Single fraction ablative preoperative radiation treatment for early-stage breast cancer: the CRYSTAL study - a phase I/II clinical trial protocol

Maria Alessia Zerella, Mattia Zaffaroni, Giuseppe Ronci, Samantha Dicuonzo, Damaris Patricia Rojas, Anna Morra, Cristiana Fodor, Elena Rondi, Sabrina Vigorito, Francesca Botta, Marta Cremonesi, Cristina Garibaldi, Silvia Penco, Viviana Enrica Galimberti, Mattia Intra, Sara Gandini, Massimo Barberis, Giuseppe Renne, Federica Cattani, Paolo Veronesi, Roberto Orecchia, Barbara Alicja Jereczek-Fossa, Maria Cristina Leonardi, Maria Alessia Zerella, Mattia Zaffaroni, Giuseppe Ronci, Samantha Dicuonzo, Damaris Patricia Rojas, Anna Morra, Cristiana Fodor, Elena Rondi, Sabrina Vigorito, Francesca Botta, Marta Cremonesi, Cristina Garibaldi, Silvia Penco, Viviana Enrica Galimberti, Mattia Intra, Sara Gandini, Massimo Barberis, Giuseppe Renne, Federica Cattani, Paolo Veronesi, Roberto Orecchia, Barbara Alicja Jereczek-Fossa, Maria Cristina Leonardi

Abstract

Background: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients.

Methods: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate.

Discussion: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale.

Trial registration: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).

Keywords: Clinical trial protocol; Early stage breast cancer; Single fraction preoperative radiotherapy; Stereotactic body radiation therapy.

Conflict of interest statement

Maria Cristina Leonardi, Barbara Alicja Jereczek-Fossa and Samantha Dicuonzo received a speaker honorarium from Accuray Inc. outside the current work. IEO received a research grant from Accuray Inc. entitled: “Data collection and analysis of Tomotherapy and CyberKnife breast clinical studies, breast physics studies and prostate study”. Maria Alessia Zerella and Giuseppe Ronci had a research fellowships from AIRC under IG 2019 - ID. 23118 project “Phase I/II clinical trial on single fraction ablative preoperative radiation treatment for early-stage breast cancer”. Mattia Zaffaroni received a research grant by the European Institute of Oncology-Cardiologic Center Monzino Foundation (FIEO-CCM), with a project entitled “Proton therapy vs photon-based IMRT for parotid gland tumors: a model based approach with Normal Tissue Complication Probability (NTCP)” outside the current study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors declare no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Overview of the study workflow

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