Improving the modelling of a multi-leaf collimator with tilted leaf sides used in radiotherapy.

Background and purpose: Multi-leaf collimators (MLCs) with tilted leaf sides have a complex transmission behaviour that is not easily matched by radiotherapy treatment planning systems (TPSs). We sought to develop an MLC model that can accurately match test fields and clinically relevant plans at different centres. Materials and methods: Two new MLC models were developed and evaluated within a research version of a commercial TPS. Prototype I used adjusted-constant transmissions and Prototype II used variable transmissions at the tongue-and-groove and leaf-tip regions. Three different centres evaluated these prototypes for a tilted MLC and compared them with their initial MLC model using test fields and patient-specific quality-assurance measurements of clinically relevant plans. For the latter, gamma passing rates (GPR) at 2 %/2mm were recorded. Results: For the prototypes the same set of MLC parameters could be used at all centres, with only a slight adjustment of the offset parameter. For centres A and C, average GPR were >95 % and within 0.5 % GPR difference between the standard, and prototype models. In center B, prototypes I and II improved the agreement in clinically relevant plans, with an increase in GPR of 2.3 % ± 0.8 % and 3.0 ± 0.8 %, respectively. Conclusions: The prototype MLC models were either similar or superior to the initial MLC model, and simpler to configure because fewer trade-offs were required. Prototype I performed comparably to the more sophisticated Prototype II and its configuration can be easily standardized, which can be useful to reduce variability and improve safety in clinical practice.

SEAFARER - A new concept for validating radiotherapy patient specific QA for clinical trials and clinical practice.

BACKGROUND: The quality of radiotherapy delivery has been shown to significantly impact clinical outcomes including patient survival. To identify errors, institutions perform Patient Specific Quality Assurance (PSQA) assessing each individual radiotherapy plan prior to starting patient treatments. Externally administered Dosimetry Audits have found problems despite institutions passing their own PSQA. Hence a new audit concept which assesses the institution's ability to detect errors with their routine PSQA is needed. METHODS: Purposefully introduced edits which simulated treatment delivery errors were embedded into radiation treatment plans of participating institutions. These were designed to produce clinically significant changes yet were mostly within treatment delivery specifications. Actual impact was centrally assessed for each plan. Institutions performed PSQA on each plan, without knowing which contained errors. RESULTS: Seventeen institutions using six radiation treatment planning systems and two delivery systems performed PSQA on twelve plans each. Seventeen erroneous plans (across seven institutions) passed PSQA despite causing >5% increase in spinal cord dose relative to the original plans. Six plans (from four institutions) passed despite a >10% increase. CONCLUSIONS: This novel audit concept evolves beyond testing an institution's ability to deliver a single test case, to increasing the number of errors caught by institutions themselves, thus increasing quality of radiation therapy and impacting every patient treated. Administered remotely this audit also provides advantages in cost, environmental impact, and logistics.

Evaluating the Propagation of Uncertainties in Biologically Based Treatment Planning Parameters.

Biologically based treatment planning is a broad term used to cover any instance in radiotherapy treatment planning where some form of biological input has been used. This is wide ranging, and the simpler forms (e.g., fractionation modification/optimization) have been in use for many years. However, there is a reluctance to use more sophisticated methods that incorporate biological models either for plan evaluation purposes or for driving plan optimizations. This is due to limited data available regarding the uncertainties in these model parameters and what impact these have clinically. This work aims to address some of these issues and to explore the role that uncertainties in individual model parameters have on the overall tissue control probability (TCP)/normal tissue control probability (NTCP) calculated, those parameters that have the largest influence and situations where extra care must be taken. In order to achieve this, a software tool was developed, which can import individual clinical DVH's for analysis using a range of different TCP/NTCP models. On inputting individual model parameters, an uncertainty can be applied. Using a normally distributed random number generator, distributions of parameters can be generated, from which TCP/NTCP values can be calculated for each parameter set for the DVH in question. These represent the spread in TCP/NTCP parameters that would be observed for a simulated population of patients all being treated with that particular dose distribution. A selection of clinical DVHs was assessed using published parameters and their associated uncertainties. A range of studies was carried out to determine the impact of individual parameter uncertainties including reduction of uncertainties and assessment of what impact fractionation and dose have on these probabilities.

The influence of lack of reference conditions on dosimetry in pre-clinical radiotherapy with medium energy x-ray beams.

Despite well-established dosimetry in clinical radiotherapy, dose measurements in pre-clinical and radiobiology studies are frequently inadequate, thus undermining the reliability and reproducibility of published findings. The lack of suitable dosimetry protocols, coupled with the increasing complexity of pre-clinical irradiation platforms, undermines confidence in preclinical studies and represents a serious obstacle in the translation to clinical practice. To accurately measure output of a pre-clinical radiotherapy unit, appropriate Codes of Practice (CoP) for medium energy x-rays needs to be employed. However, determination of absorbed dose to water (Dw) relies on application of backscatter factor (Bw) employing in-air method or carrying out in-phantom measurement at the reference depth of 2 cm in a full backscatter (i.e. 30 × 30 × 30 cm3) condition. Both of these methods require thickness of at least 30 cm of underlying material, which are never fulfilled in typical pre-clinical irradiations. This work is focused on evaluation the effects of the lack of recommended reference conditions in dosimetry measurements for pre-clinical settings and is aimed at extending the recommendations of the current CoP to practical experimental conditions and highlighting the potential impact of the lack of correct backscatter considerations on radiobiological studies.

Radiobiological Implications of Nanoparticles Following Radiation Treatment.

Materials with a high atomic number (Z) are shown to cause an increase in the level of cell kill by ionizing radiation when introduced into tumor cells. This study uses in vitro experiments to investigate the differences in radiosensitization between two cell lines (MCF-7 and U87) and three commercially available nanoparticles (gold, gadolinium, and iron oxide) irradiated by 6 MV X-rays. To assess cell survival, clonogenic assays are carried out for all variables considered, with a concentration of 0.5 mg mL-1 for each nanoparticle material used. This study demonstrates differences in cell survival between nanoparticles and cell line. U87 shows the greatest enhancement with gadolinium nanoparticles (2.02 ± 0.36), whereas MCF-7 cells have higher enhancement with gold nanoparticles (1.74 ± 0.08). Mass spectrometry, however, shows highest elemental uptake with iron oxide and U87 cells with 4.95 ± 0.82 pg of iron oxide per cell. A complex relationship between cellular elemental uptake is demonstrated, highlighting an inverse correlation with the enhancement, but a positive relation with DNA damage when comparing the same nanoparticle between the two cell lines.

Corrigendum: Evaluating the Propagation of Uncertainties in Biologically Based Treatment Planning Parameters.

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Clinical validation and benchmarking of knowledge-based IMRT and VMAT treatment planning in pelvic anatomy.

PURPOSE: The aim of this work was to determine whether a commercial knowledge-based treatment planning (KBP) module can efficiently produce IMRT and VMAT plans in the pelvic region (prostate & cervical cancer), and to assess sensitivity of plan quality to training data and model parameters. METHODS: Initial benchmarking of KBP was performed using prostate cancer cases. Structures and dose distributions from 40 patients previously treated using a 5-field IMRT technique were used for model training. Two types of model were created: one excluded statistical outliers (as identified by RapidPlan guidelines) and the other had no exclusions. A separate model for cervix uteri cancer cases was subsequently developed using 37 clinical patients treated for cervical cancer using RapidArc™ VMAT, with no exclusions. The resulting models were then used to generate plans for ten patients from each patient group who had not been included in the modelling process. Comparisons of generated RapidPlans with the corresponding clinical plans were carried out to indicate the required modifications to the models. Model parameters were then iteratively adjusted until plan quality converged with that obtained by experienced planners without KBP. RESULTS: Initial automated model generation settings led to poor conformity, coverage and efficiency compared to clinical plans. Therefore a number of changes to the initial KBP models were required. Before model optimisation, it was found that the PTV coverage was slightly reduced in the superior and inferior directions for RapidPlan compared with clinical plans and therefore PTV parameters were adjusted to improve coverage. OAR doses were similar for both RapidPlan and clinical plans (p>0.05). Excluding outliers had little effect on plan quality (p≫0.05). Manually fixing key optimisation objectives enabled production of clinically acceptable treatment plans without further planner intervention for 9 of 10 prostate test patients and all 10 cervix test patients. CONCLUSIONS: The Varian RapidPlan™ system was able to produce IMRT & VMAT treatment plans in the pelvis, in a single optimisation, that had comparable sparing and comparable or better conformity than the original clinically acceptable plans. The system allows for better consistency and efficiency in the treatment planning process and has therefore been adopted clinically within our institute with over 100 patients treated.

The effect of vitamin D supplementation on arterial stiffness in an elderly community-based population.

Vitamin D deficiency may lead to impaired vascular function and abnormalities in central arterial stiffness. We compared the effects of two different doses of vitamin D3 on arterial stiffness in an elderly population with deficient serum 25-hydroxy-vitamin D levels. A total of 119 known vitamin D deficient (<50 nmol/L) subjects were randomized to receive either 50,000 international units (IU) or 100,000 IU single intramuscular vitamin D3. In the group that received 100,000 IU vitamin D, median pulse wave velocity decreased from 12.2 m/s (range, 5.1-40.3 m/s) to 11.59 m/s (range, 4.3-14.9 m/s) after 8 weeks (P = .22). A mean decrease of 3.803 ± 1.7 (P = .032) in augmentation index (a measure of systemic stiffness) was noted. Only 3/51 (5.8%) who received 100,000 IU vitamin D reached levels of sufficiency (>75 nmol/L). A significant decrease in augmentation index was seen in the group that received 100,000 IU vitamin D. Serum levels of 25-hydroxy-vitamin D were still deficient at 8 weeks in the majority of patients, which may be attributable to impaired bioavailability.

Radiosensitization of glioblastoma cells using a histone deacetylase inhibitor (SAHA) comparing carbon ions with X-rays.

PURPOSE: Prognosis for patients with glioblastoma (GBM) remains poor, and new treatments are needed. Here we used a combination of two novel treatment modalities: Carbon ions and a histone deacetylase inhibitor (HDACi). We compared these to conventional X-rays, measuring the increased effectiveness of carbon ions as well as radiosensitization using HDACi. MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA) was used at a non-toxic concentration of 0.5 µM in combination with 85 keV µm(-1) carbon ions, and 250 kVp X-rays for comparison. Effects were assayed using clonogenic survival, γH2AX foci repair kinetics and measuring chromatin decondensation. RESULTS: Dose toxicity curves showed that human GBM LN18 cells were more sensitive to SAHA compared to U251 cells at higher doses, but there was little effect at low doses. When combined with radiation, clonogenic assays showed that the Sensitizer Enhancement Ratio with carbon ions at 50% survival (SER(50)) was about 1.2 and 1.5 for LN18 and U251, respectively, but was similar for X-rays at about 1.3. The repair half-life of γH2AX foci was slower for cells treated with SAHA and was most noticeable in U251 cells treated with carbon ions where after 24 h, more than double the number of foci remained in comparison to the untreated cells. Hoechst fluorescent dye incorporation into the nucleus showed significant chromatin decondensation and density homogenization with SAHA treatment for both cell lines. CONCLUSION: Our results suggest a vital role of histone deacetylases (HDAC) in the modulation of DNA damage response and support the use of SAHA for the treatment of GBM through the combination with heavy ion therapy.

Repeatability of the measurement of aortic pulse wave velocity (aPWV) in the clinical assessment of arterial stiffness in community-dwelling older patients using the Vicorder(®) device.

BACKGROUND: Pulse wave velocity measured using the Vicorder(®) apparatus is a non-invasive indicator of arterial stiffness. The objective of this study was to assess its repeatability in older patients when used by medical professionals with limited experience of the technique. METHODS: Aortic pulse wave velocity (aPWV) was measured using the Vicorder(®) system four times using the conventional pathway and twice by adapted pathway in 25 consecutive ambulant patients (15 male) after they rested supine for 15 min. A nurse and a doctor independently and alternately measured PWV using the same equipment and were blinded to their colleague's PWV readings. 'Within' and 'between' observer differences were assessed using intra-class correlation coefficients (rI) and 95% limits of agreement (95% LoA) derived from Bland-Altman plots. RESULTS: Mean age was 79.8 (mean blood pressure [BP] = 133/69, Mean heart rate [HR]: 70.9). Mean PWV was 11.73 (Standard Deviation [SD] 2.6-3.6). 'Between' and 'within' observer repeatability was high, with rIs ranging from 0.8-0.93. The repeatability index for 'between' nurse and doctor measures was slightly lower (rI = 0.88) when an adapted cuff measure was used in assessing PWV compared to conventional cuff measures (rI = 0.93). Mean PWV readings 'between' observers differed by only 0.094 (95% CI -0.24 to 1.59). CONCLUSION: When undertaken by operators with limited previous technical experience, both 'within' and 'between' observer repeatability of PWV measurement was high. This method has the potential to be included in the clinical assessment of arterial stiffness in older ambulant patients.