1. Mary McCormack & Jonathan Ledermann NCRI Gynae Clinical Studies Group

2.  CRT standard of care for the past decade  Meta- analysis 18 RCT in CRT (Vale et al 2008) -absolute survival benefit of 6% at 5 years - all groups benefitted 7-10% stage I-II 3% stage III-IV

3.  Overall survival with CRT 66% at 5years (Vale 2008) – but DFS only 58%  However – in those with : positive LN large volume tumours advanced stage outcome remains poor

4.  Downstage  Eradicate micrometastases  Impact on survival ? Chemotherapy : short cycle interval 7% improvement in 5 year OS (Tierney 2003)

5.  Phase II single arm NCRI feasability study  Aim to assess response rate and toxicity of a short course of dose dense weekly chemotherapy prior to definitive chemoradiation in women with LACC

6.  Dose dense schedules- enhanced cell kill ? overcome accelerated repopulation ?  Greater dose intensity (v q 3-weekly)  Well tolerated in head & neck / ovarian cancer patients

7.  Histologically confirmed FIGO stage Ib2- IVa ( Squamous, Adenocarcinoma, Adenosquamous)  PS 0,1  Age >18,no upper limit providing deemed fit to receive CRT  Adequate renal,liver,BM function,normal ECG  Informed consen t

8.  Weekly Paclitaxel (80mg/m 2 ) & Weeks 1-6  Carboplatin (AUC2)  Followed by radical ChemoRT Weeks 7-13 (cisplatin 40 mg/m 2 )

9.  50 patients with LACC- (80% power, one sided test at 5% level to detect a response rate of at least 85%)  Toxicity rate >20% - trial to be stopped

10.  46 patients recruited from 3 centres  Median age 43 (range 23-71)  Histology -72% SCC -22% Adeno - 6% Adenosq

11.  FIGO stage IB2 - 11% II - 50% ( 3/23 +PALN) III - 33% (3/15 +PALN) Iva - 6%

12. NACT CRT  G3/4 Haematological 11%  G3/4 Non-haem tox – 11%  G3/4 Haematological 45%  G3/4 Non- haem tox 21%

14.  96% (44/46 ) completed RT without delay  96% (42/44) completed brachytherapy  78% (36/46) had minimum 4 cycles weekly cisplatin

15.  44 pts assessable for response  CR/PR - Post NACT - 68% [95% CI 52-81%] -12 Weeks post CRT - 82% [95% CI 67-92%]  Positive PALN 6 pts- 5 completed all treatment 4/5 NED

16.  Dose dense NACT with weekly C&P followed by radical CRT is feasible with acceptable toxicity  High response rate (68%) to short course of induction chemotherapy  NACT did not result in any disruption to CRT

17.  89% completed CRT within 50 days and 78% completed at least 4 cycles of cisplatin  Survival at 2 years is 79% (median FU 23.2 months)  This approach merits further investigation in a randomised phase 3 trial

18. FIGO 1B2- IVACRT alone Induction chemo (6 weeks) + CRT

19.  Include all those suitable & fit for CRT  Stratify according to node status  Stratify according to RT dose / institution  Record tumour vol in addition to FIGO stage

20.  Collection of tissue for translational research  Substudy of functional imaging to assess response to IC - ?DCE- MRI  QOL assessment

21.  Primary endpoint - OS at 5 years  Secondary endpoints- PFS Toxicity QOL Pattern relapse Relationship between functional imaging and outcome

22.  Sample size of 1100 provide 80% power to detect a 7% increase in 5 year OS ( 66 to 73%) (HR 0.75, 2 sided test at 5% level)  Assumes accrual over 4 years with 4 years FU

24. Upfront chemotherapy  Short course 6 weeks  Minimal toxicity  No disruption to CRT  Overall treatment time 13 weeks Outback chemotherapy  4 cycles q3weeks  Haem/GI tox likely to be significant  Compliance likely to be poor  Overall treatment time 20 weeks

25.  differences in expertise –radiology/ nodal staging  variations in RT dose & fractitionation  quality assurance for RT etc  Potential difficulties in delivering a protracted course of treatment & in FU These need to be addressed as the participation of colleagues in developing world & Eastern Europe is essential