Department of Oncology, Division of Radiation Oncology, Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Ontario, Canada; Faculty of Medicine, Queen's University, Ontario, Canada.
Department of Oncology, Division of Radiation Oncology, Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Ontario, Canada; Faculty of Medicine, Queen's University, Ontario, Canada.
Cancer Treat Res Commun. 2023;36:100747. doi: 10.1016/j.ctarc.2023.100747. Epub 2023 Jul 26.
PURPOSE/OBJECTIVE: Around 30% of patients with non-small cell lung cancers (NSCLC) are diagnosed with stage III disease at presentation, of which about 50% are treated with definitive chemoradiation (CRT). Around 65-80% of patients will eventually develop intracranial metastases (IM), though associated risk factors are not clearly described. We report survival outcomes and risk factors for development of IM in a cohort of patients with stage III NSCLC treated with CRT at a tertiary cancer center.
MATERIALS/METHODS: We identified 195 patients with stage III NSCLC treated with CRT from January 2010 to May 2021. Multivariable logistic regression was used to generate odds ratios for covariates associated with development of IM. Kaplan-Meier analysis with the Log Rank test was used for unadjusted time-to-event analyses. P-value for statistical significance was set at < 0.05 with a two-sided test.
Out of 195 patients, 108 (55.4%) had stage IIIA disease and 103 (52.8%) had adenocarcinoma histology. The median age and follow-up (in months) was 67 (IQR 60-74) and 21 (IQR 12-43), respectively. The dose of radiation was 60 Gy in 30 fractions for148 patients (75.9%). Of the 77 patients who received treatment since immunotherapy was available and standard at our cancer center, 45 (58.4%) received at least one cycle. During follow-up, 84 patients (43.1%) developed any metastasis, and 33 (16.9%) developed IM (either alone or with extracranial metastasis). 150 patients (76.9%) experienced a treatment delay (interval between diagnosis and treatment > 4 weeks). Factors associated with developing any metastasis included higher overall stage at diagnosis (p = 0.013) and higher prescribed dose (p = 0.022). Factors associated with developing IM included higher ratio of involved over sampled lymph nodes (p = 0.001) and receipt of pre-CRT systemic or radiotherapy for any reason (p = 0.034). On multivariate logistical regression, treatment delay (OR 3.9, p = 0.036) and overall stage at diagnosis (IIIA vs. IIIB/IIIC) (OR 2.8, p = 0.02) predicted development of IM. These findings were sustained on sensitivity analysis using different delay intervals. Median OS was not reached for the overall cohort, and was 43.1 months for patients with IM and 40.3 months in those with extracranial-only metastasis (p = 0.968). In patients with any metastasis, median OS was longer (p = 0.003) for those who experienced a treatment delay (48.4 months) compared to those that did not (12.2 months), likely due to expedited diagnosis and treatment in patients with a higher symptom burden secondary to more advanced disease.
In patients with stage III NSCLC treated with definitive CRT, the risk of IM appears to increase with overall stage at diagnosis and, importantly, may be associated with experiencing a treatment delay (> 4 weeks). Metastatic disease of any kind remains the primary life-limiting prognostic factor in these patients with advanced lung cancer. In patients with metastatic disease, treatment delay was associated with better survival. Patients who experience a treatment delay and those initially diagnosed at a more advanced overall stage may warrant more frequent surveillance for early diagnosis and treatment of IM. Healthcare system stakeholders should strive to mitigate treatment delay in patients with locally NSCLC to reduce the risk of IM. Further research is needed to better understand factors associated with survival, treatment delay, and the development of IM after CRT in the immunotherapy era.
目的/目标：大约 30%的非小细胞肺癌（NSCLC）患者在就诊时被诊断为 III 期疾病，其中约 50%接受了确定性放化疗（CRT）治疗。大约 65-80%的患者最终会发展为颅内转移（IM），尽管相关的风险因素尚不清楚。我们报告了在一家三级癌症中心接受 CRT 治疗的 III 期 NSCLC 患者队列的生存结果和 IM 发展的风险因素。
材料/方法：我们从 2010 年 1 月至 2021 年 5 月确定了 195 名接受 CRT 治疗的 III 期 NSCLC 患者。多变量逻辑回归用于生成与 IM 发展相关的协变量的优势比。Kaplan-Meier 分析与对数秩检验用于未经调整的时间事件分析。统计学意义的 P 值设定为<0.05，双侧检验。
在 195 名患者中，108 名（55.4%）患有 IIIA 期疾病，103 名（52.8%）患有腺癌组织学。中位年龄和随访（月）分别为 67（IQR 60-74）和 21（IQR 12-43）。148 名患者接受了 60 Gy 分 30 次的放射剂量（75.9%）。在 77 名自我们癌症中心开始提供免疫治疗并成为标准治疗的患者中，有 45 名（58.4%）接受了至少一个周期的治疗。在随访期间，84 名患者（43.1%）发生了任何转移，33 名（16.9%）发生了 IM（单独或伴颅外转移）。150 名患者（76.9%）经历了治疗延迟（诊断和治疗之间的间隔>4 周）。与发生任何转移相关的因素包括更高的总体诊断阶段（p=0.013）和更高的处方剂量（p=0.022）。与发生 IM 相关的因素包括更多的受累淋巴结与采样淋巴结的比例（p=0.001）以及因任何原因接受 CRT 前的全身或放疗（p=0.034）。多变量逻辑回归显示，治疗延迟（OR 3.9，p=0.036）和诊断时的总体阶段（IIIA 与 IIIB/IIIC）（OR 2.8，p=0.02）预测了 IM 的发生。使用不同的延迟间隔进行敏感性分析时，这些发现仍然成立。总队列的中位 OS 未达到，IM 患者的中位 OS 为 43.1 个月，颅外转移患者的中位 OS 为 40.3 个月（p=0.968）。在有任何转移的患者中，经历治疗延迟（48.4 个月）的患者中位 OS 较长（p=0.003），而没有经历治疗延迟的患者（12.2 个月）（p=0.003），这可能是由于疾病进展导致症状负担增加，从而加速了诊断和治疗。
在接受确定性 CRT 治疗的 III 期 NSCLC 患者中，IM 的风险似乎随着诊断时的总体阶段而增加，重要的是，它可能与经历治疗延迟（>4 周）有关。这些晚期肺癌患者的任何类型的转移性疾病仍然是主要的预后因素。在有转移性疾病的患者中，治疗延迟与更好的生存相关。经历治疗延迟和最初诊断为更晚期总体阶段的患者可能需要更频繁的监测，以早期诊断和治疗 IM。医疗保健系统利益相关者应努力减少局部 NSCLC 患者的治疗延迟，以降低 IM 的风险。在免疫治疗时代，需要进一步研究以更好地了解 CRT 后与生存、治疗延迟和 IM 发展相关的因素。
