Transcript Slide 1

THE OUTBACK TRIAL
A Phase III trial of adjuvant
chemotherapy following chemoradiation
as primary treatment for locally
advanced cervical cancer compared to
chemoradiation alone
Linda Mileshkin on behalf of
ANZGOG
Background
• Concurrent cisplatin and radiation the
standard of care for locally advanced disease
for some time
• Recent data at ASCO suggested additional
benefit from the use of concurrent cisplatingemcitabine followed by 2 cycles cisplatingemcitabine (Duenes-Gonzalez et al)
- 9% improvement in PFS and OS at 3 years but
increased toxicity
Questions after ASCO
• How manageable is the toxicity given others could
not deliver cisplatin-gemcitabine/XRT?
: ≥ 1 x G3/G4 toxicity
: hospitalized
: discontinued Rx
: transfusions
215 (83%)
30
18 (7%)
128 (49%)
vs
vs
vs
vs
108 (42%)
11
1 (<1%)
70 (27%)
• What about long-term toxicity? (9 vs 2 pts)
• Is the concurrent gemcitabine necessary?
• Would further cycles of additional adjuvant
chemotherapy improve the results?
• Would different drugs be better / less toxic
• Should only higher risk patients receive extra Rx?
Patterns of failure
• Majority of recurrences are distant
• Only a small percentage fail only within the
pelvis
• Distant failure (extra-pelvic) is a common
component of first relapse
• Data supports approaches to try and
decrease distant metastases in high-risk
patients by using systemic therapy
Research Plan
Design: Randomized international phase III study
Eligibility: Stage 1B2-IVa cervical cancer suitable for
primary treatment with chemoradiation with
curative intent in addition to:
• ECOG performance status 0-2
• Histological diagnosis of squamous cell carcinoma,
adenocarcinoma or adenosquamous cell carcinoma
• WBC ≥ 3.0 x 109/L and ANC ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Bilirubin ≤ 1.5 x UNL
Inclusion Criteria - continued
• ASAT/ALAT ≤ 2.5 x UNL
• Adequate renal function: creat ≤ ULN or
calculated creat clearance (CockCroft-Gault
Formula) ≥60ml/min
• No contraindication to the use of cisplatin
or paclitaxel chemotherapy
• Written informed consent
Inclusion Criteria - continued
In order to enrich the trial population for
those at high-risk of relapse, centres with
funded access to PET and/or MRI for
staging would be asked to only enroll
patients with
a) Pelvic nodal involvement on:
- staging PET scan, OR
- frozen section during surgery leading to
abandonment of planned hysterectomy
b) Parametrial involvement on MRI
Exclusion Criteria
• Previous pelvic radiotherapy
• Para-aortic nodal involvement above the level of the
common iliac nodes or L3/L4 (biopsy proven, PET
positive or >2cm on CT)
• Previous chemotherapy for this tumour
• Evidence of distant metastases
• Prior diagnosis of Crohn’s disease or ulcerative colitis
• Peripheral neuropathy > grade 2
• Patients who have undergone hysterectomy or will
have a hysterectomy as part of their initial cervix
cancer therapy
Exclusion Criteria - continued
• Patients with other invasive malignancies, with the
exception of non-melanoma skin cancer, who had
(or have) any evidence of the other cancer present
within the last 5 years
• Patients who are pregnant or lactating
• Other serious illness or medical condition that
precludes the safe administration of the trial
treatment
• HIV positive
Objectives
• Primary objective: To determine if the addition
of adjuvant chemotherapy to standard
chemoXRT improves progression-free survival
• Secondary objectives: To determine
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Overall survival rates
Acute and long-term toxicities
Patterns of disease recurrence
Feasability of accrual
Acceptability of radiation QA
Patient quality of life, including psycho-sexual health
Design
Stage IB2-IVa
Cervical cancer:
Stratify for
- FIGO stage
- Pelvic nodal
involvement
- Uterine +ve
on MRI
Standard
chemoXRT
Standard
chemoXRT
4 cycles
Carboplatin +
Paclitaxel
Intervention
• 40 - 45 Gy of external beam XRT in 20 to 25
fractions plus brachytherapy
• Cisplatin 40mg/m2 weekly during XRT
• Within 4 weeks of completion of XRT and
following recovery from toxicities, 4 cycles of
3 weekly adjuvant chemotherapy using
Carboplatin AUC 5 and Paclitaxel 175 mg/m2
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Sample size and Statistics
Assuming
• Study powered to look for increase in PFS rate
at 3 yrs of 11% (55 to 66%)
• Accrual = 4 years, follow-up = 24 months
• Gompertz survival distribution based on a logrank test and a two-tailed comparison
• Power 80% and 95% confidence
• Median time to recurrence = 12 months
• For entire phase III: n = 650
Rationale for enriching for high-risk patients
• Prospective audit data from 436 pts treated
with primary chemoXRT for cervical cancer
• Median age = 63
Median FU = 62 months
• 226/332 (68%) had corpus invasion on MRI
• 132/252 (52%) had PET +ve nodal disease
Narayan K 2006 and 2007 and 2009
FIGO stage 1b – 4a, n = 436
Relapse rate
FIGO 1 42/157
27%
FIGO 2 56/190
29%
FIGO 3 39/77
48%
FIGO 4a 7/12
58%
FIGO stage 1b – 4a
Staged by MRI, n=332
Relapse rate
Corpus - 18/106 17%
Corpus + 103/226 46%
FIGO stage 1b – 4a
Staged by FDG-PET, n=252
Relapse rate
Node Node +
26/120
66/132
Pelvic nodes
Common Iliac nodes
Lower Para-aortic nodes
Upper Para-aortic nodes
29/75
14/29
12/17
11/11
22%
50%
Relapse rate
39%
48%
71%
100%
Distant failure the biggest
problem
Loco-regional failure in only 17/436
(4%)
: para-aortic = 12, pelvic = 5
Survival rates
• 5 year OS rate 60%
• 5 year FFS rate 55%
In pts staged with PET and MRI (n=206), nodal
status by PET was the dominant prognostic
factor.
Traditional prognostic factors of FIGO stage and
clinical diameter not significant in this group
5 year OS
Positive
PET nodal status
48%
Corpus involvement 54%
Negative
70%
71%