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Eighty-three patients with oropharyngeal, hypopharyngeal or laryngeal cancer were treated with concomitant cisplatin 40mg/m 2 once a week during the radiotherapy and IMRT up to a total dose of 70Gy. The 2-year rate of local control, overall survival and disease specific survival were 84%, 82% and 89%, respectively. The corresponding 5-year Kaplan–Meier estimates were 79%, 69% and 76%.

Background and Purpose We estimated accuracy requirements for dose and position of the major salivary glands in head and neck intensity-modulated radiotherapy (IMRT) based on the dose response characteristics of the glands obtained by using the sigmoidal dose response model. Materials and methods Dose response of the parotid and submandibular salivary glands was determined for 25 head and neck cancer patients treated by IMRT. Individual salivary gland functions were assessed by scintigraphy before and 6months after radiotherapy. Accuracy requirements were estimated by using the maximal slope of the fitted dose response model and average value of the dose gradients within the glands. In addition, systematic and random set-up errors were estimated for each patient by at least weekly portal imaging. We investigated the changes in the salivary gland mean doses ( D mean ) that would have occurred without correction of patient positioning. This was done by shifting the planned isocenter according to the obtained systematic set-up error and by recalculating the dose distribution in treatment planning system (TPS). Results The maximal slope and D 50 values of the dose response model were −0.0411/Gy and 30.4Gy, respectively. The results suggested that spared fraction of individual salivary gland function can be estimated with an accuracy of ±10%, if actual D mean of the gland is within ±2.4Gy with the planned value. On the average, this was achieved with maximal systematic positional 3D shift of 3.0mm for the parotid glands and 2.7mm for the submandibular glands. The magnitude of systematic 1D set-up errors was 1.7±1.3mm (mean±SD) while that of systematic 3D errors was 3.4±1.6mm. The SD of random set-up errors was 1.5mm. The magnitude of D mean shifts due to set-up errors was 1.5±1.4Gy. The steepness of dose gradients within the glands was 0.8±0.5Gy/mm in the most critical direction (toward the glands). Conclusions When substantial part of salivary gland function is intended to be spared in head and neck IMRT, narrow dosimetric and positional tolerances should be adopted for the major salivary glands due to steep dose response curve obtained for the glands.

Purpose The accuracy of central axis dose calculation was evaluated for 48 photon beams from 28 linear accelerators at nine centres in Finland. In addition, inter-accelerator consistency of beam data was evaluated for Varian Clinac 600 CDs and 2100 CDs, and averaged data sets were generated for output factors (OFs) and percentage depth doses (PDDs). The averaged data sets obtained were used to identify potential dosimetry reasons for local errors. Materials and methods Agreement between measured and calculated doses was determined at isocentre at 10 cm depth in water for nine different sized open square and rectangular fields. Averaged OFs were determined for nominal energies of 4, 6, 10, 15 and 18 MV both at d max and at a 10-cm depth. In order to develop a function for the OF data, OFs for square fields were parametrised through empirical model fitting. The feasibility of a simple equivalent square collimator formula was also evaluated for the presentation of OFs for rectangular fields. Averaged PDDs were determined at a 10-cm depth. Results The difference between measured and calculated doses exceeded ±3%, ±2% and ±1% for 3, 6 and 35 of the investigated 48 beams, respectively. The differences were due to errors observed in both OFs and depth dose data. When the agreement between dose calculation and measurement was within ±1%, inter-accelerator differences in OFs were within ±1.0% at both the depth of dose maximum and at 10 cm for Clinac 600 CDs and also for 2100 CDs. Differences in PDDs were within ±1.2%. Conclusions The importance of quality control for beam data was demonstrated by showing significant errors in measured data. For Clinac 600 and 2100 CDs, the quality control can be accurately performed by comparing local data to averaged reference data. Robust averaged data sets were obtained for 6, 15 and 18 MV beams of Clinac 2100 CDs.

Rationale and Objectives To compare liver perfusion parameters obtained by using an extravascular contrast agent and a blood-pool agent. Materials and Methods Fifteen rabbits were imaged with a continuous 40-second single-slice computed tomography acquisition after a bolus injection of contrast agent (physiologic bolus duration 4–5 seconds, extravascular iohexol, n = 7; experimental nanoparticulated blood-pool agent WIN8883, n = 8). Time-density curves were generated for the aorta, portal vein, and liver. From the curves, arterial, portal, and total blood flows and hepatic perfusion index (HPI, arterial-to-total perfusion ratio) were determined by using two commonly applied fundamentally different analyzing methods: the single-compartment model and the peak gradient (PG) method. Also, the gamma variate fitting method was used. Results By using the single-compartment model, the obtained HPI and total blood flow were 0.14 ± 0.04 and 2.29 ± 0.40 (mL/min/mLtissue) for WIN8883, and 0.15 ± 0.06 (P = .54) and 4.60 ± 1.14 (mL/min/mLtissue) (P = .0002) for iohexol, respectively. With the PG, HPI and total blood flow were 0.15 ± 0.08 and 1.27 ± 0.24 (mL/min/mLtissue) for WIN8883, and 0.20 ± 0.06 (P = .12) and 2.11 ± 0.25 (mL/min/mLtissue) (P = .00002) for iohexol, respectively. With the blood pool agent, similar contrast enhancement to the conventional agent was achieved with about 36% reduced dosage of iodine per body weight (mg I/kg). Conclusions HPI was found to be quite insensitive to different contrast agent types and analyzing methods. However, the arterial, portal and total liver blood flow values strongly depend on contrast agent type and modeling method.

Quality control (QC) data of radiotherapy linear accelerators, collected by Helsinki University Central Hospital between the years 2000 and 2004, were analysed. The goal was to provide information for the evaluation and elaboration of QC of accelerator outputs and to propose a method for QC data analysis. Short- and long-term drifts in outputs were quantified by fitting empirical mathematical models to the QC measurements. Normally, long-term drifts were well (or =1%) modelled by either a straight line or a single-exponential function. A drift of 2% occurred in 18 +/- 12 months. The shortest drift times of only 2-3 months were observed for some new accelerators just after the commissioning but they stabilized during the first 2-3 years. The short-term reproducibility and the long-term stability of local constancy checks, carried out with a sealed plane parallel ion chamber, were also estimated by fitting empirical models to the QC measurements. The reproducibility was 0.2-0.5% depending on the positioning practice of a device. Long-term instabilities of about 0.3%/month were observed for some checking devices. The reproducibility of local absorbed dose measurements was estimated to be about 0.5%. The proposed empirical model fitting of QC data facilitates the recognition of erroneous QC measurements and abnormal output behaviour, caused by malfunctions, offering a tool to improve dose control.

Purpose: The lack of electron density information in magnetic resonance images (MRI) poses a major challenge for MRI-based radiotherapy treatment planning (RTP). In this study the authors convert MRI intensity values into Hounsfield units (HUs) in the male pelvis and thus enable accurate MRI-based RTP for prostate cancer patients with varying tissue anatomy and body fat contents. Methods: T{sub 1}/T{sub 2}*-weighted MRI intensity values and standard computed tomography (CT) image HUs in the male pelvis were analyzed using image data of 10 prostate cancer patients. The collected data were utilized to generate a dual model HU conversion technique from MRI intensity values of the single image set separately within and outside of contoured pelvic bones. Within the bone segment local MRI intensity values were converted to HUs by applying a second-order polynomial model. This model was tuned for each patient by two patient-specific adjustments: MR signal normalization to correct shifts in absolute intensity level and application of a cutoff value to accurately represent low density bony tissue HUs. For soft tissues, such as fat and muscle, located outside of the bone contours, a threshold-based segmentation method without requirements for any patient-specific adjustments was introduced to convert MRI intensity values intomore » HUs. The dual model HU conversion technique was implemented by constructing pseudo-CT images for 10 other prostate cancer patients. The feasibility of these images for RTP was evaluated by comparing HUs in the generated pseudo-CT images with those in standard CT images, and by determining deviations in MRI-based dose distributions compared to those in CT images with 7-field intensity modulated radiation therapy (IMRT) with the anisotropic analytical algorithm and 360° volumetric-modulated arc therapy (VMAT) with the Voxel Monte Carlo algorithm. Results: The average HU differences between the constructed pseudo-CT images and standard CT images of each test patient ranged from −2 to 5 HUs and from 22 to 78 HUs in soft and bony tissues, respectively. The average local absolute value differences were 11 HUs in soft tissues and 99 HUs in bones. The planning target volume doses (volumes 95%, 50%, 5%) in the pseudo-CT images were within 0.8% compared to those in CT images in all of the 20 treatment plans. The average deviation was 0.3%. With all the test patients over 94% (IMRT) and 92% (VMAT) of dose points within body (lower than 10% of maximum dose suppressed) passed the 1 mm and 1% 2D gamma index criterion. The statistical tests (t- and F-tests) showed significantly improved (p ≤ 0.05) HU and dose calculation accuracies with the soft tissue conversion method instead of homogeneous representation of these tissues in MRI-based RTP images. Conclusions: This study indicates that it is possible to construct high quality pseudo-CT images by converting the intensity values of a single MRI series into HUs in the male pelvis, and to use these images for accurate MRI-based prostate RTP dose calculations.« less

Background We estimated sufficient setup margins for head-and-neck cancer (HNC) radiotherapy (RT) when 2D kV images are utilized for routine patient setup verification. As another goal we estimated a threshold for the displacements of the most important bony landmarks related to the target volumes requiring immediate attention. Methods We analyzed 1491 orthogonal x-ray images utilized in RT treatment guidance for 80 HNC patients. We estimated overall setup errors and errors for four subregions to account for patient rotation and deformation: the vertebrae C1-2, C5-7, the occiput bone and the mandible. Setup margins were estimated for two 2D image guidance protocols: i) imaging at first three fractions and weekly thereafter and ii) daily imaging. Two 2D image matching principles were investigated: i) to the vertebrae in the middle of planning target volume (PTV) (MID_PTV) and ii) minimizing maximal position error for the four subregions (MIN_MAX). The threshold for the position errors was calculated with two previously unpublished methods based on the van Herk’s formula and clinical data by retaining a margin of 5 mm sufficient for each subregion. Results Sufficient setup margins to compensate the displacements of the subregions were approximately two times larger than were needed to compensate setup errors for rigid target. Adequate margins varied from 2.7 mm to 9.6 mm depending on the subregions related to the target, applied image guidance protocol and early correction of clinically important systematic 3D displacements of the subregions exceeding 4 mm. The MIN_MAX match resulted in smaller margins but caused an overall shift of 2.5 mm for the target center. Margins ≤ 5mm were sufficient with the MID_PTV match only through application of daily 2D imaging and the threshold of 4 mm to correct systematic displacement of a subregion. Conclusions Adequate setup margins depend remarkably on the subregions related to the target volume. When the systematic 3D displacement of a subregion exceeds 4 mm, it is optimal to correct patient immobilization first. If this is not successful, adaptive replanning should be considered to retain sufficiently small margins. BioMed Central open access

Purpose: Magnetic resonance (MR) images are used increasingly in external radiotherapy target delineation because of their superior soft tissue contrast compared to computed tomography (CT) images. Nevertheless, radiotherapy treatment planning has traditionally been based on the use of CT images, due to the restrictive features of MR images such as lack of electron density information. This research aimed to measure absorbed radiation doses in material behind different bone parts, and to evaluate dose calculation errors in two pseudo-CT images; first, by assuming a single electron density value for the bones, and second, by converting the electron density values inside bones from T1/T2*-weighted MR image intensity values. Methods: A dedicated phantom was constructed using fresh deer bones and gelatine. The effect of different bone parts to the absorbed dose behind them was investigated with a single open field at 6 and 15 MV, and measuring clinically detectable dose deviations by an ionization chamber matrix. Dose calculation deviations in a conversion-based pseudo-CT image and in a bulk density pseudo-CT image, where the relative electron density to water for the bones was set as 1.3, were quantified by comparing the calculation results with those obtained in a standard CT image by superposition and Monte Carlo algorithms. Results: The calculations revealed that the applied bulk density pseudo-CT image causes deviations up to 2.7% (6 MV) and 2.0% (15 MV) to the dose behind the examined bones. The corresponding values in the conversion-based pseudo-CT image were 1.3% (6 MV) and 1.0% (15 MV). The examinations illustrated that the representation of the heterogeneous femoral bone (cortex denser compared to core) by using a bulk density for the whole bone causes dose deviations up to 2% both behind the bone edge and the middle part of the bone (diameter

AimThe aim was to find an optimal setup image matching position and minimal setup margins to maximally spare the organs at risk in breast radiotherapy.BackgroundRadiotherapy of breast cancer is a routine task but has many challenges. We investigated residual position errors in whole breast radiotherapy when orthogonal setup images were matched to different bony landmarks.Materials and methodsA total of 1111 orthogonal setup image pairs and tangential field images were analyzed retrospectively for 50 consecutive patients. Residual errors in the treatment field images were determined by matching the orthogonal setup images to the vertebrae, sternum, ribs and their compromises. The most important region was the chest wall as it is crucial for the dose delivered to the heart and the ipsilateral lung. Inter-observer variation in online image matching was investigated.ResultsThe best general image matching position was the compromise of the vertebrae, ribs and sternum, while the worst position was the vertebrae alone (p≤0.03). The setup margins required for the chest wall varied from 4.3mm to 5.5mm in the lung direction while in the superior–inferior (SI) direction the margins varied from 5.1mm to 7.6mm. The inter-observer variation increased the minimal margins by approximately 1mm. The margin of the lymph node areas should be at least 4.8mm.ConclusionsSetup margins can be reduced by proper selection of a matching position for the orthogonal setup images. To retain the minimal margins sufficient, systematic error of the chest wall should not exceed 4mm in the tangential field image.

To evaluate the patterns of locoregional relapse and survival following submandibular gland (SMG)-sparing intensity modulated radiotherapy (IMRT).Eighty patients with laryngeal (n = 15), oropharyngeal (n = 50), hypopharyngeal (n = 11) or nasopharyngeal cancer (n = 4) were treated by submandibular gland-sparing IMRT for head and neck squamous cell cancer between July 2000 and December 2008. All patients were treated by bilateral IMRT. Thirty-nine (49%) received definitive radiotherapy (RT) and 41 (51%) postoperative RT. The contralateral parotid gland (PG) and SMG were included in the dose optimization planning program with intent to keep the mean doses for PG and SMG below 23 Gy and 28-30 Gy, respectively. The ipsilateral glands were also spared when considered feasible.During a median follow-up time of 51 months (range, 24-117 months) nine local recurrent tumors were observed. Four of these nine patients were salvaged by surgery with no further recurrence. All local recurrences were located within the high-dose CTVs. None of the locally recurrent cancers were located at the vicinity of the spared PGs or SMGs. No recurrent tumors were observed in the contralateral neck. The Kaplan-Meier estimate for local control at five years following IMRT was 88% for the whole cohort and the corresponding figure for local control following salvage surgery was 94%. The estimates for five-year overall survival and disease-specific survival were 85% and 90%, respectively.In selected head and neck cancer patients who are estimated to have a low risk of cancer recurrence at the nodal levels I-II and who are treated with SMG-sparing IMRT the risk of cancer recurrence at the vicinity of the spared salivary glands is low.

The aim of the present study was to investigate in vitro the effect of hypo- and hyperthermia alone or in combination with irradiation on natural killer cell (NK) cytotoxicity, recovery of this function and the possibility of preventing damage to or enhancing cytotoxicity recovery using interferons (IFNs) α, β, and γ and interleukin-2 (IL-2).We used non-selected NK cells and measured their cytotoxicity using the (51)Cr release assay. Temperatures ranging from 31-45°C and thermal treatment times from 0-180 min were assessed. IFNs were applied at concentrations from 0-1,000 IU/ml and IL-2 from 0-450 IU/ml. The range of irradiation dose was from 0-30 Gy.We detected no significant differences in cytotoxicity at temperatures from 31-37°C. The most significant decrease in cytotoxicity was observed between 41 and 42°C (p=0.0010), and heating NK cells at 42°C for 180 min almost completely abolished this function. NK cell cytotoxicity largely recovered during the first 24 h, depending on the heating time. IFN-α, β, and γ demonstrated no concentration-dependent ability to aid in recovery when used before or after the thermal treatment. In contrast, IL-2 restored cytotoxicity in a concentration- and incubation time-dependent manner and was equally active when used before, during or after heating. NK cells were heated at 42°C for various times and then irradiated with a single dose or first irradiated and then heated; however, no statistically significant differences were observed (p=0.520). An approach of IL-2 treatment followed by radiation and heating was the most effective in restoring NK cytotoxicity (p=0.000).NK cell cytotoxicity is impaired in vitro at 42°C and above, with possible partial recovery. IL-2, but not IFNs, was able to restore NK cell cytotoxicity in a concentration-dependent manner. IL-2 can also reverse the damage caused by combined hyperthermia and irradiation.

New version 13.6.23 of the electron Monte Carlo (eMC) algorithm in Varian Eclipse™ treatment planning system has a model for 4MeV electron beam and some general improvements for dose calculation. This study provides the first overall accuracy assessment of this algorithm against full Monte Carlo (MC) simulations for electron beams from 4MeV to 16MeV with most emphasis on the lower energy range. Beams in a homogeneous water phantom and clinical treatment plans were investigated including measurements in the water phantom. Two different material sets were used with full MC: (1) the one applied in the eMC algorithm and (2) the one included in the Eclipse™ for other algorithms. The results of clinical treatment plans were also compared to those of the older eMC version 11.0.31. In the water phantom the dose differences against the full MC were mostly less than 3% with distance-to-agreement (DTA) values within 2mm. Larger discrepancies were obtained in build-up regions, at depths near the maximum electron ranges and with small apertures. For the clinical treatment plans the overall dose differences were mostly within 3% or 2mm with the first material set. Larger differences were observed for a large 4MeV beam entering curved patient surface with extended SSD and also in regions of large dose gradients. Still the DTA values were within 3mm. The discrepancies between the eMC and the full MC were generally larger for the second material set. The version 11.0.31 performed always inferiorly, when compared to the 13.6.23.

Natural killer (NK) cells are important in destroying tumor cells. However, they are damaged by radiation therapy. We studied the effects of single and fractionated irradiation on the viability and cytotoxicity of human non-selected NK cells and sub-groups with cluster of differentiation (CD) CD16(+) and CD56(+) in vitro. Only very few studies dealing with the standard radiobiological parameters for characterizing NK cells exist in the literature.NK cell populations were isolated from buffy coats using different methods and irradiated with single doses up to 80 Gy and fractionated doses of 10 or 30 Gy with different numbers of applications and at different intervals. The study end-points were viability using propidium iodide (PI), trypan blue and intracellular adenosine triphosphate (ATP) assays, and cytotoxicity using the (51)Cr-release assay. The standard radiobiological parameters α and β of the linear-quadratic (L-Q) model and the mean inactivation dose D̅ taken as the area under the curve (AUC) were calculated to characterize the radiosensitivity of different NK cell populations.The AUC values of the 51Cr release data in the dose range of 0-40 Gy were as follows: for non-selected NK cells, 23.6-20.9 Gy; for CD16(+) and CD56(+) cells, 14.5-13.2 Gy. The AUC values of ATP, trypan blue and propidium iodide methods equally well described the viability of irradiated NK cells. The α/β ratio for cytotoxicity and viability data in the L-Q model corresponded to the acutely responding tissues. Splitting a 30-Gy dose into two fractions applied at different intervals caused a significant rise in ATP levels and cytotoxicity. Dividing the total dose into four doses applied at fixed intervals also resulted in significant elevations of ATP content and cytotoxicity of NK cells at 10 Gy.According to the L-Q method, irradiated NK cells behaved similarly to acutely responding human tissues with respect to cytotoxicity and viability. The AUC proved very useful for comparing the effects of irradiation on NK cells.

Background and purposes: Permanent xerostomia as a result of radiation-induced salivary gland damage remains a common side effect of radiotherapy (RT) of the head and neck. The purpose of this study was to evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the post-RT salivary gland function in patients with head and neck cancer (HNC). Materials and methods: In this prospective study, 20 HNC patients scheduled for bilateral neck chemoradiotherapy (CRT) with weekly cisplatin went through diffusion-weighted magnetic resonance imaging (DW-MRI) and salivary gland scintigraphy (SGS) prior to and at a mean of six months after completing the treatment. The changes in apparent diffusion coefficient (ADC) before and after treatment were compared with ejection fraction (EF) measured with SGS and the radiation dose absorbed by the salivary glands. Results: As a result of gustatory stimulation with ascorbic acid, the ADC showed a biphasic response with an initial increase and subsequent decrease. This pattern was seen both before and after RT. Post-RT ADC increased as a function of RT dose absorbed by the salivary glands. A moderate statistical correlation between pre- and post-RT ADCs at rest and EF measured with SGS was found. Conclusions: DW-MRI seems a promising tool for detection of physiological and functional changes in major salivary glands after RT. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

The aim of this study was to find optimal planning approach for large planning targets with complicated geometry requiring wide field openings. The study presents a novel approach for arc geometry design for pelvic targets with extensive nodal involvement. A total of 15 patients with anorectal carcinoma or vulvar cancer were selected retrospectively. For each patient, one seven-field IMRT plan and three VMAT plans were calculated: one with two 360° arcs with no limitations for the field size (VMATw); one with two asymmetrically field-size-restricted 360° arcs (VMATr); and the proposed novel approach which consisted of one 360° arc with the field size restricted to the central PTV, and another arc divided into two 180° arcs, restricting the field sizes with the focus on the lymph nodes. The techniques were compared in terms of PTV coverage (VPTV(95%)), dose maximum (D(max)), dose conformity index (CI), homogeneity index (HI), and organs at risk doses. The proposed novel approach with one full and two half arcs tended to have better PTV coverage (VPTV(95%) = 97% ± 2%, compared to 95% ± 3%, 95% ± 3%, and 97% ± 2% in VMATw, VMATr, and 7f-IMRT, respectively) and lower maxima (D(max) = 107% ± 1%, compared to 110% ± 3%, 110% ± 4%, and 110% ± 4% in VMATw, VMATr, and 7f-IMRT, respectively); and lower or equal organs at risk doses. The superiority of the proposed technique (CI = 1.16 ± 0.05, HI = 9 ± 2) was more pronounced compared with the VMATw plans (CI = 1.41 ± 0.10, paired t-test p < 0.001; HI = 12 ± 2, p < 0.001), but the proposed technique was slightly better also in comparison with the VMATr plans (CI = 1.21 ± 0.07, p < 0.001; HI= 11 ± 4, p = 0.015) and 7f-IMRT plans (CI = 1.18 ± 0.03, p = 0.016; HI = 10 ± 2, p = 0.215). Radiotherapy treatment planning for large and complicated treatment volumes benefits not only from restricting the field size but also from careful field design that considers PTV geometry. This optimizes multileaf collimator movements, leading to better dose conformity and homogeneity.