Evaluation of the clinical impact of the differences between planned and delivered dose in prostate cancer radiotherapy based on CT-on-rails IGRT and patient-reported outcome scores.

PURPOSE: To estimate the clinical impact of differences between delivered and planned dose using dose metrics and normal tissue complication probability (NTCP) modeling. METHODS: Forty-six consecutive patients with prostate adenocarcinoma between 2010 and 2015 treated with intensity-modulated radiation therapy (IMRT) and who had undergone computed tomography on rails imaging were included. Delivered doses to bladder and rectum were estimated using a contour-based deformable image registration method. The bladder and rectum NTCP were calculated using dose-response parameters applied to planned and delivered dose distributions. Seven urinary and gastrointestinal symptoms were prospectively collected using the validated prostate cancer symptom indices patient reported outcome (PRO) at pre-treatment, weekly treatment, and post-treatment follow-up visits. Correlations between planned and delivered doses against PRO were evaluated in this study. RESULTS: Planned mean doses to bladder and rectum were 44.9 ± 13.6 Gy and 42.8 ± 7.3 Gy, while delivered doses were 46.1 ± 13.4 Gy and 41.3 ± 8.7 Gy, respectively. D10cc for rectum was 64.1 ± 7.6 Gy for planned and 60.1 ± 9.3 Gy for delivered doses. NTCP values of treatment plan were 22.3% ± 8.4% and 12.6% ± 5.9%, while those for delivered doses were 23.2% ± 8.4% and 9.9% ± 8.3% for bladder and rectum, respectively. Seven of 25 patients with follow-up data showed urinary complications (28%) and three had rectal complications (12%). Correlations of NTCP values of planned and delivered doses with PRO follow-up data were random for bladder and moderate for rectum (0.68 and 0.67, respectively). CONCLUSION: Sensitivity of bladder to clinical variations of dose accumulation indicates that an automated solution based on a DIR that considers inter-fractional organ deformation could recommend intervention. This is intended to achieve additional rectum sparing in cases that indicate higher than expected dose accumulation early during patient treatment in order to prevent acute severity of bowel symptoms.

Stereotactic body radiotherapy optimization to reduce the risk of carotid blowout syndrome using normal tissue complication probability objectives.

PURPOSE: To determine the possibility of further improving clinical stereotactic body radiotherapy (SBRT) plans using normal tissue complication probability (NTCP) objectives in order to minimize the risk for carotid blowout syndrome (CBOS). METHODS: 10 patients with inoperable locally recurrent head and neck cancer, who underwent SBRT using CyberKnife were analyzed. For each patient, three treatment plans were examined: (1) cone-based without delineation of the ipsilateral internal carotid (clinical plan used to treat the patients); (2) cone-based with the carotid retrospectively delineated and spared; and (3) Iris-based with carotid sparing. The dose-volume histograms of the target and primary organs at risk were calculated. The three sets of plans were compared based on dosimetric and TCP/NTCP (tumor control and normal tissue complication probabilities) metrics. For the NTCP values of carotid, the relative seriality model was used with the following parameters: D50 = 40 Gy, γ = 0.75, and s = 1.0. RESULTS: Across the 10 patient plans, the average TCP did not significantly change when the plans were re-optimized to spare the carotid. The estimated risk of CBOS was significantly decreased in the re-optimized plans, by 14.9% ± 7.4% for the cone-based plans and 17.7% ± 7.1% for the iris-based plans (p = 0.002 for both). The iris-based plans had significant (p = 0.02) reduced CBOS risk and delivery time (20.1% ± 7.4% time reduction, p = 0.002) compared to the cone-based plans. CONCLUSION: A significant improvement in the quality of the clinical plans could be achieved through the delineation of the internal carotids and the use of more modern treatment delivery modalities. In this way, for the same target coverage, a significant reduction in the risk of CBOS could be achieved. The range of risk reduction varied depending on the proximity of carotid artery to the target.

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.

NTCP modeling and dose-volume correlations for acute xerostomia and dry eye after whole brain radiation.

BACKGROUND: Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models. METHODS: Patients received WBRT to 25-40 Gy in 10-20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0-100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models. RESULTS: Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V10Gy-V20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69-0.71 for bother score. The values for the D50, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D50, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V10Gy-V15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively. CONCLUSIONS: Xerostomia was most associated with parotid V10Gy-V20Gy, and dry eye with lacrimal V10Gy-V15Gy. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT.

Investigating the role of constrained CVT and CVT in HIPO inverse planning for HDR brachytherapy of prostate cancer.

PURPOSE: The purpose of this study is to investigate the role of the centroidal Voronoi tessellation (CVT) and constrained CVT (CCVT) in inverse planning in combination with the Hybrid Inverse Planning Optimization (HIPO) algorithm in HDR brachytherapy of prostate cancer. HIPO implemented in Oncentra© Prostate treatment planning system, is used for three-dimensional (3D)-ultrasound-based intraoperative treatment planning in high dose rate brachytherapy. HIPO utilizes a hybrid iterative process to determine the most appropriate placement of a given number of catheters to fulfil predefined dose-volume constraints. The main goals of the current investigation were to identify a way of improving the performance of HIPO inverse planning; accelerating the HIPO, and to evaluate the effect of the two CVT-based initialization methods on the dose distribution in the sub-region of prostate that is not accessible by catheters, when trying to avoid perforation of urethra. METHODS: We implemented the CVT algorithm to generate initial catheter configurations before the initialization of the HIPO algorithm. We introduced the CCVT algorithm to improve the dose distribution to the sub-volume of prostate within the bounding box of the urethra contours including its upper vertical extension (U-P). For the evaluation, we considered a total of 15 3D ultrasound-based HDRBT prostate implants. Execution time and treatment plan quality were evaluated based on the dose-volume histograms of prostate (PTV), its sub-volume U-P, and organs at risk (OARs). Furthermore, the conformity index COIN, the homogeneity index HI and the complication-free tumor control probability (P+ ) were used for our treatment plan comparisons. Finally, the plans with the recommended HIPO execution mode were compared to the clinically used intraoperative pre-plans. RESULTS: The plan quality achieved with CCVT-based HIPO initialization was superior to the default HIPO initialization method. Focusing on the U-P sub-region of the prostate, the CCVT method resulted in a significant improvement of all dosimetric indices compared to the default HIPO, when both were executed in the adaptive mode. For that recommended HIPO execution mode, and for U-P, CCVT demonstrated in general higher dosimetric indices than CVT. Additionally, the execution time of CCVT initialized HIPO was lower compared to both alternative initialization methods. This is also valid for the values of the aggregate objective function with the differences to the default initialization method being highly significant. Paired non-parametric statistical tests (Wilcoxon signed-rank) showed a significant improvement of dose-volume indices, COIN and P+ for the plans generated by the CCVT-based catheter configuration initialization in HIPO compared to the default HIPO initialization process. Furthermore, in ten out of 15 cases, the CCVT-based HIPO plans fulfilled all the clinical dose-volume constraints in a single trial without any need for further catheter position adaption. CONCLUSION: HIPO with CCVT-based initialization demonstrates better performance regarding the aggregate objective function and convergence when compared to the CVT-based and default catheter configuration initialization methods. This improved performance of HIPO inverse planning is clearly not at the cost of the dosimetric and radiobiologically evaluated plan quality. We recommend the use of the CCVT method for HIPO initialization especially in the adaptive planning mode.

Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy.

BACKGROUND: To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptoms during post-prostatectomy radiotherapy (RT). To evaluate the goodness-of-fit and the correlation of those models with those symptoms. METHODS: Ninety-three consecutive patients treated from 2010 to 2015 with post-prostatectomy image-guided intensity modulated radiotherapy (IMRT) were included in this study. Patient-reported urinary symptoms were collected pre-RT and weekly during treatment using the validated Prostate Cancer Symptom Indices (PCSI). The assessed symptoms were flow, dysuria, urgency, incontinence, frequency and nocturia using a Likert scale of 1 to 4 or 5. For this analysis, an increase by ≥2 levels in a symptom at any time during treatment compared to baseline was considered clinically significant. The dose volume histograms of the bladder were calculated. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS) and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC) and Odds Ratio methods. RESULTS: For the symptoms of urinary urgency, leakage, frequency and nocturia, the derived LKB model parameters were: 1) D50 = 64.2Gy, m = 0.50, n = 1.0; 2) D50 = 95.0Gy, m = 0.45, n = 0.50; 3) D50 = 83.1Gy, m = 0.56, n = 1.00; and 4) D50 = 85.4Gy, m = 0.60, n = 1.00, respectively. The AUC values for those symptoms were 0.66, 0.58, 0.64 and 0.64, respectively. The differences in AIC between the different models were less than 2 and ranged within 0.1 and 1.3. CONCLUSIONS: Different dose metrics were correlated with the symptoms of urgency, incontinence, frequency and nocturia. The symptoms of urinary flow and dysuria were poorly associated with dose. The values of the parameters of three NTCP models were determined for bladder regarding four acute urinary symptoms. All the models could fit the clinical data equally well. The NTCP predictions of urgency showed the best correlation with the patient reported outcomes.

Fitting NTCP models to SBRT dose and carotid blowout syndrome data.

PURPOSE: To estimate the radiobiological parameters of three popular NTCP models, which describe the dose-response relations of carotid blowout syndrome (CBOS) after stereotactic body radiotherapy (SBRT). To evaluate the goodness-of-fit and the correlation of those models with CBOS. METHODS: The study included 61 patients with inoperable locally recurrent head and neck cancer treated with SBRT using CyberKnife (Accuray, Sunnyvale, CA) at the Department of Radiation Oncology, Hacettepe University, Ankara, Turkey between June 2007 and March 2011. The dose-volume histograms of the internal carotid were exported from the plans of all the patients. The follow-up results regarding the end point of carotid blowout syndrome were collected retrospectively. Initially, univariable analyses (Wilcoxon rank-sum or Chi-square tests) and a multivariate logistic regression analysis were performed between the outcome data and a list of clinical and treatment factors to identify significant correlations. Additionally, the Lyman-Kutcher-Burman (LKB), Relative Seriality (RS), and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC), and Odds Ratio methods. RESULTS: The clinical/treatment factors that were found to have a significant or close to significant correlations with acute CBOS were Age at the time of CK (P-value = 0.03), Maximum carotid dose (P-value = 0.06), and CK prescription dose (P-value = 0.08). Using Dmax , physical DVH, and EQD2 Gy -DVH as the dosimetric metrics in the NTCP models, the derived LKB model parameters were: (a) D50  = 45.8 Gy, m = 0.24, n = n/a; (b) D50  = 44.8 Gy, m = 0.28, n = 0.01; and (c) D50  = 115.8 Gy, m = 0.45, n = 0.01, respectively. The AUC values for the dosimetric metrics were 0.70, 0.68, and 0.61, respectively. The differences in AIC between the different models were less than 2 and ranged within ±0.9. CONCLUSION: The maximum dose to the internal carotid less than 34 Gy appears to significantly reduce the risk for CBOS. Age at the time of CK, Maximum carotid dose, and CK prescription dose were also found to correlate with CBOS. The values of the parameters of three NTCP models were determined for this endpoint. A threshold of gEUD <34.5 Gy appears to be significantly associated with lower risks of CBOS.

Dose-volume toxicity modeling for de-intensified chemo-radiation therapy for HPV-positive oropharynx cancer.

BACKGROUND AND PURPOSE: The aim is to determine the radiobiological parameters of four popular normal tissue complication probability (NTCP) models that describe the dose-response relations of salivary glands and pharyngeal constrictors to the severity of patient reported xerostomia and dysphagia, respectively 6 and 12months post chemo-radiotherapy, furthermore, to evaluate the goodness-of-fit of the NTCP models for different combinations of glands and constrictors. MATERIAL AND METHODS: Forty-three patients were treated on a prospective multi-institutional phase II study (ClinicalTrials.gov, NCT01530997) assessing the efficacy of de-intensified chemoradiotherapy in patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma. All patients received 60Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatinum. All patients reported severity of their xerostomia and dysphagia (pre- and post-treatment) using the patient reported outcome version of the CTCAE (PRO-CTCAE). A change in severity (from baseline) of ≥2 was considered clinically meaningful. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS), Logit, and Relative Seriality Logit (RSL) NTCP models were used to fit the patients' dose/volume data to changes in PRO-CTCAE severity of xerostomia and dysphagia (from baseline to 6 and 12months post-treatment). The correlation of the models with the patient outcomes was performed for different combinations of salivary glands and different sections of pharyngeal constrictors. The goodness-of-fit of the different models was assessed through the area under the receiver operating characteristic curve (AUC), maximum of the log-likelihood function, normal error distribution and Akaike information criterion (AIC). RESULTS: The dose/volume metrics of the combined contralateral (parotid+submandibular) glands appear to correlate best with xerostomia, at both 6- and 12-months. Among the different sections of pharyngeal constrictors, the dose/volume metrics of the superior pharyngeal constrictors appear to correlate best with dysphagia at 6months. The AUC values ranged from 0.72 to 0.85 in the case of xerostomia and 0.73 to 0.74 in the case of dysphagia over the different models. The four NTCP models showed similar goodness-of-fit. The differences in AIC between the different models were less than 2 and ranged within 0.7 and 0.8 in the cases of xerostomia and dysphagia, respectively. The calculated parameters of the LKB model were D50=26.9Gy, m=0.63, n=1.0 for the combined contralateral glands at 12months and D50=62.0Gy, m=0.10, n=0.49 for the superior pharyngeal constrictors at 6months. CONCLUSIONS: The values of the parameters of four NTCP models were determined for salivary glands and pharyngeal constrictors. All four models could fit the clinical data equally well. The NTCP predictions of the combined contralateral glands and superior pharyngeal constrictors showed the best correlation with the patient reported outcomes of xerostomia and dysphagia, respectively.