Normal Tissue Complication Probability Curve Research Articles

Biomedical advances and future prospects of high-precision three-dimensional radiotherapy and four-dimensional radiotherapy.

Biomedical advances of external-beam radiotherapy (EBRT) with improvements in physical accuracy are reviewed. High-precision (±1 mm) three-dimensional radiotherapy (3DRT) can utilize respective therapeutic open doors in the tumor control probability curve and in the normal tissue complication probability curve instead of the one single therapeutic window in two-dimensional EBRT. High-precision 3DRT achieved higher tumor control and probable survival rates for patients with small peripheral lung and liver cancers. Four-dimensional radiotherapy (4DRT), which can reduce uncertainties in 3DRT due to organ motion by real-time (every 0.1-1 s) tumor-tracking and immediate (0.1-1 s) irradiation, have achieved reduced adverse effects for prostate and pancreatic tumors near the digestive tract and with similar or better tumor control. Particle beam therapy improved tumor control and probable survival for patients with large liver tumors. The clinical outcomes of locally advanced or multiple tumors located near serial-type organs can theoretically be improved further by integrating the 4DRT concept with particle beams.

Toxicity Analysis of a Modified Prostate Bed CTV Based on PSMA-PET Patterns of Failure.

After radical prostatectomy (RP), about 20-50% of prostate cancer patients experience biochemical failure, and many can be cured with salvage radiotherapy (sRT). Adding androgen deprivation and pelvic lymph node (PLN) RT to sRT decreases risk of disease progression at the cost of increased toxicity. PSMA PET patterns of local failure after RP show failures outside the RTOG prostate bed CTV (RTOG_CTV) occurring postero-laterally and inferiorly, while in much of the covered bladder local failures are not seen. A modified CTV (m_CTV) encompassing all sites of observed local failures and less of the bladder would potentially reduce dose to the bladder but increase dose to rectum. Herein, we compared sRT plans using RTOG_CTV vs. m_CTV and assessed predicted genitourinary (GU) and gastrointestinal adverse events (AEs). Volumes for RTOG_CTV, m_CTV, PLN CTV, and OARs were retrospectively contoured on planning CT scans of 28 post-RP patients. Plans were generated for each RTOG_CTV and m_CTV. Doses to prostate bed PTV (CTV + 8mm expansion, 6mm posteriorly) and PLN CTV were 68 Gy and 52.7 Gy, respectively, all in in 34 fractions. Dose-volume histogram (DVH) data for bladder, rectum, and bowel of each plan were extracted. Normal Tissue Complication Probability (NTCP) curves were generated using Lyman-Kutcher-Burman model to predict risk of late G≥3 GU AEs, early GU urgency, leakage, frequency, nocturia, late GI bleed, and late G≥3 GI AEs. Data were compared using 2 sample t-test and Wilcox signed rank test. Correlation of bladder volume and differences in DVH and NTCP data between plans was assessed using Pearson coefficient. The m_CTV and RTOG_CTV had a median volume of 70.56cc (IQR 59.72-82.17cc) and 132.14cc (IQR 109.33-155.84cc), respectively. Use of m_CTVs resulted in mean absolute decrease of 20.22% and 17.94% in bladder V65 Gy and V40 Gy, respectively (p<0.01 for both), without differences in rectum V65 Gy (p = 0.44), rectum V40 Gy (p = 0.11), or bowel V45 Gy (p = 0.29). Per NTCP curves, m_CTV plans had mean absolute decrease of 24.89% in predicted late G≥3 GU AEs (p<0.01). For predicted early GU AEs, there were mean absolute decreases ranging from 4.85 to 10.21% (p<0.01 for all). Predicted late GI bleed (p = 0.98) and late G≥3 GI AEs (p = 0.99) were not significantly different between plans. When assessed as a continuous variable, smaller bladder volumes had strong correlation with more benefit from m_CTV in bladder V65 Gy (r = -0.71, p<0.01) and moderate correlation with less early GU AEs (r -0.59 to -0.56, p<0.01 for all). There was no correlation with bladder V40 Gy (p = 0.27) or late G≥3 GU AEs (p = 0.14). The m_CTV plans had significantly less dose to the bladder, no increased dose to the rectum and significantly lower predicted rates of early and late GU toxicity. Using a m_CTV encompassing observed local failures from PSMA PET could improve the therapeutic ratio for patients undergoing sRT. Further clinical validation is warranted.

A systematic review of the normal tissue complication probability models and parameters: Head and neck cancers treated with conformal radiotherapy.

This systematic review study aims to provide comprehensive data on different radiobiological models, parameters, and endpoints used for calculating the normal tissue complication probability (NTCP) based on clinical data from head and neck cancer patients treated with conformal radiotherapy. A systematic literature search was carried out according to the PRISMA guideline for the identification of relevant publications in six electronic databases of Embase, PubMed, Scopus, and Google Scholar to July 2022 using specific keywords in the paper's title and abstract. The initial search resulted in 1368 articles for all organs for the review article about the NTCP parameters. One hundred and seventy-eight articles were accepted for all organs with complete parameters for the mentioned models and finally, 20 head and neck cancer articles were accepted for review. Analysis of the studies shows that the Lyman-Kutcher-Burman (LKB) model properly links the NTCP curve parameters to the postradiotherapy endpoints. In the LKB model for esophagus, the minimum, and maximum corresponding parameters were reported as TD50 = 2.61 Gy with grade ≥3 radiation-induced esophagitis endpoints as the minimum TD50 and TD50 = 68 Gy as the maximum ones. nmin = 0.06, nmax = 1.04, mmin = 0.1, and mmax = 0.65, respectively. Unfortunately, there was not a wide range of published articles on other organs at risk like ear or cauda equina except Burman et al. (Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys Ther. 1991;21:123-135). Findings suggest that the validation of different radiobiological models and their corresponding parameters need to be investigated in vivo and in vitro for developing a more accurate NTCP model to be used for radiotherapy treatment planning optimization.

Dose-Response Prediction for SBRT of Prostate Cancer Based on Measured Cell Survival Curves Using a Unified Multi-Activation Model

<h3>Purpose/Objective(s)</h3> Hypofractionated external beam radiotherapy with 10 to 30 fractions (fx) and stereotactic body radiation therapy (SBRT) for prostate cancer (PC) have similar rates of cancer control and toxicity at 5 years as compared to conventional treatment. There is a lack of a radiobiological modeling from lab experiments to guide this transition. By assuming a unified multi-activation (UMA) model of lab-measured radiosensitivity (RS) of the cell lines to the entire dose range, we explored the clinical dose-response, modeling tumor-control probability (TCP) and normal-tissue complication probability (NTCP). <h3>Materials/Methods</h3> Published cell survival curves (CSC) with experimental error bars for PC of 5 DU145 CSCs, 3 CP3 CSCs, 6 LNCaP + 2 LnCaP with BCL2 overexpressed or down-regulated CSCs, 3 wild-type (WT)-22RV1 CSCs, 3 post-radiation radioresistant (RR)-22RV1 CSCs, 2 hypoxia-22RV1 CSCs, 3 urothelial HCV-29 CSCs and 4 large intestine (LI) or small intestine (SI) stem cell and organoid CSCs were fitted with a UMA model by using a logit transformation and c²-regression to obtain the model parameters of g and n and their deviations. Cell survival at any fractional dose (=total dose/fx) and TCP and NTCP for the total number of cancer cells or normal tissue cells corresponding to a grade of toxicity were analytically determined from the parameters. <h3>Results</h3> All of the CSCs had been excellently fitted with R² > 0.95 and Q-factor > 0.2 excepting for two in-vivo LI/SI crypt CSCs each with an outline point. We identified radiobiological parameters and predicted TCP/NTCP curves and listed the data for the 8Gyx5 SBRT of PC in Table 1 that are comparable with the results listed in the HyTEC papers. The 0% TCP to RR or hypoxia PC and 100% NTCP to SI are similar to conventional EBRT. The Dg reflects the major uncertainties in the lab-measured RS. D50, the total dose at 50% TCP or NTCP, correlated with RS and number of cells. Cell heterogeneity greatly changed RS and shapes of TCP and NTCP curves. <h3>Conclusion</h3> These findings may be useful for the design and evaluation of new clinical treatment schemes in PC translating lab work into clinical application.

Mean heart dose-based normal tissue complication probability model for pericardial effusion: a study in oesophageal cancer patients

We investigated the normal tissue complication probability (NTCP) of the incidence of pericardial effusion (PCE) based on the mean heart dose (MHD) in patients with oesophageal cancer treated with definitive chemoradiotherapy. The incidences of PCE in any grade (A-PCE) and symptomatic PCE (S-PCE) were evaluated separately. To identify predictors for PCE, several clinical and dose-volume parameters were analysed using a receiver operating characteristic (ROC) curve and multivariate regression analysis. To validate its clinical applicability, the generated NTCP model was compared to the Lyman–Kutcher–Burman (LKB) model. Among 229 eligible patients, A-PCE and S-PCE were observed in 100 (43.7%) and 18 (7.9%) patients, respectively. MHD showed a preferable area under the curve (AUC) value for S-PCE (AUC = 0.821) and A-PCE (AUC = 0.734). MHD was the only significant predictor for A-PCE; MHD and hypertension were selected as significant factors for S-PCE. The estimated NTCP, using the MHD-based model, showed excellent correspondence to the LKB model in A-PCE and S-PCE. The NTCP curve of A-PCE was gentler than that of S-PCE and had no threshold. The MHD-based NTCP model was simple but comparable to the LKB model for both A-PCE and S-PCE. Therefore, the estimated NTCP may provide clinically useful parameters for predicting PCE.

Optimal Allocation of Proton Therapy Slots in Combined Proton-Photon Radiation Therapy.

Proton therapy is a limited resource that is not available to all patients who may benefit from it. We investigated combined proton-photon treatments, in which some fractions are delivered with protons and the remaining fractions with photons, as an approach to maximize the benefit of limited proton therapy resources at a population level. To quantify differences in normal-tissue complication probability (NTCP) between protons and photons, we considered a cohort of 45 patients with head and neck cancer for whom intensity modulated radiation therapy and intensity modulated proton therapy plans were previously created, in combination with NTCP models for xerostomia and dysphagia considered in the Netherlands for proton patient selection. Assuming limited availability of proton slots, we developed methods to optimally assign proton fractions in combined proton-photon treatments to minimize the average NTCP on a population level. The combined treatments were compared with patient selection strategies in which patients are assigned to single-modality proton or photon treatments. There is a benefit of combined proton-photon treatments compared with patient selection, owing to the nonlinearity of NTCP functions; that is, the initial proton fractions are the most beneficial, whereas additional proton fractions have a decreasing benefit when a flatter part of the NTCP curve is reached. This effect was small for the patient cohort and NTCP models considered, but it may be larger if dose-response relationships are better known. In addition, when proton slots are limited, patient selection methods face a trade-off between leaving slots unused and blocking slots for future patients who may have a larger benefit. Combined proton-photon treatments with flexible proton slot assignment provide a method to make optimal use of all available resources. Combined proton-photon treatments allow for better use of limited proton therapy resources. The benefit over patient selection schemes depends on the NTCP models and the dose differences between protons and photons.

Effects From Nonuniform Dose Distribution in the Spinal Nerves of Pigs: Analysis of Normal Tissue Complication Probability Models

Our purpose was to evaluate normal tissue complication probability (NTCP) models for their ability to describe the increase in tolerance as the length of irradiated spinal nerve is reduced in a pig. Common phenomenological and semimechanistic NTCP models were fit using the maximum likelihood estimate method to dose-response data from spinal nerve irradiation studies in pigs. Statistical analysis was used to compare how well each model fit the data. Model parameters were then applied to a previously published dose distribution used for spinal cord irradiation in rats under the assumption of a similar dose-response. The Lyman-Kutcher-Burman model, relative seriality, and critical volume model fit the spinal nerve data equally well, but the mean dose logistic and relative seriality models gave the best fit after penalizing for the number of model parameters. The minimum dose logistic regression model was the only model showing a lack of fit. When extrapolated to a 0.5-cm simulated square-wave-like dose distribution, the serial behaving models showed negligible increase in dose-response curve. The Lyman-Kutcher-Burman model and relative seriality models showed significant shifting of NTCP curves due to parallel behaving parameters. The critical volume model gave the closest match to the rat data. Several phenomenological and semimechanistic models were observed to adequately describe the increase in the radiation tolerance of the spinal nerves when changing the irradiated length from 1.5 to 0.5 cm. Contrary to common perception, model parameters suggest parallel behaving tissue architecture. Under the assumption that the spinal nerve response to radiation is similar to that of the spinal cord, only the critical volume model was robust when extrapolating to outcome data from a 0.5-cm square-wave-like dose distribution, as was delivered in rodent spinal cord irradiation research.

Can Mean Pericardial Irradiated Dose (MPD) Predict Pericardial Effusion after Chemoradiotherapy in Esophageal Cancer Patients? Normal Tissue Complication Probability (NTCP) Model-Based Analyses

We previously reported MPD is the most useful predictor for the incidence of symptomatic pericardial effusion in esophageal cancer patients after concurrent chemoradiotherapy (CCR). The purpose of this study is to validate the usefulness of the MPD to predict the incidence using the Lyman–Kutcher–Burman (LKB) NTCP model. We retrospectively reviewed consecutive primary esophageal cancer patients treated with CCR between 2001 and 2014. Inclusion criteria were as follows: newly diagnosed and first treatment for esophageal cancer; disease including thoracic esophagus; follow-up ≥6 months; conventional fractionation and irradiated larger than 50 Gy; WHO performance status ≤2; available computed tomography (CT) data to analyze dose volume of pericardium and MPD; intact of malignant pericardial diseases. Symptomatic effusion was defined as pericardial effusion ≥ grade 3, according to the CTCAE version 4.0. Pericardial effusion was reviewed on follow-up chest CT. Generalized equivalent uniform dose (gEUD) based LKB NTCP parameters (n, m, and TD50) were estimated using maximum likelihood method. The optimum parameters were determined by the gradient descent method. Linear and probit regression was performed for MPD and estimated NTCP for each patient. In the probit regression using MPD, LKB NTCP parameters um and TD50 were estimated under the situation of n = 1, presuming pericardium as an organ with large volume effect. In this case, TD50 means MPD, instead of gEUD. Overall, 229 patients were met the criteria. The median follow up was 37 months (ranged 6 to 178 months). Pericardial effusion in any grade and symptomatic effusion were observed in 100 (44%) and 18 (8%) patients, respectively. Onset of pericardial effusion ranged from 2 to 75 months. The aggregated dose-volume data were preferably fitted by NTCP curve, in particular for symptomatic effusion. The estimated TD50 for symptomatic effusion and pericardial effusion in any grade were 56.0 Gy (m = 0.19, n = 0.43) and 41.0 Gy (m = 0.47, n = 0.38), respectively. The calculated NTCP curve for the regression using the MPD for symptomatic effusion showed similar sigmoid curve with a cut-off. The estimated TD50 (MPD) was 54.8 Gy (m = 0.25). While the NTCP curve for the regression using the MPD for pericardial effusion in any grade were approximated by the slope of 0.014 per Gy and intercept of 0.04 for linear regression. The estimated TD50 (MPD) was 34.4 Gy (m = 0.76). The MPD based NTCP model for symptomatic effusion showed similar results as with the original model and supported MPD as a practical predictor. Meanwhile, the model for pericardial effusion in any grade displayed different shape and parameter, as with the original model, might be indicating influence of other factors than MPD.

OA187] Transfer of minibeam radiation therapy into a cost-effective equipment: A proof of concept

Introduction Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to very high doses [1] . MBRT seem to involve different biological mechanisms (not well understood yet) different from those in standard RT. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to evaluate the feasibility of the implementation of MBRT into cost-effective equipment. Materials and methods A series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In particular, an adapted collimator was designed by means of Monte Carlo simulations (Geant4). Peak to valley dose ratio values and full width half at maximum similar to those obtained at the European synchrotron radiation facility (ESRF) [2] were used as figure of merit. As a proof of concept, the whole brain of two groups were irradiated: a first group received conventional (broad beam) irradiations, the second series was irradiated with MBRT. The same average dose was deposited in both cases, 20 ± 1 Gy, which corresponds to 58 Gy peak dose in the MBRT case. The animals were followed-up for 6.5 months. At the end of the study a magnetic resonance imaging (MRI) evaluation and histological analysis were performed. Results The dosimetric features of our system were shown to be similar to the synchrotron ones [2] . Concerning the in vivo experiment, rats treated with conventional irradiation exhibited very important brain damage, including radionecrosis. In contrast, no substantial brain damage was observed in the animals of the MBRT group. Conclusions This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator [3] . This is the first time that such an evaluation is done with millimetre-sized minibeams in the brain, which opens the door for future implementations with less technically demanding and very compact systems.

Model Based Radiation Therapy: Submandibular Dose-Response NTCP-Curve Based on Objective Measurements

Submandibular gland (SMG) normal tissue complication probability (NTCP) curves will be part of model-based indication for proton therapy in the Netherlands. Subjective measurements of xerostomia and sticky saliva reflect whole saliva, and are not suitable for the determination of the SMG NTCP curve. Therefore, we performed direct measurements of salivary flow, including the SMG flow. Based on a large database with a broad mean SMG dose distribution we obtained NTCP curves 6 weeks and 1 year after therapy. We utilized dose-response data of 200 head-and-neck patients, obtained from prospective salivary gland function studies. SMG flow was measured before, 6 weeks, and 1 year after therapy. Thirty patients were treated after unilateral neck dissection. Patients with N2c or N3 nodes were excluded. Tumors were localized in the oropharynx (69%), larynx (14%), nasopharynx (9%), oral cavity (4%), and hypopharynx (3%), 38% were N0, 32% T3-4. Treatment consisted of conventional RT, non-SMG sparing IMRT, SMG sparing IMRT, in 34, 84, and 82 patients, respectively. The mean dose to the ipsilateral submandibular gland was 62Gy, for the contralateral submandibular gland 47 Gy (range 0-72 Gy). Flow rates were converted to the baseline unilateral SMG flow rate, and compared with the contralateral SMG mean dose. Data were fitted to logistic regression (LR) and the Lyman-Kutcher-Burman (LKB) model, with a complication defined as a flow 6 weeks/ 1 year after therapy <25% of the flow before therapy [1]. There was a highly significant correlation between increasing mean SMG dose and decreasing absolute and relative SMG flow 6 weeks and 1 year after therapy. Mean contralateral SMG dose could be divided in five groups: ≤30 Gy (n=30), 30-40 Gy (28) 40-50 Gy (32), 50-60 Gy (57), > 60 Gy (53), the complication rate at 6 weeks was 22%, 50%, 73%, 76% and 86%, respectively; at 1 year 30%, 31%, 75%, 86% and 94%, respectively (P<.001). The D50 after 6 weeks was 31 Gy (95% CI 24-37), and 28 Gy (95% CI 21-34) after 1 year after analysis with the LKB model; 33 Gy (26-40) and 34 Gy (28-40), respectively, using the LR model. This NTCP-curve for submandibular gland function is based on the largest database of objective measurements in the literature. For planning purposes, usually a mean SMG-dose constraint of 40 Gy is chosen. We recommend a mean SMG dose of less than 30 Gy. [1] Dijkema et al. Int J Radiat Oncol Biol Phys. 2010:78;449-453.

Transfer of Minibeam Radiation Therapy into a cost-effective equipment for radiobiological studies: a proof of concept

Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator.

Theoretical dosimetric evaluation of carbon and oxygen minibeam radiation therapy.

Charged particles have several advantages over x-ray radiations, both in terms of physics and radiobiology. The combination of these advantages with those of minibeam radiation therapy (MBRT) could help enhancing the therapeutic index for some cancers with poor prognosis. Among the different ions explored for therapy, carbon ions are considered to provide the optimum physical and biological characteristics. Oxygen could be advantageous due to a reduced oxygen enhancement ratio along with a still moderate biological entrance dose. The aforementioned reasons justified an in-depth evaluation of the dosimetric features of carbon and oxygen minibeam radiation therapy to establish the interest of further explorations of this avenue. The GATE/Geant4 6.2 Monte Carlo simulation platform was employed to simulate arrays of rectangular carbon and oxygen minibeams (600 μm × 2 cm) at a water phantom entrance. They were assumed to be generated by means of a magnetic focusing. The irradiations were performed with a 2-cm-long spread-out Bragg peak (SOBP) centered at 7-cm-depth. Several center-to-center (c-t-c) distances were considered. Peak and valley doses, as well as peak-to-valley dose ratio (PVDR) and the relative contribution of nuclear fragments and electromagnetic processes were assessed. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. Carbon and oxygen MBRT lead to very similar dose distributions. No significant advantage of oxygen over carbon ions was observed from physical point of view. Favorable dosimetric features were observed for both ions. Thanks to the reduced lateral scattering, the standard shape of the depth dose curves (in the peaks) is maintained even for submillimetric beam sizes. When a narrow c-t-c is considered (910-980 μm), a (quasi) homogenization of the dose can be obtained at the target, while a spatial fractionation of the dose is maintained in the proximal normal tissues with low PVDR. In contrast when a larger c-t-c is used (3500 μm) extremely high PVDR (≥50) are obtained in normal tissues, corresponding to very low valley doses. This suggests that carbon and oxygen MBRT might lead to a significant reduction of normal tissue complication probability. The main participant to the valley doses are secondary nuclear products at all depths. Among them the highest yield in normal tissues corresponds to the lightest fragments, neutrons and protons. Heavier fragments are dominant in the valleys only at the target position, which might favor tumor control. The computed dose distributions suggest that a spatial fractionation of the dose combined to the use of submillimetric field sizes might allow profiting from the high efficiency of carbon and oxygen ions for the treatment of radioresistant tumors, while preserving normal tissues. Only biological experiments could confirm the shifting of the normal tissue complication probability curves. The authors' results support the further exploration of this avenue.

Estimation of late rectal normal tissue complication probability parameters in carbon ion therapy for prostate cancer

PurposeThe aim of this study was to estimate normal tissue complication probability (NTCP) parameters for late rectal complications after carbon ion radiotherapy (C-ion RT) for prostate cancer. Methods and materialsA total of 163 patients were used to derive NTCP parameters. These patients were treated with relative biological effectiveness (RBE)-weighted dose ranging from 57.6Gy (RBE) up to 72Gy (RBE) and included in dose escalation trials. The Lyman–Kutcher–Burman (LKB) model was used and the model parameters were fit to the relation between dose and complication observed after C-ion RT. ResultsThe resulting NTCP parameters were the volume effect parameter; n=0.035 (95% CI: 0.024–0.047), the steepness of the NTCP curve; m=0.10 (0.084–0.13), the tolerance dose associated with 50% probability of complication; TD50=63.6Gy (RBE) (61.8–65.4Gy (RBE)) for Grade⩾1, n=0.012 (0.0050–0.023), m=0.046 (0.033–0.062), TD50=69.1Gy (RBE) (67.6–70.9Gy (RBE)) for Grade⩾2. ConclusionA new set of rectal NTCP parameters in C-ion RT was determined. The rather small n values suggest that the rectum was consistent with being strictly serial organ. The new derived parameter values facilitate estimation of rectal NTCP in C-ion RT.

Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study.

This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue. The gate/geant4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 μm × 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 μm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary fragments in valleys. The computed dose distributions suggest that a spatial fractionation of the dose combined to the use of submillimetric field sizes might allow profiting from the high efficiency of neon and heavier ions for the treatment of radioresistant tumors, while preserving normal tissues. The authors' results support the further exploration of this avenue. Next steps include the realization of biological experiment to confirm the shifting of normal tissue complication probability curves.

Impact of Chemotherapy on Normal Tissue Complication Probability Models of Acute Hematologic Toxicity in Patients Receiving Pelvic Intensity Modulated Radiation Therapy

To determine how chemotherapy agents affect radiation dose parameters that correlate with acute hematologic toxicity (HT) in patients treated with pelvic intensity modulated radiation therapy (P-IMRT) and concurrent chemotherapy. We assessed HT in 141 patients who received P-IMRT for anal, gynecologic, rectal, or prostate cancers, 95 of whom received concurrent chemotherapy. Patients were separated into 4 groups: mitomycin (MMC) + 5-fluorouracil (5FU, 37 of 141), platinum ± 5FU (Cis, 32 of 141), 5FU (26 of 141), and P-IMRT alone (46 of 141). The pelvic bone was contoured as a surrogate for pelvic bone marrow (PBM) and divided into subsites: ilium, lower pelvis, and lumbosacral spine (LSS). The volumes of each region receiving 5-40 Gy were calculated. The endpoint for HT was grade ≥3 (HT3+) leukopenia, neutropenia or thrombocytopenia. Normal tissue complication probability was calculated using the Lyman-Kutcher-Burman model. Logistic regression was used to analyze association between HT3+ and dosimetric parameters. Twenty-six patients experienced HT3+: 10 of 37 (27%) MMC, 14 of 32 (44%) Cis, 2 of 26 (8%) 5FU, and 0 of 46 P-IMRT. PBM dosimetric parameters were correlated with HT3+ in the MMC group but not in the Cis group. LSS dosimetric parameters were well correlated with HT3+ in both the MMC and Cis groups. Constrained optimization (0<n≤ 1) of the Lyman-Kutcher-Burman model resulted in n=1, m = 0.11, TD50 = 31 Gy for LSS in the MMC group and n=1, m = 0.27, TD50 = 35 Gy for LSS in the Cis group. The incidence of HT3+ depends on type of chemotherapy received. Patients receiving P-IMRT ± 5FU have better bone marrow tolerance than those receiving irradiation concurrent with either Cis or MMC. Treatment with MMC has a lower TD50 and more steeply rising normal tissue complication probability curve compared with treatment with Cis. Dose tolerance of PBM and the LSS subsite may be lower for patients treated with MMC compared with Cis.

Dosimetric Parameters Predictive of Acute Gastrointestinal Toxicity in Patients with Anal Carcinoma Treated with Concurrent Chemotherapy and Intensity-Modulated Radiation Therapy

Objective: To determine the dosimetric parameters predictive of acute gastrointestinal (GI) toxicity in anal cancer patients treated with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy. Methods: Fifty-eight anal cancer patients were treated with concurrent chemotherapy and IMRT. The bowel was delineated on the planning CT and included the intestinal cavity. Regression models with multiple independent predictors were used to test associations of clinical factors and dosimetric parameters with clinically significant GI toxicity (grade ≥3). Significant dosimetric factors were fitted to a normal tissue complication probability curve using a logit function and subsequently analyzed at multiple bowel volumes to determine the threshold for clinically significant GI toxicity. Results: Two patients (3.4%) experienced no acute GI toxicity, whereas 20 (34.5%) experienced grade 1 toxicity, 20 (34.5%) experienced grade 2, 16 (27.6%) experienced grade 3 and none experienced grade 4. Analysis showed that the volumes of bowel receiving 30 Gy (V30) and 40 Gy (V40) both correlated with clinically significant acute GI toxicity. In patients whose V30 was >310 cm³, the rate of clinically significant acute GI toxicity was 38.9%, compared to 9.1% if V30 was ≤310 cm³ (p = 0.016). If V40 was ≤70 cm³, the rate of acute grade ≥3 toxicity was 6.3%, versus 35.7% if V40 was >70 cm³ (p = 0.045). Conclusion: This analysis demonstrates that the bowel dosimetric parameters are associated with clinically significant acute GI toxicity when IMRT is used in the management of anal cancer patients.

SU-E-T-720: Maintaining Prostate IMRT Plan Quality Using the Fraction of Rectum Overlapping the PTV

Purpose: It is clinically meaningful to generate the optimal intensity‐modulated radiation therapy (IMRT) treatment plans within the restricted time with equally good quality for different patients, which is planner‐dependent. We developed a planner‐independent method for a clinical decision of prostate IMRT plan using the rectal complication probability with the volume of rectum overlapping the PTV. Methods: Eighteen prostate IMRT plans were retrospectively analyzed. The prescription dose in the all the planning target volumes (PTVs) was normalized with 76 Gy in 2 Gy fractions. We found a correlation between the fraction of rectum overlapping the PTV and the rectal normal tissue complication probability (NTCP), which is the predictable NTCP curve, which means the lower bound of the rectal NTCP. The plans beyond the predictable NTCP criteria were generated again with seven 10 MV beams from the Varian Clinac iX linear accelerator. The beams were arranged coplanar at: 0, 50, 100, 140, 220, 260, and 310. IMRT plans were generated using direct machine parameter optimization in the Pinnacle3. Results: All the regenerated plans came to be included in the predictable NTCP criteria. In our patient data, two plans were re‐planned: the NTCP for patient 7 was changed from 10.9 to 8.8 and the other NTCP for patient 14 was from 15.6 to 12.9. The rectal NTCP is clinically more meaningful than the mean dose of rectum. Conclusion: This model can predict the rectum NTCP before IMRT planning, to control the IMRT plan quality during planning. Hence we can maintain prostate IMRT plan quality using the fraction of rectum overlapping the PTV.

On the use of biomathematical models in patient‐specific IMRT dose QA

To investigate the use of biomathematical models such as tumor control probability (TCP) and normal tissue complication probability (NTCP) as new quality assurance (QA) metrics. Five different types of error (MLC transmission, MLC penumbra, MLC tongue and groove, machine output, and MLC position) were intentionally induced to 40 clinical intensity modulated radiation therapy (IMRT) patient plans (20 H&N cases and 20 prostate cases) to simulate both treatment planning system errors and machine delivery errors in the IMRT QA process. The changes in TCP and NTCP for eight different anatomic structures (H&N: CTV, GTV, both parotids, spinal cord, larynx; prostate: CTV, rectal wall) were calculated as the new QA metrics to quantify the clinical impact on patients. The correlation between the change in TCP∕NTCP and the change in selected DVH values was also evaluated. The relation between TCP∕NTCP change and the characteristics of the TCP∕NTCP curves is discussed. ΔTCP and ΔNTCP were summarized for each type of induced error and each structure. The changes/degradations in TCP and NTCP caused by the errors vary widely depending on dose patterns unique to each plan, and are good indicators of each plan's "robustness" to that type of error. In this in silico QA study the authors have demonstrated the possibility of using biomathematical models not only as patient-specific QA metrics but also as objective indicators that quantify, pretreatment, a plan's robustness with respect to possible error types.

Parotid Gland Function After Radiotherapy: The Combined Michigan and Utrecht Experience

To analyze the combined and updated results from the University of Michigan and University Medical Center Utrecht on normal tissue complication probability (NTCP) of the parotid gland 1 year after radiotherapy (RT) for head-and-neck (HN) cancer. A total of 222 prospectively analyzed patients with various HN malignancies were treated with conventional and intensity-modulated RT. Stimulated individual parotid gland flow rates were measured before RT and 1 year after RT using Lashley cups at both centers. A flow ratio <25% of pretreatment was defined as a complication. The data were fitted to the Lyman-Kutcher-Burman model. A total of 384 parotid glands (Michigan: 157; Utrecht: 227 glands) was available for analysis 1 year after RT. Combined NTCP analysis based on mean dose resulted in a TD(50) (uniform dose leading to 50% complication probability) of 39.9 Gy and m (steepness of the curve) of 0.40. The resulting NTCP curve had good qualitative agreement with the combined clinical data. Mean doses of 25-30 Gy were associated with 17-26% NTCP. A definite NTCP curve for parotid gland function 1 year after RT is presented, based on mean dose. No threshold dose was observed, and TD(50) was equal to 40 Gy.

Large Cohort Dose–Volume Response Analysis of Parotid Gland Function After Radiotherapy: Intensity-Modulated Versus Conventional Radiotherapy

To compare parotid gland dose-volume response relationships in a large cohort of patients treated with intensity-modulated (IMRT) and conventional radiotherapy (CRT). A total of 221 patients (64 treated with IMRT, 157 with CRT) with various head-and-neck malignancies were prospectively evaluated. The distribution of tumor subsites in both groups was unbalanced. Stimulated parotid flow rates were measured before and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from computed tomography-based treatment planning. The normal tissue complication probability (NTCP) model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow ratio <25% of the pretreatment flow rate. The relative risk of complications was determined for IMRT vs. CRT and adjusted for the mean parotid gland dose using Poisson regression modeling. One year after radiotherapy, NTCP curves for IMRT and CRT were comparable with a TD(50) (uniform dose leading to a 50% complication probability) of 38 and 40 Gy, respectively. Until 6 months after RT, corrected for mean dose, different complication probabilities existed for IMRT vs. CRT. The relative risk of a complication for IMRT vs. CRT after 6 weeks was 1.42 (95% CI 1.21-1.67), after 6 months 1.41 (95% CI; 1.12-1.77), and at 1 year 1.21 (95% CI 0.87-1.68), after correcting for mean dose. One year after radiotherapy, no difference existed in the mean dose-based NTCP curves for IMRT and CRT. Early after radiotherapy (up to 6 months) mean dose based (Lyman) models failed to fully describe the effects of radiotherapy on the parotid glands.