Secondary cancer risk from modern external-beam radiotherapy of prostate cancer patients: Impact of fractionation and dose distribution

Modern radiotherapy (RT) uses altered fractionation, long beam-on time and image-guided procedure. This study aimed to compare secondary cancer risk (SCR) associated with primary field, scatter/leakage radiations and image-guided procedure in prostate treatment using intensity-modulated RT (IMRT), CyberKnife stereotactic body RT (CK-SBRT) in relative to 3-dimensional conformal RT (3D-CRT). Prostate plans were generated for 3D-CRT, IMRT (39 fractions of 2 Gy), and CK-SBRT (five fractions of 7.25 Gy). Excess absolute risk (EAR) was calculated for organs in the primary field using Schneider’s mechanistic model and concept of organ equivalent dose (OED) to account for dose inhomogeneity. Doses from image-guided procedure and scatter/leakage radiations were determined by phantom measurements. The results showed that hypofractionation relative to conventional fractionation yielded lower SCR for organs in primary field (p ≤ 0.0001). SCR was further modulated by dose-volume distribution. For organs near the field edge, like the rectum and pelvic bone, CK-SBRT plan rendered better risk profiles than IMRT and 3D-CRT because of the absence of volume peak in high dose region (relative risk [RR]: 0.65, 0.22, respectively, p ≤ 0.0004). CK-SBRT and IMRT generated more scatter/leakage and imaging doses than 3D-CRT (p ≤ 0.0002). But primary field was the major contributor to SCR. EAR estimates (risk contributions, primary field: scatter/leakage radiations: imaging procedure) were 7.1 excess cases per 10⁴ person–year (PY; 3.64:2.25:1) for CK-SBRT, 9.93 (7.32:2.33:1) for IMRT and 8.24 (15.99:2.35:1) for 3D-CRT (p ≤ 0.0002). We conclude that modern RT added more but small SCR from scatter/leakage and imaging doses. The primary field is a major contributor of risk which can be mitigated by the use of hypofractionation.     

Preoperative chemoradiotherapy for locally advanced low rectal cancer using intensity-modulated radiotherapy to spare the intestines: a single-institutional pilot trial

The irradiated volume of intestines is associated with gastrointestinal toxicity in preoperative chemoradiotherapy for rectal cancer. The current trial prospectively explored how much of the irradiated volume of intestines was reduced by intensity-modulated radiotherapy (IMRT) compared with 3-dimensional conformal radiotherapy (3DCRT) and whether IMRT might alleviate the acute gastrointestinal toxicity in this population. The treatment protocol encompassed preoperative chemoradiotherapy using IMRT plus surgery for patients with clinical T3–4, N0–2 low rectal cancer. IMRT delivered 45 Gy per 25 fractions for gross tumors, mesorectal and lateral lymph nodal regions, and tried to reduce the volume of intestines receiving 15 Gy (V_{15 Gy}) < 120 cc and V_{45 Gy} ≤ 0 cc, respectively, while keeping target coverage. S-1 and irinotecan were concurrently administered. Acute gastrointestinal toxicity, rates of clinical downstaging, sphincter preservation, local regional control (LRC) and overall survival (OS) were evaluated. Twelve enrolled patients completed the chemoradiotherapy protocol. The volumes of intestines receiving medium to high doses were reduced by the current IMRT protocol compared to 3DCRT; however, the predefined constraint of V_{15 Gy} was met only in three patients. The rate of ≥ grade 2 gastrointestinal toxicity excluding anorectal symptoms was 17%. The rates of clinical downstaging, sphincter preservation, three-year LRC and OS were 75%, 92%, 92% and 92%, respectively. In conclusion, preoperative chemoradiotherapy using IMRT for this population might alleviate acute gastrointestinal toxicity, achieving high LRC and sphincter preservation; although further advancement is required to reduce the irradiated volume of intestines, especially those receiving low doses.     

Incorporation of gantry angle correction for 3D dose prediction in intensity-modulated radiation therapy

Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0° using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0° may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0° gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0° gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal.     

Definitive radiotherapy with stereotactic or IMRT boost with or without radiosensitization strategy for operable breast cancer patients who refuse surgery

For breast cancer (BC) patients who refused surgery, we developed a definitive treatment employing modern sophisticated radiation techniques. Thirty-eight operable BC patients were treated by conventionally fractionated whole-breast (WB) radiotherapy in combination with stereotactic (for primary tumor) or intensity-modulated (for primary tumor with/without regional lymph nodes [LN]) radiotherapy (IMRT) boost. Standard doses were 50 Gy/25 fractions, 21 Gy/3 fractions and 20 Gy/8 fractions, respectively, for the three radiation modalities. Disease stages were 0 (ductal carcinoma in situ [DCIS]) in seven patients, I in 12, II in 16 and III in three. In 26 patients, intratumoral hydrogen peroxide injection or hyperthermia with oral tegafur-gimeracil-oteracil potassium (S-1) was also used to sensitize the tumors to radiation. Hormonal and standard systemic therapy were administered in 25 and 13 patients, respectively. Complete and partial responses were obtained in 19 patients each; in patients with partial response, no further regrowth of the residual mass was observed, except for two patients who developed local recurrence. During a follow-up of 8–160 months (median, 50 months for living patients), two, one and two patients developed local relapse, sub-clavicular node metastasis and distant metastasis, respectively. The 5-year rates for overall, progression-free and local relapse-free survival were 97.2, 90.9 and 93.4%, respectively. Fourteen patients developed Grade 3 radiation dermatitis but all recovered after treatment. In 47%, the affected breast became better-rounded, and the nipple of the irradiated breast became higher by ≥1 cm than the contralateral nipple. Our method might be a treatment option for operable BC patients.     

Accuracy and efficiency of published film dosimetry techniques using a flat-bed scanner and EBT3 film

Gafchromic EBT3 film is widely used for patient specific quality assurance of complex treatment plans. Film dosimetry techniques commonly involve the use of transmission scanning to produce TIFF files, which are analysed using a non-linear calibration relationship between the dose and red channel net optical density (netOD). Numerous film calibration techniques featured in the literature have not been independently verified or evaluated. A range of previously published film dosimetry techniques were re-evaluated, to identify whether these methods produce better results than the commonly-used non-linear, netOD method. EBT3 film was irradiated at calibration doses between 0 and 4000 cGy and 25 pieces of film were irradiated at 200 cGy to evaluate uniformity. The film was scanned using two different scanners: The Epson Perfection V800 and the Epson Expression 10000XL. Calibration curves, uncertainty in the fit of the curve, overall uncertainty and uniformity were calculated following the methods described by the different calibration techniques. It was found that protocols based on a conventional film dosimetry technique produced results that were accurate and uniform to within 1%, while some of the unconventional techniques produced much higher uncertainties (>?25% for some techniques). Some of the uncommon methods produced reliable results when irradiated to the standard treatment doses (<?400 cGy), however none could be recommended as an efficient or accurate replacement for a common film analysis technique which uses transmission scanning, red colour channel analysis, netOD and a non-linear calibration curve for measuring doses up to 4000 cGy when using EBT3 film.     

Dosimetric verification for intensity-modulated arc therapy plans by use of 2D diode array,radiochromic film and radiosensitive polymer gel

Several tools are used for the dosimetric verification of intensity-modulated arc therapy (IMAT) treatment delivery. However, limited information is available for composite on-line evaluation of these tools. The purpose of this study was to evaluate the dosimetric verification of IMAT treatment plans using a 2D diode array detector (2D array), radiochromic film (RCF) and radiosensitive polymer gel dosimeter (RPGD). The specific verification plans were created for IMAT for two prostate cancer patients by use of the clinical treatment plans. Accordingly, the IMAT deliveries were performed with the 2D array on a gantry-mounting device, RCF in a cylindrical acrylic phantom, and the RPGD in two cylindrical phantoms. After the irradiation, the planar dose distributions from the 2D array and the RCFs, and the 3D dose distributions from the RPGD measurements were compared with the calculated dose distributions using the gamma analysis method (3% dose difference and 3-mm distance-to-agreement criterion), dose-dependent dose difference diagrams, dose difference histograms, and isodose distributions. The gamma passing rates of 2D array, RCFs and RPGD for one patient were 99.5%, 96.5% and 93.7%, respectively; the corresponding values for the second patient were 97.5%, 92.6% and 92.9%. Mean percentage differences between the RPGD measured and calculated doses in 3D volumes containing PTVs were –0.29 ± 7.1% and 0.97 ± 7.6% for the two patients, respectively. In conclusion, IMAT prostate plans can be delivered with high accuracy, although the 3D measurements indicated less satisfactory agreement with the treatment plans, mainly due to the dosimetric inaccuracy in low-dose regions of the RPGD measurements.     

A dosimetric comparison of two-phase adaptive intensity-modulated radiotherapy for locally advanced nasopharyngeal cancer

The purpose of this investigation was to evaluate the potential dosimetric benefits of a two-phase adaptive intensity-modulated radiotherapy (IMRT) protocol for patients with locally advanced nasopharyngeal cancer (NPC). A total of 17 patients with locally advanced NPC treated with IMRT had a second computed tomography (CT) scan after 17 fractions in order to apply and continue the treatment with an adapted plan after 20 fractions. To simulate the situation without adaptation, a hybrid plan was generated by applying the optimization parameters of the original treatment plan to the anatomy of the second CT scan. The dose–volume histograms (DVHs) and dose statistics of the hybrid plan and the adapted plan were compared. The mean volume of the ipsilateral and contralateral parotid gland decreased by 6.1 cm³ (30.5%) and 5.4 cm³ (24.3%), respectively. Compared with the hybrid plan, the adapted plan provided a higher dose to the target volumes with better homogeneity, and a lower dose to the organs at risk (OARs). The Dmin of all planning target volumes (PTVs) increased. The Dmax of the spinal cord and brainstem were lower in 94% of the patients (1.6–5.9 Gy, P < 0.001 and 2.1–9.9 Gy, P < 0.001, respectively). The D_mean of the contralateral parotid decreased in 70% of the patients (range, 0.2–4.4 Gy). We could not find a relationship between dose variability and weight loss. Our two-phase adaptive IMRT protocol improves dosimetric results in terms of target volumes and OARs in patients with locally advanced NPC.     

EBT2 radiochromic film for quality assurance of complex IMRT treatments of the prostate: micro-collimated IMRT,RapidArc, and TomoTherapy

In response to the clinical need for a dosimetry system with both high resolution and minimal angular dependence, this study demonstrates the utility of Gafchromic EBT2 radiochromic dosimetry film for the quality assurance of micro-collimated IMRT, RapidArc and TomoTherapy treatments. Firstly, preliminary measurements indicated that the dose response of EBT2 film does not appreciably vary with either the angle of incidence of the radiation beam or the depth in water at which the film is placed. Secondly, prostate treatment plans designed for delivery using static-beam IMRT (collimated using the BrainLab m3 microMLC), RapidArc and TomoTherapy were investigated by comparing dose planes obtained from treatment planning calculations with EBT2 film measurements. For all treatment plans, the proportion of dose points agreeing with the film measurements to within γ (3%,3 mm) was found to be above 95%, with all points agreeing within 5%. The film images provided sufficient information to verify that the treatments could be delivered with an acceptable level of accuracy, while also providing additional information on low-level dose variations that were not predicted by the treatment planning systems. This information included: the location and extent of dose from inter-leaf leakage (in the RapidArc plan) and helical field junctioning (in the TomoTherapy plan), as well as the existence of small regions where the treatment planning system under-predicted the dose from very small treatment segments (in the micro-collimated IMRT plan).     

Comparison of intensity-modulated radiotherapy with the 5-field technique,helical tomotherapy and volumetric modulated arc therapy for localized prostate cancer

The outcomes of three methods of intensity-modulated radiation therapy (IMRT) for localized prostate cancer were evaluated. Between 2010 and 2018, 308 D’Amico intermediate- or high-risk patients were treated with 2.2 Gy daily fractions to a total dose of 74.8 Gy in combination with hormonal therapy. Overall, 165 patients were treated with 5-field IMRT using a sliding window technique, 66 were then treated with helical tomotherapy and 77 were treated with volumetric modulated arc therapy (VMAT). The median age of patients was 71 years. The median follow-up period was 75 months. Five-year overall survival (OS) and biochemical or clinical failure-free survival (FFS) rates were 95.5 and 91.6% in the 5-field IMRT group, 95.1 and 90.3% in the tomotherapy group and 93.0 and 88.6% in the VMAT group, respectively, with no significant differences among the three groups. The 5-year cumulative incidence of late grade ≥2 genitourinary and gastrointestinal toxicities were 7.3 and 6.2%, respectively, for all patients. Late grade ≥2 gastrointestinal toxicities were less frequent in patients undergoing VMAT (0%) than in patients undergoing 5-field IMRT (7.3%) and those undergoing tomotherapy (11%) (P = 0.025), and this finding appeared to be correlated with the better rectal DVH parameters in patients undergoing VMAT. Other toxicities did not differ significantly among the three groups, although bladder dose-volume parameters were slightly worse in the tomotherapy group than in the other groups. Despite differences in the IMRT delivery methods, X-ray energies and daily registration methods, all modalities may be used as IMRT for localized prostate cancer.     

Evaluating positional accuracy using megavoltage cone-beam computed tomography for IMRT with head-and-neck cancer

Accurate dose delivery is essential for the success of intensity-modulated radiation therapy (IMRT) for patients with head-and-neck (HN) cancer. Reproducibility of IMRT dose delivery to HN regions can be critically influenced by treatment-related changes in body contours. Moreover, some set-up margins may not be adaptable to positional uncertainties of HN structures at every treatment. To obtain evidence for appropriate set-up margins in various head and neck areas, we prospectively evaluated positional deviation (δ values) of four bony landmarks (i.e. the clivus and occipital protuberance for the head region, and the mental protuberance and C5 for the neck region) using megavoltage cone-beam computed tomography during a treatment course. Over 800 δ values were analyzed in each translational direction. Positional uncertainties for HN cancer patients undergoing IMRT were evaluated relative to the body mass index. Low positional accuracy was observed for the neck region compared with the head region. For the head region, most of the δ was distributed within ±5 mm, and use of the current set-up margin was appropriate. However, the δ values for the neck region were within ±8 mm. Especially for overweight patients, a few millimeters needed to be added to give an adequate set-up margin. For accurate dose delivery to targets and to avoid excess exposure to normal tissues, we recommend that the positional verification process be performed before every treatment.     

Dosimetric benefits of placing dose constraints on the brachial plexus in patients with nasopharyngeal carcinoma receiving intensity-modulated radiation therapy: a comparative study

This study aimed to evaluate whether placing dose constraints on the brachial plexus (BP) could provide dosimetric benefits in patients with nasopharyngeal carcinoma (NPC) undergoing intensity-modulated radiation therapy (IMRT). Planning CT images for 30 patients with NPC treated with definitive IMRT were retrospectively reviewed. Target volumes, the BP and other critical structures were delineated; two separate IMRT plans were designed for each patient: one set no restrictions for the BP; the other considered the BP as a critical structure for which a maximum dose limit of ≤66 Gy was set. No significant differences between the two plans were observed in the conformity index, homogeneity index, maximum dose to the planning target volumes (PTVs), minimum dose to the PTVs, percentages of the volume of the PTVnx and PTVnd receiving more than 110% of the prescribed dose, or percentages of the volume of the PTVs receiving 95% and > 93% of the prescribed dose. Dose constraints significantly reduced the maximum dose, mean dose, V45, V50, V54, V60, V66 and V70 to the BP. Dose constraints significantly reduced the maximum dose to the BP, V45, V60 and V66 in both N0–1 and N2–3 disease; however, the magnitude of the dosimetric gain for each parameter between N0–1 and N2–3 disease was not significantly different, except for the V60 and V66. In conclusion, placing dose constraints on the BP can significantly decrease the irradiated volume and dose, without compromising adequate dose delivery to the target volume.     

Ionizing radiation alters organoid forming potential and replenishment rate in a dose/dose-rate dependent manner

Intestinal organoids are an in vitro cultured tissue model generated from intestinal stem cells, and they contain a mixture of epithelial cell types. We previously established an efficient ‘one cell/well’ sorting method, and defined organoid-forming potential (OFP) as a useful index to evaluate the stemness of individual cells. In this study, we assessed the response to radiation dose and dose-rate by measuring both OFP and the percentage of stem cells in the crypts. After high-dose-rate (HDR, 0.5 Gy/min) irradiation in vivo, the percentage of stem cells in the harvested crypt cells decreased, and the replenishment of cycling stem cells originating from dormant cells was enhanced, but OFP increased in cells irradiated with a total dose of >1 Gy. In contrast, at a total dose of 0.1 Gy the percentage of stem cells reduced slightly, but neither replenishment rate nor OFP changed. Furthermore, the response to 1 Gy of low-dose-rate (LDR) irradiation was similar to the response to 0.1 Gy HDR irradiation. These results suggest that 0.1 Gy HDR irradiation or 1 Gy LDR irradiation does not alter stemness. Additionally, the OFP increase in the colon in response to irradiation was smaller than that in the duodenum, similar to the percentage of stem cells. Understanding the differences in the response of stem cells between the colon and the duodenum to radiation is important to clarify the mechanisms underlying the development of radiation-associated intestinal cancers.     

Radiotherapy for gastric lymphoma: a planning study of 3D conformal radiotherapy,the half-beam method,and intensity-modulated radiotherapy

During radiotherapy for gastric lymphoma, it is difficult to protect the liver and kidneys in cases where there is considerable overlap between these organs and the target volume. This study was conducted to compare the three radiotherapy planning techniques of four-fields 3D conformal radiotherapy (3DCRT), half-field radiotherapy (the half-beam method) and intensity-modulated radiotherapy (IMRT) used to treat primary gastric lymphoma in which the planning target volume (PTV) had a large overlap with the left kidney. A total of 17 patients with gastric diffuse large B-cell lymphoma (DLBCL) were included. In DLBCL, immunochemotherapy (Rituximab + CHOP) was followed by radiotherapy of 40 Gy to the whole stomach and peri-gastric lymph nodes. 3DCRT, the half-field method, and IMRT were compared with respect to the dose–volume histogram (DVH) parameters and generalized equivalent uniform dose (gEUD) to the kidneys, liver and PTV. The mean dose and gEUD for 3DCRT was higher than for IMRT and the half-beam method in the left kidney and both kidneys. The mean dose and gEUD of the left kidney was 2117 cGy and 2224 cGy for 3DCRT, 1520 cGy and 1637 cGy for IMRT, and 1100 cGy and 1357 cGy for the half-beam method, respectively. The mean dose and gEUD of both kidneys was 1335 cGy and 1559 cGy for 3DCRT, 1184 cGy and 1311 cGy for IMRT, and 700 cGy and 937 cGy for the half-beam method, respectively. Dose–volume histograms (DVHs) of the liver revealed a larger volume was irradiated in the dose range <25 Gy with 3DCRT, while the half-beam method irradiated a larger volume of liver with the higher dose range (>25 Gy). IMRT and the half-beam method had the advantages of dose reduction for the kidneys and liver.     

In vitro and in vivo studies on radiobiological effects of prolonged fraction delivery time in A549 cells

Intensity-modulated radiation therapy, when used in the clinic, prolongs fraction delivery time. Here we investigated both the in vivoand in vitroradiobiological effects on the A549 cell line, including the effect of different delivery times with the same dose on A549 tumor growth in nude mice. The in vitroeffects were studied with clonogenic assays, using linear-quadratic and incomplete repair models to fit the dose-survival curves. Fractionated irradiation of different doses was given at one fraction per day, simulating a clinical dose-time-fractionation pattern. The longer the interval between the exposures, the more cells survived. To investigate the in vivoeffect, we used sixty-four nude mice implanted with A549 cells in the back legs, randomly assigned into eight groups. A 15 Gy radiation dose was divided into different subfractions. The maximum and minimum tumor diameters were recorded to determine tumor growth. Tumor growth was delayed for groups with prolonged delivery time (40 min) compared to the group receiving a single dose of 15 Gy (P< 0.05), and tumors with a 20 min delivery time had delayed growth compared to those with a 40 min delivery time [20′ (7.5 Gy × 2 F) vs 40′ (7.5 Gy × 2 F), P= 0.035; 20′ (3 Gy × 5 F) vs 40′ (3 Gy × 5 F); P= 0.054; 20′ (1.67 Gy × 9 F) vs 40′ (1.67 Gy × 9 F), P= 0.028]. A prolonged delivery time decreased the radiobiological effects, so we strongly recommend keeping the delivery time as short as possible.     

Mean esophageal radiation dose is predictive of the grade of acute esophagitis in lung cancer patients treated with concurrent radiotherapy and chemotherapy

The intention of this research was to define the predictive factors for acute esophagitis (AE) in lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. The data for 72 lung cancer patients treated with concurrent chemoradiotherapy between 2008 and 2010 were prospectively evaluated. Mean lung dose, mean dose of esophagus, volume of esophagus irradiated and percentage of esophagus volume treated were analysed according to esophagitis grades. The mean esophageal dose was associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P < 0.001). However, the mean lung dose and the volume of esophagus irradiated were not associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P = 0.50 and P = 0.41, respectively). The mean radiation dose received by the esophagus was found to be highly correlated with the duration of Grade 2 esophagitis (Spearman test, r = 0.82, P < 0.001). The mean dose of esophagus ≥28 Gy showed statistical significance with respect to AE Grade 2 or worse (receiver operating characteristic curve analysis, 95% CI, 0.929–1.014). In conclusion, the mean esophageal dose was significantly associated with a risk of esophageal toxicity in patients with lung cancer treated with concurrent radiotherapy and chemotherapy.     

Development of raster scanning IMRT using a robotic radiosurgery system

Treatment time with the CyberKnife frameless radiosurgery system is prolonged due to the motion of the robotic arm. We have developed a novel scanning irradiation method to reduce treatment time. We generated treatment plans mimicking eight-field intensity-modulated radiotherapy (IMRT) plans generated for the Novalis radiosurgery system. 2D dose planes were generated with multiple static beam spots collimated by a fixed circular cone. The weights of the uniformly distributed beam spots in each dose plane were optimized using the attraction–repulsion model. The beam spots were converted to the scanning speed to generate the raster scanning plan. To shorten treatment time, we also developed a hybrid scanning method which combines static beams with larger cone sizes and the raster scanning method. Differences between the Novalis and the scanning plan’s dose planes were evaluated with the criterion of a 5% dose difference. The mean passing rates of three cases were > 85% for cone sizes ≤ 12.5 mm. Although the total monitor units (MU) increased for smaller cone sizes in an inverse-square manner, the hybrid scanning method greatly reduced the total MU, while maintaining dose distributions comparable to those with the Novalis plan. The estimated treatment time of the hybrid scanning with a 12.5 mm cone size was on average 22% shorter than that of the sequential plans. This technique will be useful in allowing the CyberKnife with conventional circular cones to achieve excellent dose distribution with a shortened treatment time.