CT number calibration audit in photon radiation therapy.

BACKGROUND: Inadequate computed tomography (CT) number calibration curves affect dose calculation accuracy. Although CT number calibration curves registered in treatment planning systems (TPSs) should be consistent with human tissues, it is unclear whether adequate CT number calibration is performed because CT number calibration curves have not been assessed for various types of CT number calibration phantoms and TPSs. PURPOSE: The purpose of this study was to investigate CT number calibration curves for mass density (ρ) and relative electron density (ρe ). METHODS: A CT number calibration audit phantom was sent to 24 Japanese photon therapy institutes from the evaluating institute and scanned using their individual clinical CT scan protocols. The CT images of the audit phantom and institute-specific CT number calibration curves were submitted to the evaluating institute for analyzing the calibration curves registered in the TPSs at the participating institutes. The institute-specific CT number calibration curves were created using commercial phantom (Gammex, Gammex Inc., Middleton, WI, USA) or CIRS phantom (Computerized Imaging Reference Systems, Inc., Norfolk, VA, USA)). At the evaluating institute, theoretical CT number calibration curves were created using a stoichiometric CT number calibration method based on the CT image, and the institute-specific CT number calibration curves were compared with the theoretical calibration curve. Differences in ρ and ρe over the multiple points on the curve (Δρm and Δρe,m , respectively) were calculated for each CT number, categorized for each phantom vendor and TPS, and evaluated for three tissue types: lung, soft tissues, and bones. In particular, the CT-ρ calibration curves for Tomotherapy TPSs (ACCURAY, Sunnyvale, CA, USA) were categorized separately from the Gammex CT-ρ calibration curves because the available tissue-equivalent materials (TEMs) were limited by the manufacturer recommendations. In addition, the differences in ρ and ρe for the specific TEMs (ΔρTEM and Δρe,TEM , respectively) were calculated by subtracting the ρ or ρe of the TEMs from the theoretical CT-ρ or CT-ρe calibration curve. RESULTS: The mean ± standard deviation (SD) of Δρm and Δρe,m for the Gammex phantom were -1.1 ± 1.2 g/cm3 and -0.2 ± 1.1, -0.3 ± 0.9 g/cm3 and 0.8 ± 1.3, and -0.9 ± 1.3 g/cm3 and 1.0 ± 1.5 for lung, soft tissues, and bones, respectively. The mean ± SD of Δρm and Δρe,m for the CIRS phantom were 0.3 ± 0.8 g/cm3 and 0.9 ± 0.9, 0.6 ± 0.6 g/cm3 and 1.4 ± 0.8, and 0.2 ± 0.5 g/cm3 and 1.6 ± 0.5 for lung, soft tissues, and bones, respectively. The mean ± SD of Δρm for Tomotherapy TPSs was 2.1 ± 1.4 g/cm3 for soft tissues, which is larger than those for other TPSs. The mean ± SD of Δρe,TEM for the Gammex brain phantom (BRN-SR2) was -1.8 ± 0.4, implying that the tissue equivalency of the BRN-SR2 plug was slightly inferior to that of other plugs. CONCLUSIONS: Latent deviations between human tissues and TEMs were found by comparing the CT number calibration curves of the various institutes.

Dose-Volume and Radiobiological Model-Based Comparative Evaluation of the Gastrointestinal Toxicity Risk of Photon and Proton Irradiation Plans in Localized Pancreatic Cancer Without Distant Metastasis.

Background: Radiobiological model-based studies of photon-modulated radiotherapy for pancreatic cancer have reported reduced gastrointestinal (GI) toxicity, although the risk is still high. The purpose of this study was to investigate the potential of 3D-passive scattering proton beam therapy (3D-PSPBT) in limiting GI organ at risk (OAR) toxicity in localized pancreatic cancer based on dosimetric data and the normal tissue complication probability (NTCP) model. Methods: The data of 24 pancreatic cancer patients were retrospectively analyzed, and these patients were planned with intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), and 3D-PSPBT. The tumor was targeted without elective nodal coverage. All generated plans consisted of a 50.4-GyE (Gray equivalent) dose in 28 fractions with equivalent OAR constraints, and they were normalized to cover 50% of the planning treatment volume (PTV) with 100% of the prescription dose. Physical dose distributions were evaluated. GI-OAR toxicity risk for different endpoints was estimated by using published NTCP Lyman-Kutcher-Burman (LKB) models. Analysis of variance (ANOVA) was performed to compare the dosimetric data, and ΔNTCPIMRT-PSPBT and ΔNTCPVMAT-PSPBT were also computed. Results: Similar homogeneity and conformity for the clinical target volume (CTV) and PTV were exhibited by all three planning techniques (P > 0.05). 3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (D max and V 50 GyE) in comparison with IMRT and VMAT (P < 0.05). Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT. Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT. 3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range. However, this result needs to be further evaluated in future clinical studies.

Radiobiological model-based approach to determine the potential of dose-escalated robust intensity-modulated proton radiotherapy in reducing gastrointestinal toxicity in the treatment of locally advanced unresectable pancreatic cancer of the head.

BACKGROUND: The purpose of this study was to determine the potential of escalated dose radiation (EDR) robust intensity-modulated proton radiotherapy (ro-IMPT) in reducing GI toxicity risk in locally advanced unresectable pancreatic cancer (LAUPC) of the head in term of normal tissue complication probability (NTCP) predictive model. METHODS: For 9 patients, intensity-modulated radiotherapy (IMRT) was compared with ro-IMPT. For all plans, the prescription dose was 59.4GyE (Gray equivalent) in 33 fractions with an equivalent organ at risk (OAR) constraints. Physical dose distribution was evaluated. GI toxicity risk for different endpoints was estimated using published NTCP Lyman Kutcher Burman (LKB) models for stomach, duodenum, small bowel, and combine stomach and duodenum (Stoduo). A Wilcoxon signed-rank test was used for dosimetry parameters and NTCP values comparison. RESULT: The dosimetric results have shown that, with similar target coverage, ro-IMPT achieves a significant dose-volume reduction in the stomach, small bowel, and stoduo in low to high dose range in comparison to IMRT. NTCP evaluation for the endpoint gastric bleeding of stomach (10.55% vs. 13.97%, P = 0.007), duodenum (1.87% vs. 5.02%, P = 0.004), and stoduo (5.67% vs. 7.81%, P = 0.008) suggest reduced toxicity by ro-IMPT compared to IMRT. ∆NTCP IMRT - ro-IMPT (using parameter from Pan et al. for gastric bleed) of ≥5 to < 10% was seen in 3 patients (33%) for stomach and 2 patients (22%) for stoduo. An overall GI toxicity relative risk (NTCPro-IMPT/NTCPIMRT) reduction was noted (0.16-0.81) for all GI-OARs except for duodenum (> 1) with endpoint grade ≥ 3 GI toxicity (using parameters from Holyoake et al.). CONCLUSION: With similar target coverage and better conformity, ro-IMPT has the potential to substantially reduce the risk of GI toxicity compared to IMRT in EDR of LAUPC of the head. This result needs to be further evaluated in future clinical studies.

MR signal changes in superparamagnetic iron oxide nanoparticle-labeled macrophages in response to X irradiation.

To investigate whether MR signals associated with macrophages labeled with superparamagnetic iron oxide nanoparticles (SPIONs) change in response to X irradiation, we performed in vitro MRI of SPION-labeled macrophage-like J774A.1 cells that were subsequently X irradiated. We labeled the cells with ferucarbotran at a concentration of 10 µg iron/mL in culture medium for 16 h and subsequently performed X irradiation at doses of 0, 2, 10, or 20 Gy using a low-energy X-ray unit. On Days 3 and 6, we suspended the cells in agar at a concentration of 2 × 106 cells/mL and acquired multi-gradient echo and multi-spin echo images of the cell samples using a 3 T scanner to estimate R2 * and R2 . In addition, we microscopically investigated the relationship among the MR signal changes, intracellular SPIONs, and acidic organelles. Our data showed that X irradiation of labeled cells caused increased SPION deposition in lysosomes compared with the non-irradiated control. On Day 3, R2 * and R2 values in the 0 to 10 Gy irradiated samples were dose-dependently increased 5.4- and 1.5-fold compared with 17 ± 2 and 13 ± 1/s, respectively, in the non-irradiated control; these values plateaued at more than 10 Gy. Although the increases in R2 *, R2 , and SPION deposition were still observed in the 10 and 20 Gy samples on Days 6 and 7, the 2 Gy samples showed recovery in these parameters as cell growth was restored. Acidic organelles were temporarily increased in the irradiated cells, which suggests that the reduction in lysosomal acidity was not attributable to SPION deposition. In conclusion, X irradiation of macrophages can cause SPION deposition and R2 * and R2 elevation in a specific dose range. MRI of SPION-labeled and subsequently X-irradiated macrophages may be utilized as a novel technique for investigating macrophage responses to X irradiation.

Liver phantom design and dosimetric verification in participating institutions for a proton beam therapy in patients with resectable hepatocellular carcinoma: Japan Clinical Oncology Group trial (JCOG1315C).

BACKGROUND AND PURPOSE: In Japan, the first domestic clinical trial of proton beam therapy for the liver was initiated as the Japan Clinical Oncology Group trial (JCOG1315C: Non-randomized controlled study comparing proton beam therapy and hepatectomy for resectable hepatocellular carcinoma). Purposes of this study were to develop a new dosimetric verification system and to carry out a credentialing for the JCOG1315C clinical trial. MATERIALS AND METHODS: Accuracy and differences in doses in proton treatment planning among participating institutions were surveyed and investigated. We designed and developed a suitable water tank-type liver phantom for a dosimetric verification of proton beam therapy for liver. In a visiting survey of five institutions participating in the clinical trial, we performed the dosimetric verification using the liver phantom and an air-filled ionization chamber. RESULTS: The shape of the dose distributions calculated in proton treatment planning was characteristic and dependent on the manufacturers of the proton beam therapy system, the proton treatment planning system and the setup at the participating institutions. Widths of the lateral penumbra were 5.8-12.7 mm among participating institutions. The accuracy between the calculated and the measured doses in the proton irradiation was within 3% at five measurement points including both points on the isocenter and off the isocenter. CONCLUSIONS: These findings confirmed the accuracy of the delivery doses in the institutions participating in the clinical trial, and the clinical trial with integration of all institutions (five institutions) could be initiated.

Hypofractionated proton beam therapy for centrally located lung cancer.

INTRODUCTION: To clarify the efficacy and safety of hypofractionated proton beam therapy (PBT) for centrally located lung cancer. METHODS: We retrospectively reviewed 39 patients who received hypofractionated [≧3 Gy (relative biological effectiveness: RBE)/fraction] PBT for centrally located cT1-2N0M0 (8th edition) lung cancer between 1999 and 2015. A tumour within 2 cm of the proximal bronchial tree was defined as a centrally located tumour. RESULTS: Twenty-four patients (62%) were treated with 80 Gy (RBE) in 20 fractions (112 Gy10 ), whereas eight (21%) were treated with 66 Gy (RBE) in 10 fractions (109.56 Gy10 ). The median follow-up period for censored patients was 48 months (range: 4-140). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 86 and 100% for T1 disease and 56 and 94% for T2 disease, respectively. Patients who received 110 Gy10 or higher showed significantly better PFS than those who received less than 110 Gy10 , while no significant difference was noted in OS between the two groups. The sites of the first progression were local in six patients (27%), regional in seven (32%), distant in seven (32%), and local and distant in two (9%). Among the 13 patients with loco-regional recurrence, only two (15%) received treatments with curative intent. Dyspnoea of grade 3 was noted in one patient (3%), and pneumonitis of grade 2 was noted in four patients (10%). CONCLUSION: Hypofractionated PBT may be a very safe and effective treatment option for centrally located early lung cancer.

Effect of 5-fluorouracil on cellular response to proton beam in esophageal cancer cell lines according to the position of spread-out Bragg peak.

INTRODUCTION: To investigate enhancement by 5-fluorouracil (5-FU) of the sensitivity of cancer cells to proton beam irradiation and clarify the differences in the responses of the 5-FU-treated cells to proton beam irradiation according to the position of the cells on the spread-out Bragg peak (SOBP). METHODS: OE21 human esophageal squamous cells were irradiated with a 235-MeV proton beam at four different positions on the SOBP. The effects of the irradiation plus 5-FU treatment on the cell survival were assessed by clonogenic assays and determination of the sensitizer enhancement ratio (SER). In addition, DNA double-strand breaks were estimated by measuring phospho-histone H2AX (γH2AX) foci formation in the cells at 0.5 and 24 h after irradiation. RESULTS: The relative biological effectiveness (RBE) of proton beam irradiation against vehicle-control cells tended to increase with an increase in the depth of the cells on the SOBP. On the other hand, the degree of enhancement of the cellular sensitivity to proton beam irradiation by 5-FU was similar across all the positions on the SOBP. Furthermore, a marked increase in the number of residual γH2AX foci at 24 h post-irradiation was observed in the cells at the distal end of the SOBP. CONCLUSIONS: Our data indicated that the degree of enhancement by 5-FU of the sensitivity of OE21 cells to 235-MeV proton beam irradiation did not differ significantly depending on the position of the cells on the SOBP. Furthermore, the degree of increase in the number of γH2AX foci at 24 h after proton beam irradiation with or without 5-FU exposure did not differ significantly according to the position on the SOBP. The effect of 5-FU in enhancing the effect of proton beam irradiation on cancer cells may be constant for all positions on the SOBP.

Usefulness of hybrid deformable image registration algorithms in prostate radiation therapy.

To evaluate the accuracy of commercially available hybrid deformable image registration (DIR) algorithms when using planning CT (pCT) and daily cone-beam computed tomography (CBCT) in radiation therapy for prostate cancer. The hybrid DIR algorithms in RayStation and MIM Maestro were evaluated. Contours of the prostate, bladder, rectum, and seminal vesicles (SVs) were used as region-of-interest (ROIs) to guide image deformation in the hybrid DIR and to compare the DIR accuracy. To evaluate robustness of the hybrid DIR for prostate cancer patients with organs with volume that vary on a daily basis, such as the bladder and rectum, the DIR algorithms were performed on ten pairs of CT volumes from ten patients who underwent prostate intensity-modulated radiation therapy or volumetric modulated arc therapy. In a visual evaluation, MIM caused unrealistic image deformation in soft tissues, organs, and pelvic bones. The mean dice similarity coefficient (DSC) ranged from 0.46 to 0.90 for the prostate, bladder, rectum, and SVs; the SVs had the lowest DSC. Target registration error (TRE) at the centroid of the ROIs was about 2 mm for the prostate and bladder, and about 6 mm for the rectum and SVs. RayStation did not cause unrealistic image deformation, and could maintain the shape of pelvic bones in most cases. The mean DSC and TRE at the centroid of the ROIs were about 0.9 and within 5 mm generally. In both software programs, the use of ROIs to guide image deformation had the possibility to reduce any unrealistic image deformation and might be effective to keep the DIR physically reasonable. The pCT/CBCT DIR for the prostate cancer did not reduce the DIR accuracy because of the use of ROIs to guide the image deformation.

Range optimization for target and organs at risk in dynamic adaptive passive scattering proton beam therapy - A proof of concept.

PURPOSE: The purpose of this study was to design and develop a new range optimization for target and organs at risk (OARs) in dynamic adaptive proton beam therapy (PBT). METHODS: The new range optimization for target and OARs (RO-TO) was optimized to maintain target dose coverage but not to increase the dose exposure of OARs, while the other procedure, range optimization for target (RO-T), only focused on target dose coverage. A retrospective analysis of a patient who received PBT for abdominal lymph node metastases was performed to show the effectiveness of our new approach. The original plan (OP), which had a total dose of 60 Gy (relative biological effectiveness; RBE), was generated using six treatment fields. Bone-based registration (BR) and tumor-based registration (TR) were performed on each pretreatment daily CT image dataset acquired once every four fractions, to align the isocenter. RESULTS: Both range adaptive approaches achieved better coverage (D95%) and homogeneity (D5%-D95%) than BR and TR only. However, RO-T showed the greatest increases in D2cc and Dmean values of the small intestine and stomach and exceeded the limitations of dose exposure for those OARs. RO-TO showed comparable or superior dose sparing compared with the OP for all OARs. CONCLUSIONS: Our results suggest that BR and TR alone may reduce target dose coverage, and that RO-T may increase the dose exposure to the OARs. RO-TO may achieve the planned dose delivery to the target and OARs more efficiently than the OP. The technique requires testing on a large clinical dataset.

Late radiological changes after passive scattering proton beam therapy for Stage I lung cancer.

This study aimed to examine late radiological changes after proton beam therapy (PBT) for early-stage non-small cell lung cancer (NSCLC) and to clarify correlations between mass-like radiological changes and patient characteristics. CT scans of patients who underwent passive scattering PBT for T1-2N0M0 NSCLC were analyzed retrospectively. Patients were considered eligible if follow-up CT was performed for at least 2 years, with no definite evidence of local recurrence. The following five periods were defined: (i) 6-12 months, (ii) 12-24 months, (iii) 24-36 months, (iv) 36-48 months and (v) 48-60 months after PBT. Late (≥6 months) radiological changes were scored by consensus of three radiation oncologists according to classifications set forth by Koenig (Radiation injury of the lung after three-dimensional conformal radiation therapy. AJR Am J Roentgenol 2002;178:1383-8.). CT scans of 113 patients (median follow-up, 36 months; range, 24-137 months) were evaluated. Late radiological changes during Periods (i), (ii), (iii), (iv) and (v) included modified conventional pattern (80%, 79%, 72%, 58% and 56%, respectively), mass-like changes (8%, 9%, 14%, 22% and 18%, respectively), scar-like changes (4%, 9%, 11%, 17% and 24%, respectively) and no increased density (8%, 3%, 3%, 2% and 2%, respectively). Mass-like changes were observed in 23 patients (20%). Among patients who developed mass-like changes, the median interval between the initiation of PBT and the onset of mass-like changes was 19 months (range, 6-62 months). In multivariate analysis, a peripheral location was found to be a significant factor (P = 0.035; odds ratio: 4.44; 95% confidence interval: 1.12-21.28). In conclusion, mass-like changes were observed in 20% of patients who underwent PBT. Patients with peripheral tumors showed a higher incidence of mass-like changes.

Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to perform a dosimetric comparison between proton beam therapy (PBT) and photon radiation therapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were treated with PBT in our institution. In addition, we evaluated the correlation between toxicities and dosimetric parameters, especially the doses to normal lung or heart tissue, to clarify the clinical advantage of PBT over photon radiation therapy. METHODS: A total of 37 consecutive patients with Stage III thoracic ESCC who had received PBT with or without concurrent chemotherapy between October 2012 and December 2015 were evaluated in this study. The dose distributions of PBT were compared with those of dummy 3-dimensional conformal radiation therapy (3DCRT) and Intensity Modulated Radiation Therapy (IMRT), focusing especially on the doses to organs at risk, such as normal lung and heart tissue. RESULTS: Of the 37 patients, the data from 27 patients were analyzed. Among these 27 patients, four patients (15%) developed grade 2 pericardial effusion as a late toxicity. None of the patients developed grade 3 or worse acute or late pulmonary and cardiac toxicities. When the dosimetric parameters between PBT and planned 3DCRT were compared, all the PBT domestic variables for the lung dose except for lung V10 GyE and V15 GyE were significantly lower than those for the dummy 3DCRT plans, and the PBT domestic variables for the heart dose were also significantly lower than those for the dummy 3DCRT plans. When the PBT and IMRT plans were compared, all the PBT domestic variables for the doses to the lung and heart were significantly lower than those for the dummy IMRT plans. Regarding the correlation between the grades of toxicities and the dosimetric parameters, no significant correlation was seen between the occurrence of grade 2 pericardial effusion and the dose to the heart. CONCLUSIONS: When the dosimetric parameters of the dose distributions for the treatment of patients with locally advanced stage III ESCC were compared between PBT and 3DCRT or IMRT, PBT enabled a significant reduction in the dose to the lung and heart, compared with 3DCRT or IMRT.

Feasibility of dynamic adaptive passive scattering proton therapy with computed tomography image guidance in the lung.

PURPOSE: Hypo-fractionated proton beam therapy (PBT) is an approach that has been increasingly explored over the past decade. It requires high geometric accuracy for targeting of the PBT beams. However, image-guided PBT is currently commonly performed with kV X-ray images of bony anatomy. A dynamic adaptive passive scattering PBT system using computed tomography-based three-dimensional image guidance was developed, and its effectiveness was then evaluated retrospectively in patients with nonsmall cell lung cancer (NSCLC). METHODS: The dynamic adaptive PBT system consisted of computed tomography-based image registration and proton dose calculation using a simplified Monte Carlo algorithm, with a range adaptation system that could adjust the range shifter thickness to alter the dose distribution. Three patients were retrospectively analyzed. All plans, which each had a total dose of 60 Gy (relative biological effectiveness; RBE), were generated using two fields (Gantry angles: 270 degree and 180 degree) in a passive scattering method. Three dose distributions were generated for each patient according to the following different registrations: bone registration, tumor registration, and tumor registration with range adaptation. The following dosimetric parameters were compared with the original plan: target dose coverage at D95% for the clinical target volume (CTV), homogeneity of D5% to D95% for the CTV, and dose distributions in normal tissue (Dmax of Spinal cord and V20 Gy of lung). RESULTS: For the bone registration method, the average D95% and D5% to D95% for the CTV showed average differences from the original plan of -3.7 ± 4.1 Gy (mean ± 1SD; RBE) and 3.6 ± 3.9 Gy (RBE) respectively. The tumor registration method achieved better coverage than the bone registration method, although the dosimetric parameters for coverage and homogeneity still showed average differences in -2.0 ± 2.3 Gy (RBE) and 1.9 ± 2.2 Gy (RBE) respectively. The range adaptive plan showed comparable coverage and homogeneity [D95%: -1.0 ± 1.3 Gy (RBE) and D5% to D95%: 0.9 ± 1.0 Gy (RBE) on average] to the original plan, as well as demonstrating similar normal tissue sparing. The approach could be completed in less than 10 min, including CT acquisition, image registration, dose recalculation with range optimization, and the operator's visual verification. CONCLUSIONS: The tumor dose coverage in patients with NSCLC may deteriorate as a result of respiratory or body movement if daily proton range adaptation is not performed. Our approach may provide higher geometric accuracy for localization of the tumor, and the dynamic range adaptation enables us to achieve the planned dose distribution for hypo-fractionated PBT in the lung.

Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread out Bragg peak.

BACKGROUND: Cellular responses to proton beam irradiation are not yet clearly understood, especially differences in the relative biological effectiveness (RBE) of high-energy proton beams depending on the position on the Spread-Out Bragg Peak (SOBP). Towards this end, we investigated the differences in the biological effect of a high-energy proton beam on the target cells placed at different positions on the SOBP, using two human esophageal cancer cell lines with differing radiosensitivities. METHODS: Two human esophageal cancer cell lines (OE21, KYSE450) with different radiosensitivities were irradiated with a 235-MeV proton beam at 4 different positions on the SOBP (position #1: At entry; position #2: At the proximal end of the SOBP; position #3: Center of the SOBP; position #4: At the distal end of the SOBP), and the cell survivals were assessed by the clonogenic assay. The RBE10 for each position of the target cell lines on the SOBP was determined based on the results of the cell survival assay conducted after photon beam irradiation. In addition, the number of DNA double-strand breaks was estimated by quantitating the number of phospho-histone H2AX (γH2AX) foci formed in the nuclei by immunofluorescence analysis. RESULTS: In regard to differences in the RBE of a proton beam according to the position on the SOBP, the RBE value tended to increase as the position on the SOBP moved distally. Comparison of the residual number of γH2AX foci at the end 24 h after the irradiation revealed, for both cell lines, a higher number of foci in the cells irradiated at the distal end of the SOPB than in those irradiated at the proximal end or center of the SOBP. CONCLUSIONS: The results of this study demonstrate that the RBE of a high-energy proton beam and the cellular responses, including the DNA damage repair processes, to high-energy proton beam irradiation, differ according to the position on the SOBP, irrespective of the radiosensitivity levels of the cell lines.

Proton beam therapy for olfactory neuroblastoma.

PURPOSE: To clarify the efficacy and feasibility of proton beam therapy (PBT) for olfactory neuroblastoma (ONB). METHODS AND MATERIALS: We retrospectively reviewed 42 consecutive patients who received PBT with curative intent for ONB at National Cancer Center Hospital East from November 1999 to March 2012. RESULTS: Five patients (12%) had Kadish A disease, nine (21%) had Kadish B, and twenty-eight (67%) had Kadish C. All patients except one received a total dose of 65Gy (relative biological effectiveness: RBE) in 26 fractions. Twenty-four patients (57%) received induction and/or concurrent chemotherapy. The median follow-up for all eligible patients was 69months (7-186). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 100% and 80% for Kadish A, 86 and 65% for Kadish B, and 76% and 39% for Kadish C, respectively. The sites of the first progression were local in six patients (30%), regional in eight (40%), distant in two (10%), local and regional in two (10%), and local and distant in two (10%). Late adverse events of grade 3-4 were seen in six patients (ipsilateral visual impairment, 3; bilateral visual impairment, 1; liquorrhea, 1; cataract, 1). CONCLUSION: PBT was a safe and effective modality for ONB.

Development of Continuous Line Scanning System Prototype for Proton Beam Therapy.

PURPOSE: Taking advantage of the continuous, high-intensity beam of the cyclotron at the National Cancer Center Hospital East, we developed a continuous line scanning system (CLSS) prototype for prostate cancer in collaboration with Sumitomo Heavy Industries, Ltd (Tokyo, Japan). MATERIALS AND METHODS: The CLSS modulates dose distribution at each beam energy level by varying scanning speed while keeping the beam intensity constant through a beam-intensity control system and a rapid on/off beam-switching system. In addition, we developed a beam alignment system to improve the precision of the beam position. The scanning control system is used to control the scanning pattern and set the value of the nozzle apparatus. It also collects data for monitoring and for cyclotron parameters and transmits information to the scanning power supplies and monitor amplifiers, which serve as the measurement system, and to the nozzle-control and beam-transfer systems. The specifications of the line scanning beam were determined in performance tests. Finally, a patient-specific dosimetric measurement for prostate cancer was also performed. RESULTS: The beam size, position, intensity, and scanning speed of our CLSS were found to be well within clinical requirements. The CLSS produced an accurate 3-dimensional dose distribution for clinical treatment planning. CONCLUSION: The performance of our new CLSS was confirmed to comply with clinical requirements. We have been employing it in prostate cancer treatments since October 23, 2015.

Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced non-small cell lung cancer.

OBJECTIVE: To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer. METHODS: The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated. RESULTS: Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44-87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60-66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9-32%), and the mean normal lung dose was 11.9 GyE (range: 6.0-19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01-63.6%), the mean heart V40 GyE was 13.4% (range: 1.4-29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9-48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities. CONCLUSIONS: Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters.

Application of dose kernel calculation using a simplified Monte Carlo method to treatment plan for scanned proton beams.

Full Monte Carlo (FMC) calculation of dose distribution has been recognized to have superior accuracy, compared with the pencil beam algorithm (PBA). However, since the FMC methods require long calculation time, it is difficult to apply them to routine treatment planning at present. In order to improve the situation, a simplified Monte Carlo (SMC) method has been introduced to the dose kernel calculation applicable to dose optimization procedure for the proton pencil beam scanning. We have evaluated accuracy of the SMC calculation by comparing a result of the dose kernel calculation using the SMC method with that using the FMC method in an inhomogeneous phantom. The dose distribution obtained by the SMC method was in good agreement with that obtained by the FMC method. To assess the usefulness of SMC calculation in clinical situations, we have compared results of the dose calculation using the SMC with those using the PBA method for three clinical cases of tumor treatment. The dose distributions calculated with the PBA dose kernels appear to be homogeneous in the planning target volumes (PTVs). In practice, the dose distributions calculated with the SMC dose kernels with the spot weights optimized with the PBA method show largely inhomogeneous dose distributions in the PTVs, while those with the spot weights optimized with the SMC method have moderately homogeneous distributions in the PTVs. Calculation using the SMC method is faster than that using the GEANT4 by three orders of magnitude. In addition, the graphic processing unit (GPU) boosts the calculation speed by 13 times for the treatment planning using the SMC method. Thence, the SMC method will be applicable to routine clinical treatment planning for reproduction of the complex dose distribution more accurately than the PBA method in a reasonably short time by use of the GPU-based calculation engine.

Evaluation of monitor unit calculation based on measurement and calculation with a simplified Monte Carlo method for passive beam delivery system in proton beam therapy.

Calibrating the dose per monitor unit (DMU) for individual patients is important to deliver the prescribed dose in radiation therapy. We have developed a DMU calculation method combining measurement data and calculation with a simplified Monte Carlo method for the double scattering system in proton beam therapy at the National Cancer Center Hospital East in Japan. The DMU calculation method determines the clinical DMU by the multiplication of three factors: a beam spreading device factor FBSD, a patient-specific device factor FPSD, and a field-size correction factor FFS(A). We compared the calculated and the measured DMU for 75 dose fields in clinical cases. The calculated DMUs were in agreement with measurements in ± 1.5% for all of 25 fields in prostate cancer cases, and in ± 3% for 94% of 50 fields in head and neck (H&N) and lung cancer cases, including irregular shape fields and small fields. Although the FBSD in the DMU calculations is dominant as expected, we found that the patient-specific device factor and field-size correction also contribute significantly to the calculated DMU. This DMU calculation method will be able to substitute the conventional DMU measurement for the majority of clinical cases with a reasonable calculation time required for clinical use.

Experimental verification of dose calculation using the simplified Monte Carlo method with an improved initial beam model for a beam-wobbling system.

A beam delivery system using a single-radius-beam-wobbling method has been used to form a conformal irradiation field for proton radiotherapy in Japan. A proton beam broadened by the beam-wobbling system provides a non-Gaussian distribution of projection angle different in two mutually orthogonal planes with a common beam central axis, at a certain position. However, the conventional initial beam model for dose calculations has been using an approximation of symmetric Gaussian angular distribution with the same variance in both planes (called here a Gaussian model with symmetric variance (GMSV)), instead of the accurate one. We have developed a more accurate initial beam model defined as a non-Gaussian model with asymmetric variance (NonGMAV), and applied it to dose calculations using the simplified Monte Carlo (SMC) method. The initial beam model takes into account the different distances of two beam-wobbling magnets from the iso-center and also the different amplitudes of kick angle given by each magnet. We have confirmed that the calculation using the SMC with NonGMAV reproduced the measured dose distribution formed in air by a mono-energetic proton beam passing through a square aperture collimator better than with the GMSV and with a Gaussian model with asymmetric variance (GMAV) in which different variances of angular distributions are used in the two mutually orthogonal planes. Measured dose distributions in a homogeneous phantom formed by a modulated proton beam passing through a range shifter and an L-shaped range compensator, were consistent with calculations using the SMC with GMAV and NonGMAV, but in disagreement with calculations using the SMC with GMSV. Measured lateral penumbrae in a lateral direction were reproduced better by calculations using the SMC with NonGMAV than by those with GMAV, when an aperture collimator with a smaller opening was used. We found that such a difference can be attributed to the non-Gaussian angular distribution of the initial beam at a lateral position for the beam-wobbling system. Calculations using the SMC with NonGMAV are effective to reproduce dose distributions formed by a beam-wobbling system more accurately than that with GMSV or that with GMAV.

In vivo proton dosimetry using a MOSFET detector in an anthropomorphic phantom with tissue inhomogeneity.

When in vivo proton dosimetry is performed with a metal-oxide semiconductor field-effect transistor (MOSFET) detector, the response of the detector depends strongly on the linear energy transfer. The present study reports a practical method to correct the MOSFET response for linear energy transfer dependence by using a simplified Monte Carlo dose calculation method (SMC). A depth-output curve for a mono-energetic proton beam in polyethylene was measured with the MOSFET detector. This curve was used to calculate MOSFET output distributions with the SMC (SMC(MOSFET)). The SMC(MOSFET) output value at an arbitrary point was compared with the value obtained by the conventional SMC(PPIC), which calculates proton dose distributions by using the depth-dose curve determined by a parallel-plate ionization chamber (PPIC). The ratio of the two values was used to calculate the correction factor of the MOSFET response at an arbitrary point. The dose obtained by the MOSFET detector was determined from the product of the correction factor and the MOSFET raw dose. When in vivo proton dosimetry was performed with the MOSFET detector in an anthropomorphic phantom, the corrected MOSFET doses agreed with the SMC(PPIC) results within the measurement error. To our knowledge, this is the first report of successful in vivo proton dosimetry with a MOSFET detector.