External validity refers to the appropriateness of extrapolating trial outcomes from one population to another. It is a complex concept whose determinants are based more on clinical rather than statistical expertise and on factors such as selection criteria, comorbidity, or new therapies. The declining effect of docetaxel-containing triple agent regimens in first-line treatment of advanced gastric cancer is illustrative of this situation.
In 2006, the phase III TAX325 international RCT confirmed the benefit of the triplet of docetaxel combined with platin-fluoropyrimidine (DPF) in first-line. Nonetheless, the effect on overall survival (OS) of DPF vs cisplatin and 5FU was moderated (median 9.2 vs 8.6 months, hazard ratio (HR) 0.77, P-value=0.02) and was attained at the cost of substantially increased severe toxicity. The 2017 update of Wagner’s meta-analysis, with eight comparative studies, lowered the prospect of benefit (HR 0.86, 95% confidence interval (CI) 0.78-0.95). More recently, adding docetaxel to cisplatin and S-1, appraised in the Japanese JCOG1013 phase III RCT, did not enhance OS (HR 0.99, 95% CI, 0.85-1.16), although it did increase adverse events (e.g., grade 3-4 neutropenia, 59% vs 32%).
In clinical practice, this series of results revealing progressively smaller magnitude poses the clinician with a twofold question. The first is whether the effect of docetaxel varies on the basis of time factors or geographical variables, including epidemiological or clinical practice parameters. The second question is to what group of patients are RCTs of docetaxel in first line still applicable.