Chemotherapy Plus Radiotherapy Versus Radiotherapy Alone For ...

Disclosures• Grant support from the National CancerInstitute to RTOG, SWOG, ECOG, CCOPand NCCTG and the Canadian CancerSociety Research Institute to NCIC-CTG• IRB & Patient Consent• No conflicts of interest2

Study Context - Circa 1992• Anaplastic oligodendrogliomas respond to PCV• Anaplastic oligoastrocytomas also respond to PCV• RT is the standard of care for all anaplastic gliomas• Dose-intense chemo thought to give better results• Genetics of oligodendroglioma being elucidated• Temozolomide chemotherapy under development• Question: Does I-PCV prior to RT prolong life?3

9402 Study Design(pure & mixed histologies)STRATIFYAge

Accrual and Other Features• 299 patients accrued at 76 institutions over 8 years• Eight randomized cases were ineligible (four / arm)• 148 randomized to PCV+RT; 143 to RT alone arm• Arms balanced for clinical and pathological factors• 46% of patients tolerated 4 full-dose cycles of I-PCV• Two deaths were attributable to I-PCV neutropenia• 79% in RT arm got “PCV” at progression (p

% ALIVE% ALIVE% ALIVE% ALIVE W/O PROGRESSION% ALIVE W/O PROGRESSION10075//////// / ////Total Dead MSTPCV/RT 147 75 4.9RT 142 83 4.7// // // / / // // / / /// // ///// //10075/ / ///Total Failed MSTPCV/RT 147 89 2.6RT 142 111 1.7/ / / / /// / // / // / / /5050/ // ////// // // //// /////// //// // // / / / // / // // ///// //// / // ///2525//// / // ///Patients at riskPCV/RTRT00 1 2 3 4 5 6 7YEARS FROM RANDOMIZATION147142123127100101434619110Patients at riskPCV/RTRT0 1 2 3 4 5 6 7YEARS FROM RANDOMIZATION147142999280633319134100Patients at risk1p,19q deletedone, neither7550250/////// //////// / / // / //// /// / /////// /// / / /// // ///Total Dead MST1p,19q deleted 93 32 -one, neither 108 78 2.8/ // ////// ///0 1 2 3 4 5 6 7YEARS FROM RANDOMIZATION93108888679644126157100755025Patients at riskPCV/RT; p19q deletedRT; 1p19q deletedPCV/RT; one, neitherRT; one, neither0/ / ////////// /// / //// / / / ////// ////// /// / /// /// // /// // / ////////0 1 2 3 4 5 6 7YEARS FROM RANDOMIZATION43505751*Total Dead MSTPCV/RT; 1p19q deleted 43 13 -RT; 1p19q deleted 50 19 6.6PCV/RT; one, neither 57 38 2.7RT; one, neither 51 40 2.8414744423742343017241313/10543100755025Patients at riskPCV/RT; p19q deletedRT; p19q deletedPCV/RT; one, neitherRT; one, neither0//// //// //// / / / / /// /0 1 2 3 4 5 6 7YEARS FROM RANDOMIZATION43505751/3741352332272617/Total Failed MSTPCV/RT; 1p19q deleted 43 18 -RT; 1p19q deleted 50 37 2.6PCV/RT; one, neither 57 45 1.4RT; one, neither 51 46 1.0//// ///13973/////////87111

Limitations of 2006 AnalysisDeath had occurred in

18 years after thefirst patient wasrandomizedmedian follow-up 11.3 years and1p/19q data on 90% of participants9

Overall Survival (%)All Case Overall Survival by RX100/75/ // // / //Median SurvivalPCV+RT: 4.6 yearsRT alone: 4.7 years50/ //(2006)/ //// / / /// / / / / /// / /250PCV+RTRTDead96113Total148143/ /// / / / / /p= 0.1HR=0.79 (0.60, 1.04)0 1 2 3 4 5 6 7 8 9 10 11 12Years after Randomization10

Adjusted Survival AnalysisStep-wise Cox Hazards Model:[age at diagnosis, steroid use, number of lesions,neurological function, KPS, type of surgery, pureversus mixed histology, degree of anaplasia,treatment assignment and co-deletion status]Overall Survival: HR 0.67; p=0.0111

Overall Survival (%)Overall Survival by R X for 126 Co-deleted Cases1007550//(2006)Median SurvivalPCV+RT: 14.7 yearsRT alone: 7.3 years/// // / ////// //250PCV+RTRTDead2847Total5967/// / /p= 0.03HR=0.59 (0.37, 0.95)0 1 2 3 4 5 6 7 8 9 10 11 12Years after Randomization12

Overall Survival (%)Overall Survival by R X for 137 Non-co-deleted Cases100/7550////(2006)Median SurvivalPCV+RT: 2.6 yearsRT alone: 2.7 years250PCV+RTRTDead5853Total7661/ / // / / / /p= 0.39HR=0.85 (0.58, 1.23)0 1 2 3 4 5 6 7 8 9 10 11 12Years after Randomization// / /13

No difference in median survival by R X for1p del only, 19q del only, or neither deleted,but those with isolated 19q del lived longer14

Conclusions from Long Term Results• Median survival time is not prolonged byPCV+RT, but the adjusted survival is longer• Patients with 1p/19q co-deleted tumors livesignificantly longer after PCV+RT, but thisconclusion is from an unplanned analysis• Some patients with non-co-deleted tumorsalso live longer after PCV+RT, but currentlythey can not be identified in advance of R x15

Other Conclusions• 1p/19q co-deletion may be a predictive aswell as prognostic biomarker, but like MGMTin GBM, seems not to identify all who benefit• Forthcoming analyses of cognitive functionand quality of life could modify our view ofPCV+RT, and data on late toxicity is sparse• The standard arm in the NCCTG-led ‘co-del’trial is being revisited based on these data16