Evaluation of X-ray and carbon-ion beam irradiation with chemotherapy for the treatment of cervical adenocarcinoma cells in 2D and 3D cultures.

BACKGROUND: Cervical cancer is the second most common cancer in women and causes more than 250,000 deaths worldwide. Among these, the incidence of cervical adenocarcinomas is increasing. Cervical adenocarcinoma is not only difficult to detect and prevent in the early stages with screening, but it is also resistant to chemotherapy and radiotherapy, and its prognosis worsens significantly as the disease progresses. Furthermore, when recurrence or metastasis is observed, treatment options are limited and there is no curative treatment. Recently, heavy-particle radiotherapy has attracted attention owing to its high tumor control and minimal damage to normal tissues. In addition, heavy particle irradiation is effective for cancer stem cells and hypoxic regions, which are difficult to treat. METHODS: In this study, we cultured cervical adenocarcinoma cell lines (HeLa and HCA-1) in two-dimensional (2D) or three-dimensional (3D) spheroid cultures and evaluated the effects of X-ray and carbon-ion (C-ion) beams. RESULTS: X-ray irradiation decreased the cell viability in a dose-dependent manner in 2D cultures, whereas this effect was attenuated in 3D spheroid cultures. In contrast, C-ion irradiation demonstrated the same antitumor effect in 3D spheroid cultures as in 2D cultures. In 3D spheroid cultures, X-rays and anticancer drugs are attenuated because of hypoxia inside the spheroids. However, the impact of the C-ion beam was almost the same as that of the 2D culture, because heavy-particle irradiation was not affected by hypoxia. CONCLUSION: These results suggest that heavy-particle radiotherapy may be a new therapeutic strategy for overcoming the resistance of cervical adenocarcinoma to treatment.

Interfractional robustness of scanning carbon ion radiotherapy for prostate cancer: An analysis based on dose distribution from daily in-room CT images.

PURPOSE: We analyzed interfractional robustness of scanning carbon ion radiotherapy (CIRT) for prostate cancer based on the dose distribution using daily in-room computed tomography (CT) images. MATERIALS AND METHODS: We analyzed 11 consecutive patients treated with scanning CIRT for localized prostate cancer in our hospital between December 2015 and January 2016. In-room CT images were taken under treatment conditions in every treatment session. The dose distribution on each in-room CT image was recalculated, while retaining the pencil beam arrangement of the initial treatment plan. Then, the dose-volume histogram (DVH) parameters including the percentage of the clinical target volume (CTV) with 95% and 90% of the prescribed dose area (V95% of CTV, V90% of CTV) and V80% of rectum were calculated. The acceptance criteria for the CTV and rectum were set at V95% of CTV ≥95%, V90% of CTV ≥98%, and V80% of rectum < 10 ml. RESULTS: V95% of CTV, V90% of CTV, and V80% of rectum for the reproduced plans were 98.8 ± 3.49%, 99.5 ± 2.15%, and 4.39 ± 3.96 ml, respectively. Acceptance of V95% of CTV, V90% of CTV, and V80% of rectum was obtained in 123 (94%), 125 (95%) and 117 sessions (89%), respectively. Acceptance of the mean dose of V95% of CTV, V90% of CTV, and V80% of rectum for each patient was obtained in 10 (91%), 10 (91%), and 11 patients (100%), respectively. CONCLUSIONS: We demonstrated acceptable interfractional robustness based on the dose distribution in scanning CIRT for prostate cancer.

External dosimetry audit for quality assurance of carbon-ion radiation therapy clinical trials.

PURPOSE: The QA team of the Japan carbon-ion radiation oncology study group (J-CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon-ion radiation therapy centers in Japan. MATERIALS AND METHODS: A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. RESULTS: For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (-2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. CONCLUSIONS: The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

Planning strategies for robust carbon-ion scanning radiotherapy for stage I esophageal cancer: a retrospective study.

This study aimed to establish a treatment planning strategy with carbon-ion scanning radiotherapy (CIRTs) for stage I esophageal cancer. The clinical data of seven patients treated with CIRTs were used. The setup error and interfractional and intrafractional motion error were analyzed using in-room computed tomography (CT) images for each treatment day. Finally, the planning target volume (PTV) margin was identified according to the accuracy of the treatment system. To ensure robustness against the positional displacements of the target and organs at risk (OAR), the replacement areas were placed as a contour adjacent to the tumor or OAR on the CT-image. The CT values of these areas were replaced by those of the target or OAR. Further, the dose distributions were optimized. Moreover, the variations in the target coverage from the initial plan for each treatment day (ΔV95%) were evaluated. By contrast, the risk of OAR was not evaluated in this study. The setup error was within 1.0 mm. The interfractional and intrafractional target motion errors were 2.8 and 5.0 mm, respectively. The PTV margins were 6.5 and 6.8 mm in the axial and depth directions, respectively. The robustness to target and OAR displacement was evaluated. The results showed that the target coverage with replacement could suppress decreased target coverage more than that without replacement. The PTV determination and replacement methods used in this study improved the target coverage in CIRTs for stage I esophageal cancer. Despite the need for a clinical follow-up, this method may help to improve clinical outcomes.

Induced Radionuclides and Their Activity Concentration in Gel Dosimeters Irradiated by Carbon Ion Beam.

Radioactivity was measured in a micellar gel dosimeter, a polymer gel dosimeter, and water was irradiated by carbon ion beams at various beam energy conditions. Monte Carlo simulation was also performed to estimate the radioactivity. Short-lived positron-emitting nuclides were observed immediately after irradiation, but they decayed rapidly into the background. At 24 h post-irradiation, the dominant measured radioactivity was of 7Be. The simulation also showed minor activity of 24Na and 3H; however, they were not experimentally observed. The measured radioactivity was independent of the type of gel dosimeter under all irradiation conditions, suggesting that the radioactivity was induced by the interaction of carbon ions with water (the main component of the gel dosimeters). The ratio between the simulated and measured radioactivity was within 0.9-1.5. The activity concentration of 7Be was found to be less than 1/10 of the value derived using the exemption concept proposed by the International Atomic Energy Agency. This result should be applicable to irradiated gel dosimeters containing mainly water and 0-4 wt.% C and 0-1.7 wt.% N.

Evaluation of Safety for Scanning Carbon-Ion Radiotherapy in Hemodialysis Patients With Prostate Cancer.

Background/Aim The efficacy and safety of carbon-ion radiotherapy (CIRT) for prostate cancer have already been demonstrated. The number of hemodialysis (HD) patients is increasing. Although the toxicity of CIRT in HD patients may be more severe, it has been insufficiently investigated. Therefore, we retrospectively analyzed the safety of CIRT for HD patients with prostate cancer in the present study. Materials and methods Five HD patients with prostate cancer who underwent CIRT at the Kanagawa Cancer Center during November 2015-2020 were included in this study. CIRT was delivered by the raster scanning method (sCIRT). Adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0. The dose-volume histogram (DVH) parameters of the target volume and normal organs were evaluated between initial planning computed tomography (CT) and in-room CT images. Results In the acute phase, Grade 1 genitourinary toxicity was recorded in one patient. In the late phase, Grade 1 genitourinary toxicity was recorded in two patients. No gastrointestinal toxicities were noted during the follow-up period. In-room CT analysis revealed no significant differences among all DVH parameters of the target volume and normal organs when compared with the treatment plan dose. Conclusions The safety of sCIRT for prostate cancer in HD patients was investigated in the present study. In-room CT analysis suggested the robustness of the treatment plan. According to the present results, sCIRT for prostate cancer can be safely performed in HD patients.

Robust treatment planning in scanned carbon-ion radiotherapy for pancreatic cancer: Clinical verification using in-room computed tomography images.

Purpose: Carbon-ion beam (C-beam) has a sharp dose distribution called the Bragg peak. Carbon-ion radiation therapy, such as stereotactic body radiotherapy in photon radiotherapy, can be completed in a short period by concentrating the radiation dose on the tumor while minimizing the dose to organs at-risk. However, the stopping position of C-beam is sensitive to density variations along the beam path and such variations can lower the tumor dose as well as cause the delivery of an unexpectedly high dose to the organs at risk. We evaluated the clinical efficacy of a robust planning technique considering gastrointestinal gas (G-gas) to deliver accurate radiation doses in carbon-ion radiotherapy for pancreatic cancer. Materials and methods: We focused on the computed tomography (CT) value replacement method. Replacement signifies the overwriting of CT values in the CT images. The most effective replacement method for robust treatment planning was determined by verifying the effects of the three replacement patterns. We selected 10 consecutive patients. Pattern 1 replaces the CT value of the G-gas contours with the value of the region without G-gas (P1). This condition indicates a no-gas state. Pattern 2 replaces each gastrointestinal contour using the mean CT value of each contour (P2). The effect of G-gas was included in the replacement value. Pattern 3 indicates no replacement (P3). We analyzed variations in the target coverage (TC) and homogeneity index (HI) from the initial plan using in-room CT images. We then performed correlation analysis on the variations in G-gas, TC, and HI to evaluate the robustness against G-gas. Results: Analysis of variations in TC and HI revealed a significant difference between P1 and P3 and between P2 and P3. Although no statistically significant difference was observed between P1 and P2, variations, including the median, tended to be fewer in P2. The correlation analyses for G-gas, TC, and HI showed that P2 was less likely to be affected by G-gas. Conclusion: For a treatment plan that is robust to G-gas, P2 mean replacement method should be used. This method does not necessitate any particular software or equipment, and is convenient to implement in clinical practice.

Comparison of Dose Distribution Between VMAT-SBRT and Scanning Carbon-ion Radiotherapy for Early-stage NSCLC.

BACKGROUND/AIM: The purpose of this study was to compare the dose distribution between scanning carbon-ion radiotherapy (sCIRT) and volumetric-modulated arc therapy with stereotactic body radiation therapy (VMAT-SBRT) for stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with early-stage NSCLC who underwent sCIRT at Kanagawa Cancer Center between 2018-2020 were enrolled. Dose-volume histogram parameters of the planned target volume and normal organs for sCIRT and VMAT-SBRT were evaluated. RESULTS: The homogeneity index of the target volume of sCIRT was significantly lower than that of VMAT-SBRT. The dose of sCIRT was significantly lower than that of VMAT-SBRT at low volumes in the lung, heart, spinal cord, and esophagus. CONCLUSION: The dose distribution of sCIRT for early-stage NSCLC was better than that of VMAT-SBRT.

Dosimetric Comparison Between Carbon-ion Radiotherapy and Photon Radiotherapy for Stage I Esophageal Cancer.

BACKGROUND/AIM: The present study aimed to compare the radiation dose distribution of carbon-ion radiotherapy (CIRT) for stage I esophageal cancer with three-dimensional conformal radiotherapy (3DCRT) and volumetric modulated arc therapy (VMAT). PATIENTS AND METHODS: Fifteen patients with cT1bN0M0 esophageal cancer who received 3DCRT at Kanagawa Cancer Center between January 2014 and April 2019 were enrolled. The dose-volume histogram parameters of the target volume and normal organs planned with CIRT, 3DCRT, and VMAT were evaluated. RESULTS: The homogeneity index for the target volume of CIRT was significantly lower than that of 3DCRT and VMAT. In addition, the radiation dose of CIRT to the heart, lungs, spinal cord, and skin was significantly lower than that of 3DCRT and VMAT. CONCLUSION: Favorable dose distributions with CIRT were demonstrated compared with 3DCRT and VMAT for esophageal cancer.

Performance of the NIRS fast scanning system for heavy-ion radiotherapy.

PURPOSE: A project to construct a new treatment facility, as an extension of the existing HIMAC facility, has been initiated for the further development of carbon-ion therapy at NIRS. This new treatment facility is equipped with a 3D irradiation system with pencil-beam scanning. The challenge of this project is to realize treatment of a moving target by scanning irradiation. To achieve fast rescanning within an acceptable irradiation time, the authors developed a fast scanning system. METHODS: In order to verify the validity of the design and to demonstrate the performance of the fast scanning prior to use in the new treatment facility, a new scanning-irradiation system was developed and installed into the existing HIMAC physics-experiment course. The authors made strong efforts to develop (1) the fast scanning magnet and its power supply, (2) the high-speed control system, and (3) the beam monitoring. The performance of the system including 3D dose conformation was tested by using the carbon beam from the HIMAC accelerator. RESULTS: The performance of the fast scanning system was verified by beam tests. Precision of the scanned beam position was less than +/-0.5 mm. By cooperating with the planning software, the authors verified the homogeneity of the delivered field within +/-3% for the 3D delivery. This system took only 20 s to deliver the physical dose of 1 Gy to a spherical target having a diameter of 60 mm with eight rescans. In this test, the average of the spot-staying time was considerably reduced to 154 micros, while the minimum staying time was 30 micros. CONCLUSIONS: As a result of this study, the authors verified that the new scanning delivery system can produce an accurate 3D dose distribution for the target volume in combination with the planning software.

A proposal of an open PET geometry.

The long patient port of a PET scanner tends to put stress on patients, especially patients with claustrophobia. It also prevents doctors and technicians from taking care of patients during scanning. In this paper, we proposed an 'open PET' geometry, which consists of two axially separated detector rings. A long and continuous field-of-view (FOV) including a 360 degrees opened gap between two detector rings can be imaged enabling a fully 3D image reconstruction of all the possible lines-of-response. The open PET will become practical if iterative image reconstruction methods are applied even though image reconstruction of the open PET is analytically an incomplete problem. First we implemented a 'masked' 3D ordered subset expectation maximization (OS-EM) in which the system matrix was obtained from a long 'gapless' scanner by applying a mask to detectors corresponding to the open space. Next, in order to evaluate imaging performance of the proposed open PET geometry, we simulated a dual HR+ scanner (ring diameter of D = 827 mm, axial length of W = 154 mm x 2) separated by a variable gap. The gap W was the maximum limit to have axially continuous FOV of 3W though the maximum diameter of FOV at the central slice was limited to D/2. Artifacts, observed on both sides of the open space when the gap exceeded W, were effectively reduced by inserting detectors partially into unnecessary open spaces. We also tested the open PET geometry using experimental data obtained by the jPET-D4. The jPET-D4 is a prototype brain scanner, which has 5 rings of 24 detector blocks. We simulated the open jPET-D4 with a gap of 66 mm by eliminating 1 block-ring from experimental data. Although some artifacts were seen at both ends of the opened gap, very similar images were obtained with and without the gap. The proposed open PET geometry is expected to lead to realization of in-beam PET, which is a method for an in situ monitoring of charged particle therapy, by letting the beams pass through the gap. The proposed open PET geometry will also allow simultaneous PET/CT measurements of the same PET FOV as the CT FOV, in contrast to the conventional PET/CT where each FOV is separated by several tens of centimeters.

Design study of a raster scanning system for moving target irradiation in heavy-ion radiotherapy.

A project to construct a new treatment facility as an extension of the existing heavy-ion medical accelerator in chiba (HIMAC) facility has been initiated for further development of carbon-ion therapy. The greatest challenge of this project is to realize treatment of a moving target by scanning irradiation. For this purpose, we decided to combine the rescanning technique and the gated irradiation method. To determine how to avoid hot and/or cold spots by the relatively large number of rescannings within an acceptable irradiation time, we have studied the scanning strategy, scanning magnets and their control, and beam intensity dynamic control. We have designed a raster scanning system and carried out a simulation of irradiating moving targets. The result shows the possibility of practical realization of moving target irradiation with pencil beam scanning. We describe the present status of our design study of the raster scanning system for the HIMAC new treatment facility.

Carbon ion therapy for ocular melanoma: planning orthogonal two-port treatment.

We recently started orthogonal two-port carbon ion therapy for choroidal melanoma with the intent to reduce the incidence of radiation complications that occur with mono-port therapy. Treatment planning techniques involving therapeutic beam characteristics are described here. The vertical (140 MeV/u) and horizontal (170 MeV/u) carbon ion beams from the synchrotron at the NIRS were shaped, using the passive beam delivery system, to irradiate the target volume. The range modulating ridge filters were designed to produce spread-out Bragg peaks (SOBPs) with a region of uniform HMV-I cell killing. The apertures and range compensators were designed for individual patients. A commercial treatment planning system, which was customized to our general carbon ion therapy, was tested for applicability to this treatment. Dose distributions were calculated with either a broad beam or a pencil beam algorithm using parameters determined by measurements and calculations. We evaluated the accuracy of the system software features, and replaced or added some other features to the software. The system was used for 12 patients during the past year. For nine patients two-port treatment was assessed to be more effective than mono-port therapy and these patients were treated with two fractions of vertical beams and three fractions of horizontal beams.

Three-dimensional velocity mapping of lung motion using vessel bifurcation pattern matching.

We present a new quantification technique for three-dimensional (3D) lung motion by means of tracking the anatomical features inside the lung using a set of sequential 3D-CT images (a 4D-CT image). The method is based on the conservation of topology, such as connections and junctions of vessels, during the motion. Lung CT images are used to do lung volume modeling, lung vessel extracting and thinning, and coordinates of vessel bifurcations are derived as feature points. Such feature points are tracked in a series of 3D-CT images, i.e., the points are individually tracked between two successive 3D-CT images, in which the lung is deformed. Consequently, 3D displacement vectors are obtained. The feature point tracking is carried out using point pattern matching with a probabilistic relaxation method. We examined this technique using a lung 3D-CT image and artificially deformed one, and separately scanned CT images for a rigid bifurcation phantom. The studies estimated that the error of the vectors is within approximately 1 voxel, i.e., 1 mm or less. Therefore, the accuracy is expected to be high enough for radiation therapy. This technique enables us to quantify realistic 3D organ motion without any fiducial markers. It can be applied to the quantification of tumor (target volume) deformation by gridding interpolation into all voxels. We expect it to be useful for dose estimation in mobile organs and for 4D treatment planning in radiation therapy.

Commissioning of a conformal irradiation system for heavy-ion radiotherapy using a layer-stacking method.

The commissioning of conformal radiotherapy system using heavy-ion beams at the Heavy Ion Medical Accelerator in Chiba (HIMAC) is described in detail. The system at HIMAC was upgraded for a clinical trial using a new technique: large spot uniform scanning with conformal layer stacking. The system was developed to localize the irradiation dose to the target volume more effectively than with the old system. With the present passive irradiation method using a ridge filter, a scatterer, a pair of wobbler magnets, and a multileaf collimator, the width of the spread-out Bragg peak (SOBP) in the radiation field could not be changed. With dynamic control of the beam-modifying devices during irradiation, a more conformal radiotherapy could be achieved. In order to safely perform treatments with this conformal therapy, the moving devices should be watched during irradiation and the synchronousness among the devices should be verified. This system, which has to be safe for patient irradiations, was constructed and tested for safety and for the quality of the dose localization realized. Through these commissioning tests, we were successfully able to prepare the conformal technique using layer stacking for patients. Subsequent to commissioning the technique has been applied to patients in clinical trials.

Estimating uncertainties of the geometrical range of particle radiotherapy during respiration.

PURPOSE: To propose a method for estimating uncertainties of the range calculation in particle radiotherapy associated with patient respiration. MATERIALS AND METHODS: A set of sequential CT images at every 0.2 s was reconstructed from continuous X-ray projection data accumulated by dynamic helical scanning. At the same time that CT data was acquired, the respiratory signal of the patient and the X-ray on/off signal on CT scanner were recorded. Each CT image was timed according to the phase of respiration waveform. Conversion of the CT number to the water equivalent path length (WEL) was performed with our treatment planning system that included a conversion table. As an illustration, the CT images of a patient with liver cancer at the right upper lobe were analyzed. The geometric size of the liver and WELs from body surface to isocenter were measured in each CT image. RESULTS: Variations of WEL from body surface to isocenter at the anterior-posterior and posterior-anterior direction were 6.2 mm and 18.9 mm, respectively. Liver size changed by 35.2 mm. However, these variations were shown to be considerably reduced by gated irradiation. CONCLUSIONS: A method using sequential CT images with respiration waveform was proposed. It appeared to be useful in evaluating the uncertainties of the range calculation associated with patient breathing.

A CT calibration method based on the polybinary tissue model for radiotherapy treatment planning.

A method to establish the relationship between CT number and effective density for therapeutic radiations is proposed. We approximated body tissues to mixtures of muscle, air, fat and bone. Consequently, the relationship can be calibrated only with a CT scan of their substitutes, for which we chose water, air, ethanol and potassium phosphate solution, respectively. With simple and specific corrections for non-equivalencies of the substitutes, a calibration accuracy of 1% will be achieved. We tested the calibration method with some biological materials to verify that the proposed method would offer the accuracy, simplicity and specificity required for a standard in radiotherapy treatment planning, in particular with heavy charged particles.

A new method for tracking organ motion on diagnostic ultrasound images.

PURPOSE: Respiratory-gated irradiation is effective in reducing the margins of a target in the case of abdominal organs, such as the liver, that change their position as a result of respiratory motion. However, existing technologies are incapable of directly measuring organ motion in real-time during radiation beam delivery. Hence, the authors proposed a novel quantitative organ motion tracking method involving the use of diagnostic ultrasound images; it is noninvasive and does not entail radiation exposure. In the present study, the authors have prospectively evaluated this proposed method. METHODS: The method involved real-time processing of clinical ultrasound imaging data rather than organ monitoring; it comprised a three-dimensional ultrasound device, a respiratory sensing system, and two PCs for data storage and analysis. The study was designed to evaluate the effectiveness of the proposed method by tracking the gallbladder in one subject and a liver vein in another subject. To track a moving target organ, the method involved the control of a region of interest (ROI) that delineated the target. A tracking algorithm was used to control the ROI, and a large number of feature points and an error correction algorithm were used to achieve long-term tracking of the target. Tracking accuracy was assessed in terms of how well the ROI matched the center of the target. RESULTS: The effectiveness of using a large number of feature points and the error correction algorithm in the proposed method was verified by comparing it with two simple tracking methods. The ROI could capture the center of the target for about 5 min in a cross-sectional image with changing position. Indeed, using the proposed method, it was possible to accurately track a target with a center deviation of 1.54±0.9 mm. The computing time for one frame image using our proposed method was 8 ms. It is expected that it would be possible to track any soft-tissue organ or tumor with large deformations and changing cross-sectional position using this method. CONCLUSIONS: The proposed method achieved real-time processing and continuous tracking of the target organ for about 5 min. It is expected that our method will enable more accurate radiation treatment than is the case using indirect observational methods, such as the respiratory sensor method, because of direct visualization of the tumor. Results show that this tracking system facilitates safe treatment in clinical practice.