Chemoradiation for Locally Advanced Cervical Cancer what next

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Chemoradiation for Locally Advanced Cervical
Cancer- what next?

• Mary McCormack Jonathan Ledermann NCRI Gynae
  Clinical Studies Group

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The current status- LACC

• 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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Current Status

• 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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Neo-adjuvant /Induction chemotherapy -Rationale

• Downstage
• Eradicate micrometastases
• Impact on survival ?
• Chemotherapy short cycle interval
• 7 improvement in 5
  year OS
• 
  (Tierney 2003)

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CX II Study

• 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

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Why weekly treatment ?

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

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Eligibility Criteria

• Histologically confirmed FIGO stage Ib2- IVa
• (Squamous, Adenocarcinoma,
  Adenosquamous)
• PS 0,1
• Age gt18,no upper limit providing deemed fit to
• receive CRT
• Adequate renal,liver,BM function,normal ECG
• Informed consent

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CX II Study

• Weekly Paclitaxel (80mg/m2)
• 
  Weeks 1-6
• Carboplatin (AUC2)
• Followed by radical ChemoRT Weeks
  7-13
• (cisplatin 40 mg/m2)
  

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Statistical considerations

• 50 patients with LACC- (80 power , one sided
  test at 5 level to detect a response rate of at
  least 85)
• Toxicity rate gt20 - trial to be stopped

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Results

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

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Results

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

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Results -Toxicity

• NACT

• CRT

• G3/4 Haematological 11
• G3/4 Non-haem tox 11

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

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Results- NACT Compliance
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Results- Radiotherapy Compliance

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

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Outcome

• 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

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Conclusions -1

• Dose dense NACT with weekly CP 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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Conclusions - 2

• 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

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Proposed Phase 3 trial in LACC
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Proposal for 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

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Proposal contd

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

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Outcome measures

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

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Statistics

• 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

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(No Transcript)
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What next?

• 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

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Acknowledge Address problems /limitations of
conducting a large international study where

• 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