After surgical resection, 289 patients were assigned to observation, CT alone, CRT, or CRT followed by CT (36). In addition, investigators had the option of enrolling patients in 2 similar concurrent trials (one testing CRT vs. observation and one testing CT alone vs. observation), and the data across the 3 trials were pooled for analysis. CRT regimen was similar to those of the GITSG and EORTC trials although the total radiation dose could be 40 or 60 Gy at the discretion of the treating physician. The results showed a beneficial effect of adjuvant CT upon OS, but a deleterious effect of CRT on survival. A more recent

Tivantinib price analysis included only patients from the 2 x 2 factorial Inhibitors,research,lifescience,medical design trial and again showed a benefit for adjuvant chemotherapy (37). The results of three historical trials evaluating concurrent chemo-radiotherapy (CRT) are confounded Inhibitors,research,lifescience,medical by poor design of the trials, sub-optimal compliance of the intended therapy and analysis. The GITSG study was criticized for slow accrual, small sample size, and suboptimal radiotherapy with a low dose delivered in a split-course fashion. The EORTC trial also employed suboptimal radiotherapy similar to the GITSG study. The omission of maintenance 5-FU, small sample size, high proportion of patients forgoing the assigned therapy, and the inclusion of patients with positive surgical margins without stratification

were all considered as study design flaws Inhibitors,research,lifescience,medical (38). In addition, it has been argued that statistical significance of this possible benefit is achieved with a one-sided log-rank Inhibitors,research,lifescience,medical test, which could have been justified at the time this trial was designed (P = 0.049) (39). The ESPAC-1 trial has been strongly critiqued for allowing uncontrolled and previous therapy in a substantial number of patients, introducing a selection bias in the enrollment process and using suboptimal radiotherapy (40). There was also a high rate of non-compliance to the treatment regiments, which questions Inhibitors,research,lifescience,medical the validity of any analysis and therefore its conclusions (42). As mentioned above, all trials employed an outdated radiotherapy regimen using low doses and a split-course delivery; unless and there was absence

of central radiation quality control. All of these factors could have easily adversely impacted the outcomes against the CRT arms. As evidence for this adverse impact, a recent secondary analysis of the Radiation Therapy Oncology Group (RTOG) 97-04 clinical trial showed that failure to adhere to prospectively designated criteria for radiotherapy delivery was associated with inferior survival (43). The above available randomized trials have generated conflicting results, and so the role of adjuvant CRT remains controversial. In light of this dilemma, several recent studies analyzed survival outcomes in patients who did or did not receive postoperative RT using the Surveillance, Epidemiology, and End Results (SEER) database (44)-(46).