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