von der Grün Jens, Winkelmann Ria, Burck Iris, Martin Daniel, Rödel Franz, Wild Peter Johannes, Bankov Katrin, Weigert Andreas, Kur Ivan-Maximiliano, Brandts Christian, Filmann Natalie, Issing Christian, Thönissen Philipp, Tanneberger Anna Maria, Rödel Claus, Ghanaati Shahram, Balermpas Panagiotis
Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Front Oncol. 2022 Mar 24;12:817692. doi: 10.3389/fonc.2022.817692. eCollection 2022.
To study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC).
The INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate.
Seventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT.
nCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs.
研究新辅助放化疗（nCRT）及局部晚期口腔癌（LA - OCC）反应的潜在预测因素。
INVERT试验是一项正在进行的单中心、前瞻性2期原则性验证试验。符合条件的是患有Ⅲ - ⅣA期口腔鳞状细胞癌的可手术患者，接受由60 Gy顺铂和5 - 氟尿嘧啶同步进行的nCRT。在nCRT完成后6 - 8周安排手术。对治疗前肿瘤标本进行探索性多重免疫组织化学（IHC），并在nCRT之前、期间（第15天）和手术前进行扩散加权磁共振成像（DW - MRI），以识别潜在的预测生物标志物和成像特征。主要终点是病理完全缓解（pCR）率。
本次中期分析纳入了17例ⅣA期口腔癌患者。所有患者均完成nCRT。1例患者在nCRT后手术前10周死于肺炎。16/17例患者实现了肿瘤完全切除（R0），其中7例（41%，95%CI：18 - 67%）显示pCR。根据Clavien - Dindo分类，分别有4例（25%）和5例（31%）患者出现3a级和3b级并发症；未发生4 - 5级并发症。nCRT第15天的MRI与手术前之间表观扩散系数信号强度的变化增加与更好的反应相关（p = 0.022）。程序性细胞死亡蛋白1（PD1）阳性细胞毒性T细胞（p = 0.012）、PD1 + 巨噬细胞（p = 0.046）和癌症相关成纤维细胞（CAFs，p = 0.036）丰度较高与nCRT反应不完全相关。
LA - OCC先行nCRT再行根治性手术是可行的，且显示出高反应率。需要来自随机试验的更大患者队列来进一步研究nCRT和预测生物标志物，如DW - MRI信号强度变化、肿瘤浸润免疫细胞和CAFs。
