Three-monthly Dynamic Evaluation of CEA and CA15-3 and 18-FDG PET Vs Usual Practice in the Follow-Up of Early Breast Cancer Patients: a Prospective, Multicenter, Randomized Trial (KRONOS - Patient-Oriented New Surveillance-Study Italy).

Background: Current guidelines for breast cancer (BC) surveillance in asymptomatic patients (pts) recommend only annual mammography and periodical physical examination. These recommendations arise from trials conducted in the 1980’s: since then our knowledge on breast cancer biology, diagnosis of metastases and treatment has deeply improved. The aim of this prospective randomized trial is to verify if the serial measurement of CEA and CA15-3 followed by 18-FDG PET can anticipate the diagnosis of BC recurrence compared to control arm by estimation of the difference of restricted mean survival time (RMST) between the two arms. If the end-point will be met a subsequent extension trial will investigate the impact of the earlier diagnosis of distant metastases on survival. Methods: Pts diagnosed with stage I-III BC, who underwent adequate surgery are eligible. Special histologies and low-risk cases according to St. Gallen criteria are excluded. The study includes pts at the beginning of the follow-up after the conclusion of primary treatment (cohort 1), and pts that have concluded without relapse the first 5 years of follow-up (cohort 2). Eligible pts will be randomized in a 1:1 ratio to follow-up according to local practice (control arm) or to three-monthly serial dosing of CEA and CA15-3 and subsequent 18 FDG-PET only in case of an increase of CEA and/or CA 15.3 greater than a critical difference compared to baseline (experimental arm). The following stratification factors will be used: node negative vs positive, HER2 negative vs positive, ER positive vs negative. Eight-hundred pts will be enrolled over 3 years. For such a calculation, we made the assumption of a 20% baseline 5-year incidence of relapse. The target reduction of three months in RMST implies a median time of diagnostic anticipation, conditional on having BC recurrence, of 10 months. The follow-up will continue until 10 years from surgery. Since 23rd October 2014 625 pts have been enrolled. The present trial was approved by the Ethical Committee of each participating centre and is registered on clinicaltrials.gov (NCT02261389).