Uncomplicated Tumor Control Research Articles

The radiobiological effect of using Acuros XB vs anisotropic analytical algorithm on hepatocellular carcinoma stereotactic body radiation therapy.

The purpose of this work was to study the radiobiological effect of using Acuros XB (AXB) vs Analytic Anisotropic Algorithm (AAA) on hepatocellular carcinoma (HCC) stereotactic body radiation therapy (SBRT). Seventy SBRT volumetric modulated arc therapy (VMAT) plans for HCC were calculated using AAA and AXB respectively with the same treatment parameters. Published tumor control probability (TCP) and normal tissue complication probability (NTCP) models were used to quantify the effect of dosimetric difference between AAA and AXB on TCP, NTCP and uncomplicated tumor control probability (UTCP). There was an average decrease of 2.5% in 6-month TCP. Normal liver has the largest average decrease in NTCP which was 59.7%. Bowels followed with 26.6% average decrease in NTCP. Duodenum, stomach and esophagus had 10.2%, 5.1%, and 4.3% average decrease in NTCP. There was an average decrease of 1.8% and up to 7.2% in 6-month UTCP. There was an overall decrease in TCP, NTCP, and UTCP for HCC SBRT plans calculated using AXB compared to AAA which could be clinically significant.

Analysis of Hepatocellular Carcinoma Stereotactic Body Radiation Therapy Dose Prescription Method Using Uncomplicated Tumor Control Probability Model

PurposeThis work was to establish an uncomplicated tumor control probability (UTCP) model using hepatocellular carcinoma (HCC) stereotactic body radiation therapy (SBRT) clinical data in our institution. The model was then used to analyze the current dose prescription method and to seek the opportunity for improvement. Methods and MaterialsA tumor control probability (TCP) model was generated based on local clinical data using the maximum likelihood method. A UTCP model was then formed by combining the established TCP model with the normal tissue complication probability model based on the study by Dawson et al. The authors investigated the dependence of maximum achievable UTCP on planning target volume equivalent uniform dose (EUD) at various ratio between planning target volume EUD and normal liver EUD (T/N EUD ratios). A new term uncomplicated tumor control efficiency (UTCE) was also introduced to analyze the outcome. A UTCE value of 1 implied that the theoretical maximum UTCP for the corresponding T/N EUD ratio was achieved. ResultsThe UTCE of the HCC SBRT patients based on the current dose prescription method was found to be 0.93 ± 0.05. It was found that the UTCE could be increased to 0.99 ± 0.03 by using a new dose prescription scheme, for which the UTCP could be maximized while keeping the normal tissue complication probability value smaller than 5%. ConclusionsThe dose prescription method of the current HCC SBRT in our institution was analyzed using a UTCP model established based on local clinical data. It was shown that there could be a potential to increase the prescription dose of HCC SBRT. A new dose prescription scheme was proposed to achieve better UTCP. Additional clinical trials would be required to validate the proposed dose prescription scheme in the future.

Radiobiological Comparison of Teardrop Technique for Breast Cancer Radiotherapy Treatment Planning on a Tomotherapy System.

Breast cancer is one of the most common cancer worldwide with large morbidity. In Mexico, it is the first cause of death by cancer in women. Radiotherapy has proven to be a great tool to control such ailments and TomoTherapy is a relatively new technology to accomplish it. To obtain good clinical outcomes, tight dosimetric constraints are placed on organs at risk (OARs) to maximize tumor control and minimize normal tissue complication probabilities. The teardrop technique helps meeting these constraints by placing a virtual block over parts of the ipsilateral lung and the heart but it contributes to lengthen the treatment time. In this work, we present our experience in using this technique and compare its radiobiological estimations with similar plans without it. Ten patients diagnosed with breast cancer were planned twice, with and without the teardrop technique. Dose-volume histograms were obtained and analyzed to get uncomplicated tumor control probability (UTCP) and optimization estimator (fEUD) parameters. Classical dosimetrical parameters for planning target volumes (PTVs): conformity index, homogeneity index, and coverage were also recorded and statistically described. Several dosimetrical parameters for OARs were recorded and analyzed. The UTCP parameter had a mean value of 0.968 ± 0.023 when no block was used and 0.966 ± 0.022 with the teardrop. The fEUD parameter values were: 0.515 ± 0.049 without blocks and 0.541 ± 0.057 with the teardrop. Optimization of every plan was stopped only after all constraints were met, and it was easier to accomplish this goal with the teardrop technique. The teardrop technique permitted a 5% gain in fEUD. The teardrop technique was observed to have a net radiobiological benefit with little impact on patient scheduling.

A Novel Approach to Design and Evaluate BNCT Neutron Beams Combining Physical, Radiobiological, and Dosimetric Figures of Merit.

Simple SummaryClinical potential and safety are presented as novel criteria to evaluate neutron beams designed for boron neutron capture therapy (BNCT). The presently used figures of merit are a set of physical quantities calculated in air, related to the neutron flux, the collimation, and the spectral characteristics. However, the capability of the beam to deliver an effective and safe treatment to patients should be the most important criterion in view of the clinical application. This work presents the design of a neutron beam produced by a proton accelerator coupled to a beryllium target and the use of new figures of merit to choose the best beam among different candidates. These figures of merit use tridimensional dosimetry simulated in phantoms and patients, to calculate the probability of tumor control without affecting healthy tissues, employing proper radiobiological models. Moreover, the dose absorbed by out-of-field healthy organs is used as a criterion to establish the safest beam for clinical treatments. Results show that beams that would be rejected by physical in-air quantities demonstrate a clinical performance comparable to existing neutron beams successfully used for patients, and that the presented criteria allow a clear selection of the most adequate beam among the ones presented.(1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams; however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom; the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment.

Improving geometric sparing and therapeutic effectiveness of lung SBRT for central and ultra-central tumors.

The use of stereotactic body radiotherapy (SBRT) for central- and ultra-central lung tumors is a major therapeutic challenge since there are trade-offs between delivering adequate dose to the tumor and minimizing toxicity to critical mediastinal organs. This work investigates improving the therapeutic effectiveness of such SBRT treatments by enhancing the geometric sparing of normal tissue and systematically applying a planning target volume (PTV) margin smaller than the conventional values. Using plans from 10 previously SBRT-treated patients, we retrospectively created highly conformal plans with a reduced PTV margin of 2 mm and compared them to the clinical plans with a standard 5 mm PTV margin. We compared various dosimetric and biological parameters. We calculated the geometrical sparing factor (GSF) (ratio of biological dose between normal tissue and targets) for the mediastinal organs and the uncomplicated tumor control probability (UTCP) for the esophagus. We tracked tumor fraction doses using cone-beam computed tomography (CBCT) images. With geometric sparing, the median dose for critical mediastinal organs (proximal bronchial tree, great vessels, esophagus, and heart) dropped by 10 Gy (p ≤ 0.006). Dose sparing for the spinal cord and chest wall was 5 Gy and 8 Gy, respectively (p = 0.002). The geometrical sparing factor (GSF) dropped by 50% for the esophagus and the proximal bronchial tree (PBT) and 40% for the great vessels (p < 0.05). The CBCT fractional tumor dose varied by 2.7% (0.2 Gy) for the initially intended treatment volume and 4% (0.3 Gy) when accounting for daily volume changes. The expected delivered dose was above the prescribed value. Systematically reducing the PTV margin to 2 mm in lung SBRT of central and ultra-central tumors is feasible and ensures consistency in contouring and dose prescribing. It allows safe delivery of highly conformal treatments with significantly higher therapeutic effectiveness, potentially reducing treatment-related complications. Consequently, it may enable safer dose escalation, more effective fractionations, and safer management of retreatments and treatments of multiple synchronous lung tumors.

Monte Carlo evaluation of target dose coverage in lung stereotactic body radiation therapy with flattening filter-free beams.

Previous studies showed that replacing conventional flattened beams (FF) with flattening filter-free (FFF) beams improves the therapeutic ratio in lung stereotactic body radiation therapy (SBRT), but these findings could have been impacted by dose calculation uncertainties caused by the heterogeneity of the thoracic anatomy and by respiratory motion, which were particularly high for target coverage. In this study, we minimized such uncertainties by calculating doses using high-spatial-resolution Monte Carlo and four-dimensional computed tomography (4DCT) images. We aimed to evaluate more reliably the benefits of using FFF beams for lung SBRT. For a cohort of 15 patients with early stage lung cancer that we investigated in a previous treatment planning study, we recalculated dose distributions with Monte Carlo using 4DCT images. This included fifteen FF and fifteen FFF treatment plans. Compared to Monte Carlo, the treatment planning system (TPS) over-predicted doses in low-dose regions of the planning target volume. For most patients, replacing FF beams with FFF beams improved target coverage, tumor control, and uncomplicated tumor control probabilities. Monte Carlo tends to reveal deficiencies in target coverage compared to coverage predicted by the TPS. Our data support previously reported benefits of using FFF beams for lung SBRT.

Using FFF Beams to Improve the Therapeutic Ratio of Lung SBRT.

To investigate the extent to which lung stereotactic body radiotherapy (SBRT) treatment plans can be improved by replacing conventional flattening filter (FF) beams with flattening filter-free (FFF) beams. We selected 15 patients who had received SBRT with conventional 6-MV photon beams for early-stage lung cancer. We imported the patients' treatment plans into the Eclipse 13.6 treatment planning system, in which we configured the AAA dose calculation model using representative beam data for a TrueBeam accelerator operated in 6-MV FFF mode. We then created new treatment plans by replacing the conventional FF beams in the original plans with FFF beams. The FFF plans had better target coverage than the original FF plans did. For the planning target volume, FFF plans significantly improved the D98, D95, D90, homogeneity index, and uncomplicated tumor control probability. In most cases, the doses to organs at risk were lower in FFF plans. FFF plans significantly reduced the mean lung dose, V10, V20, V30, and normal tissue complication probability for the total lung and improved the dosimetric indices for the ipsilateral lung. For most patients, FFF beams achieved lower maximum doses to the esophagus, heart, and the spinal cord; and a lower chest wall V30. Compared with FF beams, FFF beams achieved lower doses to organs at risk, especially the lung, without compromising tumor coverage; in fact, FFF beams improved coverage in most cases. Thus, replacing FF beams with FFF beams can achieve a better therapeutic ratio.

Proposals of models for new formulations of the current complication-free cure (P+) and uncomplicated tumor control probability (UTCP) concepts, and total normal tissue complication probability of late complications

This study proposes phenomenological models for total normal tissue complication probability (TNTCP) and NTCP0. NTCP0 is a new acronym for reformulating the current complication-free cure (P+) and uncomplicated tumor control probability (UTCP) concepts, and TNTCP will reformulate the current NTCP involving multiple organs at risks. The current probabilistic concepts are incoherently formulated with mathematical operations of tumor control probability (TCP) and normal tissue complication probability (NTCP) that are associated with different stochastic processes and random variables. NTCP0 is equal to NTCP0 (normal tissue non-complication probability) that is calculated as the ratio of a number of patients of a population without late complications and a total of them. As a cumulative distribution function (CDF) of late complications, TNTCP = sum(NTCPi), where NTCPi is the NTCP of the ith late complication. TNTCP is also a new acronym, and the probabilistic complement of NTCP0, then NTCP0 = 100% − TNTCP. The NTCP0/TNTCP (D(d)) proposing models are based on the relationship between the NTCP0/TNTCP and total dose (D = n×d; where d = dose per fraction, and n = number of fractions). TNTCP(D) model will be correlated with LKB model (the normal CDF) that is an increasing function; and NTCP0(D) model with a decreasing function, which additionally will define clear limits of three possible regions for NTCP0: 0 and 100% deterministic, and a stochastic. These models are function D, which is widely used for characterizing radiation therapies.

The essential role of radiobiological figures of merit for the assessment and comparison of beam performances in boron neutron capture therapy

PurposeBoron Neutron Capture Therapy (BNCT) is a treatment modality that uses an external neutron beam to selectively inactive boron10-loaded tumor cells. This work presents the development and innovative use of radiobiological probability models to adequately evaluate and compare the therapeutic potential and versatility of beams presenting different neutron energy spectra. M&MAforementioned characteristics, collectively refer to as the performance of a beam, were defined on the basis of radiobiological probability models for the first time in BNCT. A model of uncomplicated tumor control probability (UTCP) for HN cancer was introduced. This model considers a NTCP able to predict severe mucositis and a TCP for non-uniform doses derived herein. A systematic study comprising a simplified HN cancer model is presented as a practical application of the introduced radiobiological figures of merit (FOM) for assessing and comparing the performance of different clinical beams. Applications involving treated HN cancer patients were also analyzed. ResultsThe maximum UTCP proved suitable and sensitive to assess the performance of a beam, revealing particularities of the studied sources that the physical FOMs do not highlight. The radiobiological FOMs evaluated in patients showed to be useful tools both for retrospective analysis of the BNCT treatments, and for prospective studies of beam optimization and feasibility. ConclusionsThe presented developments and applications demonstrated that it is possible to assess and compare performances of completely different beams fairly and adequately by assessing the radiobiological FOM UTCP. Thus, this figure would be a practical and essential aid to guide treatment decisions.

Calculating the Individualized Fraction Regime in Stereotactic Body Radiotherapy for Non-Small Cell Lung Cancer Based on Uncomplicated Tumor Control Probability Function

To calculate the individualized fraction regime (IFR) in stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) patients using the uncomplicated tumor control probability (UTCP, P+) function. 33 patients with peripheral lung cancer or lung metastases who had undergone SBRT were analyzed. Treatment planning was performed using the dose regime of 48 Gy in 4 fractions. Dose volume histogram (DVH) data for the gross tumor volume (GTV), lung, chest wall (CW) and rib were exported and the dose was multiplied from 1% to 200% at a resolution of 1%. For each dose fraction, P+ values were calculated by considering the tumor control probability (TCP), radiation-induced pneumonitis (RIP), chest wall pain (CWP) and radiation-induced rib fracture (RIRF). UTCP values as a function of physical dose were plotted and the maximum P+ values corresponded to the optimal therapeutic gain. IFR in 3 fractions was also calculated with the same method by converted the dose using the linear quadratic (LQ) model. 33 patients attained an IFR using the introduced methods. All the patients achieved TCP value higher than 92.0%. The IFR ranged from 3×10.8 Gy to 3×12.5 Gy for 3 fraction regimes and from 4×9.2 Gy to 4×10.7 Gy for 4 fraction regimes, respectively. Four patients with typical tumor characteristics demonstrated the IFR was patient-specific and could maximize the therapeutic gain. Patients with large tumor were associated with lower TCP, UTCP and smaller fractional dose than patients with small tumor. Patients with tumor adjacent to the organ at risk (OAR) or at high risk of RIP showed lower UTCP and smaller fractional dose compared with patients with tumor away from the OAR. The proposed method is capable of predicting the IFR for NSCLC patients undergoing SBRT. Further validation is required in clinical samples.

Calculating the individualized fraction regime in stereotactic body radiotherapy for non-small cell lung cancer based on uncomplicated tumor control probability function

BackgroundTo calculate the individualized fraction regime (IFR) in stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) patients using the uncomplicated tumor control probability (UTCP, P+) function.MethodsThirty-three patients with peripheral lung cancer or lung metastases who had undergone SBRT were analyzed. Treatment planning was performed using the dose regime of 48 Gy in 4 fractions. Dose volume histogram (DVH) data for the gross tumor volume (GTV), lung, chest wall (CW) and rib were exported and the dose bin was multiplied by a certain percentage of the dose in that bin which ranged from 1 to 200% in steps of 1%. For each dose fraction, P+ values were calculated by considering the tumor control probability (TCP), radiation-induced pneumonitis (RIP), chest wall pain (CWP) and radiation-induced rib fracture (RIRF). UTCP values as a function of physical dose were plotted and the maximum P+ values corresponded to the optimal therapeutic gain. The IFR in 3 fractions was also calculated with the same method by converting the dose using the linear quadratic (LQ) model.ResultsThirty-three patients attained an IFR using the introduced methods. All the patients achieved a TCP value higher than 92.0%. The IFR ranged from 3 × 10.8 Gy to 3 × 12.5 Gy for 3 fraction regimes and from 4 × 9.2 Gy to 4 × 10.7 Gy for 4 fraction regimes. Four patients with typical tumor characteristics demonstrated that the IFR was patient-specific and could maximize the therapeutic gain. Patients with a large tumor had a lower TCP and UTCP and a smaller fractional dose than patients with a small tumor. Patients with a tumor adjacent to the organ at risk (OAR) or at a high risk of RIP had a lower UTCP and a smaller fractional dose compared with patients with a tumor located distant from the OAR.ConclusionsThe proposed method is capable of predicting the IFR for NSCLC patients undergoing SBRT. Further validation in clinical samples is required.

SDE-driven modeling of phenotypically heterogeneous tumors: The influence of cancer cell stemness

We deduce cell population models describing the evolution of a tumor (possibly interacting with its environment of healthy cells) with the aid of differential equations. Thereby, different subpopulations of cancer cells allow accounting for the tumor heterogeneity. In our settings these include cancer stem cells known to be less sensitive to treatment and differentiated cancer cells having a higher sensitivity towards chemo- and radiotherapy. Our approach relies on stochastic differential equations in order to account for randomness in the system, arising e.g., due to the therapy-induced decreasing number of clonogens, which renders a pure deterministic model arguable. The equations are deduced relying on transition probabilities characterizing innovations of the two cancer cell subpopulations, and similarly extended to also account for the evolution of normal tissue. Several therapy approaches are introduced and compared by way of tumor control probability (TCP) and uncomplicated tumor control probability (UTCP). A PDE approach allows to assess the evolution of tumor and normal tissue with respect to time and to cell population densities which can vary continuously in a given set of states. Analytical approximations of solutions to the obtained PDE system are provided as well.

P259] Radiobiological method for the clinical validation of models dose-to-water versus dose-to-meduim in radiotherapy

Purpose A present challenge in medical physics is to implement the most accurate dose calculation algorithm, close to Monte Carlo simulations, with the highest safety to obtain the expected tumour control probability (TCP) and acceptable normal tissue complication probabilities (NTCP). The purpose is to propose dosimetric and radiobiological criteria to safely implement new algorithms in radiotherapy. Methods Lung tumors are taken as examples to demonstrate this transition. The doses were calculated using three types of algorithm: type (a) as pencil beam kernels model, like PBC; type (b) as point kernels model, like AAA and type (c) as Acuros-XB based on the deterministic resolution of the Boltzmann linear transport equation. Acuros-XB offers results close to Monte Carlo simulations and propose two options: dose to water (AXB-Dw) and dose to medium (AXB-Dm). The monitor units (MUs) are retrieved from the reference plan to recalculate the dose distribution with the new one. The equivalent uniform dose (EUD), TCP, NTCP and Uncomplicated Tumor Control Probability (UTCP) were calculated to measure the clinical benefit – toxicity. Results The more advanced algorithms showed that irradiating the lung tumor according to the same prescription, would increase the MUs (5–10%) when moving from pencil kernel to point kernel, and ∼ 2% when moving from AXB-Dw to AXB-Dm, p Conclusion The adjustment of prescribed dose depends on transition types and prescription method. In the lung, a reduction of prescription is advisable when moving from pencil beam model to point kernels model (e.g, 3 × 18 Gy instead of 3 × 20 Gy for SBRT and 5% for 3DCRT). In addition, an optimization should be carried out to obtain the same UTCP. To keep the same TCP and NTCP, we recommend respectively that the EUD for the target ⩾ prescription dose and EUD for healthy lung

Radiobiological assessment of dose-to-medium or dose-to-water with Acuros XB algorithm compared with Anisotropic Analytical Algorithm for lung cancer radiotherapy- What should we know to manage the transition?

Purpose: To track the dosimetric changes for similar dose prescriptions, when dose calculation algorithms are upgraded in the treatment planning system (TPS). Clinically significant representations of the treatment outcomes are used to provide interpretable data for radiation oncologists, as the equivalent uniform dose (EUD), the tumor control probability (TCP), the late toxicity as normal tissue complication probability (NTCP) and the uncomplicated tumor control probability (UTCP) scores. Results are presented and discussed in a clinical perspective. Methods: Ten lung cancer patients were included in this study. For each patient, five treatment plans were generated. The doses were calculated using Anisotropic Analytical Algorithm (AAA) and both Acuros XB (AXB) dose reporting modes: dose-to-medium AXB D(m,m) and dose-to-water AXB D(w,m). In plans 1, 2 and 3, the doses were calculated respectively with AAA, AXB D(m,m) and AXB D(w,m) using exactly the same prescription dose and beam set-up. The doses in plans 4 and 5 were calculated using both AXB dose reporting modes using, as input, the same number of monitor units (MUs) as yielded by AAA, with the same beam set-up. The EUD, TCP and NTCP were computed using the assumed radiobiological parameters from literature. The Wilcoxon paired test was used to calculate p-values. Results: Using the same prescription dose, TCP values were higher with AXB than with AAA, and corresponding UTCP scores were 1-2% better with p < 0.05. In addition, absolute NTCP values were slightly increased with AXB. Both AXB dose reporting modes yielded comparable lower TCP and NTCP values (again in the order of 1-2%) than with AAA, when using same MU numbers as with AAA. Conclusion: Compared to AAA, taken as reference, both AXB dose reporting modes yielded better results. AAA showed very close values to AXB D(w,m), but it is difficult to give recommendation between D(w,m) and D(m,m) yet, due to the lack of recommended radiobiological parameters associated with these dose reporting modes. We suggest doing experimental and modelling studies to determine the real radiobiological effects in both targets and organs at risks. Should the differences be substantial in some conditions and relevant to clinical practice, discussions regarding dose prescription and optimization of the tolerance doses to OAR should be undertaken between medical physicists and radiation oncologists.

Optimization of radiotherapy fractionation schedules based on radiobiological functions.

To present a method for optimizing radiotherapy fractionation schedules using radiobiological tools and taking into account the patient´s dose-volume histograms (DVH). This method uses a figure of merit based on the uncomplicated tumour control probability (P+) and the generalized equivalent uniform dose (gEUD). A set of doses per fraction is selected in order to find the dose per fraction and the total dose, thus maximizing the figure of merit and leading to a biologically effective dose that is similar to the prescribed schedule. As a clinical example, a fractionation schedule for a prostate treatment plan is optimized and presented herein. From a prescription schedule of 70 Gy/35 × 2 Gy, the resulting optimal schema, using a figure of merit which only takes into account P+, is 54.4 Gy/16 × 3.4 Gy. If the gEUD is included in that figure of merit, the result is 65 Gy/26 × 2.5 Gy. Alternative schedules, which include tumour control probability (TCP) and the normal tissue complication probability (NTCP) values are likewise shown. This allows us to compare different schedules instead of solely finding the optimal value, as other possible clinical factors must be taken into account to make the best decision for treatment. The treatment schedule can be optimized for each patient through radiobiological analysis. The optimization process shown below offers physicians alternative schedules that meet the objectives of the prescribed radiotherapy. Advances in knowledge: This article provides a simple, radiobiological-function-based method to take advantage of a patient's dose-volume histograms in order to better select the most suitable treatment schedule.

Using Indocyanine Green Extraction to Predict Liver Function After Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

To test the hypothesis that mid-treatment measures of the retention of indocyanine green after 15 minutes (ICGR15) would improve the prediction of posttreatment liver function in the setting of hepatocellular carcinoma. Between 2006 and 2015, 144 patients with hepatocellular carcinoma received 175 courses of stereotactic body radiation therapy (SBRT). Patient data, such as age, sex, portal vein thrombosis, cirrhosis, Child-Pugh (CP) score, prior liver-directed therapies, and liver function tests, including albumin-bilirubin (ALBI) and ICG clearance, and dosimetric data, such as tumor volume and radiation dose, were collected. Toxicity was evaluated as a 2-point increase in CP score or a change in ALBI score at 3 months from start of SBRT. Logistic or linear regression was used to build toxicity prediction models based on patient and tumor characteristics and ICG clearance variables. Performance of the models for the binary CP outcome was summarized using area under the curve and receive operating characteristic curves. Likelihood ratio tests were used to evaluate whether the model fit improved after incorporating the ICG variable information. In multivariable analysis age, baseline ICGR15, and change in ICGR15 were associated with toxicity defined by increased CP score. For the continuous ALBI outcome, being female, having cirrhosis, and increasing radiation dose were associated with increased toxicity. When incorporating ICGR15 into these models, an increase in ICGR15 from baseline to mid-treatment was most consistently significantly associated with an increase in toxicity. Incorporation of ICGR15 variables significantly improves the prediction of post-SBRT liver function. The use of ICGR15 can facilitate the delivery of the maximum safe dose of radiation for patients with hepatocellular carcinoma and has the potential to improve uncomplicated tumor control and survival.

Impact of dose calculation models on radiotherapy outcomes and quality adjusted life years for lung cancer treatment: do we need to measure radiotherapy outcomes to tune the radiobiological parameters of a normal tissue complication probability model?

The equivalent uniform dose (EUD) radiobiological model can be applied for lung cancer treatment plans to estimate the tumor control probability (TCP) and the normal tissue complication probability (NTCP) using different dose calculation models. Then, based on the different calculated doses, the quality adjusted life years (QALY) score can be assessed versus the uncomplicated tumor control probability (UTCP) concept in order to predict the overall outcome of the different treatment plans. Nine lung cancer cases were included in this study. For the each patient, two treatments plans were generated. The doses were calculated respectively from pencil beam model, as pencil beam convolution (PBC) turning on 1D density correction with Modified Batho's (MB) method, and point kernel model as anisotropic analytical algorithm (AAA) using exactly the same prescribed dose, normalized to 100% at isocentre point inside the target and beam arrangements. The radiotherapy outcomes and QALY were compared. The bootstrap method was used to improve the 95% confidence intervals (95% CI) estimation. Wilcoxon paired test was used to calculate P value. Compared to AAA considered as more realistic, the PBCMB overestimated the TCP while underestimating NTCP, P<0.05. Thus the UTCP and the QALY score were also overestimated. To correlate measured QALY's obtained from the follow-up of the patients with calculated QALY from DVH metrics, the more accurate dose calculation models should be first integrated in clinical use. Second, clinically measured outcomes are necessary to tune the parameters of the NTCP model used to link the treatment outcome with the QALY. Only after these two steps, the comparison and the ranking of different radiotherapy plans would be possible, avoiding over/under estimation of QALY and any other clinic-biological estimates.

47 - The use of radiobiological TCP and NTCP models to validate the dose calculation algorithm and readjust the prescribed dose

Purpose: This study introduces an advanced method to evaluate and extent the adjustment of the prescribed dose to maintain the same clinical results, when changing the dose calculation algorithm type (a), i.e density correction method to more recently type (b) algorithm, i.e AAA. Material and methods: 10 cases with lung cancer were studied. For each case, 3 treatment plans were generated. Plan 1 was generated using type (a) algorithm, and Plan 2 using type (b) algorithm. In plan 3 the dose was calculated with type (b) algorithm using monitor units from plan 1 as input. A global analysis based on 2D and 3D gamma (γ) was made to evaluate the under / overestimation of calculated dose. Clinical evaluation was carried out using Tumour Control Probability (TCP) and Normal Tissue Complication Probabilities (NTCP) based on Uniform Equivalent Dose model. Assuming a constant TCP, the ratio “R= TCP/NTCP” and Uncomplicated Tumor Control Probability (UTCP) were calculated to measure the clinical benefit – toxicity. Wilcoxon test was used to evaluate the significance of the differences and the correlation coefficient (r) was calculated using Spearman’s rank test. Results: The dose calculated with algorithm type (b) was significantly overestimated to organs at risks while the delivered dose in MU was underestimated, p < 0.001. Therefore, γ maps confirmed the dosimetric results. Moreover, there were a significant difference for NTCP for lung and heart. The ratio “R” from plan 1 and plan 2 were significantly different, indicating that to maintain the same effect benefit and toxicity the prescribed dose should be readjusted. Conclusion: We assessed the prescribed dose using the radiobiological models. The ratio of benefit was significantly changed when moving from type (a) algorithm to type (b) algorithm. This indicate that the prescribed dose should be readjusted when type (b) algorithm will be integrated in radiation oncology. A discussion between oncologist and physicist is quite necessary in order to readjust the prescribed dose.

RADBIOMOD: A simple program for utilising biological modelling in radiotherapy plan evaluation

PurposeRadiotherapy plan evaluation is currently performed by assessing physical parameters, which has many limitations. Biological modelling can potentially allow plan evaluation that is more reflective of clinical outcomes, however further research is required into this field before it can be used clinically. MethodsA simple program, RADBIOMOD, has been developed using Visual Basic for Applications (VBA) for Microsoft Excel that incorporates multiple different biological models for radiotherapy plan evaluation, including modified Poisson tumour control probability (TCP), modified Zaider–Minerbo TCP, Lyman–Kutcher–Burman normal tissue complication probability (NTCP), equivalent uniform dose (EUD), EUD-based TCP, EUD-based NTCP, and uncomplicated tumour control probability (UTCP). RADBIOMOD was compared to existing biological modelling calculators for 15 sample cases. ResultsComparing RADBIOMOD to the existing biological modelling calculators, all models tested had mean absolute errors and root mean square errors less than 1%. ConclusionsRADBIOMOD produces results that are non-significantly different from existing biological modelling calculators for the models tested. It is hoped that this freely available, user-friendly program will aid future research into biological modelling.

Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers.

Positron emission tomography (PET) with [(18)F]-fluoromisonidazole ([(18)F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [(18)F]-FMISO-PET for head-and-neck cancers (HNC). Ten patients with inoperable stages III-IV HNC underwent [(18)F]-FMISO-PET before radiotherapy. Hypoxic target volumes (HTV) were segmented automatically by using the fuzzy locally adaptive Bayesian method. Retrospectively, two VMAT plans were generated delivering 70 Gy to the gross tumour volume (GTV) defined on computed tomography simulation or 79.8 Gy to the HTV. A dosimetric comparison was performed, based on calculations of tumour control probability (TCP), normal tissue complication probability (NTCP) for the parotid glands and uncomplicated tumour control probability (UTCP). The mean hypoxic fraction, defined as the ratio between the HTV and the GTV, was 0.18. The mean average dose for both parotids was 22.7 Gy and 25.5 Gy without and with dose escalation respectively. FMISO-guided dose escalation led to a mean increase of TCP, NTCP for both parotids and UTCP by 18.1, 4.6 and 8% respectively. A dose escalation up to 79.8 Gy guided by [(18)F]-FMISO-PET with VMAT seems feasible with improvement of TCP and without excessive increase of NTCP for parotids.