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.

Intensified preoperative chemotherapy after (chemo)radiotherapy, (Total Neoadjuvant Therapy–TNT), increases pathological complete response (pCR) rates and local control. In cases of clinically complete response (cCR) and close follow-up, non-operative management (NOM) is feasible. We report early outcomes and toxicities of a long-term TNT regime in a single-center cohort. Fifteen consecutive patients with distal or middle-third locally advanced rectal cancer (UICC stage II–III) were investigated, who received neoadjuvant chemoradiotherapy (total adsorbed dose: 50.4 Gy in 28 fractions and two concomitant courses 5-fluorouracil (250 mg/m2/d)/oxaliplatin (50 mg/m2), followed by consolidating chemotherapy (nine courses of FOLFOX4). NOM was offered if staging revealed cCR 2 months after TNT, with resection performed otherwise. The primary endpoint was complete response (pCR + cCR). Treatment-related side effects were quantified for up two years after TNT. Ten patients achieved cCR, of whom five opted for NOM. Ten patients (five cCR and five non-cCR) underwent surgery, with pCR confirmed in the five patients with cCR. The main toxicities comprised leukocytopenia (13/15), fatigue (12/15) and polyneuropathy (11/15). The most relevant CTC °III + IV events were leukocytopenia (4/15), neutropenia (2/15) and diarrhea (1/15). The long-term TNT regime resulted in promising response rates that are higher than the response rates of short TNT regimes. Overall tolerability and toxicity were comparable with the results of prospective trials.

Hintergrund Beim lokal fortgeschrittenen Rektumkarzinom sind verschiedene Konzepte mit intendiertem Organerhalt im Rahmen klinischer Studien erfolgreich geprüft worden. Die vielversprechenden Komplettremissionsraten und die gute Verträglichkeit lassen dieses Vorgehen in Deutschland zunehmend zum Standard werden. Bei frühen Tumorstadien (Union internationale contre le cancer, UICC, Stadium I bzw. T1/T2-N0-Tumoren) ist bisher die primäre Resektion hingegen Therapie der Wahl, birgt aber gerade bei multimorbiden alten Patienten ein höheres Op.-assoziiertes Nebenwirkungsrisiko. Für diese Patientengruppe sind bisher nur wenige Arbeiten verfügbar und insbesondere der Organerhalt wird im UICC-Stadium I dabei kaum betrachtet. Die britische TREC-Studie untersuchte ein organerhaltendes Vorgehen beim Adenokarzinom des Rektums im UICC-Stadium I. Eine Kurzzeitbestrahlung (5 × 5 Gy) mit anschließender transanaler endoskopischer Resektion wurde randomisiert mit einer totalen mesorektalen Exzision (TME) verglichen [2]. In der jetzt publizierten Unteranalyse der Studie wird auf die Verträglichkeit und das onkologische Outcome im 3-Jahres-Follow-up bei älteren Patienten fokussiert. In dieser Arbeit wurde die Subgruppe der Pa-Originalpublikation Gilbert A, Homer A, Brock K et al ( 2022) Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision. Lancet Healthy Longev 3:e825-38.

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