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) –

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
and
of a
prior to definitive chemoradiation in women with LACC


Dose dense schedulesenhanced 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 consen t

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


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

Induction chemo (6 weeks) + CRT
FIGO 1B2- IVA
CRT alone


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