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Real-world acute toxicity and 90-day mortality in patients with stage I non-small cell lung cancer treated with stereotactic body radiotherapy

Peter S.N. van Rossum, Nienke Wolfhagen, Liselotte W. van Bockel, Ida E.M. Coremans, Corine A. van Es, Annelies M. van der Geest, Katrien E.A. De Jaeger, Barbara Wachters, Hans P. Knol, Friederike L.A. Koppe, Jacqueline Pomp, Bart J.T. Reymen, Dominic A.X. Schinagl, Femke O.B. Spoelstra, Caroline J.A. Tissing-Tan, Max Peters, Noëlle C.M.G. van der Voort van Zijp, Antoinet M. van der Wel, Erwin M. Wiegman, Robin Wijsman, Ronald A.M. Damhuis, José S.A. Belderbos

JTO July 21, 2024

Introduction: Stereotactic body radiotherapy (SBRT) has firmly established its role in stage I non-small cell lung cancer (NSCLC). Clinical trial results may not fully apply to real-world scenarios. This study aimed to uncover the real-world incidence of acute toxicity and 90-day mortality in SBRT-treated stage I NSCLC patients and develop prediction models for these outcomes.

背景：立体定向体部放射治疗（SBRT）已牢固确立其在I期非小细胞肺癌（SOC）中的作用。临床试验结果可能不完全适用于现实世界的场景。这项研究旨在揭示接受SBRT治疗的I期非小细胞肺癌患者的真实急性副反应的发生率和90天死亡率，并开发预测以上结局的预测模型。

Methods: Prospective data from the Dutch Lung Cancer Audit for Radiotherapy (DLCA-R) were collected nationally. Patients with stage I NSCLC (cT1-2aN0M0) treated with SBRT in 2017-2021 were included. Acute toxicity was assessed, defined as grade ≥2 radiation-pneumonitis or grade ≥3 non-hematologic toxicity ≤90 days after SBRT. Prediction models for acute toxicity and 90-day mortality were developed and internally validated.

方法：本研究的前瞻性数据由荷兰肺癌放射治疗登记处（DLCA-R）在全国范围内收集。纳入了2017-2021年接受SBRT治疗的I期非小细胞肺癌（cT 1 - 2aN 0 M0）患者。评估了急性毒性，定义为SBRT后90天内发生至少2级放射性肺炎或至少3级非血液学毒性。开发并内部验证了急性毒性和90天死亡率的预测模型。

RESULTS: Among 7,279 patients, the mean age was 72.5 years, with 21.6% being >80 years. Most were female (50.7%), had WHO scores 0-1 (73.3%), and cT1a-b tumors (64.6%), predominantly in upper lobes (65.2%). Acute toxicity was observed in 280 (3.8%) of patients and 90-day mortality in 122 (1.7%). Predictors for acute toxicity included WHO ≥2, lower FEV1 and DLCO, no pathology confirmation, middle/lower lobe tumor location, cT1c-cT2a stage, and higher mean lung dose (c-statistic 0.68). Female gender, WHO ≥2, and acute toxicity predicted higher 90-day mortality (c-statistic 0.73).

结果：7，279名患者中，平均年龄为72.5岁，其中21.6%的患者年龄>80岁。大多数是女性（50.7%），WHO评分为0-1（73.3%），cT 1a-b肿瘤（64.6%），主要位于上叶（65.2%）。280名患者（3.8%）观察到急性毒性，122名患者（1.7%）90天死亡。急性毒性的预测因素包括WHO≥2、FEV 1和DLCO较低、未经病理证实、中/下叶肿瘤位置、cT 1c-cT 2a分期和较高的平均肺剂量（c统计量0.68）。女性、WHO≥2和急性毒性预测90天死亡率较高（c统计量0.73）。

Conclusion: This nationwide study revealed a low rate of acute toxicity and an acceptable 90-day mortality rate in SBRT-treated stage I NSCLC patients. Notably, advanced age did not increase acute toxicity or mortality risk. Our predictive models, with satisfactory performance, offer valuable tools for identifying high-risk patients.

结论：这项全国性研究显示，接受SBRT治疗的I期非小细胞肺癌患者的急性毒性发生率较低，90天死亡率可接受。值得注意的是，高龄不会增加急性毒性或死亡风险。我们的预测模型具有令人满意的性能，为识别高风险患者提供了宝贵的工具。

Keywords: non-small cell lung cancer; SBRT; stereotactic radiotherapy; toxicity; mortality

An International Registry Study of Early-Stage NSCLC treatment variations (LUCAEUROPE) in Europe and the USA highlighting variations

Philip Baum a, Rafael Cardoso b, Jacopo Lenzi c, Ronald A.M. Damhuis d, Ad F.T.M. Verhagen e, Cindy De Gendt f, Hanna Peacock f, Paul De Leyn g, Niels L. Christensen h, Kaire Innos i, Kersti Oselin j, Vesna Zadnik k, Tina Zagarv k, Hermann Brenner b l, Hauke Winter a m

EJC 19 July 2024

Background: Harmonized European NSCLC incidence, treatment approach, and survival based on national tumor registries are unclear.

背景：基于国家肿瘤登记处的欧洲非小细胞肺癌发病率、治疗方法和生存率尚不清楚。

Summary background data: Surgery has the potential to cure NSCLC and significantly prolong survival. This large-scale international study aimed to investigate treatment variations in Europe and the USA, as well as the determinants for its utilization.

背景数据：手术有潜力治愈非小细胞肺癌并显着延长生存期。这项大规模国际研究旨在调查欧洲和美国的治疗差异，以及其利用的决定因素。

Methods: The retrospective cohort study analyzed data from six European national population-based cancer registries (Belgium, Denmark, Estonia, Germany, the Netherlands, and Slovenia) and the US SEER database from 2010–2015.

方法：这项回顾性队列研究分析了2010年至2015年来自欧洲六个国家基于人群的癌症登记处（比利时、丹麦、爱沙尼亚、德国、荷兰和斯洛文尼亚）和美国SEER数据库的数据。

RESULTS: The study computed cancer incidence, survival, and age-standardized proportions of the use of various therapies. Multivariable logistic regression models were used to assess associations between resection and demographic and clinical parameters. A total of 428,107 records were analyzed. Among all countries, Estonia had the highest surgical resection rate (79.3 %) and the lowest radiation rate (7.3 %) for stage I patients. The Netherlands had the highest rate of radiotherapy across all years of investigation and the lowest surgery rate between 2012 and 2015. The primary treatment for early-stage NSCLC showed significant international variation, with the USA having a decrease in surgical rates from 67.6 % to 59.5 %. Resection was less frequently performed as tumor stage increased, patients aged, other lung cancer besides adenocarcinoma was present, and when the tumor site overlapped multiple lobes.

结果：该研究计算了癌症发病率、生存率和使用各种疗法的年龄标准化比例。使用多变量逻辑回归模型来评估切除与人口统计学和临床参数之间的关联。总共分析了428，107条记录。在所有国家中，爱沙尼亚的I期患者手术切除率最高（79.3%），放射率最低（7.3%）。荷兰的放射治疗率在所有调查年中最高，而2012年至2015年期间手术率最低。早期非小细胞肺癌的主要治疗在国际上表现出显着差异，美国的手术率从67.6%下降至59.5%。随着肿瘤分期增加、患者年龄增加、存在除腺癌以外的其他肺癌以及肿瘤部位与多个肺叶重叠，切除的频率就会减少。

Interpretation: Resection rates have declined in some studied European countries and the USA and resection rates vary substantially among countries. Interpretation of current scientific lung cancer evidence and international guidelines results in wide variations in patient treatment.

结论：在一些研究的欧洲国家和美国，切除率有所下降，各国的切除率差异很大。对当前科学肺癌证据和国际指南的解释导致患者治疗存在很大差异。

Keywords: Lung cancer, Surgery, Radiotherapy, SBRT, Incidence, Survival

目录

1. INTRODUCTION

2. Methods 

    2.1 Study population  

    2.2 Outcome assessment

    2.3 Predictor selection 

    2.4 Data verification

    2.5 Statistical Analysis 

3. Results

    3.1 Acute toxicity (Table 1-2)(Figure 1 A-B)(Figure 2)

    3.2 Ninety-day mortality (Table 3)(Figure 1 C-D)(Figure 3)

4. Discussion

— 图表汇总—

3. Results

    3.1 Acute toxicity

Table 1 Baseline characteristics stratified for acute toxicity after SBRT. 

Table 2 Univariable and multivariable logistic regression analyses for acute toxicity. 

Figure 1 ROC curve analysis and calibration plot of the final model for acute toxicity (A, B) 

Figure 2 Pretreatment clinical nomogram for predicting acute toxicity after SBRT for stage I NSCLC. The points listed at the top line of the figure indicate the points assigned per variable. By summing all points, the predicted risk of acute toxicity can be read out by drawing a straight vertical line from the sum score line to the bottom line of the figure.  

    3.2 Ninety-day mortality

Table 3 Baseline characteristics stratified for 90-day mortality after SBRT

Table 4 Univariable and multivariable logistic regression analyses for 90-day mortality. 

Figure 1 ROC curve analysis and calibration plot of the final model for 90-day mortality (C,D). 

Figure 3 Pretreatment clinical nomogram for predicting 90-day mortality after SBRT for stage I NSCLC. The points listed at the top line of the figure indicate the points assigned per variable. By summing all points, the predicted risk of 90-day mortality can be read out by drawing a straight vertical line from the sum score line to the bottom line of the figure.  

目录

1. INTRODUCTION

2. Methods 

    2.1 Registries (Supplemental Table 1)(Table 1)

    2.2 Statistical Analysis 

3. Results (Table 2)(Fig 1-2)(Table 3)(Supplementary Figure 1)

4. Discussion

— 图表汇总—

2. Methods 

    2.1 Registries

Supplemental Table 1. Information on tumor registries

Table 1 Information on participating registries.

    2.2 Statistical Analysis 

3. Results

Table 2 Demographic and Clinical Characteristics of Patients with Non-Small Cell Lung Cancer Diagnosed between 2010 and 2015, by Country.

Fig 1 Stage distribution of age-standardized non-small cell lung cancer incidence between 2010 and 2015, by country.

Fig 2 Trends in age-standardized proportions of primary surgical resection and primary radiation for stage i non-small cell lung cancers diagnosed between 2010 and 2015, by Country.

Notes: The Netherlands (−7.9 % [95 % CI −10.1, −5.7]) and the United States (−2.7 % [95 % CI −3.1, −2.4]) had a significant annual %decrease in resection rates.

Fig.3 Age-Standardized Surgical Resection Rates for Stage I, II and III Non-Small Cell Lung Cancers from 2010 to 2015, by Country. 

Notes: The Netherlands (−7.9 % [95 % CI −10.1, −5.7]) and the United States (−2.7 % [95 % CI −3.1, −2.4]) had a significant annual % decrease in resection rates for Stage I cancers. The United States had a significant annual % decrease in resection rates for Stage II cancers (−1.7 % [95 % CI −2.4, −0.9]). The Netherlands had a significant annual % increase in resection rates for Stage III cancers (4.1 [95 % CI 0.3, 7.6]), while the United States exhibited a significant decrease (−2.2 % [95 % CI −2.8, −1.7]).

Table 3. Association of demographic and clinical parameters with surgical resection versus non-resection with for patients with NSCLC in population-based registries estimated by multivariable logistic regression

Supplementary Figure 1. Stage-dependent overall survival from 2010-2015 in population-based registries. (Stage I = blue, Stage II = red, Stage III = green, Stage IV = yellow)

Supplemental Table 2. Primary Therapy of Stage I Non-Small Cell Lung Cancer, by Country

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