Inoperable Early-stage Lung Cancer Research Articles

Executive Summary of the American Radium Society® (ARS) Appropriate Use Criteria (AUC) for Non-Small Cell Lung Cancer in a Central/Ultra-Central Location: Systematic Review and Guidelines

IntroductionDefinitive radiation therapy is considered standard therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). However, for patients with tumors located near to structures like the proximal tracheobronchial tree, esophagus, heart, spinal cord, and brachial plexus, the optimal management regimen is controversial. The objective was to develop expert multidisciplinary consensus guidelines on the management of medically inoperable NSCLC located in a central or ultra-central location relative to critical organs-at-risk. Materials and MethodsCase variants regarding centrally and ultra-centrally located lung tumors were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel. A comprehensive review of the English medical literature was performed from 1/1/46 to 12/31/23 to inform consensus guidelines. Modified Delphi methodology was used by the panel to evaluate the variants and procedures, with ≤3 rating points from median defining agreement/consensus. The guideline was then approved by the ARS Executive Committee and released for public comment per established ARS procedures. ResultsThe Thoracic ARS AUC Panel identified 90 relevant references and obtained consensus in all variants. Radiotherapy alone was considered appropriate, with additional immunotherapy to be considered primarily in the clinical trial setting. Hypofractionated radiotherapy in 8-18 fractions was considered appropriate for ultra-central lesions near proximal tracheobronchial tree, upper trachea, and esophagus. For other ultra-central lesions near heart, great vessels, brachial plexus, and spine, or for non-ultra-central but still central lesions, 5-fraction SBRT was also considered an appropriate option. Intensity-modulated radiotherapy was considered appropriate and 3D-conformal radiotherapy inappropriate for all variants. Other treatment planning techniques to decrease the risk of overdosing critical organs-at-risk were also considered. DiscussionThe ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of stage I NSCLC in a central or ultra-central location.

Survival analysis after stereotactic ablative radiotherapy for early stage non-small cell lung cancer: a single-institution cohort study

BackgroundStereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small cell lung cancer (ES-NSCLC), but which patients benefit from stereotactic radiotherapy is unclear. The aim of this study was to analyze prognostic factors for early mortality.MethodsFrom August 2010 to 2022, 617 patients with medically inoperable, peripheral or central ES-NSCLC were treated with SABR at our institution. We retrospectively evaluated the data from 172 consecutive patients treated from 2018 to 2020 to analyze the prognostic factors associated with overall survival (OS). The biological effective dose was > 100 Gy10 in all patients, and 60 Gy was applied in 3–5 fractions for a gross tumor volume (GTV) + 3 mm margin when the tumor diameter was < 1 cm; 30–33 Gy was delivered in one fraction. Real-time tumor tracking or an internal target volume approach was applied in 96% and 4% of cases, respectively. In uni- and multivariate analysis, a Cox model was used for the following variables: ventilation parameter FEV1, histology, age, T stage, central vs. peripheral site, gender, pretreatment PET, biologically effective dose (BED), and age-adjusted Charlson comorbidity index (AACCI).ResultsThe median OS was 35.3 months. In univariate analysis, no correlation was found between OS and ventilation parameters, histology, PET, or centrality. Tumor diameter, biological effective dose, gender, and AACCI met the criteria for inclusion in the multivariate analysis. The multivariate model showed that males (HR 1.51, 95% CI 1.01–2.28; p = 0.05) and AACCI > 5 (HR 1.56, 95% CI 1.06–2.31; p = 0.026) were significant negative prognostic factors of OS. However, the analysis of OS showed that the significant effect of AACCI > 5 was achieved only after 3 years (3-year OS 37% vs. 56%, p = 0.021), whereas the OS in one year was similar (1-year OS 83% vs. 86%, p = 0.58).ConclusionSABR of ES-NSCLC with precise image guidance is feasible for all medically inoperable patients with reasonable performance status. Early deaths were rare in our real-life cohort, and OS is clearly higher than would have been expected after best supportive care.

Invasive Nodal Staging via Endobronchial Ultrasound and Outcome in Patients Treated with Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer – Results from a Single Institution Study

IntroductionStereotactic body radiation therapy (SBRT) is an effective treatment for medically inoperable early-stage non-small cell lung cancer (NSCLC). The prognostic value of invasive nodal staging (INS) for patients undergoing SRBT has not been studied extensively. Herein, we report the impact of INS in addition to 18F-FDG-PET on treatment outcome for patients with NSCLC undergoing SBRT. Materials and MethodsPatients with stage I/ II NSCLC who underwent SBRT were included with IRB approval. Clinical, dosimetric, and radiological data were obtained. Overall survival (OS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), and distant recurrence free survival (DRFS) were analyzed using Kaplan Meyer method. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to assess the relationship between the variables and the outcomes. ResultsA total of 376 patients were included in the analysis. Median follow up was 43 months (IQ 32.6-45.8). Median OS, LRFS, RRFS, DRFS were 40, 32, 32, 33 months, respectively. The 5-year local, regional, and distant failure rates were 13.4%, 23.5% and 25.3%, respectively. The 1-year, 3-year and 5-year OS were 83.8%, 55.6%, and 36.3%, respectively. On MVA, INS was not a predictor of either improved overall or any recurrence free survival endpoints while larger tumor size, age, and adjusted Charleston co-morbidity index (aCCI) were significant for inferior LRFS, RRFS, and DRFS. ConclusionInvasive nodal staging did not improve overall or recurrence free survival among patients with early-stage NSCLC treated with SBRT whereas older age, aCCI, and larger tumor size were significant predictors of LRFS, RRFS, and DRFS.

Could Poor Outcomes for Patients with Limited Lung Function Treated with SAbR Necessitate PULSAR?

Stereotactic ablative radiotherapy (SAbR) employs precise targeting and delivery of ablative radiation doses in patients with medically inoperable early-stage non-small cell lung cancer, as well as patients with pulmonary metastases. SAbR is well tolerated with few studies reporting a minimal decline in pulmonary function tests (PFTs). However, poor pulmonary function is considered a risk factor for radiation induced lung toxicity. Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) is an adaptive radiation therapy regimen where radiation pulses are delivered over longer periods of time, thereby allowing for modification of the treatment based on the patient's response, as well as limiting toxicities. As such, we hypothesize that treating patients with poor pulmonary function using a PULSAR approach is better tolerated in when compared to patients treated with SAbR. We performed a retrospective review of our institutional database of patients treated with SAbR to lung lesions from 2005 to 2022. We assessed the overall survival in stage-matched patients with normal vs poor lung function who received SAbR (40 patients in each cohort). Patients with decreased lung function included those with a diagnosis of moderate/severe COPD, restrictive lung disease, or patients needing home oxygen at the time of treatment. We then analyzed PFTs changes for patients receiving SAbR, and evaluated these changes relative to treatment delivery. Stage-matched Kaplan-Meier analysis of patients with normal vs poor lung function receiving SAbR revealed a statistically significant difference in survival with Log-rank test p = 0.007. Of the patients with PFTs, 45 (90%) received SAbR with two to three treatments weekly, while 5 (10%) were treated on a PULSAR regimen with one fraction every week to three weeks. No trends or significant differences are observed in the changes of total lung capacity (TLC), the first second of exhalation (FEV1), forced vital capacity (FVC) or FEV1/FVC ratios. However, we did note variations in the diffusing capacity of the lung for carbon monoxide (DLCO). The mean difference in DLCO for the SAbR and PULSAR groups were -26.07% (95% CI: -31.28 to -20.87, p < 0.0001), and -10.52% (95% CI: -40.74 to 19.69, p = 0.388), respectively. We observed a significant difference in overall survival between patients with normal vs poor lung function receiving SAbR. In a preliminary analysis, we discovered a small decline in DLCO for patients treated with regularly scheduled SAbR treatments. In the patients treated on the PULSAR regimen, however, this change in DLCO is not statistically significant. While this data suggests that increasing the time frame between individual doses of radiation may result in better toleration of radiotherapy in this patient population, the sample size of patients treated via PULSAR is limited, and longer follow-up is needed to further evaluate the potential benefits.

Pretreatment and Posttreatment Tumor Metabolic Activity Assessed by FDG-PET/CT as Predictors of Tumor Recurrence and Survival Outcomes in Early-Stage Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy

Stereotactic body radiation therapy (SBRT) is considered the standard of care for medically inoperable early-stage non-small cell lung cancer. There is mixed evidence on the prognostic significance of tumor metabolic activity assessed by positron emission tomography combined with computed tomography (PET/CT) using F-18 fluorodeoxyglucose (FDG). The objectives of this study were to evaluate the maximum standardized uptake value (SUVmax) pretreatment and at 3 and 6 months after SBRT for prediction of tumor control and survival outcomes. Consecutive patients from a single institution with T12N0M0 non-small cell lung cancer receiving primary treatment with SBRT with pretreatment FDG-PET/CT (n=163) and follow-up FDG-PET/CT at 3 or 6 months (n=71) were included. Receiver operator characteristic analysis was performed to dichotomize variables for Kaplan-Meier survival analysis. Multivariate analysis was performed with Cox proportional hazards regression. Median follow-up was 19 months. For the whole cohort, 1-year and 2-year local control, progression-free survival (PFS), and overall survival (OS) were 95.0% and 80.3%, 87.1% and 75.4%, and 67.0% and 49.6% respectively. The following pre-SBRT SUVmax cutoffs were significant: SUV > 4.0 for distant failure-free survival (adjusted hazard ratio [aHR], 3.33, P=.006), >12.3 for PFS (aHR, 2.80, P=.011), and >12.6 for OS (aHR, 3.00, P=.003). SUVmax decreases of at least 45% at 3 months (aHR, 0.15, P=.018), and 53% at 6 months (aHR, 0.12, P=.046) were associated with improved local failure-free survival. Pre-SBRT SUVmax cutoffs can predict distant failure, PFS, and OS. At both 3 and 6 months after SBRT, cutoffs for percentage change in SUVmax can potentially stratify risk of local recurrence.

The Impacts of Angiotensin Receptor Blockers (ARBs) or Angiotensin-Converting Enzyme Inhibitors (ACEIs) on Patients with Stereotactic Body Radiation Therapy (SBRT) for Early-Stage NSCLC

Purpose: Stereotactic body radiation therapy (SBRT) has emerged as an alternative to surgery for patients with inoperable early-stage non-small cell lung cancer (NSCLC). The majority of inoperable NSCLC patients are elderly and frequently have comorbidities including cardiovascular diseases for which they frequently receive angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs). The interactions of these medications with SBRT are not clear. The objective of the current study is to investigate the interaction of ARBs and ACEIs with SBRT for the outcomes of early-stage NSCLC. Methods and Materials: A retrospective chart review of patients treated with SBRT for Stage I and II NSCLC (AJCC 7th edition) at a single institution between 2006 and 2017 was conducted. Information on the use of ARBs, ACEIs, demographics, and tumor-related factors was collected. Kaplan-Meier and Cox proportional hazard analyses were performed to assess the impact of ARBs and ACEIs combined with SBRT respectively on the treatment outcomes of these patients. Results: In total, 116 patients were included in the study, among whom 38/116 (32.76%) received ACEIs, and 20/116 (17.24%) received ARBs. In the multivariable analysis, the use of ARBs, but not ACEIs, with SBRT, was significantly associated with the increased risk of dissemination (Hazard Ratio (HR): 2.97; CI: 1.40-6.27; p &lt; 0.004) compared to SBRT without ARBs. The tumor size of &gt; = 3 cm was associated with significantly decreased time to local failure and OS compared to tumor size &lt;3cm. Conclusion: In the current retrospective study, the use of ARBs, in combination with SBRT, was associated with a significantly increased risk of disease dissemination in early-stage NSCLC compared to SBRT alone. The findings warrant further investigations on the concurrent use of ARBs, ACEIs, and other medicines used for chronic diseases with SBRT for early-stage NSCLC.

Five-year follow-up after stereotactic body radiotherapy for medically inoperable early-stage non-small cell lung cancer: a multicenter study.

Stereotactic body radiotherapy (SBRT) has proven to provide high rates of tumor control for patients with early-stage non-small cell lung cancer (NSCLC). We are reporting a multicenter experience of long-term clinical outcomes and adverse effect profiles of patients with medically inoperable early-stage NSCLC treated with SBRT. A total of 145 early-stage NSCLC patients underwent SBRT at the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Shandong Cancer Hospital and Institute, and Shanghai Pulmonary Hospital between October 2012 and March 2019. Four-dimensional computed tomography (4D-CT) simulation was used for all patients. All received a biologically effective dose (BED; α/β=10) of 96-120 Gy with the prescribed isodose line covering >95% of the planning target volume (PTV). Survival was analyzed by the Kaplan-Meier method. Survival was estimated using the Kaplan-Meier method. The median tumor diameter was 2.2 (range, 0.5-5.2) cm. The median follow-up was of 65.6 months. Thirty-five patients (24.1%) developed disease recurrence. The rates of local, regional, and distant disease recurrence were, respectively, 5.1%, 7.4%, and 13.2% at 3 years; and 9.6%, 9.8%, and 15.8% at 5 years. Progression-free survival (PFS) rates at 3 and 5 years were 69.2% and 60.5% respectively; the overall survival (OS) rates were 78.1% and 70.1%, respectively. Five patients (3.4%) experienced grade 3 treatment-related adverse events (AEs). No patient experienced grade 4 or 5 toxicity. From our retrospective analysis with long-term follow-up in Chinese population, SBRT achieved high rate of local control (LC) and low toxicity in patients with early-stage NSCLC. This study offered robust long-term outcome data of SBRT in the Chinese population, which was very rarely reported in China before.

PO-01-050 STRUCTURAL CARDIAC CHANGES DETECTED BY MRI AFTER STEREOTACTIC BODY RADIOTHERAPY FOR TARGETS IN CLOSE PROXIMITY TO THE HEART

Stereotactic body radiation therapy (SBRT) has become a standard of care for inoperable early-stage non-small cell lung cancer and in case of pulmonary oligometastases. Recent studies indicate that incidental irradiation of the heart may be associated with an increased risk of non-cancer-related deaths. This study aims to assess and examine structural cardiac changes following peri- and myocardial SBRT using a systematic cardiac follow-up protocol including cardiac magnetic resonance (CMR) imaging. For 1485 patients treated with local-ablative SBRT from January 2014 to February 2022 at our institution, the distance between the planning target volume (PTV) and the heart was measured. Forty-eight out of 134 patients treated in close proximity (<2cm) to the heart were alive at follow-up. Of those, 20 were randomly invited to undergo a structured cardiac follow-up protocol including CMR. Ten patients consented to participate and underwent a structural follow-up protocol. Registration of CMR image data and the SBRT treatment plan was performed to examine a possible correlation between the dose delivered to the myocardium and structural cardiac changes assessed by CMR. Among the 10 participating patients, the most common primary tumors were non-small cell lung cancer (n=3) and small-cell lung cancer (n=2) (Table 1). Five patients presented with pre-SBRT cardiovascular comorbidities. Seven patients received SBRT for pulmonary or vertebral metastases and three patients for primary lung cancer with a median dose of 42.5 Gy (30.0-48.0 Gy) in 3-10 fractions. The mean heart dose (Dmean) and maximum heart dose (Dmax) were 4.9 Gy (0.7-8.4 Gy) and 36.2 Gy (8.3 – 64.1 Gy), respectively. On CMR, five patients showed myocardial alterations, such as late gadolinium enhancement and edema after a median follow-up time of 5.6 years (0.1-6.3 years) as shown in Figure 1. In patients with structural changes of the myocardium the median distance between the treated lesion and myocardium with 0.0 (0.0-1.08) cm vs. 1.4 (0.41-2.0) cm was significantly lower (p=0.015). Additionally, patients with structural changes on CMR showed significantly higher Dmax (135.4 Gy vs. 25.4 Gy, p=0.009), Dmean (4.4 Gy vs. 3.4 Gy, p=0.05). In this pilot study, patients treated with SBRT for pulmonary targets with PTV overlapping the heart showed structural changes of the myocardium in CMR. The presence of structural changes correlates with higher heart doses.

Comparison of Changes in Pulmonary Function After Stereotactic Body Radiation Therapy Versus Conventional 3-Dimensional Conformal Radiation Therapy for Stage I and IIA Non-Small Cell Lung Cancer: An Analysis of the TROG 09.02 (CHISEL) Phase 3 Trial

The [Anonymized for Review] trial compared conventional radiotherapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomised to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the six-minute walk test (SMWT) between patients who received SBRT and those who received CRT. We analyzed the PFTs and SMWT of all patients recruited to the [Anonymized for Review] trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12-months post-treatment. 101 patients were enrolled, 33 patients were treated with CRT, 61 with SBRT and 7 did not receive treatment. Primary tumor size was similar between arms, SBRT 25mm (SD 9mm) and CRT 28mm (SD 9mm). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. PTV size was significantly larger in the CRT arm, 142.79 cc (SD 61.14cc) compared to the SBRT group 46.15 cc (SD 23.39 cc). The mean Biological Equivalent Dose (BED) received by the target was significantly larger in the SBRT group 125.92 Gy (SD 21.58 Gy) compared to CRT 65.49 Gy (6.32Gy). Mean dose to the lungs - iGTV was 8.9 Gy (SD 2.34 Gy) in the CRT group and 4.37 Gy (SD 1.42 Gy) in the SBRT group. Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the two groups.

Prognosis Analysis of Early-stage Non-small Cell Lung Cancer Patients Treated with Stereotactic Body Radiotherapy

With the aging of the population and the increased importance of lung cancer screening, the number of early-stage lung cancer patients has been on the rise in recent years, which can be classified into operable early-stage lung cancer and inoperable early-stage lung cancer. The most common pathological type is non-small cell lung cancer (NSCLC). Stereotactic body radiation therapy (SBRT) is the optimal treatment for inoperable early-stage NSCLC. The aim of this study was to investigate the prognosis of early-stage NSCLC patients treated with SBRT and its influencing factors in order to reduce the side effects of radiotherapy and improve the survival and quality of life. Clinical data and follow-up outcomes of early-stage NSCLC patients treated with SBRT in our hospital from August 2010 to August 2020 were collected. Kaplan-Meier method was used to assess the prognosis, and the Cox proportional risk model was used for multivariate prognostic analysis. A total of 165 patients were included with a median follow-up time of 43.2 (range: 4.8-132.1) mon. The local control (LC) rates at 1-yr, 2-yr and 5-yr were 98.1%, 94.8% and 86.5% respectively. Karnofsky performance status (KPS) score greater than 80 was an independent prognostic factor for LC (P=0.02). The overall survival (OS) rates at 1-yr, 2-yr and 5-yr were 97.6%, 93.0% and 68.9% respectively. A biological equivalent dose when α/β=10 (BED10) greater than 132 Gy was an independent prognostic factor for OS (P=0.04). Progression-free survival (PFS) rates at 1-yr, 2-yr and 5-yr were 93.3%, 79.5% and 55.3% respectively. The distance metastasis free survival (DMFS) rates at 1-yr, 2-yr and 5-yr were 94.5%, 83.2% and 58.4% respectively. BED10 greater than 150 Gy was an independent prognostic factor for DMFS (P=0.02). The regional control (RC) rates at 1-yr, 2-yr and 5-yr were 98.8%, 95.4% and 87.9% respectively. SBRT is effective in treating early-stage NSCLC. KPS greater than 80 is an independent prognostic factor for LC; BED10 greater than 132 Gy is an independent prognostic factor for OS; BED10 greater than 150 Gy is an independent prognostic factor for DMFS.

93P A phase II study of camrelizumab plus chemotherapy in patients with medically inoperable early-stage non-small cell lung cancer

93P A phase II study of camrelizumab plus chemotherapy in patients with medically inoperable early-stage non-small cell lung cancer

Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients

Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients’ outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.

Toxicity Profile for Connective Tissue Disease Patients Treated with Lung Stereotactic Body Radiation Therapy (SBRT)

<h3>Purpose/Objective(s)</h3> Connective tissue diseases (CTDs) have historically been considered as presenting contraindications to radiotherapy (RT), in particular lung RT, due to concern for increased rates of severe toxicity. Improving medical management of CTDs may lead to an increasing number patients with CTDs requiring lung RT. As a subset of lung RT, stereotactic body radiation therapy (SBRT) used for inoperable early-stage lung cancer or oligometastases is associated with very low rates of high-grade toxicity. The present study seeks to detail the safety of lung SBRT in CTD patients. <h3>Materials/Methods</h3> A single institution prospective lung SBRT registry was surveyed for all patients treated for primary cancer, oligometastasis or salvage from 2006 – 2021. Tumors were identified as peripheral or central per RTOG criteria. Treatment-related toxicity was graded per CTCAE version 3.0. Medical management of CTDs was recorded at time of cancer consultation. <h3>Results</h3> A total of 91 CTD patients undergoing 122 courses of lung SBRT were available for analysis. Median age of the cohort was 72 years (64 – 80, IQR) comprised of 27 (30%) males and 64 (70%) females. Median KPS was 80 (70 – 90, IQR). Median follow-up was 20 months (8 – 42, IQR). CTD patients included 43 (47%) with rheumatoid arthritis (RA), 14 (15%) with systemic lupus, 18 (20%) with CTD associated interstitial/idiopathic lung disease, 5 (6%) with scleroderma, and 37 (41%) with other CTDs. Thirty-five (38%) patients had multiple CTDs. At SBRT, 47 (52%) patients were on active medical treatment and two (2%) had prior lung transplantation. For a range of fractionation schedules, SBRT median BED₁₀ was 106 Gy (100 – 149, IQR). Nine (10%) patients were treated with synchronous lesions, with two (2%) patients receiving five simultaneous treatments for oligometastatic disease. Twenty-six tumors (21%) were central. Median tumor size was 1.7 cm (1.2 – 2.7, IQR). Overall, 25 (21%) treatments resulted in grade 2 and greater toxicity, with four (3%) grade 3 and no grade 4 or 5 toxicities. Lung toxicities included 12 (10%) pneumonitis, 10 (8%) chest wall pain, 2 (2%) cough, and 1 (1%) pleural effusion. Grade 3 pneumonitis rate was 10% for CTD associated interstitial/idiopathic lung disease, 2% for RA, and 0% for lupus and scleroderma. <h3>Conclusion</h3> Lung SBRT for CTD patients was not generally associated with increased rates of high-grade toxicity but on subset analysis, patients with CTD associated interstitial/idiopathic lung disease may be at risk for grade 3 pneumonitis.

Role of Stereotactic Radiation Therapy in Operable and Inoperable Early-Stage Non-small Cell Lung Cancer.

Radiation therapy is becoming an increasingly important part of non-small cell lung cancer (NSCLC) management. Approximately 60% of all cancer patients require radiation therapy (RT) as part of their treatment. For lung cancer, this number is even higher, reaching approximately 77% of all patients, from radical to palliative modalities of RT. This percentage may even be underestimated, as it may not account for the more recent use of RT in oligometastatic lung cancer patients. Thus, we can estimate that each year there will be approximately 21,890 new lung cancer patients in the USA requiring RT. These numbers are expected to continue to rise, as lung cancer radiation techniques continue to improve. There is growing interest in determining the best treatment options for early-stage NSCLC patients. There is well-established data showing the benefit of RT for inoperable patients, and more recent encouraging data even in operable patients.

Rationale for Combing Stereotactic Body Radiation Therapy with Immune Checkpoint Inhibitors in Medically Inoperable Early-Stage Non-Small Cell Lung Cancer.

Simple SummaryThe rate of recurrence remains high for lymph node negative early-stage non-small cell lung cancer that are over 2–3 cm in size following stereotactic body radiation therapy (SBRT). This is due to the increased incidence of out-of-field failures, which warrants the addition of systemic therapy. Immune checkpoint inhibitors (ICIs), a class of immunotherapy, may induce a strong distant therapeutic effect known as the “abscopal” effect. This makes them a very suitable class of drugs to be combined with SBRT when treating early lung cancer with high-risk features, such as larger tumor size. In this review, we discuss the rationale and evidence for doing so.Stereotactic body radiation therapy (SBRT) has been widely adopted as an alternative to lobar resection in medically inoperable patients with lymph-node negative (N0) early-stage (ES) non-small cell lung cancer (NSCLC). Excellent in-field local control has been consistently achieved with SBRT in ES NSCLC ≤ 3 cm in size. However, the out-of-field control following SBRT remains suboptimal. The rate of recurrence, especially distant recurrence remains high for larger tumors. Additional systemic therapy is warranted in N0 ES NSCLC that is larger in size. Radiation has been shown to have immunomodulatory effects on cancer, which is most prominent with higher fractional doses. Strong synergistic effects are observed when immune checkpoint inhibitors (ICIs) are combined with radiation doses in SBRT’s dose range. Unlike chemotherapy, ICIs can potentiate a strong systemic response outside of the irradiated field when combined with SBRT. Together with their less toxic nature, ICIs represent a very suitable class of systemic agents to be combined with SBRT when treating ES NSCLC with high-risk features, such as larger tumor size. In this review, we describe the rationale and emerging evidence, as well as ongoing investigations in this area.

A Comparative Study of Patients With Early-Stage Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy Using CyberKnife and Linear Accelerator–Based Volumetric Modulated Arc Therapy

PurposeStereotactic body radiation therapy (SBRT) has become the standard of care for medically inoperable early-stage non-small cell lung cancer. We investigated 2 modalities of lung SBRT, CyberKnife (CK) and volumetric modulated arc therapy (VMAT), for differences in dosimetric parameters, tumor control, and clinical outcomes. Methods and MaterialsPatients who underwent SBRT for T1-2N0M0 non-small cell lung cancer from 2012 to 2018 were included. Dosimetric parameters for target volume coverage and organ-at-risk dose distribution were collected. Survival outcomes were evaluated using the Kaplan-Meier method with log-rank test. A multivariate Cox proportional hazards model was analyzed for local, regional, and distant tumor control; overall survival (OS) and progression-free survival; and radiation pneumonitis. ResultsTwo hundred twenty-seven patients (142 CK, 85 VMAT SBRT) met inclusion criteria. Overall, the local, regional, and distant control rates were 89.3%, 86.3%, and 87.4% at 2 years, and the OS was 67.5% and 32.8% at 2 and 5 years, respectively. VMAT delivered higher maximum doses to the gross tumor volume and planning target volume and had a lower lung and heart V5. Although there was no difference in local or distant failure, progression-free survival, or OS, VMAT was associated with superior freedom from regional failure (adjusted hazard ratio, 0.26; P = .045). With no difference between treatment modalities, 11.9% of patients developed grade 1 to 2 radiation pneumonitis. There were no grade 3+ events of radiation pneumonitis. ConclusionsThis study revealed that VMAT and CK provided comparable local and distant control and survival outcomes; however, VMAT exhibited better regional control. Further study in this regard is imperative.

Recent Advances in the Diagnosis and Management of Multiple Primary Lung Cancer

Simple SummaryWith the wide application of computed tomography and lung cancer screening, the incidence of multiple primary lung cancer, that is, the occurrence of two or more primary malignant lung tumors in a patient, has been increasingly reported. The optimal strategy for the diagnosis and treatment of multiple primary lung cancers is controversial. Surgery remains the main treatment modality, whereas other treatment methods, including radiotherapy and local ablation, are also feasible, particularly for inoperable patients. Next-generation sequencing and novel therapies, such as targeted agents and immune-checkpoint inhibitors, have provided new insights into this topic.With the wide application of computed tomography in lung cancer screening, the incidence of multiple primary lung cancer (MPLC) has been increasingly reported. Despite the established criteria, the differentiation between MPLC and intrapulmonary metastasis remains challenging. Although histologic features are helpful in some circumstances, a molecular analysis is often needed. The application of next-generation sequencing could aid in distinguishing MPLCs from intrapulmonary metastasis, decreasing ambiguity. For MPLC management, surgery with lobectomy is the main operation method. Limited resection does not appear to negatively affect survival, and it is a reasonable alternative. Stereotactic ablative radiotherapy (SABR) has become a standard of care for patients refusing surgery or for those with medically inoperable early-stage lung cancer. However, the efficacy of SABR in MPLC management could only be found in retrospective series. Other local ablation techniques are an emerging alternative for the control of residual lesions. Furthermore, systemic therapies, such as targeted therapy for oncogene-addicted patients, and immunotherapy have shown promising results in MPLC management after resection. In this paper, the recent advances in the diagnosis and management of MPLC are reviewed.

Comparison of stereotactic body radiotherapy and radiofrequency ablation for early-stage non-small cell lung cancer: a systematic review and meta-analysis.

BackgroundStereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) are recommended for patients with inoperable early-stage non-small cell lung cancer (NSCLC), with both offering promising results. However, it is largely unknown which of these two treatment modalities provides superior benefits for patients. Therefore, this systematic review and meta-analysis compared clinical outcomes and safety between SBRT and RFA in patients with inoperable early-stage NSCLC.MethodsEligible studies published between 2001 and 2020 were obtained through a comprehensive search of the PubMed, Medline, Embase, and Cochrane Library databases. Original English-language studies on the treatment of early-stage NSCLC with SBRT or RFA were included. Local control (LC) rates, overall survival (OS) rates, and adverse events were obtained by pooled analyses.ResultsEighty-seven SBRT studies (12,811 patients) and 18 RFA studies (1,535 patients) met the eligibility criteria. For SBRT, the LC rates (with 95% confidence intervals) at 1, 2, 3, and 5 years were 98% (97–98%), 95% (95–96%), 92% (91–93%), and 92% (91–93%), respectively, which were significantly higher than those for RFA [75% (69–82%), 31% (22–39%), 67% (58–76%), and 41% (30–52%), respectively] (P<0.01). There were no significant differences in short-term OS between SBRT and RFA [1-year OS rate: 87% (86–88%) versus 89% (88–91%), P=0.07; 2-year OS rate: 71% (69–72%) versus 69% (64–74%), P=0.42]. Regarding long-term OS, the 3- and 5-year OS rates for SBRT were 58% (56–59%) and 39% (37–40%), respectively, which were significantly (P<0.01) superior to those for RFA [48% (45–51%) and 21% (19–23%), respectively]. The most common complication of SBRT was radiation pneumonitis (grade ≥2), making up 9.1% of patients treated with SBRT, while pneumothorax was the most common complication of RFA, making up 27.2% of patients treated with RFA.DiscussionCompared with RFA, SBRT has superior LC and long-term OS rates but similar short-term OS rates. Prospective randomized trials with large sample sizes comparing the efficacy of SBRT and RFA are warranted.

Bibliometric Analysis of the Top-Cited Publications and Research Trends for Stereotactic Body Radiotherapy

ObjectiveThis study aims to analyze the 100 most cited papers and research trends on stereotactic body radiotherapy (SBRT).MethodsWe used Web of Science to identify the 100 most frequently cited papers on SBRT on September 29, 2021 and extracted the following data: publication year, source title, country/region, organization, total citations, and average number of citations per year. The research type and research domain were classified independently by the authors. Then we carried out a bibliometric analysis to determine the trends in research on SBRT.ResultsThese 100 papers were cited a total of 26,540 times, and the median number of citations was 190 (range, 138-1688). “Stereotactic body radiation therapy for inoperable early stage lung cancer” by Timmerman et al. had the highest number of total citations (1688 times). International Journal of Radiation Oncology, Biology, Physics published the largest number of papers (37 papers), followed by Journal of Clinical Oncology (13 papers). The USA contributed the most papers (67 papers), followed by Canada (18 papers). Primary lung cancer (33 papers, 10,683 citations) and oligometastases (30 papers, 7,147 citations) were the most cited research areas.ConclusionsTo the best of our knowledge, this is the first bibliometric analysis of the most frequently cited papers on SBRT. Our results provide insight into the historical development of SBRT and important advances in its application to cancer treatment. Early-stage non–small-cell lung cancer and oligometastases were the most cited research areas in the top 100 publications on SBRT, and SBRT combined with immunotherapy was a hot topic in the past few years. This study is helpful for researchers to identify the most influential papers and current research hotspots on SBRT.

Tumor Control and Survival Outcomes Based on Maximum Standardized Uptake Value on FDG-PET/CT in T1-2 NSCLC Treated With SBRT

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) is standard of care in medically inoperable early-stage non-small cell lung cancer (NSCLC). Assessment of maximum standardized uptake value (SUVmax) on FDG-PET/CT before and after SBRT may stratify tumor control and survival outcomes. <h3>Materials/Methods</h3> Retrospective chart review identified patients with T1-2N0M0 NSCLC who were only treated with SBRT between 2012 and 2019. Pretreatment SUVmax and percent change in SUVmax at 3 and 6 months following SBRT were assessed as independent predictors of local control (LC), regional failure-free survival (RFFS), distant failure-free survival (DFFS), progression-free survival (PFS), and overall survival (OS). Receiver operator characteristic (ROC) analysis yielded optimal cut points for comparison. Survival analyses were performed with Kaplan-Meier estimates with log rank testing, and Cox proportional hazards models including age, sex, T stage, histology, and performance status. <h3>Results</h3> 71 (43.6%) out of 163 patients underwent repeat PET/CT within 6 months of SBRT completion. Median follow-up was 19 months (range 1 – 94 months). For the whole cohort, 1-year and 2-year LC, PFS, and OS were 95.0% and 80.3%, 75.9% and 47.7%, and 87.1% and 67.0%, respectively. For DFFS, pretreatment SUVmax greater than 4 had an aHR of 3.33 (95% CI 1.42 – 7.84, <i>P</i> = 0.006). Pre-SBRT SUVmax over 12.3 had an aHR of 2.80 (95% CI 1.3 – 6.2, <i>P</i> = 0.011) for PFS, and a cut point of 12.6 had an aHR of 3.00 (95% CI 1.6 – 5.8, <i>P</i> = 0.003) for OS. Pretreatment SUVmax did not significantly predict LC or RFFS. At 3 months following SBRT, an SUVmax decrease of at least 45% was associated with improved LC (aHR = 0.15, 95% CI 0.02 – 0.91, <i>P</i> = 0.018). A 6-month SUVmax decrease of more than 53% was associated with better LC (<i>P</i> = 0.038), and a decrease over 11% was associated with improved RFFS (aHR = 0.12, 95% CI 0.02 – 0.96, <i>P</i> = 0.046). Change in SUVmax was not significantly associated with DFFS, PFS, or OS at either time point. No factors other than performance status for PFS and OS were significant. <h3>Conclusion</h3> At 3 and 6 months following SBRT, cut points for percentage change in SUVmax can stratify risk of local recurrence and possibly regional recurrence. Pretreatment SUVmax cutoffs can predict distant failure, progression-free survival, and overall survival in early-stage NSCLC.