Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
JAMA Netw Open. 2024 Sep 3;7(9):e2436407. doi: 10.1001/jamanetworkopen.2024.36407.
Given high rates of locoregional control after definitive management of head and neck squamous cell carcinoma (HNSCC), better methods are needed to project distant metastasis (DM) risk. Tumor hypoxia on 18F-fluoromisonidazole (FMISO) positron emission tomography (PET) is associated with locoregional failure, but data demonstrating an association with DM are limited.
To determine whether tumor hypoxia on FMISO PET is associated with DM risk after chemoradiotherapy (CRT) for HNSCC.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study assessed patients with HNSCC enrolled in 2 prospective clinical trials at a single academic referral center from 2004 to 2021 in which participants received FMISO PET before and during CRT. Data analysis occurred from May 2023 to May 2024.
FMISO PET scans before and 1 to 2 weeks after starting CRT were evaluated for tumor hypoxia by nuclear medicine physicians.
The primary outcome was DM, defined as biopsy-proven HNSCC outside the primary site and regional lymph nodes. Time to DM was modeled with competing risk regression, with death as a competing risk. Overall survival (OS) was assessed secondarily and modeled with Cox regression.
Among 281 patients (median [range] age at CRT, 58.7 [25.5-85.6] years; 251 male [89.3%]) included in this study, 242 (86.1%) had oropharyngeal primary cancer, and 266 (94.7%) had human papillomavirus-positive disease. Of all patients, 217 (77.2%) had T stage 1 or 2, and 231 patients (82.2%) had N stage 2b or less. De-escalated 30 Gy CRT was delivered to 144 patients (51.2%), and the remainder received standard 70 Gy CRT. On FMISO PET examination, 73 patients (26.0%) had hypoxia-negative disease before CRT, 138 patients (49.1%) had hypoxia-positive disease before CRT and then hypoxia-negative disease during CRT, and 70 patients (24.9%) persistently had hypoxia-positive disease before and during CRT. At a median (IQR) 58 (46-91) months of follow-up, 12 DM events and 22 deaths were observed. Persistent intratreatment hypoxia was associated with increased DM risk (hazard ratio, 3.51; 95% CI, 1.05-11.79; P = .04) and worse OS (hazard ratio, 2.66; 95% CI, 1.14-6.19; P = .02). No patients with hypoxia-negative disease before CRT experienced DM.
In this cohort study using pooled analysis of prospective nonrandomized clinical trials incorporating FMISO PET in the definitive management of HNSCC, persistent intratreatment hypoxia was associated with increased risk of DM and worse OS. Conversely, all patients with hypoxia-negative disease before treatment remained free of DM. These findings suggest that pretreatment and intratreatment FMISO PET results may serve as biomarkers for DM risk and aid in identifying candidates for escalated therapeutic strategies.
重要性：鉴于头颈部鳞状细胞癌（HNSCC）明确治疗后的局部区域控制率较高，需要更好的方法来预测远处转移（DM）风险。18F-氟米索硝唑（FMISO）正电子发射断层扫描（PET）上的肿瘤缺氧与局部区域失败相关，但数据表明与 DM 相关的有限。
目的：确定 FMISO PET 上的肿瘤缺氧是否与 HNSCC 放化疗（CRT）后的 DM 风险相关。
设计、地点和参与者：这项队列研究评估了 2004 年至 2021 年期间在单一学术转诊中心参加 2 项前瞻性临床试验的 HNSCC 患者，参与者在 CRT 前和期间接受 FMISO PET。数据分析于 2023 年 5 月至 2024 年 5 月进行。
暴露：核医学医师评估 CRT 开始前和开始后 1 至 2 周的 FMISO PET 扫描以评估肿瘤缺氧。
主要结果和措施：主要结局是 DM，定义为原发性部位和区域淋巴结以外的活检证实的 HNSCC。采用竞争风险回归对 DM 时间进行建模，死亡为竞争风险。其次评估总生存（OS）并采用 Cox 回归进行建模。
结果：在这项纳入 281 例患者（CRT 时的中位[范围]年龄，58.7 [25.5-85.6] 岁；251 例男性[89.3%]）的研究中，242 例（86.1%）患有口咽原发性癌症，266 例（94.7%）患有 HPV 阳性疾病。所有患者中，217 例（77.2%）为 T 分期 1 或 2，231 例（82.2%）为 N 分期 2b 或更低。144 例（51.2%）接受了降级 30 Gy 的 CRT，其余患者接受了标准的 70 Gy CRT。在 FMISO PET 检查中，73 例（26.0%）在 CRT 前为低氧阴性疾病，138 例（49.1%）在 CRT 前为低氧阳性疾病，然后在 CRT 期间为低氧阴性疾病，70 例（24.9%）在 CRT 前和期间持续为低氧阳性疾病。在中位（IQR）58（46-91）个月的随访中，观察到 12 例 DM 事件和 22 例死亡。治疗期间持续存在缺氧与 DM 风险增加相关（风险比，3.51；95%CI，1.05-11.79；P=0.04）和 OS 更差（风险比，2.66；95%CI，1.14-6.19；P=0.02）。在 CRT 前没有低氧阴性疾病的患者没有发生 DM。
结论和相关性：在这项使用前瞻性非随机临床试验的汇总分析纳入 FMISO PET 对 HNSCC 进行明确治疗的队列研究中，治疗期间持续存在缺氧与 DM 风险增加和 OS 更差相关。相反，所有在治疗前有低氧阴性疾病的患者均未发生 DM。这些发现表明，治疗前和治疗期间的 FMISO PET 结果可能作为 DM 风险的生物标志物，并有助于确定需要强化治疗策略的候选者。
