Locally Advanced Cervical Cancer-

Mary McCormack & Jonathan Ledermann NCRI Gynae Clinical Studies Group

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

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

Downstage

Eradicate micrometastases

Impact on survival ? Chemotherapy : short cycle interval 7% improvement in 5 year OS (Tierney 2003)

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

Dose dense schedules- enhanced cell kill ? overcome accelerated repopulation ?

Greater dose intensity (v q 3-weekly) Well tolerated in head & neck / ovarian cancer patients

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 consent

Weekly Paclitaxel (80mg/m2) & Weeks 1-6 Carboplatin (AUC2)

Followed by radical ChemoRT Weeks 7-13 (cisplatin 40 mg/m2)

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

46 patients recruited from 3 centres

Median age 43 (range 23-71)

Histology -72% SCC -22% Adeno - 6% Adenosq

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

NACT CRT

G3/4 Haematological 11%

G3/4 Non-haem tox – 11%

G3/4 Haematological 45%

G3/4 Non- haem tox 21%

96% (44/46 ) completed RT without delay

96% (42/44) completed brachytherapy

78% (36/46) had minimum 4 cycles weekly cisplatin

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

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

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

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

Collection of tissue for translational research

Substudy of functional imaging to assess response to IC - ?DCE- MRI

QOL assessment

Primary endpoint - OS at 5 years

Secondary endpoints- PFS Toxicity QOL Pattern relapse Relationship between functional imaging

and outcome

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

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

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