Investigation of ionization chamber perturbation factors using proton beam and Fano cavity test for the Monte Carlo simulation code PHITS.

The reference dose for clinical proton beam therapy is based on ionization chamber dosimetry. However, data on uncertainties in proton dosimetry are lacking, and multifaceted studies are required. Monte Carlo simulations are useful tools for calculating ionization chamber dosimetry in radiation fields and are sensitive to the transport algorithm parameters when particles are transported in a heterogeneous region. We aimed to evaluate the proton transport algorithm of the Particle and Heavy Ion Transport Code System (PHITS) using the Fano test. The response of the ionization chamber f Q and beam quality correction factors k Q were calculated using the same parameters as those in the Fano test and compared with those of other Monte Carlo codes for verification. The geometry of the Fano test consisted of a cylindrical gas-filled cavity sandwiched between two cylindrical walls. f Q was calculated as the ratio of the absorbed dose in water to the dose in the cavity in the chamber. We compared the f Q calculated using PHITS with that of a previous study, which was calculated using other Monte Carlo codes (Geant4, FULKA, and PENH) under similar conditions. The flight mesh, a parameter for charged particle transport, passed the Fano test within 0.15%. This was shown to be sufficiently accurate compared with that observed in previous studies. The f Q calculated using PHITS were 1.116 ± 0.002 and 1.124 ± 0.003 for NACP-02 and PTW-30013, respectively, and the k Q were 0.981 ± 0.008 and 1.027 ± 0.008, respectively, at 150 MeV. Our results indicate that PHITS can calculate the f Q and k Q with high precision.

Impact of Dose Perturbations Around Brachytherapy Seeds in External-Beam Radiotherapy Planning: A Fundamental and Clinical Validation Using Treatment Planning System-Based Monte Carlo Simulations.

Background This study evaluates dose perturbations caused by nonradioactive seeds in clinical cases by employing treatment planning system-based Monte Carlo (TPS-MC) simulation. Methodology We investigated dose perturbation using a water-equivalent phantom and 20 clinical cases of prostate cancer (10 cases with seeds and 10 cases without seeds) treated at Fujita Health University Hospital, Japan. First, dose calculations for a simple geometry were performed using the RayStation MC algorithm for a water-equivalent phantom with and without a seed. TPS-independent Monte Carlo (full-MC) simulations and film measurements were conducted to verify the accuracy of TPS-MC simulation. Subsequently, dose calculations using TPS-MC were performed on CT images of clinical cases of prostate cancer with and without seeds, and the dose distributions were compared. Results In clinical cases, dose calculations using MC simulations revealed hotspots around the seeds. However, the size of the hotspot was not correlated with the number of seeds. The maximum difference in dose perturbation between TPS-MC simulations and film measurements was 3.9%, whereas that between TPS-MC simulations and full-MC simulations was 3.7%. The dose error of TPS-MC was negligible for multiple beams or rotational irradiation. Conclusions Hotspots were observed in dose calculations using TPS-MC performed on CT images of clinical cases with seeds. The dose calculation accuracy around the seeds using TPS-MC simulations was comparable to that of film measurements and full-MC simulations, with differences within 3.9%. Although the clinical impact of hotspots occurring around the seeds is minimal, utilizing MC simulations on TPSs can be beneficial to verify their presence.

Relationship between Delayed Breast Cancer Diagnosis and Behavioral Economic Factors and Personality Characteristics.

BACKGROUND: Delays in breast cancer diagnosis can allow the disease to progress to an incurable stage. However, factors that cause patients to delay seeking treatment are unclear. In this study, we aimed to identify behavioral economic factors and personality characteristics of patients with breast cancer who had a delayed diagnosis. METHODS: We analyzed questionnaires completed by 41 patients with breast cancer. A delayed diagnosis was defined if the time between the first symptom and the medical visit was more than 6 months. RESULTS: We found 11 patients who had a delayed diagnosis. The significant characteristics associated with patients with breast cancer who had delayed diagnosis were: (i) less experience with breast cancer screening; (ii) progressive disease stage; and (iii) low time and future time preference. We found no significant behavioral economic factors other than time preference, and personality that differed between patients with breast cancer who did and did not have a delayed diagnosis. CONCLUSION: Low time preference rate is a characteristic of patients with breast cancer who had a delayed diagnosis.

Evaluation of radiophotoluminescent glass dosimeter response for therapeutic spot scanning proton beam: suggestion of linear energy transfer-based correction.

A radiophotoluminescent glass dosimeter (RGD) is used for a postal audit of a photon beam because of its various excellent characteristics. However, it has not been used for scanning proton beams because its response characteristics have not been verified. In this study, the response of RGD to scanning protons was investigated to develop a dosimetry protocol using the linear energy transfer (LET)-based correction factor. The responses of RGD to four maximum-range-energy-pattern proton beams were verified by comparing it with ionization chamber (IC) dosimetry. The LET at each measurement depth was calculated via Monte Carlo (MC) simulation. The LET correction factor ( k LET RGD ) was the ratio between the uncorrected RGD dose ( D raw RGD ) and the IC dose at each measurement depth. k LET RGD can be represented as a function of LET using the following equation: k LET RGD LET = - 0.035 LET + 1.090 . D raw RGD showed a linear under-response with increasing LET, and the maximum dose difference between the IC dose and D raw RGD was 15.2% at an LET of 6.07 keV/µm. The LET-based correction dose ( D LET RGD ) conformed within 3.6% of the IC dose. The mean dose difference (±SD) of D raw RGD and D LET RGD was -2.5 ± 6.9% and 0.0 ± 1.6%, respectively. To achieve accurate dose verification for scanning proton beams using RGD, we derived a linear regression equation based on LET. The results show that with appropriate LET correction, RGD can be used for dose verification of scanning proton beams.

Oral care and oral assessment guide in breast cancer patients receiving everolimus and exemestane: subanalysis of a randomized controlled trial (Oral Care-BC).

BACKGROUND: Oral mucositis is a clinically significant adverse event linked to cancer therapy; it reduces the quality of life of patients and may result in the discontinuation of treatment and a poorer prognosis. Based on level 3 evidence, the Mucositis Study Group of Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology recommend oral care for all patients receiving cancer chemotherapy and radiotherapy, although no data from large-scaled randomized controlled trials support the efficacy of oral care in preventing oral mucositis. Therefore, this randomized, controlled, multicenter, open-label, phase III study sought to determine whether professional oral care reduces oral mucositis in everolimus and exemestane-treated estrogen receptor-positive metastatic breast cancer patients. METHODS: Altogether, 169 patients were randomized into the professional oral care (n=82) and control (n=87) groups. The professional oral care group received oral health instruction, professional mechanical tooth and tongue cleaning, gargling with a benzethonium chloride mouthwash, and dexamethasone ointment when grade 1 mucositis manifested. The control group received oral health instruction and gargling. Eight weeks after the everolimus and exemestane administration, the oral status (Oral Assessment Guide criteria) and oral mucositis status (Common Terminology Criteria for Adverse Events functional and clinical examinations) were evaluated. RESULTS: The incidence of oral mucositis of any grade and grade 2 severe mucositis was significantly lower in the professional oral care group, based on the Common Terminology Criteria for Adverse Events functional and clinical examinations. The total Oral Assessment Guide score, total Oral Assessment Guide grade, and Oral Assessment Guide score of teeth/dentures and mucous membranes were significantly different between the two groups. The Oral Assessment Guide grade for swallow, lip, teeth/dentures, mucous membrane, tongue, and saliva significantly correlated to oral mucositis severity. CONCLUSIONS: Professional oral care may prevent oral mucositis and improve teeth/denture conditions in patients receiving everolimus and exemestane.

Projections of disability-adjusted life years for major diseases due to a change in vegetable intake in 2017-2040 in Japan.

BACKGROUND: Low vegetable intake is one of the key dietary risk factors known to be associated with a range of health problems, including cardiovascular diseases (CVDs), cancer, and diabetes and kidney diseases (DKDs). Using data from Japan's National Health and Nutrition Surveys and the Global Burden of Diseases study in 2017, this study aimed to forecast the impact of change in vegetable intake on disability-adjusted life years (DALYs) between 2017 and 2040 for three diseases. METHODS: We generated a three-component model of cause-specific DALYs, including changes in major behavioural and metabolic risk predictors, the socio-demographic index and an autoregressive integrated moving average model to project future DALY rates for 2017-2040 using the data between 1990 and 2016. Data on Vegetable consumption and risk predictors, and DALY rate were obtained from Japan's National Health and Nutrition Surveys and the Global Burden of Diseases Study in 2017. We also modelled three scenarios of better, moderate and worse cases to evaluate the impact of change in vegetable consumption on the DALY rates for three diseases (CVDs, cancer, and DKDs). RESULTS: Projected mean vegetable intake in the total population showed a decreasing trend through 2040 to 237.7 g/day. A significant difference between the reference scenario and the better case scenario was observed with un-overlapped 95% prediction intervals of DALY rates in females aged 20-49 years (- 8.0%) for CVDs, the total population for cancer (- 5.6%), and in males (- 8.2%) and females (- 13.7%) for DKDs. CONCLUSIONS: Our analysis indicates that increased vegetable consumption would have a significant reduction in the burdens of CVDs, cancer and DKDs in Japan. By estimating the disease burden attributable to low vegetable intake under different scenarios of future vegetable consumption, our study can inform the design of targeted interventions for public health challenges.

Dosimetric response of a glass dosimeter in proton beams: LET-dependence and correction factor.

A radiophotoluminescent glass dosimeter (RGD) is widely used in postal audit system for photon beams in Japan. However, proton dosimetry in RGDs is scarcely used owing to a lack of clarity in their response to beam quality. In this study, we investigated RGD response to beam quality for establishing a suitable linear energy transfer (LET)-corrected dosimetry protocol in a therapeutic proton beam. The RGD response was compared with ionization chamber measurement for a 100-225 MeV passive proton beam. LET of the measurement points was calculated by the Monte Carlo method. An LET-correction factor, defined as a ratio between the non-corrected RGD dose and ionization chamber dose, of 1.226×(LET)-0.171 was derived for the RGD response. The magnitude of the LET-dependence of RGD increased with LET; for an LET of 8.2 keV/µm, the RGD under-response was up to 16%. The coefficient of determination, mean difference ± SD of non-corrected RGD dose, residual range-corrected RGD dose, and LET-corrected RGD dose to the ionization chamber are 0.923, 3.7 ± 4.2%, -2.4 ± 7.5%, and 0.04 ± 2.1%, respectively. The LET-corrected RGD dose was within 5% of the corresponding ionization chamber dose at all energies until 200 MeV, where it was 5.3% lower than the ionization chamber dose. A corrected LET-dependence of RGD using a correction factor based on a power function of LET and precise dosimetric verification close to the maximum LET were realized here. We further confirmed establishment of an accurate postal audit under various irradiation conditions.

A population-based recurrence risk management study of patients with pT1 node-negative HER2+ breast cancer: a National Clinical Database study.

PURPOSE: Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD). METHODS: We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS). RESULTS: There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p < 0.001) were significantly improved in treated compared with untreated patients. In the Cox proportional hazards model, treated patients had significantly longer OS than untreated patients in pT1b (hazard ratio (HR) 0.20) and pT1c (HR 0.54) groups. Estrogen receptor-negative tumors was also a significant predictor of survival in pT1c (HR 2.01) but not pT1ab patients. Furthermore, HR was greater in patients aged ≤ 35 years (3.18) compared to that in patients aged 50-69 years in the pT1b group. CONCLUSIONS: NCD data revealed that systemic treatment improved OS in pT1bc but not in pT1a node-negative HER2+ breast cancer patients. Future observational research using big-sized data is expected to play an important role in optimizing treatment for patients with early-stage breast cancer.

A quality assurance for respiratory gated proton irradiation with range modulation wheel.

The purpose of this study was to provide periodic quality assurance (QA) methods for respiratory-gated proton beam with a range modulation wheel (RMW) and to clarify the characteristics and long-term stability of the respiratory-gated proton beam. A two-dimensional detector array and a solid water phantom were used to measure absolute dose, spread-out Bragg peak (SOBP) width and proton range for monthly QA. SOBP width and proton range were measured using an oblique incidence beam to the lateral side of a solid water phantom and compared between with and without a gating proton beam. To measure the delay time of beam-on/off for annual QA, we collected the beam-on/off signals and the dose monitor-detected pulse. We analyzed the results of monthly QA over a 15-month period and investigated the delay time by machine signal analysis. The dose deviations at proximal, SOBP center and distal points were -0.083 ± 0.25%, 0.026 ± 0.20%, and -0.083 ± 0.35%, respectively. The maximum dose deviation between with and without respiratory gating was -0.95% at the distal point and other deviations were within ±0.5%. Proximal and SOBP center doses showed the same trend over a 15-month period. Delay times of beam-on/off for 200 MeV/SOBP 16 cm were 140.5 ± 0.8 ms and 22.3 ± 13.0 ms, respectively. Delay times for 160 MeV/SOBP 10 cm were 167.5 ± 15.1 ms and 19.1 ± 9.8 ms. Our beam delivery system with the RMW showed sufficient stability for respiratory-gated proton therapy and the system did not show dependency on the energy and the respiratory wave form. The delay times of beam-on/off were within expectations. The proposed QA methods will be useful for managing the quality of respiratory-gated proton beams and other beam delivery systems.

Societal cost-effectiveness analysis of the 21-gene assay in estrogen-receptor-positive, lymph-node-negative early-stage breast cancer in Japan.

BACKGROUND: Breast-cancer incidence and mortality have been increasing in Japan. Japanese-specific clinical validity and utility data for the 21-gene assay (Oncotype DX® Breast Cancer Assay; Genomic Health, Inc., Redwood City, USA) are now available. The objective of this study was to evaluate the cost-effectiveness of the 21-gene assay for the guidance of adjuvant chemotherapy decisions in estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer patients, from the Japanese societal perspective. METHODS: The recurrence risk group distribution by the 21-gene assay result and the assay's influence on adjuvant chemotherapy recommendations were obtained from a study of 104 patients. A state-transition cohort (Markov) model tracked time from surgery until distant recurrence and from distant recurrence to death. Adjuvant chemotherapy benefit by 21-gene assay risk group was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral centers. Utilities associated with progression and chemotherapy-related adverse events were extracted from literature. Sensitivity analyses assessed the key drivers and robustness of the primary outcomes. RESULTS: The 21-gene assay identified 48% of patients as low-risk, 36% as intermediate-risk, and 16% as high-risk. Total acute chemotherapy-related costs decreased by ¥154,066 due to less adjuvant chemotherapy usage. In the high-risk group, adjuvant chemotherapy use increased 18%, leading to survival benefits. Chemotherapy use overall decreased by 19%. Monitoring costs increased by ¥3,744 but recurrence costs declined by ¥46,113 per patient. Use of the 21-gene assay increased quality-adjusted-life-years (QALYs) by 0.241 per patient on average; the net cost per QALY gained was ¥636,752 ($6,368). CONCLUSIONS: The 21-gene assay for women with estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer is projected to be cost-effective in Japan.

[Assessment of overall spatial accuracy in image guided stereotactic body radiotherapy using a spine registration method].

Stereotactic body radiotherapy (SBRT) for lung and liver tumors is always performed under image guidance, a technique used to confirm the accuracy of setup positioning by fusing planning digitally reconstructed radiographs with X-ray, fluoroscopic, or computed tomography (CT) images, using bony structures, tumor shadows, or metallic markers as landmarks. The Japanese SBRT guidelines state that bony spinal structures should be used as the main landmarks for patient setup. In this study, we used the Novalis system as a linear accelerator for SBRT of lung and liver tumors. The current study compared the differences between spine registration and target registration and calculated total spatial accuracy including setup uncertainty derived from our image registration results and the geometric uncertainty of the Novalis system. We were able to evaluate clearly whether overall spatial accuracy is achieved within a setup margin (SM) for planning target volume (PTV) in treatment planning. After being granted approval by the Hospital and University Ethics Committee, we retrospectively analyzed eleven patients with lung tumor and seven patients with liver tumor. The results showed the total spatial accuracy to be within a tolerable range for SM of treatment planning. We therefore regard our method to be suitable for image fusion involving 2-dimensional X-ray images during the treatment planning stage of SBRT for lung and liver tumors.

[Presumption of the energy-spectrum of high-energy electron beam based on the beta-distribution model].

The energy spectra of high-energy electron beams used in radiotherapy are the most important data for evaluating absorbed doses and/or dose distributions in the body of a patient. However, it is impossible to measure the actual spectra of a high-energy electron beam. In this study, we suggest a method to presume the spectra of high-energy electron beams by use of the beta distribution model. The procedure of this method is as follows: (1) the spectrum of the high-energy electron beam was assumed to have a maximum energy Emax, and α, ß parameters of the beta probability density function. (2) The percentage depth dose (PDD) based on the assumed spectrum was calculated by a Monte Carlo simulation. (3) The best matching energy spectrum was searched in comparison with the experimental PDD curves. Finally, the optimal energy spectrum of the electron beam was estimated after reiterating the process from (1) to (3). With our method, the measured PDD curves were optimally simulated following the experimental data. It appeared that the assumed spectra approximated well to the actual spectra. However, the error between the assumed and experimental data was observed in the region under the incident surface. We believe this was due to the influence of low-energy electrons scattered at installed collimators, etc. In order to simulate PDDs in this region accurately, a further correction process is required for a spectrum based on the beta distribution model.

Women prefer adjuvant endocrine therapy to chemotherapy for breast cancer treatment.

BACKGROUND: We attempted to determine the preferences of women regarding the benefits they considered necessary to make adjuvant therapy worthwhile, and to compare preferences for adjuvant endocrine therapy, chemotherapy, and trastuzumab therapy. We also investigated the effect of information about cost on women's treatment preferences. PATIENTS AND METHODS: Consecutive women who had a medical examination at the Breast Clinic, Ota General Hospital, were included in our study. We collected a questionnaire from a total of 365 women; 297 completed responses were included in the study. RESULTS: Among 297 women, 105 had breast cancer that had been treated and 192 did not have breast cancer; 38% of women judged that a 5% or less gain in the probability of survival was sufficient to make endocrine therapy worthwhile; 28% of participants judged that chemotherapy was worthwhile; 24% of participants judged that trastuzumab therapy was worthwhile. Women indicated that they were more likely to receive adjuvant endocrine therapy than chemotherapy or trastuzumab therapy, for the same gains in the probability of survival. Cost information about treatments did not affect women's treatment preferences. Younger women tended to judge improvements in survival sufficient to make adjuvant endocrine and chemotherapy worthwhile, as compared to older women. The comparisons were statistically significant in the 10 and 20% categories for endocrine therapy and chemotherapy. CONCLUSION: Women prefer endocrine therapy to chemotherapy or trastuzumab therapy, given the same projected treatment benefits. Younger women prefer both chemotherapy and endocrine therapy as compared with older woman.

A prospective study of bone tumor response assessment in metastatic breast cancer.

BACKGROUND: In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases. METHODS: We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions. RESULTS: The median follow-up period was 26.7 months (range, 6.1-53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases. CONCLUSION: MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria.

[Dosimetric perturbation due to scattered rays released by a gold marker used for tumor tracking in external radiotherapy].

Image-guided radiation therapy using a gold marker-based tumor tracking technique provides precise patient setup and monitoring. However, the marker consists of high-Z material, and the resulting scattered rays tend to have adverse effects on the dose distribution of radiotherapy. The purpose of this study was to evaluate the dosimetric perturbation due to the use of a gold marker for radiotherapy in the lungs. The relative dose distributions were compared with film measurement, Monte Carlo simulation, and XiO calculation with the multi grid superposition algorithm using two types of virtual lung phantoms, which were composed of tough water phantoms, tough lung phantoms, cork boards, and a 2.0-mm-diameter gold ball. No dose increase and decrease in the vicinity of the gold ball was seen in the XiO calculations, although it was seen in the film measurements and the Monte Carlo simulation. The dose perturbation due to a gold marker cannot be evaluated using XiO calculation with the superposition algorithm when the tumor is near a gold marker (especially within 0.5 cm). To rule out the presence of such dose perturbations due to a gold marker, the distance between the gold marker and the tumor must therefore be greater than 0.5 cm.

Assessment of spatial uncertainties in the radiotherapy process with the Novalis system.

PURPOSE: The purpose of this study was to evaluate the accuracy of a new version of the ExacTrac X-ray (ETX) system with statistical analysis retrospectively in order to determine the tolerance of systematic components of spatial uncertainties with the Novalis system. METHODS AND MATERIALS: Three factors of geometrical accuracy related to the ETX system were evaluated by phantom studies. First, location dependency of the detection ability of the infrared system was evaluated. Second, accuracy of the automated calculation by the image fusion algorithm in the patient registration software was evaluated. Third, deviation of the coordinate scale between the ETX isocenter and the mechanical isocenter was evaluated. From the values of these examinations and clinical experiences, the total spatial uncertainty with the Novalis system was evaluated. RESULTS: As to the location dependency of the detection ability of the infrared system, the detection errors between the actual position and the detected position were 1% in translation shift and 0.1 degrees in rotational angle, respectively. As to the accuracy of patient verification software, the repeatability and the coincidence of the calculation value by image fusion were good when the contrast of the X-ray image was high. The deviation of coordinates between the ETX isocenter and the mechanical isocenter was 0.313 +/- 0.024 mm, in a suitable procedure. CONCLUSIONS: The spatial uncertainty will be less than 2 mm when suitable treatment planning, optimal patient setup, and daily quality assurance for the Novalis system are achieved in the routine workload.