles
GC: METASTATIC
� Phase III MVAC v GC
� 405 pts
� Similar ORR (49 vs
36%)
� Similar mOS (14 vs 15
months)
� Similar 5 year survival
(13 vs 15%)
� Less Toxicity
-febrile neut 2% v 14%
Every 28 days for a
maximum of 6
cycles
FUTURE DIRECTIONS – targeted therapy
� Targeted therapy
� Molecular analysis demonstrate 60% of bladder cancers have
alterations which could be exploited as a molecular target
� RAS-RAF pathway
� mTOR pathway
� Regulators of cell cycle (TP53, Rb)
� Fibroblast GF
� Ongoing trials and investigation
� Case reports of response to some agents
FUTURE DIRECTIONS – targeted therapy
� Pazopanib + Paclitaxel
� GUCS March 2015
� Phase II single arm study
� Heavily pre-treated
� 31 patients
� 50% objective response (10% complete)
� mPFS 6 months
� mOS 8 months
� Significant toxicity (but manageable)
FUTURE DIRECTIONS - immunotherapy
� Targeting T-cell co-stimulation or checkpoint pathways demonstrating emerging therapeutic success in multiple cancers
� CTLA-4 inhibitor
� PD-1 inhibitors
� PDL-1, PDL-2 inhibitors
� Pembrolizumab (anti-PDL-1 and 2) ESMO 2014
� PD-1 positive tumours (IHC) – about 50% positive (different levels)
� 33 pts heavily pre-treated met urothelial ca
� ORR 24% (10% CR)
� mOS 9.3 m