Chemotherapy plus Radiotherapy versus Radiotherapy Alone for Patients with Anaplastic Oligodendroglioma: Long Term Results of RTOG 9402 Gregory Cairncross, Meihua Wang, Edward Shaw, Berndt Scheithauer D, Robert Jenkins, David Brachman, Jan Buckner, Karen Fink, Luis Souhami, Normand Laperriere, Walter Curran & Minesh Mehta for the RTOG, SWOG, NCCTG, NCIC CTG & ECOG 1
Disclosures Grant support from the National Cancer Institute to RTOG, SWOG, ECOG, CCOP and NCCTG and the Canadian Cancer Society Research Institute to NCIC-CTG IRB & Patient Consent No conflicts of interest 2
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) S T R A T I F Y Age < vs. KPS 60-70 vs. 80 Degree of anaplasia R A N D O M I Z E Experimental Arm Intensive-PCV x 4 (q 6 wks) then RT Standard Arm RT I-PCV = procarbazine, CCNU (lomustine) and vincristine SURVIVAL 4
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<0.001) (all-case & eligible-case analyses gave similar results) 5
Initial Conclusions 2006 Overall survival was not prolonged by PCV PCV prolonged progression-free survival, a benefit associated with acute toxicity, and only seen in the 1p19q co-deleted subset Patients with co-deleted tumors lived much longer than other patients - this beneficial effect was independent of initial treatment (median duration of follow-up was 5.1 years) 6
% ALIVE % ALIVE % ALIVE WO PROGRESSION % ALIVE % ALIVE WO PROGRESSION 75 25 Total Dead MST PCVRT 147 75 4.9 RT 142 83 4.7 75 25 Total Failed MST PCVRT 147 89 2.6 RT 142 111 1.7 Patients at risk PCVRT RT 0 0 1 2 3 4 5 6 7 YEARS FROM RANDOMIZATION 147 142 123 127 101 43 46 19 11 0 Patients at risk PCVRT RT 0 1 2 3 4 5 6 7 YEARS FROM RANDOMIZATION 147 142 99 92 80 63 33 19 13 4 Patients at risk 1p,19q deleted one, neither 75 25 0 Total Dead MST 1p,19q deleted 93 32 - one, neither 108 78 2.8 0 1 2 3 4 5 6 7 YEARS FROM RANDOMIZATION 93 108 88 86 79 64 41 26 15 7 75 25 Patients at risk PCVRT; p19q deleted RT; 1p19q deleted PCVRT; one, neither RT; one, neither 0 0 1 2 3 4 5 6 7 YEARS FROM RANDOMIZATION 43 57 51 * Total Dead MST PCVRT; 1p19q deleted 43 13 - RT; 1p19q deleted 19 6.6 PCVRT; one, neither 57 38 2.7 RT; one, neither 51 40 2.8 41 47 44 42 37 42 34 30 17 24 13 13 10 5 4 3 75 25 Patients at risk PCVRT; p19q deleted RT; p19q deleted PCVRT; one, neither RT; one, neither 0 0 1 2 3 4 5 6 7 YEARS FROM RANDOMIZATION 43 57 51 37 41 35 23 32 27 26 17 Total Failed MST PCVRT; 1p19q deleted 43 18 - RT; 1p19q deleted 37 2.6 PCVRT; one, neither 57 45 1.4 RT; one, neither 51 46 1.0 13 9 7 3 8 71 1 1
Limitations of 2006 Analysis Death had occurred in <% of patients with 1p19q co-deleted tumors & molecular information was missing on 30% in the trial (followed survivors & pursued missing data) 8
18 years after the first patient was randomized median follow-up 11.3 years and 1p19q data on 90% of participants 9
Overall Survival (%) All Case Overall Survival by RX 75 Median Survival PCV+RT: 4.6 years RT alone: 4.7 years (2006) 25 0 PCV+RT RT Dead 96 113 Total 148 143 p= 0.1 HR=0.79 (0.60, 1.04) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization 10
Adjusted Survival Analysis Step-wise Cox Hazards Model: [age at diagnosis, steroid use, number of lesions, neurological function, KPS, type of surgery, pure versus mixed histology, degree of anaplasia, treatment assignment and co-deletion status] Overall Survival: HR 0.67; p=0.01 11
Overall Survival (%) Overall Survival by R X for 126 Co-deleted Cases 75 (2006) Median Survival PCV+RT: 14.7 years RT alone: 7.3 years 25 0 PCV+RT RT Dead 28 47 Total 59 67 p= 0.03 HR=0.59 (0.37, 0.95) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization 12
Overall Survival (%) Overall Survival by R X for 137 Non-co-deleted Cases 75 (2006) Median Survival PCV+RT: 2.6 years RT alone: 2.7 years 25 0 PCV+RT RT Dead 58 53 Total 76 61 p= 0.39 HR=0.85 (0.58, 1.23) 0 1 2 3 4 5 6 7 8 9 10 11 12 Years after Randomization 13
No difference in median survival by R X for 1p del only, 19q del only, or neither deleted, but those with isolated 19q del lived longer 14
Conclusions from Long Term Results Median survival time is not prolonged by PCV+RT, but the adjusted survival is longer Patients with 1p19q co-deleted tumors live significantly longer after PCV+RT, but this conclusion is from an unplanned analysis Some patients with non-co-deleted tumors also live longer after PCV+RT, but currently they can not be identified in advance of R x 15
Other Conclusions 1p19q co-deletion may be a predictive as well as prognostic biomarker, but like MGMT in GBM, seems not to identify all who benefit Forthcoming analyses of cognitive function and quality of life could modify our view of PCV+RT, and data on late toxicity is sparse The standard arm in the NCCTG-led co-del trial is being revisited based on these data 16