Dose Distribution Degradation of Carbon-ion Radiotherapy Caused by Tumor Cell-specific Relative Biological Effectiveness of Osteosarcoma: A Simulation Study Using In Vitro Experimental Results.

BACKGROUND/AIM: Dose distributions of carbon-ion radiotherapy (C-ion RT) have been created with the relative biological effectiveness (RBE) of human salivary gland cells (HSG). However, no dose distributions have been created using various tumor cell-specific RBE values. Hence, we conducted in vitro experiments to determine the RBE of human osteosarcoma cells (U2OS) and used this RBE value (RBEU2OS) to calculate the dose distribution for C-ion RT. MATERIALS AND METHODS: To obtain RBE values for various linear energy transfer (LET) levels, we exposed U2OS cells to different doses of X-rays and varying doses and LET levels of C-ion beams (13, 30, 50, and 70 keV/µm). Subsequently, we converted the RBE of HSG (RBEHSG) to RBEU2OS in the treatment planning system and reconstructed the dose distribution for a typical osteosarcoma case. We performed a dose-volume histogram (DVH) analysis, evaluating the percentage of the minimum dose that covered 98%, 50%, and 2% (D98%, D50%, and D2%, respectively), as well as the homogeneity index [HI; calculated as (D2%-D98%)/D50%]. RESULTS: The RBEU2OS values for C-ion beams with LET of 13, 30, 50, and 70 keV/µm were 1.77, 2.25, 2.72, and 4.50, respectively. When comparing DVH parameters with the planning target volume, we observed the following values: D98%, D50%, D2%, and HI for RBEHSG were 64.1, 70.1, 72.4 Gy (RBE), and 0.12, respectively. For RBEU2OS, these values were 86.2, 95.0, 107.9 Gy (RBE), and 0.23, respectively. CONCLUSION: We utilized RBEU2OS to calculate the dose distribution of carbon ion radiotherapy, revealing potential degradation in dose distribution and particularly worsening of the HI.

Assessment of a self-inspection method and reporting measured electrometer correction factors for reference-class electrometers in radiotherapy.

BACKGROUND AND PURPOSE: The standard dosimetry system of medical accelerators in radiotherapy consists of an ionization chamber, an electrometer, and cables. Guidance for TG-51 reference dosimetry reported that the electrometer correction factor (Pelec ) should be checked every few years. Therefore, continuous Pelec measurements have not been reported. The purpose of this study is to measure the Pelec with a charge generator at our institution and to evaluate variations over time. The measurements are compared with calibration data given by an Accredited Dosimetry Calibration Laboratory (ADCL). MATERIALS AND METHODS: We used four reference-class electrometers: RT521R (RTQM system/EMF Japan), Model 35040 (FLUKE), RAMTEC Duo (Toyo medic), and UNIDOS-E (PTW). Each electrometer was connected to the charge generator, and the required charge was applied. The measurement points used were the same as those used for calibration by the ADCL. From the measured charges at each point, the Pelec was obtained from the slope of the linear regression function. The measurements were repeated over a 3-month period to evaluate variations over time for each electrometer. Additionally, error budgets for the Pelec measurements were estimated, and the overall uncertainty was determined. RESULTS: The measured Pelec values were 1.0000, 0.9995, 1.0009/0.9999, and 0.9995/0.9998 for RT521R, Model 35040, the low/medium (L/M) ranges of RAMTEC Duo, and the L/M ranges of UNIDOS-E, respectively. The measured Pelec values agreed within 0.1% with those given by the ADCL. We found a small drift in the measurements for one electrometer. Additionally, the uncertainty considered was 0.26% for k = 2 (k, coverage factor). CONCLUSION: In this study, stable Pelec values were obtained for four electrometers using a charge generator over a three-month period. The measured Pelec values were within the overall uncertainty stated in the electrometer guidelines. However, performing periodic measurements for the Pelec was able to help in detecting small errors.

Linear energy transfer-independent calibration of radiochromic film for carbon-ion beams.

For carbon-ion beams, radiochromic film response depends on the dose and linear energy transfer (LET). For film dosimetry, we developed an LET-independent simple calibration method for a radiochromic film for specific therapeutic carbon-ion beams. The measured film doses were calibrated with a linear function within 5% error. The penumbra positions of the films were consistent with the differences from the planned ones within ~0.4 mm. The results indicated sufficient accuracy for use as a tool for the confirmation of the penumbra position of the fields.

An adaptive planning strategy in carbon ion therapy of pancreatic cancer involving beam angle selection.

BACKGROUND AND PURPOSE: In carbon-ion radiotherapy for pancreatic cancer, altered dose distributions due to changes in the gastrointestinal gas volume and anatomy during irradiation are an unresolved therapeutic issue. We developed and investigated an adaptive strategy involving beam angle selection to improve dose distributions in pancreatic cancer. MATERIALS AND METHODS: In the adaptive strategy, multiple beams were prepared with angles similar to those of the conventional strategy, and the beam that best reproduces the dose distribution of the treatment plan was used. The dose distributions of the adaptive strategy were compared with those of the conventional strategy for five patients. Patients underwent computed tomography (CT) before every irradiation. The adaptive strategy was evaluated using the same irradiation schedule as that of the conventional method and an adjusted method based on anatomical changes per fraction. Dose distributions on the pre-treatment CT and accumulated dose distributions on the treatment planning CT were evaluated using the volume receiving ≥95% of the prescription dose (V95) from the clinical target volume (CTV) between strategies. RESULTS: There were significant differences in the CTV V95 values for the pre-treatment CT between all strategies. The median (range) CTV V95 for the conventional strategy was 92.7% (87.1-96.1%), for the proposed adaptive strategy without adjusted schedules was 96.9% (95.1-97.8%), and for the proposed strategy with adjusted schedules was 97.8% (96.5-99.2%). CONCLUSIONS: The adaptive strategy can improve target coverage for the pre-treatment CT and accumulated dose distributions for the treatment planning CT without increasing the dose to critical organs.

Evaluation of Threshold Dose of Damaged Hepatic Tissue After Carbon-Ion Radiation Therapy Using Gd-EOB-DTPA-Enhanced Magnetic Resonance Imaging.

PURPOSE: To evaluate the threshold dose and associated factors using signal-intensity changes in the irradiated area after carbon-ion radiation therapy (C-ion RT) for patients with liver cancer. METHODS AND MATERIALS: Patients treated for the first time with C-ion RT for malignant liver tumors and followed up with 3-Tesla gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) 3 months after treatment completion were retrospectively enrolled. The volume of focal liver reaction (FLR), a low-intensity area in the hepatobiliary phase of Gd-EOB-DTPA after treatment, was measured. Corrected FLR (cFLR) volume, defined as FLR corrected for changes in tumor volume from before to after treatment, was calculated, and the threshold dose was determined by applying the cFLR volume in the dose-volume histogram. To evaluate potential mismatch in fusion images of planning computed tomography and follow-up MRI, the concordance coefficient (CC) was measured, and patients with a CC < 0.7 were excluded. Sixty patients were included. Multiple regression analysis was performed with the threshold dose as the objective variable and the age, dose, number of fractionations, Child-Pugh score, pretreatment liver volume, and pretreatment tumor volume as explanatory variables. The Student t test or Mann-Whitney U test was used as required. RESULTS: The median threshold doses for each number of dose fractionations (4 fractions, 12 fractions, and overall) were 51.6, 51.9, and 51.8 Gy (relative biological effectiveness [RBE]), respectively, in patients categorized as Child-Pugh class A and 27.0, 28.8, and 27.0 Gy (RBE), respectively, in patients categorized as Child-Pugh class B. In the multiple-regression analysis, only the Child-Pugh score was significant (P < .001). The number of dose fractionations was not statistically significant. CONCLUSIONS: Although few patients in the study had decreased liver function, baseline liver function was the only factor significantly associated with the median threshold dose. These findings facilitate appropriate patient selection to receive C-ion RT for malignant hepatic tumors.

Carbon ion radiotherapy for patients with hepatocellular carcinoma in the caudate lobe carbon ion radiotherapy for hepatocellular carcinoma in caudate lobe.

AIM: The treatment of hepatocellular carcinoma in the caudate lobe (HCCCL) is technically challenging. We aimed to investigate the efficacy and toxicity of carbon ion radiotherapy (C-ion RT) for HCCCL. METHODS: Patients with HCCCL treated with C-ion RT at our hospital between January 2011 and December 2018 were evaluated. The total dose was 52.8 or 60 Gy (relative biological effectiveness) in four or 12 fractions depending on the distance between the tumor and the gastrointestinal tract. The survival outcome, the presence or absence of recurrence (local recurrence, intrahepatic recurrence outside the irradiation field, or extrahepatic recurrence), and acute/late adverse events were evaluated. RESULTS: Nine patients were included. The median tumor size was 3.4 cm, and the median follow-up duration was 18.3 months for all patients. No patient developed local recurrence during follow-up. Five patients subsequently developed intrahepatic recurrence outside the irradiation field and two had extrahepatic metastasis. Five patients died of hepatocellular carcinoma. No acute adverse events of grade ≥2 were observed. Two patients experienced grade 2 or 3 late adverse events, including obstructive jaundice, hepatic encephalopathy, ascites, and edema. CONCLUSION: Carbon ion radiotherapy for HCCCL achieved excellent local control with acceptable adverse events and can thus be a curative treatment option for HCCCL.

Simultaneous determination of the dose and linear energy transfer (LET) of carbon-ion beams using radiochromic films.

Radiochromic films are useful as dosimeters in high-precision radiotherapy owing to their high spatial resolution. However, when a particle beam is measured using a radiochromic film, the dose cannot be estimated accurately because the film darkness varies with variations in linear energy transfer (LET). This paper proposes a novel method for estimating the LET and the dose based on the film darkness. In this method, after a high-LET particle beam, such as a carbon-ion beam, was incident on the film, the film was digitized and its net optical density was determined. Further, the non-linearity of the film response curve between the dose and the darkness, depending on LET, was used. Then, calibration curves were created using 290 MeV u-1 mono energetic carbon-ion beams. We used LETs of 20, 50, 100, and 150 keV µm-1 and a physical dose of 2-14 Gy. The calibration curves were approximated for each LET using a quadratic function. The correlations between the coefficients of the quadratic function and the LET were also obtained. To verify the proposed method, the films were irradiated under 12 different conditions corresponding to various depths and doses. Four depths of -2, -5, -10, and -20 mm with respect to the Bragg peak, and three different preset values were used for the film measurements. The films were analyzed in four groups, where each group comprised films irradiated at the same depth. The LETs obtained from the film analysis, ordered from the upstream of the beam, were 20, 41, 56, and 97 keV µm-1, and the doses for the lowest preset value were 3.95, 4.07, 4.03, and 3.99 Gy for the four groups. The LETs obtained from the film analysis increased toward the Bragg peak, and the doses measured in the ionization chamber were almost equal to 4 Gy.

Comparison of Dose Distributions When Using Carbon Ion Radiotherapy Versus Intensity-modulated Radiotherapy for Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Retrospective Analysis.

BACKGROUND/AIM: This study compared the dose distributions of carbon ion radiotherapy (C-ion RT) and intensity-modulated radiotherapy (IMRT) in patients with locally advanced hepatocellular carcinoma (LAHCC). PATIENTS AND METHODS: A retrospective analysis was conducted in 10 consecutive patients with LAHCC who had undergone C-ion RT. The dose-volume histogram parameters of clinical plans using C-ion RT at 60 Gy and simulated plans using IMRT at 60 Gy and 50 Gy were compared. We measured the percentage of the normal liver volume that received at least 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), 30 Gy (V30), 40 Gy (V40), and 50 Gy (V50). RESULTS: The V5, V10, V20, and the mean liver dose were significantly lower in patients who received 60 Gy of C-ion RT than in those who received 50 or 60 Gy of IMRT. CONCLUSION: C-ion RT exhibits a better liver dose distribution than IMRT in patients with LAHCC.

Development of a Vaginal Immobilization Device: A Treatment-planning Study of Carbon-ion Radiotherapy and Intensity-modulated Radiation Therapy for Uterine Cervical Cancer.

AIM: We developed a vaginal immobilization device for external radiotherapy in gynaecological malignancies and evaluated its bowel dose-reduction effect during carbon-ion radiotherapy (CIRT) and intensity-modulated radiation therapy (IMRT) in patients with cervical cancer. PATIENTS AND METHODS: Computed tomographic images obtained with and without the device in seven patients with cervical cancer were assessed. Treatment plans for CIRT and IMRT were generated, and dose-volume parameters (V20, V25, V35, and D2cc) of the rectum, sigmoidal colon, and bladder were evaluated. RESULTS: The mean±standard deviation of the rectal volume in CIRT for V35 with and without the device were 2.1±2.1 and 13.6±4.4 ml, respectively, and those in IMRT were 2.0±2.2 and 13.7±3.8 ml, respectively; these values were significantly lower in CIRT and IMRT using this device. CONCLUSION: Using our novel vaginal immobilization device, high rectal doses were largely reduced in CIRT and IMRT.

[Dose Distribution Optimization in Combined Intracavitary and Interstitial Brachytherapy for Cervical Cancer].

PURPOSE: Hybrid inverse treatment planning optimization (HIPO) is a new optimization tool for brachytherapy. We verified its utility using treatment plans for combined intracavitary and interstitial brachytherapy in cervical cancer. MATERIALS & METHODS: We compared the manually optimized plan and the plan optimized using HIPO. The plan using HIPO was optimized with three different methods: needle only, tandem and needle, and all applicators. The dose volume histogram (DVH) parameters such as D90 of high risk clinical target volume (HR-CTV) and D2cc of OAR (rectum, sigmoid colon and bladder) were used to evaluate each treatment plan. RESULTS: The D90 of HR-CTV in most plans was received more than 600 cGy. In addition, the D2cc of OAR also was less than the tolerance dose on the average of all plans. However, the D2cc of the rectum and bladder treatment plans optimized only with needles was significantly higher than other plans. CONCLUSIONS: The treatment plans used in clinical practice and obtained by HIPO have similar dose distributions and DVH parameters. Moreover, the time needed to create treatment plan was reducing by HIPO. We suggest that HIPO will be an effective tool in treatment planning.

The Impact of the Grid Size on TomoTherapy for Prostate Cancer.

Discretization errors due to the digitization of computed tomography images and the calculation grid are a significant issue in radiation therapy. Such errors have been quantitatively reported for a fixed multifield intensity-modulated radiation therapy using traditional linear accelerators. The aim of this study is to quantify the influence of the calculation grid size on the dose distribution in TomoTherapy. This study used ten treatment plans for prostate cancer. The final dose calculation was performed with "fine" (2.73 mm) and "normal" (5.46 mm) grid sizes. The dose distributions were compared from different points of view: the dose-volume histogram (DVH) parameters for planning target volume (PTV) and organ at risk (OAR), the various indices, and dose differences. The DVH parameters were used Dmax, D2%, D2cc, Dmean, D95%, D98%, and Dmin for PTV and Dmax, D2%, and D2cc for OARs. The various indices used were homogeneity index and equivalent uniform dose for plan evaluation. Almost all of DVH parameters for the "fine" calculations tended to be higher than those for the "normal" calculations. The largest difference of DVH parameters for PTV was Dmax and that for OARs was rectal D2cc. The mean difference of Dmax was 3.5%, and the rectal D2cc was increased up to 6% at the maximum and 2.9% on average. The mean difference of D95% for PTV was the smallest among the differences of the other DVH parameters. For each index, whether there was a significant difference between the two grid sizes was determined through a paired t-test. There were significant differences for most of the indices. The dose difference between the "fine" and "normal" calculations was evaluated. Some points around high-dose regions had differences exceeding 5% of the prescription dose. The influence of the calculation grid size in TomoTherapy is smaller than traditional linear accelerators. However, there was a significant difference. We recommend calculating the final dose using the "fine" grid size.

Clinical outcomes using carbon-ion radiotherapy and dose-volume histogram comparison between carbon-ion radiotherapy and photon therapy for T2b-4N0M0 non-small cell lung cancer-A pilot study.

The safety and efficacy of carbon-ion radiotherapy for advanced non-small cell lung cancer have not been established. We evaluated the clinical outcomes and dose-volume histogram parameters of carbon-ion radiotherapy compared with photon therapy in T2b-4N0M0 non-small cell lung cancer. Twenty-three patients were treated with carbon-ion radiotherapy between May 2011 and December 2015. Seven, 14, and 2 patients had T2b, T3, and T4, respectively. The median age was 78 (range, 53-91) years, with 22 male patients. There were 12 adenocarcinomas, 8 squamous cell carcinomas, 1 non-small cell lung carcinoma, and 2 clinically diagnosed lung cancers. Eleven patients were operable, and 12 patients were inoperable. Most patients (91%) were treated with carbon-ion radiotherapy of 60.0 Gy relative biological effectiveness (RBE) in 4 fractions or 64.0 Gy (RBE) in 16 fractions. Local control and overall survival rates were calculated. Dose-volume histogram parameters of normal lung and tumor coverages were compared between carbon-ion radiotherapy and photon therapies, including three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The median follow-up of surviving patients was 25 months. Three patients experienced local recurrence, and the 2-year local control rate was 81%. During follow-up, 5 patients died of lung cancer, and 1 died of intercurrent disease. The 2-year overall survival rate was 70%. Operable patients had a better overall survival rate compared with inoperable patients (100% vs. 43%; P = 0.04). There was no grade ≥2 radiation pneumonitis. In dose-volume histogram analysis, carbon-ion radiotherapy had a significantly lower dose to normal lung and greater tumor coverage compared with photon therapies. Carbon-ion radiotherapy was effectively and safely performed for T2b-4N0M0 non-small cell lung cancer, and the dose distribution was superior compared with those for photon therapies. A Japanese multi-institutional study is ongoing to prospectively evaluate these patients and establish the use of carbon-ion radiotherapy.

Dosimetric analysis between carbon ion radiotherapy and stereotactic body radiotherapy in stage I lung cancer.

AIM: To evaluate dosimetric differences between carbon ion radiotherapy (C-ion RT) and stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirteen stage I NSCLC cases were planned with C-ion RT and SBRT. Prescription of the dose and fractionation (fr) for stage IA and IB in C-ion RT were 52.8 Gy (RBE)/4fr and 60.0 Gy (RBE)/4fr, respectively and those in SBRT were 52.8 Gy/4fr and 60.0 Gy/4fr, respectively. RESULTS: The conformity index (CI) for planning target volume of C-ion RT was significantly lower than that of SBRT. The normal lung doses in C-ion RT were significantly lower those that in SBRT. In particularly, for a larger tumor, C-ion RT was lower CI and normal lung dose than SBRT. CONCLUSION: C-ion RT has an advantage in both target conformity and sparing of normal lung in stage I NSCLC.

Comparison of hypofractionated and conventionally fractionated whole-breast irradiation for early breast cancer patients: a single-institute study of 1,098 patients.

PURPOSE: To evaluate the efficacy and safety of hypofractionated whole-breast irradiation (HF-WBI) compared with conventionally fractionated (CF) WBI. MATERIALS AND METHODS: Patients with early breast cancer (stages 0-II and <3 positive lymph nodes) who had undergone breast-conserving surgery were eligible for the HF-WBI study. HF-WBI was administered at 43.2 Gy in 16 fractions over 3.2 weeks to the whole breast with an additional tumor-bed boost of 8.1 Gy in 3 fractions over 3 days for positive surgical margins or those <5 mm. CF-WBI was administered at 50 Gy in 25 fractions over 5 weeks to the whole breast with an additional tumor-bed boost of 16 Gy in 8 fractions over 1.4 weeks to 6 Gy in 3 fractions over 3 days, depending on margin status. RESULTS: From April 1, 2006, to December 31, 2010, 717 patients were registered and 734 breasts were treated by HF-WBI. In the same period, 381 patients and 393 breasts who matched the study criteria chose CF-WBI, so the total number of patients in this comparison was 1,098. Grade 2 acute skin reactions were observed for 24 patients (3 %) in the HF-WBI group and 53 patients (14 %) in the CF-WBI (p < 0.001) group. The median follow-up period was 27 months. Two cases of intrabreast tumor recurrence were observed in each treatment group. Regional lymph node recurrence was observed in 1 HF-WBI patient and 2 CF-WBI patients. CONCLUSION: HF-WBI is superior to CF-WBI in terms of acute skin reaction and has the same short-term efficacy.

Comparison of total MU and segment areas in VMAT and step-and-shoot IMRT plans.

We compared treatment plans for volumetric intensity-modulated arc therapy (VMAT) and step-and-shoot intensity-modulated radiation therapy (IMRT) in terms of their monitor unit (MU) and segment area at each control point to investigate the difference between the two methods. We investigated three sites: prostate (three cases), head and neck (three cases), and pleura (two cases). We used the total MU and the MU weighted average of segment area (MWSA) in each plan to compare VMAT and IMRT plans. VMAT plans tended to have a larger MWSA and a lower total MU than did IMRT plans in all sites, although there was little difference between dose indices in either irradiation technique. We conclude that VMAT is a better treatment technique due to its higher MU efficiency caused by the larger segment area.