THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy

Giuditta Chiloiro, Davide Cusumano, Luca Boldrini, Angela Romano, Lorenzo Placidi, Matteo Nardini, Elisa Meldolesi, Brunella Barbaro, Claudio Coco, Antonio Crucitti, Roberto Persiani, Lucio Petruzziello, Riccardo Ricci, Lisa Salvatore, Luigi Sofo, Sergio Alfieri, Riccardo Manfredi, Vincenzo Valentini, Maria Antonietta Gambacorta, Giuditta Chiloiro, Davide Cusumano, Luca Boldrini, Angela Romano, Lorenzo Placidi, Matteo Nardini, Elisa Meldolesi, Brunella Barbaro, Claudio Coco, Antonio Crucitti, Roberto Persiani, Lucio Petruzziello, Riccardo Ricci, Lisa Salvatore, Luigi Sofo, Sergio Alfieri, Riccardo Manfredi, Vincenzo Valentini, Maria Antonietta Gambacorta

Abstract

Background: Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model.

Methods: Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome.

Discussion: This clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients.

Trial registration: ClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

Keywords: Chemoradiotherapy; Early Regression Index; Magnetic Resonance guided Radiation Therapy; Radiomics; Rectal cancer.

Conflict of interest statement

Dr. Luca Boldrini and Dr. Davide Cusumano have active research agreements with ViewRay Inc (Mountain View, CA, USA). and received speaker honoraria for scientific presentations and travel reimbursements. Prof. Vincenzo Valentini has received departmental research grants from Varian Medical Systems, ViewRay Inc., Elekta, Merck-Serono, Roche. Prof. Riccardo Manfredi received speaker honoraria from Bracco and Bayer. Dr. Lisa Salvatore received speaker, advisory board and consultancy honoraria from Amgen, Merck, Bayer, Servier, AstraZeneca, Pierre-Fabre. Dr. Lorenzo Placidi reports a consulting agreement and research grants with ViewRay, outside the submitted work.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy treatment algorithm. LARC: locally advanced rectal cancer; CRT: chemoradiotherapy; GTV: gross tumor volume; ERI: early regression index; PTV: planning target volume; RT: radiation therapy; MR: magnetic resonance.
Fig. 2
Fig. 2
Example of dose escalation in accordance with the ERI index. Figure 2A shows the simulation plan according to the SIB 2 protocol. Figure 2B represents the dose escalation obtained at the tenth treatment fraction, where the red colourwash isodose line represents the V95% of the 60.1 Gy prescribed to PTV3. The orange colourwash isodose line represents the V95% of 55 Gy prescribed to PTV2, while the yellow colourwash isodose line represents the V95% of 45 Gy prescribed to PTV1

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