Real-World Results of Stereotactic Body Radiotherapy for 399 Medically Operable Patients with Stage I Histology-Proven Non-Small Cell Lung Cancer.

Surgery is the standard treatment for stage I non-small cell lung cancer (NSCLC); however, no clear randomized trial demonstrates its superiority to stereotactic body radiotherapy (SBRT) regarding survival. We aimed to retrospectively evaluate the treatment outcomes of SBRT in operable patients with stage I NSCLC using a large Japanese multi-institutional database to show real-world outcome. Exactly 399 patients (median age 75 years; 262 males and 137 females) with stage I (IA 292, IB 107) histologically proven NSCLC (adenocarcinoma 267, squamous cell carcinoma 96, others 36) treated at 20 institutions were reviewed. SBRT was prescribed at a total dose of 48-70 Gy in 4-10 fractions. The median follow-up period was 38 months. Local progression-free survival rates were 84.2% in all patients and 86.1% in the T1, 78.6% in T2, 89.2% in adenocarcinoma, and 70.5% in squamous cell subgroups. Overall 3-year survival rates were 77.0% in all patients: 90.7% in females, 69.6% in males, and 41.2% in patients with pulmonary interstitial changes. Fatal radiation pneumonitis was observed in two patients, all of whom had pulmonary interstitial changes. This real-world evidence will be useful in shared decision-making for optimal treatment, including SBRT for operable stage I NSCLC, particularly in older patients.

Local control correlates with overall survival in radiotherapy for early-stage non-small cell lung cancer: A systematic review.

PURPOSE: Local control (LC) is an important outcome of local cancer therapy, besides overall survival (OS). We conducted a comprehensive literature search to investigate whether a high LC rate contributes to good OS in radiotherapy for early-stage non-small cell lung cancer (ES-NSCLC). MATERIALS AND METHODS: Studies in patients receiving radiotherapy for peripheral ES-NSCLC, mainly staged as T1-2N0M0 were included for a systematic review. Relevant information was collected including, dose fractionation, T stage, median age, 3-year LC, cancer-specific survival (CSS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and OS. Correlations between outcomes and clinical variables were evaluated. RESULTS: After screening, 101 data points from 87 studies including 13,435 patients were selected for the quantitative synthesis. Univariate meta-regression analysis revealed that the coefficients between the 3-year LC and 3-year DFS, DMFS, CSS, and OS were 0.753 (95% confidence interval (CI): 0.307-1.199; p < 0.001), 0.360 (95% CI: 0.128-0.593; p = 0.002), 0.766 (95% CI: 0.489-1.044; p < 0.001), and 0.574 (95% CI: 0.275-0.822; p < 0.001), respectively. Multivariate analysis revealed that the 3-year LC (coefficient, 0.561; 95% CI: 0.254-0.830; p < 0.001) and T1 proportion (coefficient, 0.207; 95% CI: 0.030-0.385; p = 0.012) were significantly associated with the 3-year OS and CSS (coefficient for 3-year LC, 0.720; 95% CI: 0.468-0.972; p < 0.001 and T1 proportion, 0.002; 95% CI: 0.000-0.003; p = 0.012). Toxicities ≥ grade 3 were low (3.4%). CONCLUSIONS: Three-year LC was correlated with three-year OS in patients receiving radiotherapy for ES-NSCLC. A 5% increase in 3-year LC is expected to improve the 3-year CSS and OS rates by 3.8% and 2.8%, respectively.

Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines).

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance-diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described.

Relationship between Dose Prescription Methods and Local Control Rate in Stereotactic Body Radiotherapy for Early Stage Non-Small-Cell Lung Cancer: Systematic Review and Meta-Analysis.

Variations in dose prescription methods in stereotactic body radiotherapy (SBRT) for early stage non-small-cell lung cancer (ES-NSCLC) make it difficult to properly compare the outcomes of published studies. We conducted a comprehensive search of the published literature to summarize the outcomes by discerning the relationship between local control (LC) and dose prescription sites. We systematically searched PubMed to identify observational studies reporting LC after SBRT for peripheral ES-NSCLC. The correlations between LC and four types of biologically effective doses (BED) were evaluated, which were calculated from nominal, central, and peripheral prescription points and, from those, the average BED. To evaluate information on SBRT for peripheral ES-NSCLC, 188 studies were analyzed. The number of relevant articles increased over time. The use of an inhomogeneity correction was mentioned in less than half of the articles, even among the most recent. To evaluate the relationship between the four BEDs and LC, 33 studies were analyzed. Univariate meta-regression revealed that only the central BED significantly correlated with the 3-year LC of SBRT for ES-NSCLC (p = 0.03). As a limitation, tumor volume, which might affect the results of this study, could not be considered due to a lack of data. In conclusion, the central dose prescription is appropriate for evaluating the correlation between the dose and LC of SBRT for ES-NSCLC. The standardization of SBRT dose prescriptions is desirable.

Role of stereotactic body radiotherapy in multidisciplinary management of liver metastases in patients with colorectal cancer.

In the treatment of colorectal cancer patients with distant metastases, the development of new anticancer agents has considerably prolonged progression-free survival. Such survival benefits attributed to chemotherapy have increased the relative significance of local therapy in patients with limited metastases. The liver is recognized as the most common site of metastasis of colorectal cancer because of the intestinal mesenteric drainage to the portal veins. Hepatic resection of isolated liver metastases of colorectal cancer is the only option for a potential cure. However, hepatic metastases are resectable in only approximately 20% of the patients. For remaining patients with high-risk resectable liver metastases or those who are unfit for surgery, less invasive, local therapies including radiation therapy (stereotactic body radiation therapy, SBRT) may have a potential role in treatment. Although the local control rate of SBRT for colorectal liver metastases has room for improvement, its less-invasive nature and broad indications deserve consideration. Future research should include SBRT dose escalation or the selection of patients who benefit from local ablative therapies. SBRT may offer an alternative, non-invasive approach for the treatment of colorectal liver metastases in a multidisciplinary treatment strategy.

Applying Artificial Neural Networks to Develop a Decision Support Tool for Tis-4N0M0 Non-Small-Cell Lung Cancer Treated With Stereotactic Body Radiotherapy.

PURPOSE: Clear evidence indicating whether surgery or stereotactic body radiation therapy (SBRT) is best for non-small-cell lung cancer (NSCLC) is lacking. SBRT has many advantages. We used artificial neural networks (NNs) to predict treatment outcomes for patients with NSCLC receiving SBRT, aiming to aid in decision making. PATIENTS AND METHODS: Among consecutive patients receiving SBRT between 2005 and 2019 in our institution, we retrospectively identified those with Tis-T4N0M0 NSCLC. We constructed two NNs for prediction of overall survival (OS) and cancer progression in the first 5 years after SBRT, which were tested using an internal and an external test data set. We performed risk group stratification, wherein 5-year OS and cancer progression were stratified into three groups. RESULTS: In total, 692 patients in our institution and 100 patients randomly chosen in the external institution were enrolled. The NNs resulted in concordance indexes for OS of 0.76 (95% CI, 0.73 to 0.79), 0.68 (95% CI, 0.60 to 0.75), and 0.69 (95% CI, 0.61 to 0.76) and area under the curve for cancer progression of 0.80 (95% CI, 0.75 to 0.84), 0.72 (95% CI, 0.60 to 0.83), and 0.70 (95% CI, 0.57 to 0.81) in the training, internal test, and external test data sets, respectively. The survival and cumulative incidence curves were significantly stratified. NNs selected low-risk cancer progression groups of 5.6%, 6.9%, and 7.0% in the training, internal test, and external test data sets, respectively, suggesting that 48% of patients with peripheral Tis-4N0M0 NSCLC can be at low-risk for cancer progression. CONCLUSION: Predictions of SBRT outcomes using NNs were useful for Tis-4N0M0 NSCLC. Our results are anticipated to open new avenues for NN predictions and provide decision-making guidance for patients and physicians.

CT Findings and Treatment Outcomes of Ground-Glass Opacity Predominant Lung Cancer After Stereotactic Body Radiotherapy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been rapidly evolving and increasingly performed in patients with ground-glass opacity (GGO) predominant lung cancer (GGOp-LC). PURPOSE: To evaluate early-phase CT findings of GGOp-LC after SBRT. MATERIALS AND METHODS: Patients with GGOp-LC staged as cTis-2bN0M0 treated with SBRT were retrospectively identified. The CT images were analyzed using radiologists' interpretation and CT-density histograms. Long-term treatment outcomes were also assessed. RESULTS: This study evaluated 126 patients with 133 cases of GGOp-LC, comprising GGOp-LC with pure GGO (pureGGO-LC) (n = 31) and part-solid tumors (partsolid-LC) (n = 102). The median follow-up duration was 64.3 months (range, 10.8-178.9 months). Most GGOp-LC cases were interpreted as stable disease at 1 and 3 months after SBRT (96% [125/130] and 85% [62/73], respectively). However, the solid component was often interpreted as progressive disease (42% [34/82] and 60% [29/48], respectively). The GGO component was interpreted as denser in 47% (61/130) and 86% (63/73) of cases, respectively. For 25 evaluable pureGGO-LC cases at 3 months, the median tumor density values increased over time (P < .001). For 48 evaluable partsolid-LC cases at 3 months, the median areas of CT-density ≥ -160 HU increased over time (P < .001). The 5-year overall survival for GGOp-LC patients was 78.0%. No local or regional recurrence were observed. CONCLUSION: Clinical outcomes of SBRT for GGOp-LC were excellent, without local or regional recurrence. In the interpretation of early-phase follow-up CT scans of GGOp-LC after SBRT, it should be noted that most GGOp-LC remains stable disease, solid component increases in size, and GGO component is denser.

Pathological Appearance of Focal Liver Reactions after Radiotherapy for Hepatocellular Carcinoma.

We studied five pathological specimens from five patients at 1.5, 3.0, 4.0, 13.5, and 14.0 months after radiotherapy for HCC. Four needle biopsies were obtained to investigate liver parenchyma of focal liver reaction (FLR) around treated HCC, when patients had newly developed HCC or local recurrence appeared in the liver. Liver resection was performed in one case where insufficient radiotherapy effect for HCC was suspected. In all patients, FLR was recognized as a hypervascular area around the HCC on enhanced CT and enhanced Gd-EOB-DTPA (EOB-MRI). Liver specimens were analyzed to assess the pathological characteristics of FLR. FLR was recognized as prolonged liver enhancement in enhanced CT and EOB-MRI. From pathological understanding, sinusoidal dilatation with degeneration and desquamation was caused by direct endothelial cell injury following radiotherapy. Hepatocytes and endothelium fell off, and so the portal tract came close, and hepatic arteries increase simultaneously, resulting in FLR around HCC after radiotherapy. In conclusion, the prolapse of hepatocytes and sinusoidal endothelium induced neovascularization of hepatic arteries due to the repair mechanisms; in addition, these prolapse may shorten the distance between each portal region and the hepatic arteries flowing through the portal region become more prominent in FLR.

Feasibility of marker-less stereotactic body radiotherapy for hepatocellular carcinoma.

BACKGROUND: The feasibility of marker-less stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) has not yet been established, and, thus, was examined in the present study. MATERIAL AND METHODS: We retrospectively investigated patients who received marker-less SBRT for locally untreated HCC tumors between July 2005 and December 2018. Radiotherapy planning CT was performed under fixation with vacuum cushions and abdominal compression. The clinical target volume (CTV) was equivalent to the gross tumor volume (GTV). The internal target volume (ITV) margin to CTV was determined from calculations based on the motion of the diaphragm. The planning target volume (PTV) margin to ITV was 5-6 mm. In the set-up, radiotherapy planning CT and linac-integrated cone-beam CT performed in the same imaging and fixation settings were merged by referring to the anatomical components surrounding target tumors. The primary endpoint was the 3-year cumulative local tumor progression rate. The upper limit of the 95% confidence interval for the 3-year cumulative local tumor progression rate was less than 7.0%, which was interpreted as favorable local control and feasible for marker-less SBRT. Local tumor progression was assessed by mRECIST. RESULTS: We reviewed 180 patients treated with 35-40 Gy/5 fractions. The median follow-up time for the local tumor progression of censored tumors was 32.3 months (range, 0.3-104). The 3-year cumulative local tumor progression rate was 3.0% (95% CI, 1.1-6.5%). The 3-year overall survival rate was 71.6% (95% CI, 63.5-78.2%). Regarding acute hematologic toxicities, grade 3 hypoalbuminemia and thrombocytopenia were detected in 1 (0.6%) and 5 (2.9%) patients, respectively. Treatment-related death from SBRT was not observed. SBRT was initiated within 7 days after radiotherapy planning CT for 84% (152/180) of patients. CONCLUSIONS: Marker-less SBRT for HCC achieved favorable local control that fulfilled the threshold. This result suggests that marker-less SBRT with appropriate settings is a feasible treatment strategy.

Impact of Local Recurrence on Cause-Specific Death After Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer: Dynamic Prediction Using Landmark Model.

PURPOSE: The purpose of this study was to assess the impact of local recurrence (LR) on cause-specific death (CSD) in patients with non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). A dynamic prediction model that incorporated LR as a time-dependent covariate was used. METHODS AND MATERIALS: This study included 535 stage I (cT1-T2aN0M0) NSCLC patients treated with SBRT from two institutions. We developed a landmark dynamic prediction model to estimate the probability of a CSD. This model determined the probability of surviving for an additional 3 years at different prediction time points during follow-up, given the history of recurrence status. The baseline covariates included in the model were age, sex, T stage, and histology, while the time-dependent covariates were LR and regional and/or distant recurrence (RDR) status. RESULTS: Overall, 137 patients (25.6%) died of lung cancer within a median follow-up of 4.1 years. Of the 195 patients who developed recurrence, 28, 125, and 42 patients had LR only, RDR only, and both, respectively. The landmark model showed that older age, advanced T stage, LR, and RDR were significantly associated with an increased risk of subsequent CSD. Among these covariates, LR (odds ratio [OR], 8.5; 95% confidence interval [CI], 6.0-12.0; P < .001) and RDR (OR, 11.6; 95% CI, 9.1-14.9; P < .001) demonstrated strong effects on CSD within 3 years after the prediction time points. The dynamic prediction provided information on the probability of future CSD according to individual recurrence status during follow-up. CONCLUSIONS: Dynamic prediction using the landmark model showed that LR had a substantial impact on subsequent CSD, which was comparable to that of RDR. This result supports the notion that strategies to improve local control are reasonable.

Three Cases of Hepatocellular Carcinoma With Massive Macrovascular Invasion Successfully Treated With Radiotherapy.

In clinical practice, the treatment approach for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) is determined on a case-by-case basis. The common management options include systemic and local therapies, although the former is the more widely accepted approach. We present three cases of HCC with MVI successfully treated with radiotherapy. The first patient was a 62-year-old man with Child-Pugh A cirrhosis who had a 5.7-cm treatment-naïve HCC invading the bilateral branches of the portal vein. Stereotactic body radiotherapy (SBRT) was administered, with no evidence of recurrence observed at the 24-month follow-up. The second patient was an 81-year-old man with Child-Pugh A cirrhosis who had a 3.8-cm HCC invading the inferior vena cava (IVC). Transcatheter chemoembolization performed one month earlier had been ineffective, and the tumor had grown rapidly. SBRT was administered, and no evidence of recurrence was observed up to his death from pneumonia 24 months after the treatment initiation. The third patient was a 72-year-old man with Child-Pugh A cirrhosis who had a 6.7-cm treatment-naïve HCC with portal vein tumor thrombosis (PVTT) from the main trunk to the secondary branches of both lobes. PVTT was treated with hypofractionated radiotherapy, while the primary HCC and intrahepatic recurrent lesions were subsequently treated with hepatic arterial infusion chemotherapy (HAIC) and five rounds of ablation. Six months after the last ablation (48 months after initial therapy), no evidence of recurrence was observed. Our cases illustrate that radiotherapy leads to the successful treatment of HCC with MVI.

Development and validation of a prognostic model for non-lung cancer death in elderly patients treated with stereotactic body radiotherapy for non-small cell lung cancer.

This study sought to develop and validate a prognostic model for non-lung cancer death (NLCD) in elderly patients with non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Patients aged ≥65 diagnosed with NSCLC (Tis-4N0M0), tumor diameter ≤5 cm and SBRT between 1998 and 2015 were retrospectively registered from two independent institutions. One institution was used for model development (arm D, 353 patients) and the other for validation (arm V, 401 patients). To identify risk factors for NLCD, multiple regression analysis on age, sex, performance status (PS), body mass index (BMI), Charlson comorbidity index (CCI), tumor diameter, histology and T-stage was performed on arm D. A score calculated using the regression coefficient was assigned to each factor and three risk groups were defined based on total score. Scores of 1.0 (BMI ≤18.4), 1.5 (age ≥ 5), 1.5 (PS ≥2), 2.5 (CCI 1 or 2) and 3 (CCI ≥3) were assigned, and risk groups were designated as low (total ≤ 3), intermediate (3.5 or 4) and high (≥4.5). The cumulative incidences of NLCD at 5 years in the low, intermediate and high-risk groups were 6.8, 23 and 40% in arm D, and 23, 19 and 44% in arm V, respectively. The AUC index at 5 years was 0.705 (arm D) and 0.632 (arm V). The proposed scoring system showed usefulness in predicting a high risk of NLCD in elderly patients treated with SBRT for NSCLC.

Optimal application of stereotactic body radiotherapy and radiofrequency ablation treatment for different multifocal hepatocellular carcinoma lesions in patients with Barcelona Clinic Liver Cancer stage A4-B1: a pilot study.

BACKGROUND: In clinical practice, many hepatocellular carcinoma (HCC) patients in Barcelona Clinical Liver Cancer (BCLC) stage A4-B1 cannot receive the curative treatments of liver transplantation, resection, and radiofrequency ablation (RFA), which are the recommended options according to liver cancer guidelines. Our aim is to study the feasibility of RFA and stereotactic body radiotherapy (SBRT) as a curative treatment for different multifocal HCCs in BCLC stage A4-B1 patients. METHODS: From September 2014 to August 2019, 39 multifocal HCC lesions (median diameter: 16.6 mm) from 15 patients (median age: 73 years) were retrospectively selected. Among them, 23 were treated by RFA and the other 16 by SBRT because of predictable insufficiency and/or risk related to RFA performance. The indicators for evaluating this novel therapy were the tumor response, prognosis (recurrence and survival), and adverse effects (deterioration of laboratory test values and severe complications). RESULTS: The median follow-up duration was 31.3 months (range: 15.1-71.9 months). The total patients with a one-year complete response, stable disease, or disease progression were 11, 1, and 3, respectively. In total, 8 and 2 patients had confronted intrahepatic or local recurrence, respectively. The one-year progression-free survival rate and local control rate were 80% (12/15 patients) and 97.4% (38/39 lesions), respectively. The median time to progression was 20.1 (2.8-45.1) months. The one- and two-year survival rates were 100 and 88.9%, respectively. In up to five months' observation, no patient showed severe complications. Seven, four, and two patients had slight changes in their white blood cells, platelet count, or albumin-bilirubin grade, respectively. CONCLUSIONS: For patients with BCLC stage A4-B1, RFA and SBRT treatment for different multifocal HCCs may be a potential option because of the favorable prognosis and safety. However, before its application in clinical practice, prospective, controlled, large-scale studies are needed to further confirm our conclusions.

Effects of sample size and data augmentation on U-Net-based automatic segmentation of various organs.

Deep learning has demonstrated high efficacy for automatic segmentation in contour delineation, which is crucial in radiation therapy planning. However, the collection, labeling, and management of medical imaging data can be challenging. This study aims to elucidate the effects of sample size and data augmentation on the automatic segmentation of computed tomography images using U-Net, a deep learning method. For the chest and pelvic regions, 232 and 556 cases are evaluated, respectively. We investigate multiple conditions by changing the sum of the training and validation datasets across a broad range of values: 10-200 and 10-500 cases for the chest and pelvic regions, respectively. A U-Net is constructed, and horizontal-flip data augmentation, which produces left and right inverse images resulting in twice the number of images, is compared with no augmentation for each training session. All lung cases and more than 100 prostate, bladder, and rectum cases indicate that adding horizontal-flip data augmentation is almost as effective as doubling the number of cases. The slope of the Dice similarity coefficient (DSC) in all organs decreases rapidly until approximately 100 cases, stabilizes after 200 cases, and shows minimal changes as the number of cases is increased further. The DSCs stabilize at a smaller sample size with the incorporation of data augmentation in all organs except the heart. This finding is applicable to the automation of radiation therapy for rare cancers, where large datasets may be difficult to obtain.

Stereotactic Body Radiation Therapy With a High Maximum Dose Improves Local Control, Cancer-Specific Death, and Overall Survival in Peripheral Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: We investigated whether delivery of a high biologically effective dose (BED) to primary tumors affects systemic outcomes of cancer-specific death (CSD) and overall survival (OS) rates after stereotactic body radiation therapy (SBRT) in patients with early-stage non-small cell lung cancer (ES-NSCLC). METHODS AND MATERIALS: Among consecutive ES-NSCLC patients treated with SBRT between 2005 and 2019, we retrospectively identified patients who received a prescription of 50 to 60 Gy in 5 fractions with maximum doses of 62.5 to 100 Gy. Patients were categorized by maximum BED within the planning target volume with a threshold dose of 200 Gy. Outcomes were analyzed in all and matched patients. RESULTS: Overall, 433 patients were eligible, and 262 and 171 patients were categorized into HighBED and LowBED groups, respectively. After propensity score matching, pairs of 154 patients were selected. Median follow-up times for the HighBED and LowBED groups were 52.3 months (range, 0.8-107.2 months) and 121.6 months (range, 3.0-162.8 months), respectively. The local recurrence rate in the HighBED group was significantly lower than that in the LowBED group (5-year rate, 1.3% and 7.2%; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.03-0.65; P = .011). Rates of any recurrence and CSD in the HighBED group were significantly lower (5-year any recurrence: 18.1% and 32.1%; HR, 0.52; 95% CI, 0.33-0.83; P = .0058; 5-year CSD: 9.5% and 21.8%; HR, 0.38; 95% CI, 0.20-0.70; P = .002), and OS in the HighBED group was significantly better compared with the LowBED group (5-year rate: 61.7% and 51.8%; HR, 0.71; 95% CI, 0.50-1.00; P = .047). CONCLUSION: In patients with peripheral ES-NSCLC, SBRT with a high maximum dose may improve not only local control, but also any recurrence, CSD, and OS rates without increased toxicity. Further trials designed to evaluate whether higher intensity SBRT increases local control rates and contributes to improved CSD and OS outcomes are anticipated.