The impact of nutritional counseling on thyroid disorders in head and neck cancer patients after (chemo)radiotherapy: results from a prospective interventional trial.

OBJECTIVE: To analyze the impact of nutritional counseling on the development of hypothyroidism after (chemo)radiotherapy in head and neck cancer patients to propose a new normal tissue complication probability (NTCP) model. MATERIALS AND METHODS: At baseline, at the end of (chemo)radiotherapy, and during follow-up, thyroid-stimulating hormone (TSH) with free thyroxin (fT3 and fT4), nutritional status, and nutrient intake were prospectively analyzed in 46 out of 220 screened patients. Patients received (chemo)radiotherapy within an intervention (individual nutritional counseling every 2 weeks during therapy) and a control group (no nutritional counseling). RESULTS: Overall median follow-up was 16.5 [IQR: 12; 22] months. Fourteen patients (30.4%) presented with hypothyroidism after 13.5 [8.8; 17] months. During (chemo)radiotherapy, nutritional status worsened in the entire cohort: body mass index (p < 0.001) and fat-free mass index (p < 0.001) decreased, calorie deficit (p = 0.02) increased, and the baseline protein intake dropped (p = 0.028). The baseline selenium intake (p = 0.002) increased until the end of therapy. Application of the NTCP models by Rønjom, Cella, and Boomsma et al. resulted in good performance of all three models, with an AUC ranging from 0.76 to 0.78. Our newly developed NTCP model was based on baseline TSH and baseline ferritin. Model performance was good, receiving an AUC of 0.76 (95% CI: 0.61-0.87), with a sensitivity of 57.1% and specificity of 96.9% calculated for a Youden index of 0.73 (p = 0.004; area = 0.5). CONCLUSION: Baseline TSH and ferritin act as independent predictors for radiotherapy-associated hypothyroidism. The exclusion of such laboratory chemistry parameters in future NTCP models may result in poor model performance.

Dosimetric and radiobiological comparison of Cyberknife and Tomotherapy in stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND AND PURPOSE: As recent studies have suggested relatively low α/ß for prostate cancer, the interest in hypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer is rising. The aim of this study is to compare dosimetric results of Cyberknife (CK) with Tomotherapy (HT) in SBRT for localized prostate cancer. Furthermore, the radiobiologic consequences of heterogeneous dose distribution are also analyzed. MATERIAL AND METHOD: A total of 12 cases of localized prostate cancer previously treated with SBRT were collected. Treatments had been planned and delivered using CK. Then HT plans were generated for comparison afterwards. The prescribed dose was 37.5Gy in 5 fractions. Dosimetric indices for target volumes and organs at risk (OAR) were compared. For radiobiological evaluation, generalized equivalent uniform dose (gEUD) and normal tissue complication probability (NTCP) were calculated and compared. RESULT: Both CK and HT achieved target coverage while meeting OAR constraints adequately. HT plans resulted in better dose homogeneity (Homogeneity index: 1.04±0.01 vs. 1.21±0.01; p = 0.0022), target coverage (97.74±0.86% vs. 96.56±1.17%; p = 0.0076) and conformity (new vonformity index: 1.16±0.05 vs. 1.21±0.04; p = 0.0096). HT was shown to predict lower late rectal toxicity as compared to CK. Integral dose to body was also significantly lower in HT plans (46.59±6.44 Gy'L vs 57.05±11.68 Gy'L; p = 0.0029). CONCLUSION: Based on physical dosimetry and radiobiologic considerations, HT may have advantages over CK, specifically in rectal sparing which could translate into clinical benefit of decreased late toxicities.

Variable-RBE-induced NTCP predictions for various side-effects following proton therapy for brain tumors - Identification of high-risk patients and risk mitigation.

BACKGROUND AND PURPOSE: Disregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning. MATERIALS AND METHODS: We retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (DRBE, Wedenberg model) and a constant RBE-weighted dose (DRBE=1.1), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) DRBE=1.1, and (c) the difference between DRBE and DRBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients. RESULTS: Using a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) DRBE=1.1, and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs. CONCLUSION: The risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk.

Comparison of deep inspiration breath hold and free breathing intensity modulated proton therapy of locally advanced lung cancer.

Background and purpose: For locally advanced non-small cell lung cancer (LA-NSCLC), intensity-modulated proton therapy (IMPT) can reduce organ at risk (OAR) doses compared to intensity-modulated radiotherapy (IMRT). Deep inspiration breath hold (DIBH) reduces OAR doses compared to free breathing (FB) in IMRT. In IMPT, differences in dose distributions and robustness between DIBH and FB are unclear. In this study, we compare DIBH to FB in IMPT, and IMPT to IMRT. Materials and methods: Fortyone LA-NSCLC patients were prospectively included. 4D computed tomography images (4DCTs) and DIBH CTs were acquired for treatment planning and during weeks 1 and 3 of treatment. A new system for automated robust planning was developed and used to generate a FB and a DIBH IMPT plan for each patient. Plans were compared in terms of dose-volume parameters and normal tissue complication probabilities (NTCPs). Dose recalculations on repeat CTs were used to compare inter-fraction plan robustness. Results: In IMPT, DIBH reduced median lungs Dmean from 9.3 Gy(RBE) to 8.0 Gy(RBE) compared to FB, and radiation pneumonitis NTCP from 10.9 % to 9.4 % (p < 0.001). Inter-fraction plan robustness for DIBH and FB was similar. Median NTCPs for radiation pneumonitis and mortality were around 9 percentage points lower with IMPT than IMRT (p < 0.001). These differences were much larger than between FB and DIBH within each modality. Conclusion: DIBH IMPT resulted in reduced lung dose and radiation pneumonitis NTCP compared to FB IMPT. Inter-fraction robustness was comparable. OAR doses were far lower in IMPT than IMRT.

Dose-response modeling and treatment plan assessment with a python software toolkit.

This software assistant aims at calculating the dose-response relations of tumors and normal tissues, or clinically assessing already determined values by other researchers. It can also indicate the optimal dose prescription by optimizing the expected treatment outcome. The software is developed solely in python programming language, and it employs PSFL license for its Graphical User Interface (GUI), NUMPY, MATPLOTLIB, and SCIPY libraries. It comprises of two components. The first is the Dose-response relations derivation component, which takes as input the dose volume histograms (DVHs) of patients and their recorded responses regarding a given clinical endpoint to determine the parameters of different tumor control probability (TCP) or normal tissue complication probability (NTCP) models. The second is the Treatment Plan Assessment component, which uses the DVHs of a plan and the dose-response parameters values of the involved tumors and organs at risk (OARs) to calculate their expected responses. Additionally, the overall probabilities of benefit (PB), injury (PI) and complication-free tumor control (P+) are calculated. The software calculates rapidly the corresponding generalized equivalent uniform doses (gEUD) and biologically effective uniform doses (D‾‾) for the Lyman-Kutcher-Burman (LKB), parallel volume (PV) and relative seriality (RS) models respectively, determining the model parameters. In the Dose-Response Relations Derivation component, the software plots the dose-response curves of the irradiated organ with the relevant confidence internals along with the data of the patients with and without toxicity. It also calculates the odds ratio (OR) and the area under the curve (AUC) of different dose metrics or model parameter values against the individual patient outcomes to determine their discrimination capacity. It also performs a goodness-of-fit evaluation of any model parameter set. The user has the option of viewing plots like Scatter, 3D surfaces, and Bootstrap plots. In the Treatment Plan Assessment part, the software calculates the TCP and NTCP values of the involved tumors and OARs, respectively. Furthermore, it plots the dose-response curves of the TCPs, NTCPs, PB, PI, and P+ for a range of prescription doses for different treatment plans. The presented software is ideal for efficiently conducting studies of radiobiological modeling. Furthermore, it is ideal for performing treatment plan assessment, comparison, and optimization studies.

Dosimetric comparison of IMPT vs VMAT for multiple lung lesions: an NTCP model-based decision-making strategy.

To compare the dosimetric differences in volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) in stereotactic body radiation therapy (SBRT) of multiple lung lesions and determine a normal tissue complication probability (NTCP) model-based decision strategy that determines which treatment modality the patient will use. A total of 41 patients were retrospectively selected for this study. The number of patients with 1-6 lesions was 5, 16, 7, 6, 3, and 4, respectively. A prescription dose of 70 GyRBE in 10 fractions was given to each lesion. SBRT plans were generated using VMAT and IMPT. All the IMPT plans used robustness optimization with ± 3.5% range uncertainties and 5 mm setup uncertainties. Dosimetric metrics and the predicted NTCP value of radiation pneumonitis (RP), esophagitis, and pericarditis were analyzed to evaluate the potential clinical benefits between different planning groups. In addition, a threshold for the ratio of PTV to lungs (%) to determine whether a patient would benefit highly from IMPT was determined using receiver operating characteristic curves. All plans reached target coverage (V70GyRBE ≥ 95%). Compared with VMAT, IMPT resulted in a significantly lower dose of most thoracic normal tissues. For the 1-2, 3-4 and 5-6 lesion groups, the lung V5 was 29.90 ± 9.44%, 58.33 ± 13.35%, and 81.02 ± 5.91% for VMAT and 11.34 ± 3.11% (p < 0.001), 21.45 ± 3.80% (p < 0.001), and 32.48 ± 4.90% (p < 0.001) for IMPT, respectively. The lung V20 was 12.07 ± 4.94%, 25.57 ± 6.54%, and 43.99 ± 11.83% for VMAT and 6.76 ± 1.80% (p < 0.001), 13.14 ± 2.27% (p < 0.01), and 19.62 ± 3.48% (p < 0.01) for IMPT. The Dmean of the total lung was 7.65 ± 2.47 GyRBE, 14.78 ± 2.75 GyRBE, and 21.64 ± 4.07 GyRBE for VMAT and 3.69 ± 1.04 GyRBE (p < 0.001), 7.13 ± 1.41 GyRBE (p < 0.001), and 10.69 ± 1.81 GyRBE (p < 0.001) for IMPT. Additionally, in the VMAT group, the maximum NTCP value of radiation pneumonitis was 73.91%, whereas it was significantly lower in the IMPT group at 10.73%. The accuracy of our NTCP model-based decision model, which combines the number of lesions and PTV/Lungs (%), was 97.6%. The study demonstrated that the IMPT SBRT for multiple lung lesions had satisfactory dosimetry results, even when the number of lesions reached 6. The NTCP model-based decision strategy presented in our study could serve as an effective tool in clinical practice, aiding in the selection of the optimal treatment modality between VMAT and IMPT.

Dosimetric and radiobiological comparison between conventional and hypofractionated breast treatment plans using the Halcyon system.

Purpose: The objective of this research is to compare the efficacy of conventional and hypofractionated radiotherapy treatment plans for breast cancer patients, with a specific focus on the unique features of the Halcyon system. Methods and materials: The study collected and analyzed dose volume histogram (DVH) data for two groups of treatment plans implemented using the Halcyon system. The first group consisted of 19 patients who received conventional fractionated (CF) treatment with a total dose of 50 Gy in 25 fractions, while the second group comprised 9 patients who received hypofractionated (HF) treatment with a total dose of 42.56 Gy in 16 fractions. The DVH data was used to calculate various parameters, including tumor control probability (TCP), normal tissue complication probability (NTCP), and equivalent uniform dose (EUD), using radiobiological models. Results: The results indicated that the CF plan resulted in higher TCP but lower NTCP for the lungs compared to the HF plan. The EUD for the HF plan was approximately 49 Gy (114% of its total dose) while that for the CF plan was around 53 Gy (107% of its total dose). Conclusions: The analysis suggests that while the CF plan is better at controlling tumors, it is not as effective as the HF plan in minimizing side effects. Additionally, it is suggested that there may be an optimal configuration for the HF plan that can provide the same or higher EUD than the CF plan.

Heterogeneity of absorbed dose distribution in kidney tissues and dose-response modelling of nephrotoxicity in radiopharmaceutical therapy with beta-particle emitters: A review.

Absorbed dose heterogeneity in kidney tissues is an important issue in radiopharmaceutical therapy. The effect of absorbed dose heterogeneity in nephrotoxicity is, however, not fully understood yet, which hampers the implementation of treatment optimization by obscuring the interpretation of clinical response data and the selection of optimal treatment options. Although some dosimetry methods have been developed for kidney dosimetry to the level of microscopic renal substructures, the clinical assessment of the microscopic distribution of radiopharmaceuticals in kidney tissues currently remains a challenge. This restricts the anatomical resolution of clinical dosimetry, which hinders a thorough clinical investigation of the impact of absorbed dose heterogeneity. The potential of absorbed dose-response modelling to support individual treatment optimization in radiopharmaceutical therapy is recognized and gaining attraction. However, biophysical modelling is currently underexplored for the kidney, where particular modelling challenges arise from the convolution of a complex functional organization of renal tissues with the function-mediated dose distribution of radiopharmaceuticals. This article reviews and discusses the heterogeneity of absorbed dose distribution in kidney tissues and the absorbed dose-response modelling of nephrotoxicity in radiopharmaceutical therapy. The review focuses mainly on the peptide receptor radionuclide therapy with beta-particle emitting somatostatin analogues, for which the scientific literature reflects over two decades of clinical experience. Additionally, detailed research perspectives are proposed to address various identified challenges to progress in this field.

Comparison of Breast Cancer Radiotherapy Techniques Regarding Secondary Cancer Risk and Normal Tissue Complication Probability - Modelling and Measurements Using a 3D-Printed Phantom.

Background: Radiotherapy after breast-conserving therapy is a standard postoperative treatment of breast cancer, which can be carried out with a variety of irradiation techniques. The treatment planning must take into consideration detrimental effects on the neighbouring organs at risk-the lung, the heart, and the contralateral breast, which can include both short- and long-term effects represented by the normal tissue complication probability and secondary cancer risk. Patients and Methods: In this planning study, we investigate intensity-modulated (IMRT) and three-dimensional conformal (3D-CRT) radiotherapy techniques including sequential or simultaneously integrated boosts as well as interstitial multicatheter brachytherapy boost techniques of 38 patients with breast-conserving surgery retrospectively. We furthermore develop a 3D-printed breast phantom add-on to allow for catheter placement and to measure the out-of-field dose using thermoluminescent dosimeters placed inside an anthropomorphic phantom. Finally, we estimate normal tissue complication probabilities using the Lyman-Kutcher-Burman model and secondary cancer risks using the linear non-threshold model (out-of-field) and the model by Schneider et al. (in-field). Results: The results depend on the combination of primary whole-breast irradiation and boost technique. The normal tissue complication probabilities for various endpoints are of the following order: 1%-2% (symptomatic pneumonitis, ipsilateral lung), 2%-3% (symptomatic pneumonitis, whole lung), and 1%-2% (radiation pneumonitis grade ≥ 2, whole lung). The additional relative risk of ischemic heart disease ranges from +25% to +35%. In-field secondary cancer risk of the ipsilateral lung in left-sided treatment is around 50 per 10,000 person-years for 20 years after exposure at age 55. Out-of-field estimation of secondary cancer risk results in approximately 5 per 10,000 person-years each for the contralateral lung and breast. Conclusions: In general, 3D-CRT shows the best risk reduction in contrast to IMRT. Regarding the boost concepts, brachytherapy is the most effective method in order to minimise normal tissue complication probability and secondary cancer risk compared to teletherapy boost concepts. Hence, the 3D-CRT technique in combination with an interstitial multicatheter brachytherapy boost is most suitable in terms of risk avoidance for treating breast cancer with techniques including boost concepts.

A clinical trial to compare a 3D-printed bolus with a conventional bolus with the aim of reducing cardiopulmonary exposure in postmastectomy patients with volumetric modulated arc therapy.

BACKGROUND: We compared the dosimetry, application, and acute toxicity of a 3D-printed and a conventional bolus for postmastectomy radiotherapy (PMRT) with volumetric modulated arc therapy (VMAT). Materials and Methods Eligible patients (n = 75) with PMRT breast cancer were randomly selected to receive VMAT with a conventional bolus or a 3D-printed bolus. The primary endpoint was a 10% decrease in the mean heart dose to left-sided breast cancer patients. The secondary endpoint was a 5% decrease in the mean ipsilateral lung dose to all patients. A comparative analysis was carried out of the dosimetry, normal tissue complication probability (NTCP), acute skin toxicity, and radiation pneumonitis. RESULTS: Compared to a conventional bolus, the mean heart dose in left-sided breast cancer was reduced by an average of 0.8 Gy (5.5 ± 1.3 Gy vs. 4.7 ± 0.8 Gy, p = 0.035) and the mean dose to the ipsilateral lung was also reduced by an average of 0.8 Gy (12.4 ± 1.0 Gy vs. 11.6 ± 0.8 Gy, p < 0.001). The values for V50Gy of the PTV of the chest wall for the 3D-printed and conventional boluses were 95.4 ± 0.6% and 94.8 ± 0.8% (p = 0.026) and the values for the CI of the entire PTV were 0.83 ± 0.02 and 0.80 ± 0.03 (p < 0.001), respectively. The NTCP for the 3D-printed bolus was also reduced to an average of 0.14% (0.32 ± 0.19% vs. 0.18 ± 0.11%, p = 0.017) for the heart and 0.45% (3.70 ± 0.67% vs. 3.25 ± 0.18%, p < 0.001) for the ipsilateral lung. Grade 2 and Grade 1 radiation pneumonitis were 0.0% versus 7.5% and 14.3% versus 20.0%, respectively (p = 0.184). CONCLUSIONS: The 3D-printed bolus may reduce cardiopulmonary exposure in postmastectomy patients with volumetric modulated arc therapy.

Patient selection, inter-fraction plan robustness and reduction of toxicity risk with deep inspiration breath hold in intensity-modulated radiotherapy of locally advanced non-small cell lung cancer.

Background: State-of-the-art radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC) is performed with intensity-modulation during free breathing (FB). Previous studies have found encouraging geometric reproducibility and patient compliance of deep inspiration breath hold (DIBH) radiotherapy for LA-NSCLC patients. However, dosimetric comparisons of DIBH with FB are sparse, and DIBH is not routinely used for this patient group. The objective of this simulation study was therefore to compare DIBH and FB in a prospective cohort of LA-NSCLC patients treated with intensity-modulated radiotherapy (IMRT). Methods: For 38 LA-NSCLC patients, 4DCTs and DIBH CTs were acquired for treatment planning and during the first and third week of radiotherapy treatment. Using automated planning, one FB and one DIBH IMRT plan were generated for each patient. FB and DIBH was compared in terms of dosimetric parameters and NTCP. The treatment plans were recalculated on the repeat CTs to evaluate robustness. Correlations between ΔNTCPs and patient characteristics that could potentially predict the benefit of DIBH were explored. Results: DIBH reduced the median Dmean to the lungs and heart by 1.4 Gy and 1.1 Gy, respectively. This translated into reductions in NTCP for radiation pneumonitis grade ≥2 from 20.3% to 18.3%, and for 2-year mortality from 51.4% to 50.3%. The organ at risk sparing with DIBH remained significant in week 1 and week 3 of treatment, and the robustness of the target coverage was similar for FB and DIBH. While the risk of radiation pneumonitis was consistently reduced with DIBH regardless of patient characteristics, the ability to reduce the risk of 2-year mortality was evident among patients with upper and left lower lobe tumors but not right lower lobe tumors. Conclusion: Compared to FB, DIBH allowed for smaller target volumes and similar target coverage. DIBH reduced the lung and heart dose, as well as the risk of radiation pneumonitis and 2-year mortality, for 92% and 74% of LA-NSCLC patients, respectively. However, the advantages varied considerably between patients, and the ability to reduce the risk of 2-year mortality was dependent on tumor location. Evaluation of repeat CTs showed similar robustness of the dose distributions with each technique.

Development of a normal tissue complication probability (NTCP) model using an artificial neural network for radiation-induced necrosis after carbon ion re-irradiation in locally recurrent nasopharyngeal carcinoma.

Background: The aim of the present study was to build a normal tissue complication probability (NTCP) model using an artificial neural network (ANN) for radiation-induced necrosis after carbon ion re-irradiation in locally recurrent nasopharyngeal carcinoma (rNPC), and to determine the predictive parameters applied to the model. Methods: A total of 150 patients with rNPC treated at Shanghai Proton and Heavy Ion Center during 2015-2019 were selected to determine the dominant factors causing mucosal necrosis after carbon therapy. An ANN was built to study both dose-volume histogram (DVH) and clinical factors. Simple oversampling and data normalization were used in the training process. Ten-fold cross validation was conducted to prevent overfitting. Results: Of the DVH factors, the prediction accuracy ranged from 58.3-65.2%, whereas planning target volume (PTV) receiving dose more than 25 GyE (PTV.V25) yielded the best prediction accuracy. Of the clinical factors, baseline necrosis, sex, and biologically equivalent dose (BED) of initial treatment could increase the accuracy of PTV.V25 by 0.5%, 0.5%, and 1.5%, respectively. Conclusions: An ANN was built to predict radiation-induced necrosis after re-irradiation in rNPC. The best accuracy and area under receiver-operating characteristic (ROC) curve (AUC) were 66.7% and 0.689. The most predictive dosimetric and clinical parameters were PTV.V25 and BED of initial treatment.

Predictive modelling for late rectal and urinary toxicities after prostate radiotherapy using planned and delivered dose.

Background and purpose: Normal tissue complication probability (NTCP) parameters derived from traditional 3D plans may not be ideal in defining toxicity outcomes for modern radiotherapy techniques. This study aimed to derive parameters of the Lyman-Kutcher-Burman (LKB) NTCP model using prospectively scored clinical data for late gastrointestinal (GI) and genitourinary (GU) toxicities for high-risk prostate cancer patients treated using volumetric-modulated-arc-therapy (VMAT). Dose-volume-histograms (DVH) extracted from planned (DP) and accumulated dose (DA) were used. Material and methods: DP and DA obtained from the DVH of 150 prostate cancer patients with pelvic-lymph-nodes irradiation treated using VMAT were used to generate LKB-NTCP parameters using maximum likelihood estimations. Defined GI and GU toxicities were recorded up to 3-years post RT follow-up. Model performance was measured using Hosmer-Lemeshow goodness of fit test and the mean area under the receiver operating characteristics curve (AUC). Bootstrapping method was used for internal validation. Results: For mild-severe (Grade ≥1) GI toxicity, the model generated similar parameters based on DA and DP DVH data (DA-D50:71.6 Gy vs DP-D50:73.4; DA-m:0.17 vs DP-m:0.19 and DA/P-n 0.04). The 95% CI for DA-D50 was narrower and achieved an AUC of >0.6. For moderate-severe (Grade ≥2) GI toxicity, DA-D50 parameter was higher and had a narrower 95% CI (DA-D50:77.9 Gy, 95% CI:76.4-79.6 Gy vs DP-D50:74.6, 95% CI:69.1-85.4 Gy) with good model performance (AUC>0.7). For Grade ≥1 late GU toxicity, D50 and n parameters for DA and DP were similar (DA-D50: 58.8 Gy vs DP-D50: 59.5 Gy; DA-n: 0.21 vs DP-n: 0.19) with a low AUC of<0.6. For Grade ≥2 late GU toxicity, similar NTCP parameters were attained from DA and DP DVH data (DA-D50:81.7 Gy vs DP-D50:81.9 Gy; DA-n:0.12 vs DP-n:0.14) with an acceptable AUCs of >0.6. Conclusions: The achieved NTCP parameters using modern RT techniques and accounting for organ motion differs from QUANTEC reported parameters. DA-D50 of 77.9 Gy for GI and DA/DP-D50 of 81.7-81.9 Gy for GU demonstrated good predictability in determining the risk of Grade ≥2 toxicities especially for GI derived D50 and are recommended to incorporate as part of the DV planning constraints to guide dose escalation strategies while minimising the risk of toxicity.

Including Volume Effects in Biological Treatment Plan Optimization for Carbon Ion Therapy: Generalized Equivalent Uniform Dose-Based Objective in TRiP98.

We describe a way to include biologically based objectives in plan optimization specific for carbon ion therapy, beyond the standard voxel-dose-based criteria already implemented in TRiP98, research planning software for ion beams. The aim is to account for volume effects-tissue architecture-dependent response to damage-in the optimization procedure, using the concept of generalized equivalent uniform dose (gEUD), which is an expression to convert a heterogeneous dose distribution (e.g., in an organ at risk (OAR)) into a uniform dose associated with the same biological effect. Moreover, gEUD is closely related to normal tissue complication probability (NTCP). The multi-field optimization problem here takes also into account the relative biological effectiveness (RBE), which in the case of ion beams is not factorizable and introduces strong non-linearity. We implemented the gEUD-based optimization in TRiP98, allowing us to control the whole dose-volume histogram (DVH) shape of OAR with a single objective by adjusting the prescribed gEUD 0 and the volume effect parameter a, reducing the volume receiving dose levels close to mean dose when a = 1 (large volume effect) while close to maximum dose for a >> 1 (small volume effect), depending on the organ type considered. We studied the role of gEUD 0 and a in the optimization, and we compared voxel-dose-based and gEUD-based optimization in chordoma cases with different anatomies. In particular, for a plan containing multiple OARs, we obtained the same target coverage and similar DVHs for OARs with a small volume effect while decreasing the mean dose received by the proximal parotid, thus reducing its NTCP by a factor of 2.5. Further investigations are done for this plan, considering also the distal parotid gland, obtaining a NTCP reduction by a factor of 1.9 for the proximal and 2.9 for the distal one. In conclusion, this novel optimization method can be applied to different OARs, but it achieves the largest improvement for organs whose volume effect is larger. This allows TRiP98 to perform a double level of biologically driven optimization for ion beams, including at the same time RBE-weighted dose and volume effects in inverse planning. An outlook is presented on the possible extension of this method to the target.

A Novel Radiotherapeutic Approach to Treat Bulky Metastases Even From Cutaneous Squamous Cell Carcinoma: Its Rationale and a Look at the Reliability of the Linear-Quadratic Model to Explain Its Radiobiological Effects.

Introduction: Metastatic cutaneous squamous cell carcinoma (cSCC) is a very rare condition. The lack of definition of an oligometastatic subgroup means that there is no consensus for its treatment, unlike the mucosal head and neck counterpart. Like the latter, the cutaneous form is able to develop bulky tumor masses. When this happens, the classic care approach is just for palliative intent due to a likely unfavorable benefit-risk balance typical of aggressive treatments. Here we proposed a novel radiotherapy (RT) technique to treat bulky metastases from cSCC in the context of an overall limited tumor burden and tried to explain its clinical outcome by the currently available mathematical radiobiological and ad hoc developed models. Methods: We treated a case of facial cSCC with three metastases: two of them by classic stereotactic RT and the other by lattice RT supported by metabolic imaging (18F-FDG PET) due to its excessively large dimensions. For the latter lesion, we compared four treatment plans with different RT techniques in order to define the best approach in terms of normal tissue complication probability (NTCP) and tumor control probability (TCP). Moreover, we developed an ad hoc mathematical radiobiological model that could fit better with the characteristics of heterogeneity of this bulky metastasis for which, indeed, a segmentation of normoxic, hypoxic, and necrotic subvolumes might have been assumed. Results: We observed a clinical complete response in all three disease sites; the bulky metastasis actually regressed more rapidly than the other two treated by stereotactic RT. For the large lesion, NTCP predictions were good for all four different plans but even significantly better for the lattice RT plan. Neither the classic TCP nor the ad hoc developed radiobiological models could be totally adequate to explain the reported outcome. This finding might support a key role of the host immune system. Conclusions: PET-guided lattice RT might be safe and effective for the treatment of bulky lesions from cSCC. There might be some need for complex mathematical radiobiological models that are able to take into account any immune system's role in order to explain the possible mechanisms of the tumor response to radiation and the relevant key points to enhance it.

Development and validation of a normal tissue complication probability model for acquired nasal cavity stenosis and atresia after radical radiotherapy for nasopharyngeal carcinoma.

PURPOSE: Curative radiotherapy for nasopharyngeal carcinoma (NPC) can lead to acquired nasal cavity stenosis and atresia (ANCSA). As the first study to investigate risk factors of ANCSA in a large cohort of NPC patients, this article aims to develop and validate a multivariate normal tissue complication probability (NTCP) model to predict the development of ANCSA and to establish a nomogram for clinical use. METHODS AND MATERIALS: The retrospective cohort was comprised of 548 NPC patients treated with radical radiotherapy. The cohort was randomly divided into training and validation groups. Least absolute shrinkage and selection operator regression was performed for variable selection from the clinical and dosimetric characteristics in the training group. A multivariate NTCP model and a nomogram were established for the prediction of ANCSA development. Discrimination and calibration were tested using receiver operating characteristic (ROC) curves and calibration tests, respectively, for both groups. RESULTS: ANCSA was observed in 132 (24.1%) of 548 patients with NPC who underwent radical radiotherapy. The median time to ANCSA detection after treatment was 2.8 months (range, 0.0-57.7 months). Five potential predictors, including choanal invasion, low white blood cell count, high C-reactive protein level, high serum amyloid A level, and high V70Gy of the nasal cavity, were selected to develop the NTCP model based on 365 patients in the training group. The model had a fairly good discriminative power according to the ROC analysis in both the training (area under ROC curve = 0.79, 95%CI: 0.73-0.84) and validation (0.73, 0.64-0.82) groups. The calibration power was tested using the calibration test in the training (E-max = 0.069, E-avg = 0.015, p = 0.977) and validation (E-max = 0.057, E-avg = 0.032, p = 0.747) groups. CONCLUSIONS: We developed and successfully validated an NTCP model for early prediction of ANCSA in patients with NPC after radical radiotherapy. This could help clinicians assess the risk of ANCSA before the initiation of follow-ups and ensure appropriate and timely management of this complication.

Comparison of a Hybrid IMRT/VMAT technique with non-coplanar VMAT and non-coplanar IMRT for unresectable olfactory neuroblastoma using the RayStation treatment planning system-EUD, NTCP and planning study.

The purpose of this study was to compare hybrid intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (Hybrid IMRT/VMAT), with non-coplanar (nc) IMRT and nc-VMAT treatment plans for unresectable olfactory neuroblastoma (ONB). Hybrid IMRT/VMAT, nc-IMRT and nc-VMAT plans were optimized for 12 patients with modified Kadish C stage ONB. Dose prescription was 65 Gy in 26 fractions. Dose-volume histogram parameters, conformation number (CN), homogeneity index (HI), integral dose and monitor units (MUs) delivered per fraction were assessed. Equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) based on the EUD model (NTCPLogit) and the Lyman-Kutcher-Burman model (NTCPLKB) were also evaluated. We found that the Hybrid IMRT/VMAT plan significantly improved the CN for clinical target volume (CTV) and planning treatment volume (PTV) compared with the nc-VMAT plan. In general, sparing of organs at risk (OARs) is similar with the three techniques, although the Hybrid IMRT/VMAT plan resulted in a significantly reduced Dmax to contralateral (C/L) optic nerve compared with the nc-IMRT plan. The Hybrid IMRT/VMAT plan significantly reduce EUD to the ipsilateral (I/L) and C/L optic nerve in comparison with the nc-IMRT plan and nc-VMAT plan, but the difference in NTCP between the three technique was <1%. We concluded that the Hybrid IMRT/VMAT technique can offer improvement in terms of target conformity and EUD for optic nerves, while achieving equal or better OAR sparing compared with nc-IMRT and nc-VMAT, and can be a viable radiation technique for treating unresectable ONB. However, the clinical benefit of these small differences in dosimetric data, EUD and NTCP of optic nerves may be minimal.

Effective Organs-at-Risk Dose Sparing in Volumetric Modulated Arc Therapy Using a Half-Beam Technique in Whole Pelvic Irradiation.

BACKGROUND: Although there are some controversies regarding whole pelvic radiation therapy (WPRT) due to its gastrointestinal and hematologic toxicities, it is considered for patients with gynecological, rectal, and prostate cancer. To effectively spare organs-at-risk (OAR) doses using multi-leaf collimator (MLC)'s optimal segments, potential dosimetric benefits in volumetric modulated arc therapy (VMAT) using a half-beam technique (HF) were investigated for WPRT. METHODS: While the size of a fully opened field (FF) was decided to entirely include a planning target volume in all beam's eye view across arc angles, the HF was designed to use half the FF from the isocenter for dose optimization. The left or the right half of the FF was alternatively opened in VMAT-HF using a pair of arcs rotating clockwise and counterclockwise. Dosimetric benefits of VMAT-HF, presented with dose conformity, homogeneity, and dose-volume parameters in terms of modulation complex score, were compared to VMAT optimized using the FF (VMAT-FF). Consequent normal tissue complication probability (NTCP) by reducing the irradiated volumes was evaluated as well as dose-volume parameters with statistical analysis for OAR. Moreover, beam-on time and MLC position precision were analyzed with log files to assess plan deliverability and clinical applicability of VMAT-HF as compared to VMAT-FF. RESULTS: While VMAT-HF used 60%-70% less intensity modulation complexity than VMAT-FF, it showed superior dose conformity. The small intestine and colon in VMAT-HF showed a noticeable reduction in the irradiated volumes of up to 35% and 15%, respectively, at an intermediate dose of 20-45 Gy. The small intestine showed statistically significant dose sparing at the volumes that received a dose from 15 to 45 Gy. Such a dose reduction for the small intestine and colon in VMAT-HF presented a significant NTCP reduction from that in VMAT-FF. Without sacrificing the beam delivery efficiency, VMAT-HF achieved effective OAR dose reduction in dose-volume histograms. CONCLUSIONS: VMAT-HF led to deliver conformal doses with effective gastrointestinal-OAR dose sparing despite using less modulation complexity. The dose of VMAT-HF was delivered with the same beam-on time with VMAT-FF but precise MLC leaf motions. The VMAT-HF potentially can play a valuable role in reducing OAR toxicities associated with WPRT.

Impact of respiratory motion in dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy.

We investigated the organ-sparing effect of the deep inspiration breath hold (DIBH) technique among different levels of lung expansion for left-side breast radiotherapy. This retrospective study enrolled 30 patients who received adjuvant left breast radiotherapy after breast-conserving surgery (BCS). Simulation scans of both DIBH and deep breathing four-dimensional computed tomography (4DCT) were acquired, and three treatment plans were generated for each patient. One plan was based on the DIBH images, and the other two plans were based on the mid-lung expansion (ME) and initial lung expansion (IE) phases retrieved from 4DCT data sets. Dosimetric comparisons and normal tissue complication probability (NTCP) models were conducted. We used image registration for displacement analysis and sought potential factors related to the dose benefit of DIBH. The DIBH plans resulted significantly lower doses to the heart, left ventricle (LV) and left anterior descending coronary artery (LAD), including the high- to low-dose areas, followed by the ME plans and IE plans (p < 0.05). DIBH reduced the risk of long-term cardiac mortality by 40% and radiation pneumonitis of the left lung by 37.96% compared with the IE plans (p < 0.001). The reduction in the mean dose to the heart and LV significantly correlated with anterior displacement of the left lung. The DIBH technique is a feasible tool to provide dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy. Breathing pattern and the level of lung expansion seem to play an important role.

Investigate the Dosimetric and Potential Clinical Benefits Utilizing Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost Technique for Locally Advanced Pancreatic Cancer: A Comparison Between Photon and Proton Beam Therapy.

PURPOSE: To investigate the potential clinical benefits of using stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) technique for locally advanced pancreatic cancer (LAPC) among different treatment modalities and planning strategies, including photon and proton. METHOD: A total of 19 patients were retrospectively selected in this study: 13 cases with the tumor located in the head of the pancreas and 6 cases with the tumor in the body of the pancreas. SBRT-SIB plans were generated using volumetric modulated arc therapy (VMAT), two-field Intensity Modulated Proton Therapy (IMPT), and three-field IMPT. The IMPT used the robust optimization parameters of ± 3.5% range and 5-mm setup uncertainties. Root-mean-square deviation dose (RMSD) volume histograms were used to evaluate the target coverage robustness quantitatively. Dosimetric metrics based on the dose-volume histogram (DVH), homogeneity index (HI), and normal tissue complication probability (NTCP) were analyzed to evaluate the potential clinical benefits among different planning groups. RESULTS: With a similar CTV and SIB coverage, two-field IMPT provided a lower maximum dose for the stomach (median: 18.6GyE, p<0.05) and duodenum (median: 32.62GyE, p<0.05) when the target was located in the head of the pancreas compared to VMAT and three-field IMPT. The risks of gastric bleed (3.42%) and grade ≥ 3 GI toxicity (4.55%) were also decreased. However, for the target in the body of the pancreas, VMAT showed a lower maximum dose for the stomach (median 30.93GyE, p<0.05) and toxicity of gastric bleed (median: 8.67%, p<0.05) compared to two-field IMPT and three-field IMPT, while other maximum doses and NTCPs were similar. The RMSD volume histogram (RVH) analysis shows that three-field IMPT provided better robustness for targets but not for OARs. Instead, three-field IMPT increased the Dmean of organs such as the stomach, duodenum, and intestine. CONCLUSION: The results indicated that the tumor locations could play a critical role in determining clinical benefits among different treatment modalities. Two-field IMPT could be a better option for LAPC patients whose tumors are located in the head of the pancreas. It provides lower severe toxicity for the stomach and duodenum. Nevertheless, VMAT is preferred for the body with better protection for the possibility of gastric bleed.