肿瘤细胞治疗研究
英文原题：Planning adaptive treatment by longitudinal response assessment implementing MR imaging, liquid biopsy and analysis of microenvironment during neoadjuvant treatment of rectal cancer (PRIMO).
早期疗效评估是区分新辅助 CRT 期间“良好”与“不良”缓解者的关键，从而可以调整后续治疗（额外的巩固性 CTx、器官保留）。
引言：对局部晚期直肠癌（LARC）实施新辅助放化疗（CRT）并追加术前巩固化疗，即全程新辅助治疗（TNT），可改善局部控制并提高完全缓解（CR）率，因此器官保留策略受到关注。手术前评估疗效至关重要：部分LARC患者可能无需TNT强化治疗，另一些患者可能达到CR而不必切除。为避免过度治疗，LARC治疗应依据个体风险和疗效调整。“PRIMO”试点研究旨在开展早期疗效评估，为后续前瞻性多中心试验开发并验证无创疗效预测模型奠定基础；此类研究对于个体化、应答导向的治疗调整十分必要。方法：PRIMO是一项前瞻性观察性队列研究，纳入接受新辅助CRT的成年LARC患者。计划至少进行4次多参数磁共振成像（MRI）扫描（包括弥散加权成像[DWI]和缺氧敏感序列），并重复采血以分析循环肿瘤细胞（CTC）和游离循环肿瘤DNA（ctDNA）。所有患者接受盆腔放疗（50.4 Gy）联合5-氟尿嘧啶/奥沙利铂方案（计划入组50例），条件允许时随后接受FOLFOX4巩固化疗。CRT前后将检测TIL（肿瘤浸润淋巴细胞）和程序性死亡配体1（PD-L1）等免疫组化标志物。随后计划常规手术切除；达到临床完全缓解（cCR）者可选择非手术管理。主要终点为病理学应答；次要终点包括MRI、CTC和TIL的纵向变化。研究将利用这些指标预测新辅助治疗早期应答，并建立无创预测模型供后续分析。讨论：早期疗效评估是区分新辅助CRT“应答良好”和“应答不佳”患者的关键，可据此调整后续治疗（追加巩固化疗或保留器官）。本研究将推进MRI应用并验证新的替代标志物，为此提供支持；后续研究可据此制定适应性治疗策略。
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.
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