Background: Pre-operative or definitive CRT is standard for locally advanced (LA) ESCC. We previously showed that PET response after induction chemo and prior to CRT and surgery strongly predicts outcomes (Cancer 118:2820; 2012). The CALGB 80803 study also revealed a benefit for changing chemo during CRT in PETnr with E adenocarcinoma (J Clin Oncol 35:1, 2017 [abstr]). Methods: We retrospectively reviewed all pts with LA ESCC who received induction chemo and CRT; all had PET scan pre- and post-induction chemo. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test. Results: 113 pts were identified, median age 64, median KPS 80%, 75% had uN+ disease. 63 (56%) received induction chemo with platinum/paclitaxel, 43 (38%) with platinum/irinotecan, 6 (5%) with docetaxel/irinotecan +/- cisplatin and 1(1%) with capecitabine/oxaliplatin. 72 pts (64%) were PET responders (PETr; ³35% decrease in mSUV of tumor) and 41 (36%) were PETnr; <35% decrease). All PETr received same chemo during RT. Of PETnr, 16 continued same chemo and 25 were changed to alternate chemo during RT. Of 106 pts evaluable for clinical complete response (cCR), 88% of PETr achieved cCR vs 57% of PETnr/no chemo change vs 60% of PETnr/chemo change (p<0.01 for PETr vs PETnr). The cCR rate was not significantly different in the PETnr/chemo change vs PETnr/no chemo change groups (p=0.86). 31 pts had resection, 30 R0; 8 had pathologic CR (7 were PETr and 1 was a PETnr/chemo change). Median progression-free (PFS; 62.1 vs. 7.1 mos, p<0.01) and overall survival (OS; 72.2 vs. 17.3 mos, p<0.01) were significantly better for PETr vs. PETnr. Median PFS and OS for PETnr/chemo change vs. PETnr/no chemo change were 6.4 vs 8.3 mos (p=0.48) and 14.2 vs 17.2 mos (p=0.79) respectively and not significantly different. Conclusions: PET scan after induction chemo highly predicts for outcomes in ESCC pts who received CRT. However, PETnr pts did not benefit from changing chemo during RT, likely reflecting underlying poor biology. Next generation sequencing is ongoing. Future trials should utilize PET after induction chemo to select PETnr pts to receive experimental therapies.