Single Fraction Preoperative Radiotherapy for Early Stage Breast Cancer

Phase I/II Clinical Trial on Single Fraction Ablative Preoperative Radiation Treatment for Early Stage Breast Cancer

This is a phase I/II, single-arm and open-label single-centre clinical trial with the aim to test the feasibility, safety and the efficacy, in terms of complete pathological response, of preoperative ablative radiotherapy in single fraction for selected breast cancer patients.

The research plan is conceived in two sections, as follows. (i)The technical study handles the set-up, motion and dosimetric issues of the radioablation technique using CyberKnife system. (ii)The clinical section is organized in two studies: a phase I dose escalation study to identify the maximum tolerated dose (MTD) delivering 18 Gy, 21 Gy and 24 Gy in single fraction and a phase II study to evaluate the rate of pathological complete response (pCR) when a dose level is chosen according to the results of the previous phase I study. Study population includes patients affected by cT1-T2 (up to 2.5 cm) cN0, adenocarcinoma of the breast, diagnosed with conventional workup. Surgical tumor removal will be scheduled after 4-8 weeks after radioablation. Whole breast radiation therapy without boost will be performed after surgery.

To establish the recommended dose defined as the maximum tolerated dose (MTD)The dose-limiting toxicity (DLT) is defined as any G3-G4 event according to NCI CTCAE Version 4.03 scale. Dose escalation is designed as a 3+3 rule-based study. Dose escalation will be initiated from a baseline dose of 18 Gy and increased to reach 21 Gy and 24 Gy. The population size includes 18 patients.

The recommended dose from the phase I study is delivered, using Cyberknife in order to evaluate the efficacy measured in terms of pCR rate. The population size includes 61 patients.

Dose escalation is designed as a 3+3 rule-based study. Acute skin/soft tissue toxicity, measured according to NCI CTCAE v. 4.03. Any Grade 3-4 toxicity related to radioablation is considered dose limiting (DLT).

Chronic skin/soft tissue, bone, lung and heart toxicities incidence measured according to NCI CTCAE v. 4.03

Reporting of any post surgery complication (rate of infection, seroma, hematoma, necrosis, delayed wound healing)

Inclusion Criteria: Histologically proven unifocal adenocarcinoma T1-T2 Tumor size up to 2.5 cm cN0 Age ≥ 18 years old Good general condition (ECOG 0-2) Planned BCS Written informed consent Exclusion Criteria: Tumor close to skin or chest wall Pure non-invasive tumor Prior RT to the chest Neoadjuvant chemotherapy Collagenopathies Coagulation or autoimmunitary disorders Previous malignancies

Zerella MA, Zaffaroni M, Ronci G, Dicuonzo S, Rojas DP, Morra A, Fodor C, Rondi E, Vigorito S, Botta F, Cremonesi M, Garibaldi C, Penco S, Galimberti VE, Intra M, Gandini S, Barberis M, Renne G, Cattani F, Veronesi P, Orecchia R, Jereczek-Fossa BA, Leonardi MC. Single fraction ablative preoperative radiation treatment for early-stage breast cancer: the CRYSTAL study - a phase I/II clinical trial protocol. BMC Cancer. 2022 Apr 2;22(1):358. doi: 10.1186/s12885-022-09305-w.