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.

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

[This corrects the article .].

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.

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.