the outback trial a phase iii trial of adjuvant chemotherapy following chemoradiation as primary...
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THE OUTBACK TRIALA 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
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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 cisplatin-gemcitabine followed by 2 cycles cisplatin-gemcitabine (Duenes-Gonzalez et al)
- 9% improvement in PFS and OS at 3 years but increased toxicity
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Questions after ASCO• How manageable is the toxicity given others could
not deliver cisplatin-gemcitabine/XRT?: ≥ 1 x G3/G4 toxicity215 (83%) vs 108 (42%): hospitalized 30 vs 11: discontinued Rx 18 (7%) vs 1 (<1%) : transfusions 128 (49%) vs 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?
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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
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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
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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
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Inclusion Criteria - continuedIn 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 hysterectomyb) Parametrial involvement on MRI
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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
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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
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Objectives• Primary objective: To determine if the addition
of adjuvant chemotherapy to standard chemoXRT improves progression-free survival
• Secondary objectives: To determine • 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
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Design Stage IB2-IVa
Cervical cancer:Stratify for- FIGO stage- Pelvic nodal
involvement- Uterine +ve
on MRI
Standard chemoXRT
Standard chemoXRT
4 cyclesCarboplatin + Paclitaxel
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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 StatisticsAssuming• 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 log-
rank test and a two-tailed comparison • Power 80% and 95% confidence• Median time to recurrence = 12 months• For entire phase III: n = 650
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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
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FIGO stage 1b – 4a, n = 436FIGO stage 1b – 4a, n = 436
FIGO 1FIGO 1 42/15742/157 27%27%
FIGO 2FIGO 2 56/19056/190 29%29%
FIGO 3FIGO 3 39/7739/77 48%48%
FIGO 4aFIGO 4a 7/127/12 58%58%
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FIGO stage 1b – 4aFIGO stage 1b – 4aStaged by MRI, n=332Staged by MRI, n=332
Corpus -Corpus - 18/10618/106 17%17%Corpus +Corpus + 103/226103/226 46%46%
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FIGO stage 1b – 4aFIGO stage 1b – 4aStaged by FDG-PET, n=252Staged by FDG-PET, n=252
Node -Node - 26/12026/120 22%22%Node +Node + 66/13266/132 50%50%
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Pelvic nodesPelvic nodes 29/7529/75 39%39%Common Iliac nodesCommon Iliac nodes 14/2914/29 48%48%Lower Para-aortic nodesLower Para-aortic nodes 12/1712/17 71%71%Upper Para-aortic nodesUpper Para-aortic nodes 11/1111/11 100%100%
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Distant failure the biggest problem
Loco-regional failure in only 17/436 (4%): para-aortic = 12, pelvic = 5
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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 NegativePET nodal status 48% 70%Corpus involvement 54% 71%