ChemoRadCervix

Mary McCormack & Jonathan Ledermann NCRI Gynae Clinical Studies Group

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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

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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

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Downstage

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Eradicate micrometastases

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Impact on survival ?

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

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Phase II single arm NCRI feasability study

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Aim to assess response rate and toxicity of a

short course of dose dense weekly chemotherapy prior to definitive

chemoradiation in women with LACC

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Dose dense schedulesenhanced cell kill ? overcome accelerated repopulation ?

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Greater dose intensity (v q 3-weekly)

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Well tolerated in head & neck / ovarian cancer patients

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Histologically confirmed FIGO stage Ib2- IVa (Squamous, Adenocarcinoma, Adenosquamous) PS 0,1

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Age >18,no upper limit providing deemed fit to receive CRT Adequate renal,liver,BM function,normal ECG

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Informed consent

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Weekly Paclitaxel (80mg/m2) & Carboplatin (AUC2) Followed by radical ChemoRT (cisplatin 40 mg/m2)

Weeks 1-6

Weeks 7-13

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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

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46 patients recruited from 3 centres

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Median age 43 (range 23-71)

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

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FIGO stage IB2 II III Iva

- 11% - 50% ( 3/23 +PALN) - 33% (3/15 +PALN) - 6%

NACT

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G3/4 Haematological 11% G3/4 Non-haem tox – 11%

CRT

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G3/4 Haematological 45% G3/4 Non- haem tox 21%

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96% (44/46 ) completed RT without delay

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96% (42/44) completed brachytherapy

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

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44 pts assessable for response

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CR/PR - Post NACT

- 68% [95% CI 52-81%]

-12 Weeks post CRT - 82% [95% CI 67-92%]

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Positive PALN 6 pts- 5 completed all treatment 4/5 NED

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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

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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

FIGO 1B2- IVA

Induction chemo (6 weeks) + CRT

CRT alone

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Include all those suitable & fit for CRT

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Stratify according to node status

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Stratify according to RT dose / institution

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Record tumour vol in addition to FIGO stage

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

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Primary endpoint -

OS at 5 years

Secondary endpointsPFS Toxicity QOL Pattern relapse Relationship between functional imaging and outcome

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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 

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Minimal toxicity No disruption to CRT Overall treatment time 13 weeks

Outback chemotherapy  4 cycles q3weeks  

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Haem/GI tox likely to be significant Compliance likely to be poor Overall treatment time 20 weeks

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differences in expertise –radiology/ nodal staging

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variations in RT dose & fractitionation

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quality assurance for RT etc

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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