Development and evaluation of an automated EPTN-consensus based organ at risk atlas in the brain on MRI.

BACKGROUND AND PURPOSE: During radiotherapy treatment planning, avoidance of organs at risk (OARs) is important. An international consensus-based delineation guideline was recently published with 34 OARs in the brain. We developed an MR-based OAR autosegmentation atlas and evaluated its performance compared to manual delineation. MATERIALS AND METHODS: Anonymized cerebral T1-weighted MR scans (voxel size 0.9 × 0.9 × 0.9 mm3) were available. OARs were manually delineated according to international consensus. Fifty MR scans were used to develop the autosegmentation atlas in a commercially available treatment planning system (Raystation®). The performance of this atlas was tested on another 40 MR scans by automatically delineating 34 OARs, as defined by the 2018 EPTN consensus. Spatial overlap between manual and automated delineations was determined by calculating the Dice similarity coefficient (DSC). Two radiation oncologists determined the quality of each automatically delineated OAR. The time needed to delineate all OARs manually or to adjust automatically delineated OARs was determined. RESULTS: DSC was ≥ 0.75 in 31 (91 %) out of 34 automated OAR delineations. Delineations were rated by radiation oncologists as excellent or good in 29 (85 %) out 34 OAR delineations, while 4 were rated fair (12 %) and 1 was rated poor (3 %). Interobserver agreement between the radiation oncologists ranged from 77-100 % per OAR. The time to manually delineate all OARs was 88.5 minutes, while the time needed to adjust automatically delineated OARs was 15.8 minutes. CONCLUSION: Autosegmentation of OARs enables high-quality contouring within a limited time. Accurate OAR delineation helps to define OAR constraints to mitigate serious complications and helps with the development of NTCP models.

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.

Consequences of Referral Time and Volume Doubling Time in Inoperable Patients With Early Stage Lung Cancer.

BACKGROUND: Inoperable patients with early stage lung cancer are referred late. The purpose was to calculate the referral time and the volume doubling time (VDT), and to investigate its consequence with regard to staging and survival in 117 inoperable patients with early stage lung cancer treated with stereotactic body radiotherapy. MATERIALS AND METHODS: Tumor VDT was calculated using the modified Schwartz formula of exponential growth model and was on the basis of volumes measured on initial diagnostic computed tomography (CT) scans and the planning CT scan. VDT was defined as fast (<100 days), moderate (100-249 days), slow (250-399 days), and no growth (≥400 days). The referral time is the time between the diagnostic CT scan and the radiotherapy planning CT scan. RESULTS: The median referral time was 86 days. The VDT was fast in 53 patients [45%] of tumors. No significant difference in VDT was found between different tumor or patient characteristics. Patients with T1 tumors that progressed to T2 had a significant worse median survival (P = .01). The overall survival at 5 years according to VDT was 21% for fast-growing tumors, 19% for moderate growth, 31% for slow, and 46% for no growth. CONCLUSION: The median referral time was almost 3 months. VDT was considered as fast in almost half of tumors examined. This resulted in significant growth and upstaging in 35% of the tumors, with a significant worse survival if T1 tumors progressed to T2 tumors. Therefore, medically inoperable patients should also be offered a fast workup and referral.

Quality of life during 5 years after stereotactic radiotherapy in stage I non-small cell lung cancer.

PURPOSE: To determine the long-term impact of stereotactic radiotherapy (SRT) on the quality of life (QoL) of inoperable patients with early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: From January 2006 to February 2008, 39 patients with pathologically confirmed T1-2N0M0 NSCLC were treated with SRT. QoL, overall survival and local tumor control were assessed. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the lung cancer-specific questionnaire QLQ-LC13 were used to investigate changes in QoL. Assessments were done before treatment, at 3 weeks, every 2-3 months during the first two years, and then every 6 months until 5 years after the treatment or death or progressive disease. The median follow up was 38 months. RESULTS: During the 5 years after treatment with SRT for stage I NSCLC, the level of QoL was maintained: There was a slow decline (slope: -0.015) of the global health status over the 5 years (p < 0.0001). The physical functioning and the role functioning improved slowly (slope: 0.006 and 0.004, resp.) over the years and this was also significant (p < 0.0001). The emotional functioning (EF) improved significantly at 1 year compared to the baseline. Two years after the treatment dyspnea slowly increased (slope: 0.005, p = 0.006). The actuarial overall survival was 62% at 2 years and 31% at 5-years. CONCLUSION: QoL was maintained 5 years after SRT for stage I NSCLC and EF improved significantly. Dyspnea slowly increased 2 years after the treatment.

Stereotactic body radiation therapy for oligometastases to the lung: a phase 2 study.

PURPOSE: To assess, in a phase 2 study, the efficacy and toxicity of stereotactic body radiation therapy for oligometastases to the lung in inoperable patients. METHODS AND MATERIALS: Patients with lung metastases were included in this study if (1) the primary tumor was controlled; (2) patients were ineligible for or refused surgery and chemotherapy; and (3) patients had 5 or fewer metastatic lesions in no more than 2 organs. Large peripheral tumors were treated with a dose of 60 Gy (3 fractions), small peripheral tumors with 30 Gy (1 fraction), central tumors received 60 Gy (5 fractions), and mediastinal tumors or tumors close to the esophagus received 56 Gy (7 fractions). RESULTS: Thirty patients with 57 metastatic lung tumors from various primary cancers were analyzed. The median follow-up was 36 months (range, 4-60 months). At 2 years, local control for the 11 central tumors was 100%, for the 23 peripheral tumors treated to 60 Gy it was 91%, and for the 23 tumors treated in a single 30-Gy fraction it was 74% (P=.13). This resulted in an overall local control rate at 1 year of 79%, with a 2-sided 80% confidence interval of 67% to 87%. Because the hypothesized value of 70% lies within the confidence interval, we cannot reject the hypothesis that the true local control rate at 1 year is ≤70%, and therefore we did not achieve the goal of the study: an actuarial local control of the treated lung lesions at 1 year of 90%. The 4-year overall survival rate was 38%. Grade 3 acute toxicity occurred in 5 patients. Three patients complained of chronic grade 3 toxicity, including pain, fatigue, and pneumonitis, and 3 patients had rib fractures. CONCLUSIONS: The local control was promising, and the 4-year overall survival rate was 38%. The treatment was well tolerated, even for central lesions.

Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors.

PURPOSE: To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. METHODS: Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9 Gy (n = 6), then 5 fractions of 10 Gy (n = 15), and finally 5 fractions of 12 Gy (n = 22). RESULTS: Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23 months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100 Gy compared to 60% for tumors treated with a BED ≤ 100 Gy. No grade 4 or 5 toxicity was observed. Acute grade 1-2 esophagitis was observed in 11% of patients. CONCLUSION: SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions.

Stability of markers used for real-time tumor tracking after percutaneous intrapulmonary placement.

PURPOSE: To determine the stability of markers used for real-time tumor tracking after percutaneous intrapulmonary placement. METHODS AND MATERIALS: A total of 42 patients with 44 lesions, 111 markers, and ≥2 repeat computed tomography (CT) scans were studied. The tumor on the repeat CT scans was registered with the tumor on the planning CT scan. Next, the three-dimensional marker coordinates were determined on the planning CT scan and repeat CT scans. Marker stability was analyzed by the displacement of the markers and the displacement of the center of mass (COM) of the marker configurations. In addition, we assessed the reliability of using the intermarker distance as a check for displacements in the COM of the marker configurations. RESULTS: The median marker displacement was 1.3 mm (range, 0.1-53.6). The marker displacement was >5 mm in 12% of the markers and >10 mm in 5% of the markers. The causes of marker displacement >5 mm included marker migration (2 of 13) and target volume changes (5 of 13). Nonsynchronous tumor and marker movement during breathing might have been responsible for the displacements >5 mm in the other 6 of 13 markers. The median displacement in the COM of the marker configurations was 1.0 mm (range, 0.1-23.3). Displacements in the COM of the marker configurations of ≥2.0 mm were detected by changes in the intermarker distance of >1.5 mm in 96% of the treatment fractions. CONCLUSION: The median marker displacement was small (1.3 mm). Nevertheless, displacements >5 mm occurred in 12% of the markers. Therefore, we recommend the implantation of multiple markers because multiple markers will enable a quick and reliable check of marker displacement by determining the change in the intermarker distance. A displacement in the COM of the marker configuration of ≥2.0 mm was almost always detected (96%) by a change in the distance between the markers of >1.5 mm. This enabled the displaced marker to be disabled, such that tumor localization was not compromised.

Clinical introduction of Monte Carlo treatment planning: a different prescription dose for non-small cell lung cancer according to tumor location and size.

PURPOSE: To provide a prescription dose for Monte Carlo (MC) treatment planning in patients with non-small-cell lung cancer according to tumor size and location. METHODS: Fifty-three stereotactic radiotherapy plans designed using the equivalent path-length (EPL) algorithm were re-calculated using MC. Plans were compared by the minimum dose to 95% of the PTV (D95), the heterogeneity index (HI) and the mean dose to organs at risk (OARs). Based on changes in D95, the prescription dose was converted from EPL to MC. Based on changes in HI, we examined the feasibility of MC prescription to plans re-calculated but not re-optimized with MC. RESULTS: The MC fraction dose for peripheral tumors is 16-18 Gy depending on tumor size. For central tumors the MC dose was reduced less than for peripheral tumors. The HI decreased on average by 4-9% in peripheral tumors and 3-5% in central tumors. The mean dose to OARs was lower for MC than EPL, and correlated strongly (R(2)=0.98-0.99). CONCLUSION: For the conversion from EPL to MC we recommend a separate prescription dose according to tumor size. MC optimization is not required if a HI > or = 70% is accepted. Dose constraints to OARs can be easily converted due to the high EPL-MC correlation.

Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer.

As the incidence of stage I non-small cell lung cancer (NSCLC) increases among octogenarians and only selected patients are surgical candidates, an alternative treatment is necessary. This manuscript evaluates the overall survival, local tumor control rate, and treatment-related toxicity after stereotactic body radiotherapy (SBRT) in 38 octogenarians with stage I NSCLC. Treatment consisted of 45Gy (n=4) or 60Gy (n=25) in 3 fractions for patients with peripheral tumors. A risk adaptive schedule of 45-60Gy in 3-6 fractions was used for central (n=7) or large peripheral tumors (n=2). An overall survival rate of 65% at 1 year and 44% at 2 years was achieved in octogenarians after SBRT. The local tumor control rate was excellent (100% at 2 years) and no grade 4 or 5 treatment-related toxicity occurred. Despite the high incidence of comorbidity in these octogenarians (Charlson score >or=5 in 16% of patients), an approach that merely provides supportive care cannot always be justified. SBRT offers octogenarians with stage I NSCLC a good treatment alternative.

Quality of life after stereotactic radiotherapy for stage I non-small-cell lung cancer.

PURPOSE: To determine the impact of stereotactic radiotherapy on the quality of life of patients with inoperable early-stage non-small-cell lung cancer (NSCLC). Overall survival, local tumor control, and toxicity were also evaluated in this prospective study. METHODS AND MATERIALS: From January 2006 to February 2008, quality of life, overall survival, and local tumor control were assessed in 39 patients with pathologically confirmed T1 to 2N0M0 NSCLC. These patients were treated with stereotactic radiotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the QLQ LC13 lung cancer-specific questionnaire were used to investigate changes in quality of life. Assessments were done before treatment, at 3 weeks, and at 2, 4, 6, 9, and 12 months after treatment, until death or progressive disease. Toxicity was evaluated using common terminology criteria for adverse events version 3.0. RESULTS: Emotional functioning improved significantly after treatment. Other function scores and QLQ C30 and QLQ LC13 lung symptoms (such as dyspnea and coughing) showed no significant changes. The overall 2-year survival rate was 62%. After a median follow-up of 17 months, 1 patient had a local recurrence (3%). No grade 4 or 5 treatment-related toxicity occurred. Grade 3 toxicity consisted of thoracic pain, which occurred in 1 patient within 4 months of treatment, while it occurred thereafter in 2 patients. CONCLUSIONS: Quality of life was maintained, and emotional functioning improved significantly after stereotactic radiotherapy for stage I NSCLC, while survival was acceptable, local tumor control was high, and toxicity was low.

Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: clinical outcome.

PURPOSE: To report the clinical outcome of treatment using real-time tumor tracking for 70 patients with inoperable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Seventy inoperable patients with peripherally located early-stage NSCLC were treated with 45 or 60 Gy in three fractions using CyberKnife. Pathology was available in 51% of patients. Thirty-nine patients had a T1-tumor and 31 had a T2-tumor. Markers were placed using the vascular, percutaneous intra-, or extra-pulmonary approach, depending on the risk of pneumothorax. RESULTS: The actuarial 2-year local control rate for patients treated with 60 Gy was 96%, compared to 78% for patients treated with a total dose of 45 Gy (p=0.197). All local recurrences (n=4) occurred in patients with T2-tumors. Overall survival for the whole group at two years was 62% and the cause specific survival was 85%. The median follow-up was 15 months. Grade 3 toxicity occurred in two patients (3%) after marker placement. Treatment-related late grade 3 toxicity occurred in 7 patients (10%). No grade > or = 4 toxicity occurred. CONCLUSION: Excellent local control of 96% at 1- and 2-years was achieved using 60 Gy in three fractions for NSCLC patients treated with the real-time tumor tracking. Toxicity was low.