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Clinical Trials Update in Neuro-Oncology Dr Susan Short

Clinical Trials Update in Neuro-Oncology Dr Susan Short. November 2010. Chair NCRI brain tumour clinical study group CRUK Senior Fellow Consultant in Clinical Oncology, UCLH. Challenges. -0.5%. Challenges. Age distribution. From McKinney et al 2005, UK age specific incidence data

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Clinical Trials Update in Neuro-Oncology Dr Susan Short

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  1. Clinical Trials Update in Neuro-OncologyDr Susan Short November 2010

  2. Chair NCRI brain tumour clinical study group • CRUK Senior Fellow • Consultant in Clinical Oncology, UCLH

  3. Challenges -0.5%

  4. Challenges Age distribution From McKinney et al 2005, UK age specific incidence data Eurocare4 data suggest widening gap in age-related outcome

  5. Funding Annualised % spend by cancer site NCRI portfolio analysis 2006-2008

  6. Funding % spend by cancer site relative to total cancer mortality NCRI portfolio analysis 2006-2008

  7. Summary • Research questions in brain tumours • Data from recently closed studies • NCRI portfolio (and plans) • Questions

  8. Standard glioma treatment Overall Survival • Radiotherapy with concomitant and adjuvant temozolomide is associated with 5y OS ~ 12% • Majority of patients progress within 1-2 years • Salvage treatment indicated in majority; chemotherapy and/or surgery at relapse Progression Free Survival Stupp et al Lancet Oncol, May 2009.

  9. Biomarkers in glioma Subset of patients from Stupp study analysed for epigenetic regulation of repair enzyme MGMT High levels confer resistance to TMZ Down regulation of gene expression (methylation) associated with best responses to TMZ Predictive or prognostic? Should we deny TMZ to unmethylated? Hegi et al NEJM, 2008.

  10. New biomarkers • 1p 19q chromosome loss in oligodendroglioma • IDH1/2 mutation in high grade glioma • MGMT methylation in glioma Prognostic information used to group patients within studies

  11. New radiotherapy technology

  12. New radiotherapy technology Gamma knife Highly conformal Small targets Single dose

  13. New radiotherapy technology Gamma knife Highly conformal Small targets Single dose LinAc Image guidance Reproducible delivery Fractionated RT

  14. New radiotherapy technology Gamma knife Highly conformal Small targets Single dose IMRT Conformal to complex lesions LinAc Image guidance Reproducible delivery Fractionated RT

  15. New radiotherapy technology Gamma knife Highly conformal Small targets Single dose IMRT Conformal to complex lesions LinAc Image guidance Reproducible delivery Fractionated RT Protons Very sharp dose fall off High doses close to normal tissue

  16. Radiosurgery + WBRT for brain metastases EORTC 22952 study + WBRT Surgery Radiosurgery 1-3 brain metastases R - WBRT Max size 3.5cm (single) 2.5cm (multiple) Asymptomatic extracranial disease WHO 0-2 performance status Randomised Ph III study N= 340 Nov 1996 - Oct 2007

  17. Overall Survival Median: 10.9 (95%CI: 9.5-14.2) Median: 10.7 (95%CI: 9.0-14.4) Mueller, ASCO 2009 No improvement in overall survival

  18. Intracranial progression no RT 54.2% (95%CI: 46.9-61.5) WBI 31.2% (95%CI: 24.3-38.0) WBRT improved local control BUT not associated with longer survival at good PFS

  19. Conclusions from EORTC 22952 Confirmed influence of adjuvant WBRT on local control only 50% of cases randomised to no adjuvant RT avoided WBRT Justification for omitting WBRT where side effects are a concern Recent data suggest that WBRT + radiosurgery assoc withsignificantly worse memory function at 4,6 months (Chang, Lancet Oncol 2009) Opportunity for exploring other adjuvant approaches

  20. New Applications of Technology: Dose Escalation • Primary treatment of HGG • Previous approaches to dose escalation have not shown benefit • IMRT allows non-homogenous dose to tumour target • Potential to deliver ‘integrated boost’ based on sub-volumes of tumour • Means of defining boost volume critical Dose painting Cho et al. IJROBP. 2010.

  21. New Applications of Technology: Dose Escalation • Re-treatment of HGG • >30 studies in literature on glioma • Majority retrospective • Variety of techniques; brachytherapy, FSRT, Radiosurgery, conformal RT ± new agents • 2 recent reviews of the data Combs et al. J Neuro-oncol. 2008.

  22. Re-irradiation of Glioma: Target Definition • AA PET may alter target definition in relapsed high grade glioma • AA PET uptake beyond Gd-enhancement • Prospective data comparing 11-C methionine PET/123-I-a-methyl tyrosine SPECT for target definition in recurrent HGG with conventional, CT/MRI definition 44 patients (35 Gd IV, 9 Gd III) KPS 80% +TMZ in 29 patients 6x5Gy FSRT Median Survival 8 Mo Grosu et al 2005

  23. New Applications of Technology: Meningioma IMRT study at UCLH using standard dose RT for inoperable/recurrent meningioma and using PET to define tumour target

  24. Imaging research MRI is standard imaging modality Poor specificity for tumour especially following treatment Cannot define biologically distinct regions of tumour Other imaging modalities under investigation: PET, MR-spect, MR-perfusion and diffusion

  25. Imaging tumour progression Planning MRI Deterioration during adjuvant TMZ Radiological progression in high dose volume Subsequent regression Ultimate progression elsewhere Brandsma et al Lancet Oncol 08

  26. Chemotherapy for glioma • TMZ now standard with RT in GBM • Role of TMZ in other tumours? • Which chemotherapy to use at progression after RT+TMZ? • Can response to TMZ be improved by changing dose regime?

  27. BR12 Trial Histologically confirmed, recurrent WHO Grade III or IV astrocytic tumour; no prior chemotherapy RANDOMISE (1:1:2) Temozolomide Chemotherapy PCV chemotherapy Schedule A Schedule B CCNU 100mg/m2 p.o. day 1 Procarbazine 100mg/m2 p.o. days 1-10 Vincristine 1.5mg/m (max 2mg) i.v. day 1 q 6 weeks (max. 6 cycles or until progression) 200mg/m2 p.o. D1-5 q28 days 100mg/m2 p.o. D1-21 q28 days (max. 9 cycles or until progression) (max. 9 cycles or until progression) Follow-up: 12 weekly from start of chemotherapy: Neurological assessment, WHO performance status, CT/MRI scan (weeks 12 and 24 only), QoL assessment (weeks 12 and 24 only)

  28. Survival: PCV vs TMZ Median survival times (TMZ vs PCV) 7.2 vs 6.7 months HR=0.91 95% CI (0.74-1.11) p=0.35

  29. Survival: TMZ-5 vs TMZ-21 Median survival (TMZ-21 vs TMZ-5) 6.6vs 8.5months HR=1.32 95% CI (0.99, 1.75) p=0.06

  30. BR12 Summary • TMZ does not perform better than PCV in chemo-niaive • Patients • Dose dense TMZ is not better than standard dose TMZ • Biomarker analysis from these patients ongoing • ?Which should be standard treatment

  31. New drugs for glioma Ph II study of anti-VEGF targeting small molecule AZD 2171 in recurrent GBM Normalisation of vasculature Normalisation of tract structure,reduced oedema 56% radiological response rate No intra-tumoral haemorrhage From Batchelor et al, Cancer Cell 2007

  32. Issues for brain tumour research • Rare tumours • Small research community • Variable access to studies/resources • Relationship with drug industry • Relationship with national and international research community

  33. Future Look • Plethora of new agents and new technologies • Challenge to place them appropriately in brain tumour patients • Work with national/international community to address research issues in rare tumours • Continue to broaden portfolio in the UK

  34. Questions?

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