A Retrospective Long-term Follow-up Study of Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer From a Single Institution: Incidence of Late Local Recurrence

doi:10.1016/j.ijrobp.2018.01.050

International Journal of Radiation OncologyBiologyPhysics

Volume 100, Issue 5, 1 April 2018, Pages 1228-1236

https://doi.org/10.1016/j.ijrobp.2018.01.050 Get rights and content

Purpose

To assess the local recurrence (LR) rate and timing after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer using long-term follow-up data from a single institution.

Methods and Materials

Patients with primary or recurrent non-small cell lung cancer with or without pathologic verification, with tumors <3 cm, treated with SBRT (isocenter prescription of 48 Gy in 4 fractions) between April 1998 and August 2014, and with >6 months' follow-up were eligible. The LR rate was calculated by the cumulative incidence function, accounting for death as a competing risk. Univariate and multivariate analyses were performed to identify prognostic factors for LR.

Results

A total of 216 patients and 230 tumors were analyzed. The median follow-up time of tumors without LR was 3.9 years, and the crude number of LR cases was 49 (21%). The actuarial rate of LR was 19% (95% confidence interval, 14%-25%) at 5 years. The number of LR cases in each period was 10 in year 1, 17 in year 2, 9 in year 3, 3 in year 4, 3 in year 5, and 7 after 5 years. Among 73 tumors with >5 years' follow-up, we observed 7 late LRs. The tumor histology of these late LRs was adenocarcinoma in 3, squamous cell carcinoma in 2, and unknown in 2 (1 of the unknown cases was confirmed as adenocarcinoma following salvage surgery). The median time to LR was 2.1 years (interquartile range, 1.5-4.2 years) for adenocarcinoma compared with 1.3 years (interquartile range, 1.0-2.3 years) for squamous cell carcinoma. Multivariate analysis revealed that larger tumor size, squamous cell histology compared with adenocarcinoma, and use of abdominal compression for respiratory motion management were independent negative prognostic factors for LR.

Conclusions

Long-term follow-up data demonstrated that late LR was not uncommon and that careful follow-up after SBRT is needed, especially in patients with adenocarcinoma.

Introduction

The standard treatment of stage I non-small cell lung cancer (NSCLC) is surgery, but some patients are regarded as high risk or medically inoperable because of advanced age, poor general condition, and other medical comorbidities. Stereotactic body radiation therapy (SBRT) has been established as a nonsurgical alternative treatment for such frail patients 1, 2. Several prospective phase 2 trials of SBRT showed excellent outcomes with 3-year overall survival (OS) and local control rates of 56% to 60% and 85% to 98%, respectively, for medically inoperable stage I NSCLC 3, 4, 5. Although a systematic review of both prospective and retrospective studies of SBRT showed a high local control rate with limited toxicity, the follow-up time was relatively short in most studies and long-term follow-up data are lacking (6). A prospective phase 2 Nordic trial initially identified 4 local recurrences (LRs) and a 3-year local control rate of 92% (4), but long-term results of that trial identified 3 additional LRs >3 years after SBRT and the 5-year local control rate decreased to 79% (7). Our group also published a retrospective study showing that late LR even after >5 years might not be negligible (8). Thus, the need for long-term follow-up after SBRT is suggested to avoid missing LR.

The purpose of this study was to: (1) assess the rate and timing of LR; and (2) clarify the prognostic factors for LR and the incidence of late LR (>5 years after SBRT) by analyzing long-term follow-up data from large cohorts receiving SBRT with an isocenter prescription of 48 Gy in 4 fractions.

Section snippets

Patients

This retrospective study was approved by the institutional review board. We retrospectively reviewed a prospectively maintained institutional database and searched for eligible patients. Eligible patients were those who satisfied the following criteria: (1) clinical T1N0M0 (Union for International Cancer Control staging criteria, seventh edition) primary or recurrent NSCLC, with or without pathologic evidence, measuring <3 cm; (2) receipt of SBRT (isocenter prescription of 48 Gy in 4 fractions)

Patient and tumor characteristics

A total of 216 patients and 230 tumors were included. Among the 216 patients, 12 had 2 tumors and 1 had 3 tumors treated with SBRT (48 Gy in 4 fractions). Patient and tumor characteristics are shown in Table 1. The most common histology was adenocarcinoma (n = 86, 37%), followed by unknown (n = 71, 31%), squamous cell carcinoma (n = 59, 26%), and others (n = 14, 6%). The overall treatment time was <9 days for 172 tumors (75%) and ≥9 days for 58 tumors (25%). The number of tumors with a diameter

Discussion

We showed that the LR rate after SBRT of 48 Gy in 4 fractions at the isocenter was 16% at 3 years and 19% at 5 years. An isocenter prescription of 48 Gy in 4 fractions was previously the most commonly prescribed dose for lung SBRT in Japan (16). A prospective phase 2 study in Japan (JCOG [Japan Clinical Oncology Group] 0403) adopted the same regimen and reported a 3-year local control rate of 85% (5). Another prospective study reported 3- and 5-year local control rates of 86% for tumors

Acknowledgments

The authors thank Clare Cox, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this article.

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Clinical data, dosimetric data, and laboratory biomarkers from 186 patients treated with lung SBRT were collected. Univariate and multivariate logistic regression were performed to determine the predictive factors for grade ≥2 RP. Three models were developed by using the clinical, dosimetric, and combined factors, respectively.
With a median follow-up of 36 months, grade ≥2 RP was recorded in 13.4% of patients. On univariate logistic regression analysis, clinical factors of age and lung volume, dosimetric factors of treatment durations, fractional dose and V₁₀, and laboratory biomarkers of neutrophil, PLT, PLR, and Hb levels were significantly associated with grade ≥2 RP. However, on multivariate analysis, only age, lung volume, fractional dose, V₁₀, and Hb levels were independent factors. AUC values for the clinical, dosimetric, and combined models were 0.730 (95% CI, 0.660-0.793), 0.711 (95% CI, 0.641-0.775) and 0.830 (95% CI, 0.768-0.881), respectively. The combined model provided superior discriminative ability than the clinical and dosimetric models (P < .05).
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SABR has become the standard treatment for medically inoperable NSCLC and is an alternative therapy for operable disease with durable local control. With modern radiotherapy techniques, including respiratory control, treatment planning, and image-guided delivery, local failure rate ranges from 4.9% to 17%11–14 at 2–3 years and 6.3%–19% at 5 years.7,13,15 The present study showed a comparable local control rate of 90% at 3 years after SABR.
Stereotactic ablative radiotherapy (SABR) is the treatment of choice for medically inoperable, early-stage non-small cell lung cancer (ES-NSCLC). The influence of oncogenic driver alterations and comorbidities are not well known. Here we present treatment outcomes based on clinicopathologic features and molecular profiles.
We retrospectively analyzed patients treated with SABR for inoperable ES-NSCLC. Molecular features of oncogenic driver alterations included EGFR, ALK, and ROS1. Comorbidities were assessed using the age-adjusted Charlson Comorbidity Index (ACCI). Survival was calculated using the Kaplan–Meier method. The Cox regression model was performed for univariate and multivariate analyses of prognostic factors. Competing risk analysis was used to evaluate the cumulative incidence of disease progression.
From 2008 to 2020, 100 patients (median age: 82 years) were enrolled. The majority of patients were male (64%), ever-smokers (60%), and had adenocarcinoma (65%). With a median follow-up of 21.5 months, the median overall survival (OS) and real-world progression-free survival were 37.7 and 25.1 months, respectively. The competing-risk-adjusted 3-year cumulative incidences of local, regional, and disseminated failure were 8.2%, 14.5%, and 31.2%, respectively. An ACCI ≥7 was independently associated with inferior OS (hazard ratio [HR] 2.45, p = 0.03). Tumor size ≥4 cm (HR 4.16, p < 0.001) was the most important independent prognostic factor predicting real-world progression. EGFR mutation status had no impact on the outcomes.
SABR provides excellent local control in ES-NSCLC, although disseminated failures remains a major concern. ACCI is the best indicator for OS, while tumor sizes ≥4 cm predicts poor disease control.
Does Motion Management Technique for Lung SBRT Influence Local Control? A Single Institutional Experience Comparing Abdominal Compression to Breath-Hold Technique
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In looking at the impact of pulmonary function, body habitus, and SBRT immobilization on setup and reproducibility for upper lung tumors, Sio et al14 compared their 2 immobilization strategies: full-length BodyFIX for 76 lesions to thermoplastic S-frame for 17 lesions, and showed that local control was excellent at 2 years, with no significant difference between the 2 systems.14 Shintani et al15 looked at long-term data for risk factors for local recurrence after lung SBRT. For the 216 patients analyzed, 85% had no respiratory motion management, 12% had abdominal compression, and 3% had dynamic tumor tracking.
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A proportion of patients treated with curative intent will go on to develop an isolated local or regional recurrence. The exact incidence varies depending on the stage at diagnosis and type of initial curative therapy received; however, it is reported to range from 5% to 15%.3–8 There is limited prospective evidence available to guide the treatment of locoregionally recurrent NSCLC.
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Significant predictors of both OS and PFS at 5 years included age, sex, Charlson comorbidity index, diffusing capacity of carbon monoxide, systemic immune-inflammation index, and tumor size (P ≤ .01 for all). Eastern Cooperative Oncology Group performance status predicted for OS as well (P = .01), and both tumor size (P < .01) and minimum biological equivalent dose to 95% of planning target volume (PTV D95 BED₁₀; P < .01) were predictive of TTP. The C-indexes for the OS, PFS, and TTP nomograms were 0.73, 0.68, and 0.60 in the training data set and 0.72, 0.66, and 0.59 in the testing data set, respectively. Tumor size > 2.45 cm and PTV D95 BED₁₀ < 113 Gy were significantly associated with both local and distant progression.
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: This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (C) 15K09992 and Practical Research for Innovative Cancer Control (17ck0106303h0001) of the Japan Agency for Medical Research and Development (AMED). The study sponsor had no involvement in the study design and the collection, analysis, and interpretation of data and in the decision to submit the manuscript for publication.

: Conflict of interest: none.

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Clinical InvestigationA Retrospective Long-term Follow-up Study of Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer From a Single Institution: Incidence of Late Local Recurrence

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

Patient and tumor characteristics

Discussion

Acknowledgments

Chest

Ann Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

J Thorac Oncol

Chest

Radiother Oncol

Chest

Radiother Oncol

Int J Radiat Oncol Biol Phys

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

Radiother Oncol

J Thorac Oncol

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Clinical Investigation
A Retrospective Long-term Follow-up Study of Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer From a Single Institution: Incidence of Late Local Recurrence