Noninferiority for Short-HER or short-chemotherapy?
Authors: B.Y. Aktas, D.C. Guven, O. Dizdar
Journal: Annals of Oncology (2018)

Dear Editor, The Short-HER trial investigators reported that the noninferiority of 9 weeks trastuzumab administration compared with standard 1 year administration has failed to be shown [1.Conte P. Frassoldati A. Bisagni G. et al.9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.Ann Oncol. 2018; 29: 2328-2333Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar]. Five-year disease-free survival (DFS) was 88% in the 1 year and 85% in the 9 weeks arm. The hazard ratio was 1.13 [90% confidence interval (CI) 0.89–1.42], with the upper limit of the CI crossing the noninferiority margin. In this study, chemotherapy in arm A (trastuzumab 1 year) consisted of Adriamycin-Cyclophosphamide or Epirubicin-Cyclophosphamide administered every 3 weeks for four courses followed by paclitaxel 175 mg/m2 or docetaxel 100 mg/m2 every 3 weeks for four courses whereas chemotherapy in arm B (trastuzumab 9 weeks) consisted of docetaxel 100 mg/m2 every 3 weeks for three courses followed by 5 Fluorouracil-Epirubicin-Cyclophosphamide administered every 3 weeks for three courses. We suggest that differences in the chemotherapy backbone (i.e. higher anthracycline and taxane doses in arm A) might have confounded the results favoring the 1-year trastuzumab arm. Indeed, the recently reported SOLD trial [2.Joensuu H. Fraser J. Wildiers H. et al.Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial.JAMA Oncol. 2018; 4: 1199-1206Crossref PubMed Scopus (103) Google Scholar] which also compared 9-weeks and 1 year adjuvant trastuzumab therapy showed that a significant interaction (P=0.007) was found between docetaxel dosing and DFS; the 1678 patients who received docetaxel 80 mg/m2 had inferior and the 480 who received 100 mg/m2 had similar DFS to patients in the 1-year group treated with the same docetaxel dosing. An earlier randomized phase II study with identical chemotherapy backbones in two arms also [3.Schneider B.P. O'Neill A. Shen F. et al.Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198).Br J Cancer. 2015; 113: 1651-1657Crossref PubMed Scopus (28) Google Scholar] demonstrated that conventional 1 year trastuzumab therapy was not superior to abbreviated 12 weeks therapy. Two previous large phase III trials compared trastuzumab 6 months versus 1 year in the adjuvant setting. In the UK PERSEPHONE trial, noninferiority of the 6 months regimen was demonstrated [4.Earl H.M. Hiller L. Vallier A.-L. PERSEPHONE Trial Investigators et al.PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.J Clin Oncol. 2018; 36: 506Crossref Google Scholar] whereas in the French PHARE trial, noninferiority could not be shown [5.Pivot X. Romieu G. Debled M. PHARE Trial Investigators et al.6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 741-748Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar]. Details of the anthracycline and taxane dosing were not reported in either study but dose differences (if any) may account for the contradictory results. We propose that chemotherapy dose and schedule should also be considered as a confounder and appropriate adjustments should be made when interpreting the results of adjuvant trastuzumab duration trials. None declared.