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Treatment of locally advanced lung cancer is limited by toxicity and insufficient local control. Particle therapy could enable more conformal treatment than intensity modulated photon therapy, but is challenged by irregular tumor motion, associated range changes and tumor deformations.We propose a new strategy for robust, online adaptive particle therapy, synergizing 4D-optimization with real-time adaptive beam tracking. The strategy was tested and the required motion monitoring precision was determined.In multiphase 4D dose delivery (MP4D), a dedicated quasi-static treatment plan is delivered to each motion phase of a periodic 4DCT. In the new extension, 'MP4D with residual tracking' (MP4DRT), lateral beam tracking compensates for the displacement of the tumor center-of-mass relative to the current phase in the planning 4DCT. We implemented this method into the dose delivery system of a clinical carbon facility and tested it experimentally for a lung cancer plan based on a periodic subset of a virtual lung 4DCT (planned motion amplitude 20 mm). Treatments were delivered in a QA-like setting to a moving IC array. We considered variable motion amplitudes and baseline drifts. The required motion monitoring precision was evaluated by adding noise to the motion signal. Log-file based dose reconstructions were performed in silico on the entire 4DCT phantom data capable of simulating non-periodic motion. MP4DRT was compared to MP4D, rescanned beam tracking and ITV plans. Treatment quality was assessed in terms of target coverage (D95), dose homogeneity (D5-D95), conformity number and dose to heart and lung.For all considered motion scenarios and metrics, MP4DRT produced the most favorable metrics amongst the tested motion mitigation strategies and delivered high quality treatments. The conformity was similar to static treatments. The motion monitoring precision required for D9595% was 1.9 mm.With clinically feasible motion monitoring, MP4DRT is able to deliver highly conformal dose distributions to irregularly moving targets.

Purpose Radiation pneumonitis (RP) is commonly associated with thoracic radiation therapy, and its incidence is related to dose and volume of the normal lung in the path of radiation. Our aim was to investigate dose patterns associated with RP in patients enrolled in a randomized trial of intensity modulated radiation therapy (IMRT) versus passive scattering proton therapy (PSPT) for locally advanced non-small cell lung cancer. Methods We analyzed 178 patients prospectively treated with PSPT or IMRT for non-small cell lung cancer to a prescribed dose of 66 or 74 Gy in conventional daily fractionation with concurrent chemotherapy. Forty patients (22%) developed clinically symptomatic RP. Voxel-based analysis of local dose differences was done with a nonparametric permutation test accounting for multiple comparisons. From the obtained 3-dimensional significance maps, we derived clusters of voxels that exhibited dose differences between groups at a statistical significance level of 0.05. Results The voxel-based analysis highlighted that (1) significant dose differences between patients with and without RP were found in the lower part of the lungs and in the heart and (2) the anatomic regions significantly spared by PSPT and the clusters in which doses were significantly correlated with RP development were disjoint. Conclusions The analyzed trial data provide an unprecedented opportunity to substantiate previous hypotheses regarding the role of the heart and the lower lungs in the development of RP. Knowledge of this relationship between RP and thoracic regional radiosensitivity should be considered in clinical practice and in the design of future trials.

Purpose To establish a beam monitoring and dosimetry system to enable the FLASH dose-rate carbon ion irradiation and investigate, at different oxygen concentrations, the in vitro biological response in comparison to conventional dose-rate. Methods and Materials CHO-K1 cell response to irradiation at different dose-rates and at different levels of oxygenation was studied using clonogenic assay. The XXX† Heidelberg Ion-Beam Therapy Center (HIT) synchrotron, after technical improvements, was adjusted to extract ≥5 × 108 12C ions within approximately 150 ms. The beam monitors were filled with helium. Results The FLASH irradiation with beam scanning yields a dose of 7.5 Gy (homogeneity of ±5%) for a 280 MeV/u beam in a volume of at least 8 mm in diameter and a corresponding dose rate of 70 Gy s−1 (± 20%). The dose repetition accuracy is better than 2%, the systematic uncertainty is better than 2%. Clonogenic assay demonstrates a significant FLASH sparing effect which is strongly oxygenation-dependent and mostly pronounced at 0.5% O2 but absent at 0% and 21% O2. Conclusion The FLASH dose-rates >40 Gy/s were achieved with carbon beams. Cell survival analysis revealed FLASH dose rate sparing in hypoxia (0.5% - 4% O2).

Purpose The combination of radiation therapy and immunotherapy is recognized as a very promising strategy for metastatic cancer treatment. The purpose of this work is to compare the effectiveness of x-ray and high-energy carbon ion therapy in combination with checkpoint inhibitors in a murine model. Methods and Materials We used an osteosarcoma mouse model irradiated with either carbon ions or x-rays in combination with 2 immune checkpoint inhibitors (anti–PD-1 and anti–CTLA-4). LM8 osteosarcoma cells were injected in both hind limbs of female C3H/He mice 7 days before exposure to carbon ions or x-rays. In experimental groups receiving irradiation, only the tumor on the left limb was exposed, whereas the tumor on the right limb served as an abscopal mimic. Checkpoint inhibitors were injected intraperitoneally 1 day before exposure as well as concomitant to and after exposure. Tumor growth was measured regularly up to day 21 after exposure, when mice were sacrificed. Both tumors as well as lungs were extracted. Results A reduced growth of the abscopal tumor was most pronounced after the combined protocol of carbon ions and the immune checkpoint inhibitors administered sequentially. Radiation or checkpoint inhibitors alone were not sufficient to reduce the growth of the abscopal tumors. Carbon ions alone reduced the number of lung metastases more efficiently than x-rays, and in combination with immunotherapy both radiation types essentially suppressed the metastasis, with carbon ions being again more efficient. Investigation of the infiltration of immune cells in the abscopal tumors of animals treated with combination revealed an increase in CD8+ cells. Conclusions Combination of checkpoint inhibitors with high-energy carbon ion radiation therapy can be an effective strategy for the treatment of advanced tumors.

Purpose: To present the first direct experimental in vitro comparison of the biological effectiveness of rangeequivalent protons and carbon ion beams for Chinese hamsterovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model. Methodsand Materials:Cell survivalwasmeasuredinthe phantomafter irradiation withtwo opposingfields,thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation. Results: The experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions. Conclusion: Both the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy. 2010 Elsevier Inc. Ion beam therapy, Relative biological effectiveness (RBE), Biophysical model, Treatment planning.

Purpose: To measure chromosomal aberrations in peripheral blood lymphocytes from cancer patients treated with X-rays or carbon ions (C-ions). Methods and Materials: Blood samples from patients diagnosed for esophageal or uterine cervical cancer were obtained before, during, and at the end of the radiation treatment. The novel technique of interphase chromosome painting was used to detect aberrations in prematurely condensed chromosomes 2 and 4. The fraction of aberrant lymphocytes was measured as a function of the dose to the tumor volume. For comparison, blood samples were also exposed in vitro to X-rays or to carbon ions accelerated at the HIMAC. Results: C-ions were more efficient than X-rays in the induction of chromosomal aberrations in vitro . In patients with similar pathologies, tumor positions, and radiation field sizes, however, C-ions induced a lower fraction of aberrant lymphocytes than X-rays during the treatment. The initial slope of the dose–response curve for the induction of chromosomal aberrations during the treatment was correlated to the relative decrease in the number of white blood cells and lymphocytes during the treatment. Conclusion: C-ions induce a lower level of cytogenetic damage in lymphocytes than X-rays, reducing the risk of bone marrow morbidity.

Estimation of the actual delivered 4-dimensional (4D) dose in treatments of patients with mobile hepatocellular cancer with scanned carbon ion beam therapy.Six patients were treated with 4 fractions to a total relative biological effectiveness (RBE)-weighted dose of 40 Gy (RBE) using a single field. Respiratory motion was addressed by dedicated margins and abdominal compression (5 patients) or gating (1 patient). 4D treatment dose reconstructions based on the treatment records and the measured motion monitoring data were performed for the single-fraction dose and a total of 17 fractions. To assess the impact of uncertainties in the temporal correlation between motion trajectory and beam delivery sequence, 3 dose distributions for varying temporal correlation were calculated per fraction. For 3 patients, the total treatment dose was formed from the fractional distributions using all possible combinations. Clinical target volume (CTV) coverage was analyzed using the volumes receiving at least 95% (V95) and 107% (V107) of the planned doses.4D dose reconstruction based on daily measured data is possible in a clinical setting. V95 and V107 values for the single fractions ranged between 72% and 100%, and 0% and 32%, respectively. The estimated total treatment dose to the CTV exhibited improved and more robust dose coverage (mean V9587%, SD3%) and overdose (mean V1074%, SD3%) with respect to the single-fraction dose for all analyzed patients.A considerable impact of interplay effects on the single-fraction CTV dose was found for most of the analyzed patients. However, due to the fractionated treatment, dose heterogeneities were substantially reduced for the total treatment dose. 4D treatment dose reconstruction for scanned ion beam therapy is technically feasible and may evolve into a valuable tool for dose assessment.

Purpose To provide methods for quantification of uncertainties in 4-dimensional (4D) treatment during treatment planning. Methods and Materials Uncertainty information was generated by multiple 4D treatment simulations with varying parameters. Sampled data were analyzed using uncertainty visualization methods that have been added to common treatment plan evaluation methods (eg, dose-volume histogram and dose distribution analysis). To illustrate the potential of the introduced methods, uncertainty analysis was completed for a single lung cancer case using 3 motion mitigation techniques: gating, slice-by-slice rescanning, and breath-controlled rescanning. Results By repeating 4D dose calculations with varying parameters, we were able to show local uncertainties in dose distributions and to evaluate the stability of treatment setups. The new methods were found suitable for uncertainty evaluation in 4D treatment planning of moving tumors. Calculation time of the uncertainty base data was time consuming but contrivable overnight. Conclusions Uncertainty analysis and visualization for 4D treatment planning provide an important tool in the decision process for an optimal treatment approach.

Purpose A method was developed to convert clinically prescribed RBE (Relative Biological Effectiveness)-weighted doses from the approach used at the Heavy-Ion Medical Accelerator (HIMAC) at the National Institute of Radiological Science, Chiba, Japan, to the LEM (Local Effect Model)-based TReatment planning for Particles (TRiP98) approach used in the pilot project at the GSI Helmholtzzentrum, Darmstadt, and the Heidelberg Ion-Beam Therapy Center (HIT). Methods and Materials The proposed conversion method is based on a simulation of the fixed spread-out Bragg peak (SOBP) depth dose profiles as used for the irradiation at HIMAC by LEM/TRiP98 and a recalculation of the resulting RBE-weighted dose distribution. We present data according to the clinical studies conducted at GSI in the past decade (LEM I), as well as data used in current studies (refined LEM version: LEM IV). Results We found conversion factors (RBE-weighted dose LEM/RBE-weighted dose HIMAC) reaching from 0.4 to 2.0 for prescribed carbon ion doses from 1 to 60 Gy (RBE) for SOBP extensions ranging from 20 to 120 mm according to the HIMAC approach. A conversion factor of 1.0 was found for approximately 5 Gy (RBE). The conversion factor decreases with increasing prescribed dose. Slightly smaller values for the LEM IV–based data set compared with LEM I were found. A significant dependence of the conversion factor from the SOBP width could be observed in particular for LEM IV, whereas the depth dependence was found to be small. Conclusions For the interpretation and comparison of clinical trials performed at HIMAC and GSI/HIT, it is of extreme importance to consider these conversion factors because according to the various methods to determine the RBE-weighted dose, similar dose values might not necessarily be related to similar clinical outcomes.

Purpose To measure chromosomal aberrations in blood lymphocytes from breast cancer patients treated with radiotherapy after quadrantectomy or tumorectomy. Methods and materials Twenty-two breast cancer patients treated with breast-conserving surgery and radiation were evaluated. Adjuvant chemotherapy was also given to 9 patients. Blood samples were obtained before radiotherapy, after about one-half of the fractions, and at the end of the treatment of the whole breast (50 Gy). Chromosome aberrations in peripheral blood lymphocytes were measured using chemical-induced premature chromosome condensation combined with fluorescence in situ hybridization. Results Radiation treatment produced a significant increase in the yield of chromosomal aberrations. A large interindividual variability was observed. The variability was not related to field size, previous chemotherapy, or treatment morbidity. Chromosome aberrations in lymphocytes at the end of the treatment were significantly higher in the group of patients with no lymph nodes surgically removed before the treatment than in the group of patients with more than 10 lymph nodes removed. Conclusions The number of lymph nodes within the radiation field is an important factor affecting the yield of radiation-induced chromosomal aberrations in breast cancer patients.

Purpose/Objective(s): To report the initial outcomes and toxicity of SABR for oligometastases. Materials/Methods: Fifty-three patients with a minimum potential followup of 1 year were treated with SABR directed to a total of 99 metastatic sites (lung n Z 65, liver n Z 14, bone n Z 10, lymph node n Z 9, soft tissue n Z 1). The most commonly used SABR regimen was 50 Gy in 5 consecutive daily fractions using conformal arc technique with daily image guidance using CBCT. The most common primary sites were colorectal cancer (CRC; 28%), non-small cell lung carcinoma (NSCLC; 19%), soft tissue sarcoma (STS; 15%), and renal cell carcinoma (RCC; 8%). Median time to metastatic progression from initial diagnosis was 1.2 years (range, 0-13.1 years). The majority of patients were treated for solitary metastases (59%). Prior to SABR, 45% were treated for metastatic disease with surgery, chemotherapy or both. Fourteen patients received additional SABR for limited progression. Results: Median follow-up was 1.3 years (1.4 years for living patients). Local control (LC), distant-progression free survival (DPFS), causespecific survival (CSS), and overall survival (OS) at 1 and 2 years were 92%, 56%, 87%, 85%, and 74%, 40%, 70%, 69%, respectively, after the initial course of SABR. After a second course of SABR for limited progression the 1-year DPFS was only 22%. On univariate analysis there was no significant predictor for LC, although liver metastases and CRC primaries showed a trend toward decreased LC. Two-year DFPS, CSS, and OS were worse for patients with multiple metastatic sites, multiple organ involvement, increased cumulative GTV at initial SABR course, and when all measurable disease was not treated with SABR. Grade 3+ toxicity was observed in only 3 patients. Conclusions: In selected patients with limited metastatic disease, SABR resulted in durable disease control in a significant percentage of patients with minimal toxicity. Author Disclosure: R. Dagan: None. A.R. Yeung: None. R.A. Zlotecki: None. C.G. Morris: None. P. Okunieff: None.