Planning adaptive treatment by longitudinal response assessment implementing MR imaging, liquid biopsy and analysis of microenvironment during neoadjuvant treatment of rectal cancer (PRIMO).

Conducting neoadjuvant chemoradiotherapy (CRT) and additional preoperative consolidating chemotherapy (CTx), that is, total neoadjuvant therapy (TNT), improves local control and complete response (CR) rates in locally advanced rectal cancer (LARC), putting the focus on organ preservation concepts. Therefore, assessing response before surgery is crucial. Some LARC patients would either not benefit from intensification by TNT or may reach CR, making resection not mandatory. Treatment of LARC should therefore be based on patient individual risk and response to avoid overtreatment.The "PRIMO" pilot study aims to determine early response assessment to form a basis for development and validation of a noninvasive response prediction model by a subsequent prospective multicenter trial, which is highly needed for individual, response-driven therapy adaptions. PRIMO is a prospective observational cohort study including adult patients with LARC receiving neoadjuvant CRT. At least 4 multiparametric magnetic resonance imaging (MRI) scans (diffusion-weighted imaging [DWI] and hypoxia-sensitive sequences) as well as repeated blood samples in order to analyze circulating tumor cells (CTC) and cell-free tumor DNA (ctDNA) are scheduled. Pelvic radiotherapy (RT, 50.4 Gy) will be performed in combination with a 5-fluorouracil/oxaliplatin regimen in all patients (planned: N = 50), succeeded by consolidation CTx (FOLFOX4) if feasible. Additional (immuno)histochemical markers, such as tumor-infiltrating lymphocytes (TIL) and programmed death ligand 1 (PD-L1) status will be analyzed before and after CRT. Routine resection is scheduled subsequently, nonoperative management is offered alternatively in case of clinical CR (cCR).The primary endpoint is pathological response; secondary endpoints comprise longitudinal changes in MRI as well as in CTCs and TIL. These are evaluated for early response prediction during neoadjuvant therapy, in order to develop a noninvasive response prediction model for subsequent analyses. Early response assessment is the key in differentiating "good" and "bad" responders during neoadjuvant CRT, allowing adaption of subsequent therapies (additional consolidating CTx, organ preservation). This study will contribute in this regard, by advancing MR imaging and substantiating new surrogate markers. Adaptive treatment strategies might build on these results in further studies.

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Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.

Déclaration de conflit d'intérêts

The authors have no conflicts of interest to disclose. There is an institutional research cooperation with Siemens Healthineers, Erlangen and the Department of Diagnostic and Interventional Radiology (IDIR), Jena University Hospital. TF received honoraria from Bayer AG, Saegeling Medizintechnik GmbH and Medac Gmbh as well as royalties from Georg Thieme Verlag. He is part of the advisory board of Bayer AG, committee member of German S3 guideline for prostate cancer and received research funding from Zentrales Innovationsprogramm Mittelstand des Bundesministeriums für Wirtschaft und Energie (ZF4816001BA9), outside of the submitted work. MM.was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Clinician Scientist Program OrganAge (funding number 413668513) and by the Interdisciplinary Center of Clinical Research of the Medical Faculty Jena.