Pride, Prejudice, or Science: Attitudes Towards the Results of the TARGIT-A Trial of Targeted Intraoperative Radiation Therapy for Breast Cancer

There has been a divergence of attitudes to the results of the targeted intraoperative radiation therapy (TARGIT)-A trial (1, 2). In Europe and Asia, TARGIT-IntraOperative RadioTherapy (IORT) is now being included in national guidelines and is available in over 250 centers worldwide. In the United States, too, it is available in more than 60 centers; yet, it has repeatedly been subjected to fierce criticism by the same set of individuals. A recent editorial in this journal by Hepel and Wazer (3) exemplifies the latter, and we believe it necessary to address their several conceptual, scientific, and factual inaccuracies. Noninferiority We concluded (1, 2) that TARGIT-IORT was noninferior to external beam radiation therapy (EBRT). Yet, the authors allege that we claimed that the 2 treatments were equivalent, suggesting that they may not fully understand the basis of the trial design. In a noninferiority trial, if the difference between the treatments being tested (and its upper confidence limit) is less than a preset noninferiority margin, the treatments are considered noninferior even if the difference is “statistically significant” according to a log-rank test (Fig. 1). Furthermore, we recommended that TARGIT should be used during the initial lumpectomy, as in the prepathology stratum (not subgroup), where the difference between the 2 treatments was undoubtedly not statistically significant (P=.31). Finally, survival without local recurrence, where deaths are not censored, in line with recommendations by the FDA and elsewhere (4, 5), is not statistically different between the 2 arms (Fig. 2). Fig. 1 The meaning of non-inferiority: 10 examples of different scenarios that might occur in a randomized trial testing noninferiority between 2 treatments. The dots represent the absolute difference; the lines represent the confidence intervals. The green ... Fig. 2 Survival without local recurrence. This Kaplan-Meier plot is the true representation of how patients with breast cancer would fare in the first 5 years of their life after treatment with targeted intraoperative radiation therapy (TARGIT) during ... The prespecified noninferiority boundary of 2.5% absolute difference in local recurrence is very conservative and is validated in patient preference studies (6-8). It is much smaller than the 7.5% margin of the ELectron IntraOperative radioTherapy (ELIOT) trial and lower than the difference considered “acceptable” by the Cancer And Leukemia Group B (CALGB) (5% difference) and Post-operative Radiotherapy In Minimum-risk Elderly PRIME II studies (3% difference). At this boundary, TARGIT is noninferior to EBRT (Pnoninferiority<.00001). Within the trial of 3451 patients, the first 1222 patients have a median follow-up time of 5-years; the safety, efficacy, and noninferiority results in these 1222 patients were similar to those seen in all patients, as shown in Table 3 of Vaidya et al (1). The Appendix gives details of other arithmetic and factual errors of Hepel and Wazer, including those of Haviland et al (9), whom they cite.