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Chemoradiation for Locally Advanced Cervical Cancer- what next?

Chemoradiation for Locally Advanced Cervical Cancer- what next?. Mary McCormack & Jonathan Ledermann NCRI Gynae Clinical Studies Group. The current status- LACC. CRT standard of care for the past decade Meta- analysis 18 RCT in CRT (Vale et al 2008)

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Chemoradiation for Locally Advanced Cervical Cancer- what next?

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  1. Chemoradiation for Locally Advanced Cervical Cancer- what next? Mary McCormack & Jonathan Ledermann NCRI Gynae Clinical Studies Group

  2. 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

  3. 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

  4. Neo-adjuvant /Induction chemotherapy -Rationale • Downstage • Eradicate micrometastases • Impact on survival ? Chemotherapy : short cycle interval 7% improvement in 5 year OS (Tierney 2003)

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

  6. 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

  7. Eligibility Criteria • 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

  8. CX II Study • Weekly Paclitaxel (80mg/m2) & Weeks 1-6 • Carboplatin (AUC2) • Followed by radical ChemoRT Weeks 7-13 (cisplatin 40 mg/m2)

  9. 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 >20% - trial to be stopped

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

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

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

  13. Results- NACT Compliance

  14. Results- Radiotherapy Compliance • 96% (44/46 ) completed RT without delay • 96% (42/44) completed brachytherapy • 78% (36/46) had minimum 4 cycles weekly cisplatin

  15. 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

  16. Conclusions -1 • 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. 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

  18. Proposed Phase 3 trial in LACC

  19. Proposal for Phase 3 trial • Include allthose suitable & fit for CRT • Stratify according to node status • Stratify according to RT dose / institution • Record tumour vol in addition to FIGO stage

  20. Proposal cont’d • Collection of tissue for translational research • Substudy of functional imaging to assess response to IC - ?DCE- MRI • QOL assessment

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

  22. 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

  23. 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

  24. 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

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