Survival and Prognostic Factors of Ultra-Central Tumors Treated with Stereotactic Body Radiotherapy.

Introduction: Stereotactic body radiotherapy (SBRT) reported excellent outcomes and a good tolerability profile in case of central lung tumors, as long as risk-adapted schedules were adopted. High grade toxicity was more frequently observed for tumors directly touching or overlapping the trachea, proximal bronchial tree (PBT), and esophagus. We aim to identify prognostic factors associated with survival for Ultra-Central (UC) tumors. Methods: We retrospectively evaluated patients treated with SBRT for primary or metastatic UC lung tumors. SBRT schedules ranged from 45 to 60 Gy. Results: A total number of 126 ultra-central lung tumors were reviewed. The Median follow-up time was 23 months. Median Overall Survival (OS) and Progression Free Survival (PFS) was 29.3 months and 16 months, respectively. Local Control (LC) rates at 1 and 2 were 86% and 78%, respectively. Female gender, age < 70 years, and tumor size < 5 cm were significantly associated with better OS. The group of patients with tumors close to the trachea but further away from the PBT also correlated with better OS. The acute G2 dysphagia, cough, and dyspnea were 11%, 5%, and 3%, respectively. Acute G3 dyspnea was experienced by one patient. Late G3 toxicity was reported in 4% of patients. Conclusion: risk-adaptive SBRT for ultra-central tumors is safe and effective, even if it remains a high-risk clinical scenario.

Development and external validation of a nomogram to predict overall survival following stereotactic body radiotherapy for early-stage lung cancer.

BACKGROUND: Prognostication tools for early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT) are currently lacking. The purpose of this study was to develop and externally validate a nomogram to predict overall survival in individual patients with peripheral early-stage disease. METHODS: A total of 587 NSCLC patients treated with biologically effective dose > 100 Gy10 were eligible. A Cox proportional hazards model was used to build a nomogram to predict 6-month, 1-year, 3-year and 5-year overall survival. Internal validation was performed using bootstrap sampling. External validation was performed in a separate cohort of 124 NSCLC patients with central tumors treated with SBRT. Discriminatory ability was measured by the concordance index (C-index) while predictive accuracy was assessed with calibration slope and plots. RESULTS: The resulting nomogram was based on six prognostic factors: age, sex, Karnofsky Performance Status, operability, Charlson Comorbidity Index, and tumor diameter. The slope of the calibration curve for nomogram-predicted versus Kaplan-Meier-estimated overall survival was 0.77. The C-index of the nomogram (corrected for optimism) was moderate at 0.64. In the external validation cohort, the model yielded a C-index of 0.62. CONCLUSIONS: We established and validated a nomogram which can provide individual survival predictions for patients with early stage lung cancer treated with SBRT. The nomogram may assist patients and clinicians with treatment decision-making.

Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy.

Background: Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors.Material and Methods: Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/ß-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis.Results: Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV1. Grade 4-5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients.Conclusion: Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV1 and tumor location (for DFS only) as prognostic factors.

Predicting High-Grade Esophagus Toxicity After Treating Central Lung Tumors With Stereotactic Radiation Therapy Using a Normal Tissue Complication Probability Model.

PURPOSE: The treatment of central lung tumors with stereotactic body radiation therapy (SBRT) is challenged by the risk of excessive esophageal toxicity. To improve clinical decision making, we aimed to derive normal tissue complication probability (NTCP) models in a patient cohort with central lung tumors treated with SBRT and to evaluate the currently used esophagus dose constraints. METHODS AND MATERIALS: Patients with a central lung tumor who received SBRT (8 fractions of 7.5 Gy or 12 fractions of 5 Gy) were included. Doses were recalculated to an equivalent dose of 2 Gy with an α/ß-ratio of 10 Gy for acute and 3 Gy for late toxicity (the cut-off was 3 months). The esophagus was manually delineated. NTCP modeling based on logistic regression was used to relate dose-volume histogram parameters (Dmax, D1cc, D2cc, D5cc) to acute and late toxicity. Parameters with a P < .05 were included in the model. Based on the NTCP models, we determined the probability of toxicity for the currently used dose constraints: D1cc ≤40 Gy for 8 fractions and D1cc ≤48 Gy for 12 fractions. RESULTS: For this study, 188 patients with 203 tumors were eligible. Esophagus toxicity occurred in 33 patients (18%). Late high-grade toxicity consisted of 2 possible treatment-related deaths (grade 5) and 2 patients with grade 3 toxicity. Acute toxicity consisted of only grade 1 (n = 19) and grade 2 toxicity (n = 10). All investigated dose-volume histogram parameters were significantly correlated to acute and late toxicity. The probability of late high-grade toxicity is 1.1% for 8 fractions and 1.4% for 12 fractions when applying the current dose constraints. CONCLUSIONS: High-grade esophageal toxicity occurred in 2.1% of the patients, including 2 possible treatment-related deaths. The currently used dose constraints correspond to a low risk of high-grade toxicity.

Prognostic factors for local control and survival for inoperable pulmonary colorectal oligometastases treated with stereotactic body radiotherapy.

PURPOSE: The study aimed to evaluate overall survival and local control, and to identify factors independently associated with overall survival (OS) and local control (LC). MATERIALS AND METHODS: This retrospective study examined 118 patients with primary colorectal cancer, in whom 202 inoperable pulmonary oligometastases were treated with stereotactic body radiotherapy between 2005 and 2015. Primary endpoint was to evaluate OS and identify prognostic factors associated with OS. Secondary aim was to evaluate LC and identify prognostic factors associated with LC. RESULTS: Median follow-up was 31 months (range 3-88 months). Median OS was 39.2 months (95% CI 34.8-43.6 months). Two-, three-, and five-year OS was 69%, 55% and 36%, respectively. LC at 2-, 3-, and 5-year was 83%, 81% and 77% respectively. Factors independently associated with OS in the multivariable analysis included BED10 ≥ 100 Gy (HR 0.52), male gender (HR 0.52), age < 70 years (HR 0.52) and presence of single metastasis (HR 0.37). BED10 < 100 Gy (HR 3.67) and pre-SBRT chemotherapy (HR 2.66) were independently associated with poor LC in a multivariable analysis. CONCLUSIONS: SBRT was associated with 2- year OS of 69% and 2-year LC of 83%. SBRT dose ≥ 100 Gy BED10 was independently associated with both better overall survival and local control.

Survival and prognostic factors of pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for pulmonary oligometastatic disease achieves excellent treatment outcomes in terms of local control and toxicity. Patients treated with SBRT are often elderly and have multiple co-morbidities. This subset of patients may experience different survival as compared to young and fit patients subjected to radical metastasectomies. The purpose of this retrospective study was to evaluate OS and identify factors associated with OS for inoperable pulmonary oligometastases treated with SBRT. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastases limited to ≤2 organs and in total ≤5 metastases at the time of treatment. Peripheral tumors were treated with 51 Gy to 60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. Survival probabilities were estimated by means of Kaplan-Meier method and the relation between potential prognostic factors and OS was studied by means of Cox regression analyses. RESULTS: In this study, 327 inoperable pulmonary oligometastases in 206 patients were treated with SBRT from the year 2005 to 2015. Primary sites of pulmonary oligometastases included colorectal carcinoma (n = 118), lung carcinoma (n = 36), melanoma (n = 11), sarcoma (n = 10), breast carcinoma (n = 7), and other tumors sites (n = 24). Median follow-up was 26 months. Median survival was 33 months. The 2-year and 5-year OS rates were 63% and 30%, respectively. On univariate analysis synchronous oligometastases (HR 0.59) and colorectal primary (HR 0.64) were associated with improved OS. On multivariable analysis synchronous oligometastases (HR 0.56), colorectal primary (HR 0.62) and tumor size <3 cm (HR 0.68) were independently associated with OS. CONCLUSIONS: SBRT to pulmonary oligometastases was associated with a 2-year OS of 63%. Tumor size <3 cm and colorectal primary tumors experienced improved OS compared to tumors >3 cm and non-colorectal primary tumors.

Stereotactic body radiotherapy for oligometastatic soft tissue sarcoma.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is emerging as a novel treatment option in metastatic soft tissue sarcoma (STS). The aim of our study was to evaluate the effectiveness of exclusive SBRT on disease control and survival in oligometastatic (≤ 3 synchronous lesions) STS. MATERIALS AND METHODS: In total, 16 consecutive patients, accounting for 26 metastases (including 21 lung and 5 lymph node or soft tissue metastases), were treated at our institution with SBRT. Patient- and treatment-related characteristics were collected. Local control (LC), overall survival (OS), distant metastases-free survival (DMFS), and time to initiation of chemotherapy or best supportive care (corrected disease-free survival, cDFS) were assessed. RESULTS: Four-year OS was 54% and median OS was 69 months [95% confidence interval (CI) 20-118 months]. LC of 26 lesions at 4 years was 78%. Median DMFS and cDFS were 17 (95% CI 5-30 months) and 28 months (95% CI 5-52 months), respectively. Disease-free interval < 24 months from primary tumor treatment to first metastasis was the only predictor of reduced LC, cDFS, and OS (p = 0.022, 0.023, and 0.028, respectively). No acute or chronic grade ≥ 3 toxicity was observed. Median follow-up was 36 months (IQR 18-71 months). CONCLUSIONS: In patients with oligometastatic STS, SBRT yields satisfying local control with minimal toxicity. Median OS was 69 months. Repeated SBRT may be considered to extend disease-free and systemic therapy-free interval. Increased time from primary tumor to first metastasis identifies patients with potentially greater benefit from SBRT.

Factors affecting local control of pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND: Oligometastases refers to a state of limited metastatic disease. The use of local ablative therapies to patients with oligometastases can result in durable state of remission or long-term cure. Stereotactic body radiotherapy (SBRT) is a highly conformal radiation technique that delivers ablative doses to the target. The study aimed to evaluate local control (LC) and identify factors associated with poor LC in patients with pulmonary oligometastases treated with SBRT. Primary endpoint of the study was to assess LC; secondary endpoint was to determine factors associated with LC. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastatic disease limited to a maximum of two organs and no more than five metastatic lesions at time of treatment. Peripheral tumors were treated with 51-60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. RESULTS: In 206 patients, 327 pulmonary oligometastases were treated with SBRT. Median follow-up was 22 months (range 2-100). LC at 2 and 3 years was 85% and 83%, respectively. On univariate analysis, biological equivalent dose assuming an α/ß ratio of 10 (BED10) < 100 Gy (HR 3.09), single-fraction SBRT (HR 2.83), synchronous metastasis (HR 1.99), and pre-SBRT chemotherapy (HR 2.79) were significantly associated with inferior LC. In the multivariable analysis BED10 <100 Gy (HR 3.59), pre-SBRT chemotherapy (HR 2.61) and presence of synchronous metastasis (HR 2.21) remained independently associated with poor LC. CONCLUSIONS: SBRT achieved an excellent LC of 85% at 2 years. Although retrospective in nature, our study identified three factors associated with inferior LC. These factors may help to refine SBRT practice for pulmonary oligometastases in the future.

Local Reirradiation of Recurrent Non-small Cell Lung Carcinoma Resulting in Long Disease-free Survival, Although in the Presence of Osteonecrosis.

High-dose reirradiation of the thorax can be offered to patients with only local disease progression of non-small-cell lung cancer (NSCLC) resulting in promising disease-free-survival. However, much is still unknown about related side-effects and occasionally an uncommon presentation can be caused by reirradiation. In this case report, we present a patient with a 3.5-year progression-free survival, although in the presence of a late, unexpected toxicity. A dosimetric analysis was performed to investigate the possibility of radiation-induced toxicity.

Dose and Volume of the Irradiated Main Bronchi and Related Side Effects in the Treatment of Central Lung Tumors With Stereotactic Radiotherapy.

High radiation dose to the main bronchi can result in stenosis, occlusion or fistula formation, and death. Only 8 articles have reported side effects to the main bronchi from stereotactic body radiation therapy (SBRT), mostly with only one symptomatic complication per article. Therefore, we calculated the dose to the bronchial structures, such as trachea; mainstem bronchi; intermediate bronchus; upper-, middle-, and lower-lobe bronchus; and the segmental bronchi in 134 patients with central tumors and calculated the normal tissue complication probability (NTCP) for each of these structures, with toxicity determination based upon computed tomography imaging. No side effects were found in the trachea, and only stenosis occurred in the main bronchus and bronchus intermedius. Higher grades of side effects, such as occlusion and atelectasis, were only seen in the upper-, middle-, and lower bronchi and the segmental bronchi. When 0.5cc of a segmental bronchi was irradiated to 50Gy in 5 fractions, it was about 50% likely to be occluded radiographically. For grade 1 radiographically evident side effects, the 50% risk level for a 5-fraction Dmax was 55Gy for mid-bronchi and 65Gy for mainstem bronchi. To assure the relationship between clinical toxicity and side effects to the bronchi, further investigation is needed.