Twenty years of chemotherapy for colorectal cancer (CRC): Progress made, insights gleaned.

Abstract

596 Background: The past 20 years have seen progress in CRC therapy with more effective agents and better medical, surgical and supportive care. Methods: We conducted a systematic review of 101 phase III and large phase II trials in CRC to quantify benefit over time with first-line and subsequent therapies. Outcomes examined in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), overall survival (OS) and post-treatment survival (PTS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly the OS of CA improved 0.58 mos/yr likely reflecting use of experimental therapies in CA in subsequent studies and improvement in CRC care over time as suggested by: (1) modest improvements of PFS: 0.33 [EA] and 0.26 [CA] mos/yr; (2) PTS gains of 0.48 [EA] and 0.29 [CA] mos/yr, accounting for majority of OS gains; and (3) lack of OS improvement in 14 second/subsequent line trials. Using logistic regression to examine all drugs as class predictors of increasing OS, oxaliplatin [OX], bevacizumab [BEV], and irinotecan [IRI] were significant in the EA, but only OX and BEV were significant in the CA. Capecitabine [CAP] and cetuximab/panitumumab [CET/PAN] were not significant in EA or CA, with CAP odds ratio towards null and CET/PAN odds ratio away from null. The lack of IRI effect in CA concurs with observation that only IRI regimens had worse OS in CA compared with EA. The CET/PAN results likely reflect lack of efficacy/harm in patients with WT KRAS tumors. As expected PFS and PTS correlate highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD emerged as an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of CRC patients has improved gradually over past two decades, with gains from chemotherapy but also other factors, such as lead-time bias, more loco-regional approaches and improved supportive care. IRI performed better in EA than in CA. CET/PAN had negative effects in the entire population. In CRC, ORR correlates highly with OS, while SD portends a poor outcome.