OPTIMUM CONCEPT AND SCHEMA
Title
OPTIMUM: Optimising Perioperative Therapy in Muscle invasive
Urothelial Malignancy - an ANZUP intergroup randomised phase
3 trial of CG v accMVAC given before or after radical cystectomy.
Background and rationale
Cisplatin-based chemotherapy improves survival when given
before or after surgery for muscle-invasive urothelial cancer of
the bladder, but the optimal strategy is unknown and uptake in
routine practice is heterogeneous. Preoperative regimens are
the best tested, but have modest benefits (hazard rate 0.88),
whereas postoperative regimens are less well tested , but have
larger benefits (hazard rate 0.77).[ref] MVAC, CMV and cisplatin
and gemcitabine (CG) are the most widely used regimens.
Accelerated MVAC (accMVAC) is the most active regimen. A
large randomised phase 3 trial is needed to determine the
optimal timing and regimen.
Aim
To determine the optimal timing and regimen of perioperative
chemotherapy for muscle-invasive bladder cancer.
Objectives (endpoints)
Primary
Secondary
To determine the effects of timing and/or regimen on
1. Overall survival (death)
2. Progression-free survival (recurrence, progression or death)
3. pCR rates with preoperative chemotherapy
4. Adverse events (Grades 2-5 according to CTCAE v4.0)
5. Health-related quality of life (EQ-5D)
6. Preferences for chemotherapy
7. Resource use including health services and care
8. Associations between tissue biomarkers and outcomes
9. Associations between circulating biomarkers and outcomes
Tertiary/Correlative
Hypotheses
1. Chemotherapy given after surgery, rather than before
surgery, will reduce the hazard rate for death by 25% (HR
0.75)
2. Chemotherapy with accMVAC, rather than CG, will reduce the
hazard rate for death by 25% (HR 0.75)
3. The effects of timing (before v after) and regimen (accMVAC v
CG) are independent (without a significant interaction)
4. The effects of perioperative chemotherapy are not
significantly affected by the primary tumour site (bladder,
ureter, kidney)
Population and setting
Adults with muscle-invasive urothelial carcinoma of the bladder
suitable for radical surgery and 4 cycles of perioperative
cisplatin-based chemotherapy given before or after surgery.
Interventions
Timing: preoperative versus postoperative
Regimen: CG q3w x 4 vs MVAC q2w x 4
Planned interval between surgery and chemotherapy 4-8 weeks
Study design
Randomised factorial 2 x 2 phase 3 trial with dynamic balancing
for gender, age >70y, residual disease after TURBT and centre
Study procedures
Potential participants are identified at the MDT after TURBT and
if suitable, approached, consented, screened and randomised.
Clinical assessments are 2-3 weekly during chemotherapy;
before surgery; weeks 3, 6 and 12 after surgery; and,
thence 3 monthly to 5 years.
Statistical considerations
1000 participants recruited over 4 years and followed for
another 4 years provides 83% power to detect a hazard ratio of
0.75 (20 month improvement in median survival from 60
months to 80 months) with a 2-sided type 1 error of 0.05.
Feasibility
Target accrual of 25 participants per month from 50 sites in
Australia, Canada, UK…
Funding
Competitive grant funding from NHMRC and similar.
Chemotherapy drugs available on PBS.
Pegylated GCSF sought from manufacturer.
TURBT
(MIBC)
MDT
Shared decision making
Randomised
Pre OP
Post OP
Chemotherapy w/i 4 weeks of R
Cystectomy w/i 4 weeks of R
Cystectomy w/i 10-12 weeks of R
Chemotherapy w/i 10-12 weeks of R
CG
Acc
MVAC
CG
Acc
MVAC