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

Abstract

Introduction: 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.Methods: 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.Discussion: 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. Abbreviations: (c/p)CR = (clinical/pathological) complete response, ctDNA = cell-free tumor DNA, ARO = Arbeitsgemeinschaft Radiologische Onkologie of DKG (Radiation Oncology working group German Cancer Society), CRT = chemoradiotherapy, CTC = circulating tumor cell, CTx = chemotherapy, DWI = diffusion-weighted imaging, LARC = locally advanced rectal cancer, MRI = magnetic resonance imaging, NAR = Neoadjuvant Rectal Score, PD-L1 = programmed death ligand 1, QoL = quality of life, RT = radiotherapy, TIL = tumor-infiltrating lymphocytes, TNT = total neoadjuvant therapy, TRG = tumor regression grading.

Long-Term Total Neoadjuvant Therapy Leads to Impressive Response Rates in Rectal Cancer: Results of a German Single-Center Cohort

“…The promising early results reported here need to be validated through additional data to obtain a statistically significant cohort. We are currently performing a local pilot study, applying this TNT regime (PRIMO Trial, NCT 05524012) [ 21 ]. Multimodal diagnostic, comprising, e.g., multiparametric magnetic resonance imaging (MRI) and liquid biopsy, will be used to quantify tumor response longitudinally in the PRIMO trial.…”

Total Neoadjuvant Therapy Approach for the Treatment of Locally Advanced Rectal Cancer: Where Do We Stand?

“…The NCT05524012 study (PRIMO) evaluates rectal cancer patients undergoing neoadjuvant CRT using magnetic resonance imaging and circulating tumor cell (CTC) analysis. It primarily assesses tumor regression, with secondary criteria including changes in MRI, CTC, tumor-infiltrating lymphocytes (TIL), and survival [47]. Finally, the intestinal microbiome is currently a highly active field of study in gastrointestinal tumors, as seen in study NCT05079503, the impact of the intestinal microbiota on rectal cancer treatment response is being investigated.…”