Conversion of helical tomotherapy plans to step-and-shoot IMRT plans-Pareto front evaluation of plans from a new treatment planning system

Purpose: The resulting plans from a new type of treatment planning system called SharePlan (TM) have been studied. This software allows for the conversion of treatment plans generated in a TomoTherapy system for helical delivery, into plans deliverable on C-arm linear accelerators (linacs), which is of particular interest for clinics with a single TomoTherapy unit. The purpose of this work was to evaluate and compare the plans generated in the SharePlan system with the original TomoTherapy plans and with plans produced in our clinical treatment planning system for intensity-modulated radiation therapy (IMRT) on C-arm linacs. In addition, we have analyzed how the agreement between SharePlan and TomoTherapy plans depends on the number of beams and the total number of segments used in the optimization. Methods: Optimized plans were generated for three prostate and three head-and-neck (H&N) cases in the TomoTherapy system, and in our clinical treatment planning systems (TPS) used for IMRT planning with step-and-shoot delivery. The TomoTherapy plans were converted into step-and-shoot IMRT plans in SharePlan. For each case, a large number of Pareto optimal plans were created to compare plans generated in SharePlan with plans generated in the Tomotherapy system and in the clinical TPS. In addition, plans were generated in SharePlan for the three head-and-neck cases to evaluate how the plan quality varied with the number of beams used. Plans were also generated with different number of beams and segments for other patient cases. This allowed for an evaluation of how to minimize the number of required segments in the converted IMRT plans without compromising the agreement between them and the original TomoTherapy plans. Results: The plans made in SharePlan were as good as or better than plans from our clinical system, but they were not as good as the original TomoTherapy plans. This was true for both the head-and-neck and the prostate cases, although the differences between the plans for the latter were small. The evaluation of the head-and-neck cases also showed that the plans generated in SharePlan were improved when more beams were used. The SharePlan Pareto front came close to the front for the TomoTherapy system when a sufficient number of beams were added. The results for plans generated with varied number of beams and segments demonstrated that the number of segments could be minimized with maintained agreement between SharePlan and TomoTherapy plans when 10-19 beams were used. Conclusions: This study showed (using Pareto front evaluation) that the plans generated in SharePlan are comparable to plans generated in other TPSs. The evaluation also showed that the plans generated in SharePlan could be improved with the use of more beams. To minimize the number of segments needed in a plan with maintained agreement between the converted IMRT plans and the original TomoTherapy plans, 10-19 beams should be used, depending on target complexity. SharePlan has proved to be useful and should thereby be a time-saving complement as a backup system for clinics with a single TomoTherapy system installed alongside conventional C-arm linacs. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3592934

Immunization with syngeneic interferon-gamma (IFN-g) secreting tumour cells enhance the Therapeutic effect and Abscopal effect from combined treatment of subcutaneously implanted contra-lateral N29 tumours on Fischer rats with Pulsed electric fields (PEF) and 60Co-gamma radiation.

The aim of the present study is to study the Abscopal regression of subcutaneously implanted N29 rat glioma after immunization with syngeneic IFNg secreting cells and treatment of contra-lateral tumours with pulsed electric fields (PEF) and/or radiation therapy (RT). The study was performed on rats of the Fischer-344 strain with rat glioma N29 tumours implanted subcutaneously on the flank or on both the right treated hind leg and the left untreated hind leg. Once weekly for three weeks, the animals were given intra-peritoneal injections of irradiated, modified N29 tumour cells, secreting interferon-gamma (IFN-g). PEF was given with 16 exponentially decaying pulses at a maximum electric fields strength of 1400 V/cm and t1/e= 1 ms. RT was given with 60Co gamma radiation at daily fractions of 5 Gy, to a total absorbed dose of 20 Gy. The animals were arranged into controls and groups of various treatments: PEF, RT, PEF+RT and immunization (IFNg). Fitting the data obtained from consecutive measurements of tumour volume (TV) of each individual tumour to an exponential model TV = TV0*exp[TGR*t] estimated the tumours growth rate (TGR %per day) after the day of treatment (t = 0). TGR of the right-lateral treated tumour was significantly decreased for independent treatments with PEF and RT and with the combined treatment PEF+RT. With immunization (IFNg) alone and in combination with PEF there was, however, no significant decrease of the TGR of the right-lateral tumours. But in the combination of immunization with RT or PEF+RT there was a highly significant decrease of the TGR values. The Abscopal effect was evaluated by comparing the growth rate of the untreated contra lateral tumours with the treated tumours. TGR of the left-lateral untreated tumour in the groups with independent treatment of right-lateral tumours with PEF, was not significantly reduced. But the TGR values are significantly reduced in the group of rats treated with RT and the combination PEF + RT. With IFNg alone and in combinations with PEF or RT there was no significant decrease of the TGR in the left lateral tumours. But in the combination of IFNg with PEF+RT there was a highly significant decrease of the TGR values in the left lateral tumours. The specific therapeutic effect (STE = 1 - TGRExposed/ TGRCtrl ) after treatments with PEF was 0.30±0.01 and after RT 0.46±0.04 and after the combination PEF+RT 0.36+/- 0.08. After immunization with IFNg secreting tumour cells the STE 0.09+/- 0.07 is not significantly different from zero. Also for the combination of immunization and PEF the STE value of 0.07+/- 0.07 is not significantly different from zero. In the combination of immunization with RT the STE value was 0.32+/- 0.01 that is significantly different from zero and only slightly lower than for RT alone. The STE of the combination of immunization with (PEF+RT) resulted in an unexpectedly high STE value of 0.70+/- 0.08 that is highly significantly different from zero (p < 0.0001). The specific Abscopal effect (SAE = 1 - TGRUn-Exposed/ TGRCtrl ) of the contra lateral unexposed tumours in rats treated with PEF or RT are both significantly different from zero. For RT the average SAE value is 0.33+/- 0.04 and for PEF it is 0.11+/- 0.05. The SAE value for the combined treatment with PEF + RT is 0.26+/- 0.02 that is about the same as for RT alone. For immunization with IFNg secreting tumour cells only and IFNg +PEF the SAE values were not significantly different from zero. But IFNg combined with RT result in a SAE value of 0.18±0.12 and the combination of IFNg with PEF+RT results in an improved abscopal effect with the SAE value of 0.33+/- 0.06. After combined treatment with PEF + RT the average of the therapeutic enhancement ratio (TER = STEExperimental / STEIndependent) is 0.47 +/- 0.12 and the abscopal enhancement ratio (AER = SAEExperimental / SAEIndependent) is 0.61 +/- 0.1 respectively. With all three treatment modalities combined IFNg + PEF + RT and all combinations of independent treatments with PEF, RT or IFNg are considered, the average of the TER is 1.20+/- 0.15 and AER is 1.22+/- 0.20. This might indicate that there is a synergism on the tumours on both sides by combining PEF, RT and immunization with IFNg secreting cells. These results were first presented Nov 21-24, 2002, as Poster at Society of Neuro-Oncology (SNO) Annual Meeting, San Diego, USA (Persson et al 2002)

Haematological toxicity in adult patients receiving craniospinal irradiation - Indication of a dose-bath effect.

The purpose of this study was to investigate the correlation between the haematological toxicity observed in patients treated with craniospinal irradiation, and the dose distribution in normal tissue, specifically the occurrence of large volumes exposed to low dose

Comparable survival in rats with intracranial glioblastoma irradiated with single-fraction conventional radiotherapy or FLASH radiotherapy

BackgroundRadiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to conventional radiotherapy (CONV-RT).MethodsFully immunocompetent Fischer 344 rats with the GFP-positive NS1 intracranial glioblastoma model were irradiated with CONV-RT or FLASH-RT in one fraction of 20 Gy, 25 Gy or 30 Gy. Animals were monitored for survival and acute dermal side effects. The brains were harvested upon euthanasia and tumors were examined post mortem.ResultsSurvival was significantly increased in animals irradiated with CONV-RT and FLASH-RT at 20 Gy and 25 Gy compared to control animals. The longest survival was reached in animals irradiated with FLASH-RT and CONV-RT at 25 Gy. Irradiation at 30 Gy did not lead to increased survival, despite smaller tumors. Tumor size correlated inversely with irradiation dose, both in animals treated with CONV-RT and FLASH-RT. Acute dermal side effects were mild, but only a small proportion of the animals were alive for evaluation of those side effects.ConclusionThe dose response was similar for CONV-RT and FLASH-RT in the present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose

Beam control system and output fine-tuning for safe and precise delivery of FLASH radiotherapy at a clinical linear accelerator

IntroductionWe have previously adapted a clinical linear accelerator (Elekta Precise, Elekta AB) for ultra-high dose rate (UHDR) electron delivery. To enhance reliability in future clinical FLASH radiotherapy trials, the aim of this study was to introduce and evaluate an upgraded beam control system and beam tuning process for safe and precise UHDR delivery.Materials and MethodsThe beam control system is designed to interrupt the beam based on 1) a preset number of monitor units (MUs) measured by a monitor detector, 2) a preset number of pulses measured by a pulse-counting diode, or 3) a preset delivery time. For UHDR delivery, an optocoupler facilitates external control of the accelerator’s thyratron trigger pulses. A beam tuning process was established to maximize the output. We assessed the stability of the delivery, and the independent interruption capabilities of the three systems (monitor detector, pulse counter, and timer). Additionally, we explored a novel approach to enhance dosimetric precision in the delivery by synchronizing the trigger pulse with the charging cycle of the pulse forming network (PFN).ResultsImproved beam tuning of gun current and magnetron frequency resulted in average dose rates at the dose maximum at isocenter distance of &gt;160 Gy/s or &gt;200 Gy/s, with or without an external monitor chamber in the beam path, respectively. The delivery showed a good repeatability (standard deviation (SD) in total film dose of 2.2%) and reproducibility (SD in film dose of 2.6%). The estimated variation in DPP resulted in an SD of 1.7%. The output in the initial pulse depended on the PFN delay time. Over the course of 50 measurements employing PFN synchronization, the absolute percentage error between the delivered number of MUs calculated by the monitor detector and the preset MUs was 0.8 ± 0.6% (mean ± SD).ConclusionWe present an upgraded beam control system and beam tuning process for safe and stable UHDR electron delivery of hundreds of Gy/s at isocenter distance at a clinical linac. The system can interrupt the beam based on monitor units and utilize PFN synchronization for improved dosimetric precision in the dose delivery, representing an important advancement toward reliable clinical FLASH trials

Evaluation of single-fraction high dose FLASH radiotherapy in a cohort of canine oral cancer patients

BackgroundFLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the normal tissue sparing effect of FLASH RT potentially makes it especially advantageous for treating oral tumors. In this work, the objective was to study the adverse effects of dogs with spontaneous oral tumors treated with FLASH RT.MethodsPrivately-owned dogs with macroscopic malignant tumors of the oral cavity were treated with a single fraction of ≥30Gy electron FLASH RT and subsequently followed for 12 months. A modified conventional linear accelerator was used to deliver the FLASH RT.ResultsEleven dogs were enrolled in this prospective study. High grade adverse effects were common, especially if bone was included in the treatment field. Four out of six dogs, who had bone in their treatment field and lived at least 5 months after RT, developed osteoradionecrosis at 3-12 months post treatment. The treatment was overall effective with 8/11 complete clinical responses and 3/11 partial responses.ConclusionThis study shows that single-fraction high dose FLASH RT was generally effective in this mixed group of malignant oral tumors, but the risk of osteoradionecrosis is a serious clinical concern. It is possible that the risk of osteonecrosis can be mitigated through fractionation and improved dose conformity, which needs to be addressed before moving forward with clinical trials in human cancer patients

A note on the interpretation of the gamma evaluation index

The gamma evaluation method has become the gold standard for the comparison between measured and calculated absorbed dose distributions. However, test criteria and failure rate tolerance levels have hitherto normally been based on empirical evidence, rather than rigorous statistical analysis. In this work, it is proposed that the gamma-evaluation method could be reinterpreted such that the absorbed dose difference and distance-to-agreement criteria are replaced by the standard deviations of the associated uncertainties. By comparison between absorbed dose calculations and simulated measurements for clinically realistic test cases in 1D and 2D, it is then shown that the resulting squared gamma distribution follows a chi-squared distribution with one degree of freedom. This result can be used to test the statistical significance of measured deviations, and to determine proper failure rate tolerance levels in clinical radiotherapy quality control

Motion induced interplay effects for VMAT radiotherapy

The purpose of this study was to develop a method to simulate breathing motion induced interplay effects for volumetric modulated arc therapy (VMAT), to verify the proposed method with measurements, and to use the method to investigate how interplay effects vary with different patient- and machine specific parameters. VMAT treatment plans were created on a virtual phantom in a treatment planning system (TPS). Interplay effects were simulated by dividing each plan into smaller sub-arcs using an in-house developed software and shifting the isocenter for each sub-arc to simulate a sin6 breathing motion in the superior-inferior direction. The simulations were performed for both flattening-filter (FF) and flattening-filter free (FFF) plans and for different breathing amplitudes, period times, initial breathing phases, dose levels, plan complexities, CTV sizes, and collimator angles. The resulting sub-arcs were calculated in the TPS, generating a dose distribution including the effects of motion. The interplay effects were separated from dose blurring and the relative dose differences to 2% and 98% of the CTV volume (ΔD98% and ΔD2%) were calculated. To verify the simulation method, measurements were carried out, both static and during motion, using a quasi-3D phantom and a motion platform. The results of the verification measurements during motion were comparable to the results of the static measurements. Considerable interplay effects were observed for individual fractions, with the minimum ΔD98% and maximum ΔD2% being -16.7% and 16.2%, respectively. The extent of interplay effects was larger for FFF compared to FF and generally increased for higher breathing amplitudes, larger period times, lower dose levels, and more complex treatment plans. Also, the interplay effects varied considerably with the initial breathing phase, and larger variations were observed for smaller CTV sizes. In conclusion, a method to simulate motion induced interplay effects was developed and verified with measurements, which allowed for a large number of treatment scenarios to be investigated. The simulations showed large interplay effects for individual fractions and that the extent of interplay effects varied with the breathing pattern, FFF/FF, dose level, CTV size, collimator angle, and the complexity of the treatment plan

Prediction of stopping-power ratios in flattening-filter free beams.

PURPOSE: In recent years, there has been an increasing interest in flattening-filter free (FFF) beams. However, since the removal of the flattening filter will affect both the mean and the variance of the energy spectrum, current beam-quality specifiers may not be adequate for reference dosimetry in such beams. The purpose of this work was to investigate an alternative, more general beam-quality specifier. METHODS: The beam-quality specifier used in this work was a combination of the kerma-weighted mean and the coefficient of variation of the linear attenuation coefficient in water. These parameters can in theory be determined from narrow-beam transmission measurements using a miniphantom "in-air," which is a measurement condition well suited also to small and nonstandard fields. The relation between the Spencer-Attix stopping-power ratios and this novel beam-quality specifier was described by a simple polynomial. For reference, the authors used Monte Carlo calculated spectra and stopping-power data for nine different beams, with and without flattening filter. RESULTS: The polynomial coefficients were obtained by least-squares optimization. For all beams included in this investigation, the average of the differences between the predicted and the Monte Carlo calculated stopping-power ratios was 0.02 +/- 0.17% (1 SD) (including TomoTherapy and CyberKnife example beams). CONCLUSIONS: An alternative dual-parameter beam-quality specifier was investigated. The evaluation suggests that it can be used successfully to predict stopping-power ratios in FFF as well as conventional beams, regardless of filtration