Two decades of therapy in metastatic colorectal cancer (mCRC): An analysis to discern the contribution and progress made by chemotherapy.

Abstract

e14064 Background: The past 20 years have seen progress in mCRC with more effective agents and better medical, surgical and supportive care. Methods: Systematic review of 101 phase III and large phase II trials in mCRC to quantify benefit over time with first-line and subsequent therapies. Outcomes in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), and overall survival (OS). 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 OS of CA improved 0.58 mos/yr likely reflecting subsequent use of experimental regimens in CA and improvement in mCRC care over time. Chemotherapy has contributed only partly to gains in OS since (1) only modest improvements of PFS (0.33 [EA] and 0.26 [CA] mos/yr) and we have shown OS gains are proportional to PFS gains indicating other factors are as or more important than chemotherapy; and (2) lack of OS improvement in 14 second/subsequent line trials. Furthermore, to assess the contribution of each drug/drug class to improvement in OS we performed linear regression with OS the dependent variable versus time publication. We found oxaliplatin, irinotecan and bevacizumab have contributed to progress; but not cetuximab/panitumumab likely explained by inclusion of pts with tumors harboring mutant ras in studies. Not surprisingly, capecitabine in place of 5-fluorouracil had no impact on progress made. As expected PFS correlates highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD was an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of mCRC patients has improved gradually over the past two decades, with gains from chemotherapy and importantly gains from other factors, including lead-time bias, better loco-regional approaches and supportive care. Gains from first line therapies have been modest but consistent; gains from second line therapies have been disappointing. We believe future progress will be more fruitful if emphasis is given to improving second line therapies.