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 cisplatin- gemcitabine followed by 2 cycles cisplatin- gemcitabine (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 toxicity215 (83%)vs108 (42%) : hospitalized30vs11 : discontinued Rx18 (7%)vs1 (<1%) : transfusions128 (49%)vs70 (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 1B 2 -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 10 9 /L and ANC ≥ 1.5 x 10 9 /L Platelets ≥ 100 x 10 9 /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 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 IB 2 -IVa Cervical cancer: Stratify for -FIGO stage -Pelvic nodal involvement -Uterine +ve on MRI Standard chemoXRT Standard chemoXRT 4 cycles Carboplatin + Paclitaxel

Intervention Gy of external beam XRT in 20 to 25 fractions plus brachytherapy Cisplatin 40mg/m 2 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/m 2

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 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

Rationale for enriching for high-risk patients Prospective audit data from 436 pts treated with primary chemoXRT for cervical cancer Median age = 63Median 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 FIGO 1 42/15727% FIGO 2 56/19029% FIGO 3 39/7748% FIGO 4a 7/1258% Relapse rate

FIGO stage 1b – 4a Staged by MRI, n=332 Corpus - 18/10617% Corpus + 103/22646% Relapse rate

FIGO stage 1b – 4a Staged by FDG-PET, n=252 Node - 26/12022% Node + 66/13250% Relapse rate Pelvic nodes 29/7539% Common Iliac nodes 14/2948% Lower Para-aortic nodes 12/1771% Upper Para-aortic nodes 11/11100% Relapse rate

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 OSPositive Negative PET nodal status 48% 70% Corpus involvement 54% 71%