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

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%) 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?

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 - 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

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 IB2-IVa

Cervical cancer:Stratify for- FIGO stage- Pelvic nodal

involvement- Uterine +ve

on MRI

Standard chemoXRT

Standard chemoXRT

4 cyclesCarboplatin + 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

•

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

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 = 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%

Relapse rateRelapse rate

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%

Relapse rateRelapse rate

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%

Relapse rateRelapse rate

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%

Relapse rateRelapse 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 OS Positive NegativePET nodal status 48% 70%Corpus involvement 54% 71%