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Purpose: FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage)., Methods and Materials: Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated., Results: The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between -6.1%-point and 2.2%-point for optimized patterns., Conclusions: Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose and Objective: Besides a dose-rate threshold of 40-100 Gy/s, the FLASH effect may require a dose > 3.5-7 Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs)., Materials and Methods: Treatment plans for 12 patients were generated. GTV delineations were available and a 5 mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244 MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D 95%,PTV  = 100%D pres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2)., Results: Compared to ABEF, SBPF resulted in a median increase of EQD2 mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V 100% EQD2 , quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2 mean and 1.29, 1.18, 1.28 and 1.15 for V 100%,EQD2 ., Conclusion: A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: A potential challenge in single-isocenter multi-lesion lung stereotactic body radiotherapy (SBRT) is that patient positioning is not based on each lesion individually, but on the average position of all lesions. This may lead to larger margins compared to treating with one isocenter per lesion, but increases workflow efficiency. The aim of this study was to investigate whether a single-isocenter technique leads to increased normal lung dose compared to a conventional multiple-isocenters technique., Materials and Methods: A cohort of 15 NSCLC patients with two or three lesions previously treated with SBRT was subjected to treatment planning with a multiple-isocenter technique and a single-isocenter technique. For the latter, two margin approaches were evaluated: (1) identical margins for each internal target volume (ITV), assuming an average registration for all lesions in cone-beam CT (CBCT) positioning verification and (2) a smaller margin for the largest lesion, assuming an optimal registration for that lesion. For all 45 treatment plans, mean lung dose (MLD) and lungs-V 20Gy were evaluated. The study was performed following RATING guidelines., Results: The MLD was 4.9 ± 1.9 Gy (mean ± SD) for multiple-isocenters and 5.4 ± 2.1 Gy and 5.3 ± 2.2 Gy for single-isocenter approach 1 and 2, respectively. V 20Gy was 5.5 ± 3.7%, 5.5 ± 3.2% and 5.4 ± 3.3%. A median [range] increase in MLD of 11.6% [-14.9 - 26.8] was observed when comparing single-isocenter treatment plans to those with multiple isocenters. V 20Gy increased by 0.2 [-3.4 - 1.3] percentage points., Conclusion: A single-isocenter SBRT technique for lung patients with multiple targets results in clinically acceptable increases in normal lung dose., Competing Interests: Conflict of interest statement Dr. Hoogeman reports grants from Elekta, grants from Accuray, grants from Varian, other from Accuray, outside the submitted work. Dr. Tanadini-Lang reports that her husband works at Varian Medical Systems. Dr. van Timmeren, dr. Ehrbar, miss Chamberlain, dr. Mayinger, dr. Andratschke and dr. Guckenberger report no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Breathing interplay effects in Intensity Modulated Proton Therapy (IMPT) arise from the interaction between target motion and the scanning beam. Assessing the detrimental effect of interplay and the clinical robustness of several mitigation techniques requires statistical evaluation procedures that take into account the variability of breathing during dose delivery. In this study, we present such a statistical method to model intra-fraction respiratory motion based on breathing signals and assess clinical relevant aspects related to the practical evaluation of interplay in IMPT such as how to model irregular breathing, how small breathing changes affect the final dose distribution, and what is the statistical power (number of different scenarios) required for trustworthy quantification of interplay effects. First, two data-driven methodologies to generate artificial patient-specific breathing signals are compared: a simple sinusoidal model, and a precise probabilistic deep learning model generating very realistic samples of patient breathing. Second, we investigate the highly fluctuating relationship between interplay doses and breathing parameters, showing that small changes in breathing period result in large local variations in the dose. Our results indicate that using a limited number of samples to calculate interplay statistics introduces a bigger error than using simple sinusoidal models based on patient parameters or disregarding breathing hysteresis during the evaluation. We illustrate the power of the presented statistical method by analyzing interplay robustness of 4DCT and Internal Target Volume (ITV) treatment plans for a 8 lung cancer patients, showing that, unlike 4DCT plans, even 33 fraction ITV plans systematically fail to fulfill robustness requirements., (Creative Commons Attribution license.)

Background and Purpose: A single-isocenter stereotactic body radiotherapy (SBRT) approach for multiple lung metastases has the potential to lower cumulative patient dose and reduce overall treatment time. However, the magnitude of inter-lesion position variation is currently unknown and not incorporated in margin calculations. The aim of this study was to quantify inter-lesion position variation and calculate safety margins for single-isocenter lung SBRT., Materials and Methods: A total of 83 pairs of pulmonary metastases from 42 NSCLC patients were used to calculate relative inter-lesion position variation by lesion-based registration of planning CT and verification CBCT. Furthermore, β-value assessment of van Herk's margin formula was performed by evaluating the distance between planned and blurred dose profiles of simulated spherical lesions, to evaluate its validity for heterogeneously planned dose distributions. Population-based ITV to PTV margins were calculated using the entire dataset and using subgroups with significant differences in relative inter-lesion position variation., Results: The mean ± SD inter-lesion position variation was 1.2 ± 1.1 mm as 3D-vector. Inter-lesion position variation was significantly increased if ≥1 lesion was not attached to the pleura or lesions were distant. The simulation showed that the combined SD of the random errors contributed to the margin only in the SI direction with 0.25∙σ tot for a 65% dose prescription. When incorporating inter-lesion position variation, the safety margins increased from 5.6, 5.8, 5.2 mm (AP, SI, LR) to 6.0, 6.6, 5.5 mm for the entire cohort., Conclusion: Relative inter-lesion position variation is influenced by inter-target distance and location and can be compensated with additional safety margins of <1 mm using single-isocenter SBRT., Competing Interests: Conflict of interest statement Dr. Hoogeman reports grants from Elekta, grants from Accuracy, grants from Varian, other from Accuracy, outside the submitted work. Dr. Tanadini-Lang reports that her husband works at Varian Medical Systems. Dr. van Timmeren, dr. Ehrbar, dr. Mayinger, dr. Andratschke and dr. Guckenberger report no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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/β-value of 10 Gy (BED 10 ). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED 10 ; (%)PTV < 100 BED 10 . 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 BED 10 and %PTV < 100 BED 10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV 1 ) 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 FEV 1 . 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, FEV 1 and tumor location (for DFS only) as prognostic factors.

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 Gy 10 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.

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 BED 10  ≥ 100 Gy (HR 0.52), male gender (HR 0.52), age < 70 years (HR 0.52) and presence of single metastasis (HR 0.37). BED 10  < 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 BED 10 was independently associated with both better overall survival and local control., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: In 2017 the ACROP guideline on SBRT for peripherally located early stage NSCLC was published. Later that year ICRU-91 about prescribing, recording and reporting was published. The purpose of this study is to quantify the current variation in prescription practice in the institutions that contributed to the ACROP guideline and to establish the link between the ACROP and ICRU-91 recommendations., Material and Methods: From each of the eight participating centres, 15 SBRT plans for stage I NSCLC were analyzed. Plans were generated following the institutional protocol, centres prescribed 3 × 13.5 Gy, 3 × 15 Gy, 3 × 17 Gy or 3 × 18 Gy. Dose parameters of the target volumes were reported as recommended by ICRU-91 and also converted to BED 10Gy ., Results: The intra-institutional variance in D98%, Dmean and D2% of the PTV and GTV/ITV is substantially smaller than the inter-institutional spread, indicating well protocollised planning procedures are followed. The median values per centre ranged from 56.1 Gy to 73.1 Gy (D2%), 50.4 Gy to 63.3 Gy (Dmean) and 40.5 Gy to 53.6 Gy (D98%) for the PTV and from 57.1 Gy to 73.6 Gy (D2%), 53.7 Gy to 68.7 Gy (Dmean) and 48.5 Gy to 62.3 Gy (D98%) for the GTV/ITV. Comparing the variance in PTV D98% with the variance in GTV Dmean per centre, using an F-test, shows that four centres have a larger variance in GTV Dmean, while one centre has a larger variance in PTV D98% (p values <0.01). This shows some centres focus on achieving a constant PTV coverage while others aim at a constant GTV coverage., Conclusion: More detailed recommendations for dose planning and reporting of lung SBRT in line with ICRU-91 were formulated, including a minimum PTV D98% of 100 Gy BED 10Gy and minimum GTV/ITV mean dose of 150 Gy BED 10Gy and a D2% in the range of 60-70 Gy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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/β-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 (D max , D 1cc , D 2cc , D 5cc ) 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: D 1cc ≤40 Gy for 8 fractions and D 1cc ≤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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

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/β ratio of 10 (BED 10 ) < 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 BED 10 <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.

Stereotactic body radiotherapy (SBRT) for lung tumours has been gaining wide acceptance in lung cancer. Here, we review the technological evolution of SBRT delivery in lung cancer, from the first treatments using the stereotactic body frame in the 1990's to modern developments in image guidance and motion management. Finally, we discuss the impact of current technological approaches on the requirements for quality assurance as well as future technological developments., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Stereotactic body radiotherapy (SBRT) has become the standard of care for medically inoperable patients with peripherally located, early stage non-small cell lung cancer (NSCLC), and for those refusing surgical resection. Despite the availability of national and international guidelines, there exists substantial variability in many aspects of SBRT practice., Methods: The ESTRO ACROP guideline is based on a questionnaire covering all aspects of SBRT implementation and practice (n=114 items). The questionnaire was answered by the 11 faculty members of the ESTRO course "Clinical practice and implementation of image-guided SBRT" and their 8 institutions., Results: Agreement by >50% of the institutions was achieved in 72% of all items. Only 8/57 technologies and techniques were identified as mandatory for SBRT while 32/57 were considered as optional. In contrast, quality-assurance related elements were considered as mandatory in 12/24 items. A consensus of risk-adapted SBRT fractionation was achieved with 3×15Gy for peripherally located lesions and 4×12Gy (PTV D95-D99; D max <125% to <150%) for lesions with broad chest wall contact. For patients free from severe comorbidities and with favourable long-term OS expectancy, use of the maximum tolerated dose of 3×18Gy should be considered., Conclusions: This ACROP guideline achieved detailed recommendations in all aspects of SBRT implementation and practice, which will contribute to further standardization of SBRT for peripherally located early stage NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration., Material and Methods: Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2-52)., Results: The median Dmax of the lung in the summed plans was 363 Gy3 (range 123-590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose ≥70 Gy3, with a median D(max) of the heart of 115 Gy3 and 89 Gy3 for the trachea. Eight patients had in the esophagus an accumulated dose ≥70 Gy3, with a median accumulated dose of 85 Gy3. No grade 3-5 toxicity was observed., Conclusion: Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median Dmax of 363 Gy3 to the lung, as low toxicity was observed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Compared with many small circular beams used in CyberKnife treatments, beam's eye view-shaped fields are generally more time-efficient for dose delivery. However, beam's eye view-shaping devices, such as a mini-multileaf collimator (mMLC), are not presently available for CyberKnife, although a variable-aperture collimator (Iris, 12 field diameters; 5-60 mm) is available. We investigated whether the Iris can mimic noncoplanar mMLC treatments using a limited set of principal beam orientations (nodes) to produce time-efficient treatment plans., Methods and Materials: The data from 10 lung cancer patients and the beam-orientation optimization algorithm "Cycle" were used to generate stereotactic treatment plans (3 × 20 Gy) for a CyberKnife virtually equipped with a mMLC. Typically, 10-16 favorable beam orientations were selected from 117 available robot node positions using beam's eye view-shaped fields with uniform fluence. Second, intensity-modulated Iris plans were generated by inverse optimization of nonisocentric circular candidate beams targeted from the same nodes selected in the mMLC plans. The plans were evaluated using the mean lung dose, lung volume receiving ≥20 Gy, conformality index, number of nodes, beams, and monitor units, and estimated treatment time., Results: The mMLC plans contained an average of 12 nodes and 11,690 monitor units. For a comparable mean lung dose, the Iris plans contained 12 nodes, 64 beams, and 21,990 monitor units. The estimated fraction duration was 12.2 min (range, 10.8-13.5) for the mMLC plans and 18.4 min (range, 12.9-28.5) for the Iris plans. In contrast to the mMLC plans, the treatment time for the Iris plans increased with an increasing target volume. The Iris plans were, on average, 40% longer than the corresponding mMLC plans for small targets (<80 cm(3)) and ≤121% longer for larger targets. For a comparable conformality index, similar results were obtained., Conclusion: For stereotactic lung irradiation, time-efficient and high-quality plans were obtained for robotic-controlled noncoplanar treatments using a mMLC. Iris is a time-efficient alternative for small targets, with similar or better plan quality., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

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.

Purpose: To quantify the clinical accuracy of the respiratory motion tracking system of the CyberKnife treatment device., Methods and Materials: Data in log files of 44 lung cancer patients treated with tumor tracking were analyzed. Errors in the correlation model, which relates the internal target motion with the external breathing motion, were quantified. The correlation model error was compared with the geometric error obtained when no respiratory tracking was used. Errors in the prediction method were calculated by subtracting the predicted position from the actual measured position after 192.5 ms (the time lag to prediction in our current system). The prediction error was also measured for a time lag of 115 ms and a new prediction method., Results: The mean correlation model errors were less than 0.3 mm. Standard deviations describing intrafraction variations around the whole-fraction mean error were 0.2 to 1.9 mm for cranio-caudal, 0.1 to 1.9 mm for left-right, and 0.2 to 2.5 mm for anterior-posterior directions. Without the use of respiratory tracking, these variations would have been 0.2 to 8.1 mm, 0.2 to 5.5 mm, and 0.2 to 4.4 mm. The overall mean prediction error was small (0.0 +/- 0.0 mm) for all directions. The intrafraction standard deviation ranged from 0.0 to 2.9 mm for a time delay of 192.5 ms but was halved by using the new prediction method., Conclusions: Analyses of the log files of real clinical cases have shown that the geometric error caused by respiratory motion is substantially reduced by the application of respiratory motion tracking.

To evaluate the use of endovascular coils as markers for respiratory motion correction during high-dose stereotactic radiotherapy with the CyberKnife, an image-guided linear accelerator mounted on a robotic arm. Endovascular platinum embolisation coils were used to mark intrapulmonary lesions. The coils were placed in subsegmental pulmonary artery branches in close proximity to the target tumour. This procedure was attempted in 25 patients who were considered unsuitable candidates for standard transthoracic percutaneous insertion. Vascular coils (n = 87) were successfully inserted in 23 of 25 patients. Only minor complications were observed: haemoptysis during the procedure (one patient), development of pleural pain and fever on the day of procedure (one patient), and development of small infiltrative changes distal to the vascular coil (five patients). Fifty-seven coils (66% of total inserted number) could be used as tumour markers for delivery of biologically highly effective radiation doses with automated tracking during CyberKnife radiotherapy. Endovascular markers are safe and allow high-dose radiotherapy of lung tumours with CyberKnife, also in patients who are unsuitable candidates for standard transthoracic percutaneous marker insertion.

Background and Purpose: To correlate acute esophageal toxicity with dosimetric and clinical parameters for non-small cell lung cancer (NSCLC) patients treated with radiotherapy (RT) alone or with chemo-radiotherapy (CRT)., Patients and Methods: We analyzed the data of 156 patients with medically inoperable or locally advanced NSCLC. Seventy-four patients were irradiated with high dose RT only, 45 patients with sequential CRT (Gemicitabine/Cisplatin) and 37 patients with concurrent CRT (Cisplatin daily 6 mg/m(2)). The radiation dose delivered ranged from 49.5 to 94.5 Gy (2.25-2.75 Gy per fraction) with an overall treatment time of 5-6 weeks. For all patients the maximal acute esophageal toxicity (RTOG/EORTC criteria) was scored and related to dose-volume parameters, as well as to clinical and treatment-related parameters. All parameters were tested univariable and multivariable in a binary logistic regression model. The toxicity data of a homogeneous subgroup was fitted to the Lyman-Kutcher-Burman model., Results: Grade 2 acute esophageal toxicity or higher occurred in 27% (n=42) of the patient population of which nine patients developed grade 3 toxicity and one patient grade 4. All 10 patients with grade>or=3 esophageal toxicity received concurrent CRT. At multivariable analysis, the most significant clinical parameter to predict acute esophageal toxicity was the concurrent use of CRT. The most significant dosimetric parameter was the esophagus volume that received at least 35 Gy. The data of the patients who did not receive concurrent CRT were well described by the Lyman-Kutcher-Burman normal tissue complication probability model. The optimal fit of the data of non-concurrent treated patients to this model was obtained using the following values for the parameters: TD(50)=47 Gy (41-60 Gy), n=0.69 (0.18-6.3) and m=0.36 (0.25-0.55) where the numbers between brackets denote the 95% confidence interval. Acute esophageal toxicity was not significantly increased for patients treated with sequential CRT., Conclusion: Both concurrent CRT and the volume that receives at least 35 Gy were predictors of acute esophageal toxicity.

Background and Purpose: The low density of lung tissue causes a reduced attenuation of photons and an increased range of secondary electrons, which is inaccurately predicted by the algorithms incorporated in some commonly available treatment planning systems (TPSs). This study evaluates the differences in dose in normal lung tissue computed using a simple and a more correct algorithm. We also studied the consequences of these differences on the dose-effect relations for radiation-induced lung injury., Materials and Methods: The treatment plans of 68 lung cancer patients initially produced in a TPS using a calculation model that incorporates the equivalent-path length (EPL) inhomogeneity-correction algorithm, were recalculated in a TPS with the convolution-superposition (CS) algorithm. The higher accuracy of the CS algorithm is well-established. Dose distributions in lung were compared using isodoses, dose-volume histograms (DVHs), the mean lung dose (MLD) and the percentage of lung receiving >20 Gy (V20). Published dose-effect relations for local perfusion changes and radiation pneumonitis were re-evaluated., Results: Evaluation of isodoses showed a consistent overestimation of the dose at the lung/tumor boundary by the EPL algorithm of about 10%. This overprediction of dose was also reflected in a consistent shift of the EPL DVHs for the lungs towards higher doses. The MLD, as determined by the EPL and CS algorithm, differed on average by 17+/-4.5% (+/-1SD). For V20, the average difference was 12+/-5.7% (+/-1SD). For both parameters, a strong correlation was found between the EPL and CS algorithms yielding a straightforward conversion procedure. Re-evaluation of the dose-effect relations showed that lung complications occur at a 12-14% lower dose. The values of the TD(50) parameter for local perfusion reduction and radiation pneumonitis changed from 60.5 and 34.1 Gy to 51.1 and 29.2 Gy, respectively., Conclusions: A simple tissue inhomogeneity-correction algorithm like the EPL overestimates the dose to normal lung tissue. Dosimetric parameters for lung injury (e.g. MLD, V20) computed using both algorithms are strongly correlated making an easy conversion feasible. Dose-effect relations should be refitted when more accurate dose data is available.