Dosimetric Predictors Research Articles

Model development of dose and volume predictors for esophagitis induced during chemoradiotherapy for lung cancer as a step towards radiobiological treatment planning

BackgroundCurrently, radiation therapy treatment planning system intends biological optimization that relies heavily upon plan metrics from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. Implementation and expansion of TCP and NTCP models with alternative data is an important step towards reliable radiobiological treatment planning. In this retrospective single institution study, the treatment charts of 139 lung cancer patients treated with chemo-radiotherapy were reviewed and correlated dosimetric predictors with the incidence of esophagitis and established NTCP model of esophagitis grade 1 and 2 for lung cancer patients.MethodsEsophagus is an organ at risk (OAR) in lung cancer radiotherapy (RT). Esophagitis is a common toxicity induced by RT. In this study, dose volume parameters Vx (Vx: percentage esophageal volume receiving ≥ x Gy) and mean esophagus dose (MED) as quantitative dose-volume metrics, the esophagitis grade 1 and 2 as endpoints, were reviewed and derived from the treatment planning system and the electronic medical record system. Statistical analysis of binary logistic regression and probit were performed to have correlated the probability of grade 1 and 2 esophagitis to MED and Vx. IBM SPSS software version 24 at 5% significant level (α = 0.05) was used in the statistical analysis.ResultsThe probabilities of incidence of grade 1 and 2 esophagitis proportionally increased with increasing the values of Vx and MED. V20, V30, V40, V50 and MED are statistically significant good dosimetric predictors of esophagitis grade 1. 50% incidence probability (TD50) of MED for grade 1 and 2 esophagitis were determined. Lyman Kutcher Burman model parameters, such as, n, m and TD50, were fitted and compared with other published findings. Furthermore, the sigmoid shaped dose responding curve between probability of esophagitis grade 1 and MED were generated respecting to races, gender, age and smoking status.ConclusionsV20, V30, V40 and V50 were added onto Quantitative Analysis of Normal Tissue Effects in the clinic, or QUANTEC group’s dose constrains of V35, V50, V70 and MED. Our findings may be useful as both validation of 3-Dimensional planning era models and also additional clinical guidelines in treatment planning and plan evaluation using radiobiology optimization.

Significance of Radiomics in Predicting Local Control for Patients with Malignant Liver Tumors Treated Using Stereotactic Body Radiotherapy.

We routinely deliver Stereotactic Body Radiotherapy (SBRT) in malignant liver tumors using planning computed tomography (CT) and Magnetic Resonance Images (MRI) to aid target definition. In this study, we extracted radiomic features from the MR images to predict local control (LC) post-SBRT. We retrospectively analyzed patients with either hepatocellular cancers (HCCs) or liver metastases (Mets) treated with SBRT between Aug 2014 and Aug 2020. All patients had CT simulation followed by 1.5 Tesla planning MRI in treatment position. Contrast enhanced T1 VIBE and T2 Haste MR sequences were registered with planning CT for target definition. Radiomic features were extracted from Gross Tumor Volumes (GTV) masked out of 60 seconds post contrast T1 VIBE MR images using the Radiomics calculator tool RaCaT. The output included 480 (408 textural, 50 intensity and 22 morphological) features for each target. Principal Component Analysis of the outputs obtained from all the targets yielded 20 radiomic feature clusters after computational prioritization. These clusters were correlated to LC outcomes at various time points post-SBRT. LC was defined as non-progressive disease. Accuracy of predictions was measured by area under (AUC) receiver operating characteristic curve. Cox regression analysis was done to find univariate and multivariate clinical [HCCs vs. Mets, single vs. multiple lesions, previous local therapy (yes vs. no), GTV volume (≤40 vs. >40 cc)], radiomic and dosimetric predictors (continuous) of LC. In total, 97 patients received SBRT to 122 lesions. The median dose prescribed was 45 Gy (range, 30-50 Gy). Median age was 69 years (interquartile range, IQR 61-73 yrs.). 59 patients had HCCs and 38 had Mets. 24 lesions had prior ablative therapy. 75 patients had one target, and 22 had multiple targets. Median GTV was 43.5 cc (IQR 23.4-78.6 cc). Median follow up was 16.6 months (IQR 9.7-27.2 mths). Median LC was 13.6 months (IQR 8.0-23.5 mths). On univariate analysis, histology (HCCs vs. Mets; Hazard ratio (HR) 2.9, 95% CI 1.4-6.4; p < 0.006), radiomic clusters (p < 0.006) and the max., mean, and min. doses to GTV and Planning Target Volumes correlated with improved LC (all p-values < 0.05). On multivariate analysis, histology (HCCs vs. Mets; HR 4.4, 95% CI 1.6-12.3; p = 0.004), radiomic clusters (p = 0.034) and prescription dose (p = 0.048) were significant covariates. Specifically, the 20 radiomic clusters were predictive of LC, and the accuracy of predictions showed promise with AUC values of 0.74, 0.80, and 0.81 at 12, 24, and 36 months post-SBRT, respectively. AUC values for LC in HCCs vs. Mets at 12, 24, and 36 months were 0.83, 0.77, and 0.70, and 0.66, 0.77, and 0.88, respectively. MR-based radiomics predict LC post-SBRT in patients with malignant liver tumors. Further research focused on independent validation of the model is required to explore its clinical use.

Dosimetric Predictors of Toxicities and Quality of Life Following Two-Fraction Stereotactic Body Radiotherapy for Prostate Cancer.

There is emerging interest in two-fraction stereotactic body radiotherapy (2#SBRT) for localized prostate cancer. However, there is limited data to guide organs at risk (OAR) dose constraints in 2#SBRT. We aim to identify dosimetric predictors of toxicities and quality of life (QoL) using real life patient data from two prospective 2#SBRT trials. We included 60 patients who had 2#SBRT in the 2STAR (NCT02031328) and 2SMART (NCT03588819) phase 2 trials. The prescribed dose was 26Gy to the prostate +/- focal boost of 32Gy to the dominant intraprostatic lesions. Toxicities and QoL data were prospectively collected using CTCAEv4 and EPIC26 questionnaires. For QoL, we reported the minimal clinical important changes (MCIC), defined as changes in QoL score of >0.5 standard deviation from baseline QoL score. We evaluated the bladder, urethra, rectum, and penile bulb dosimetry (urethra dosimetry only available in 30 patients in 2SMART trial). Some of the dosimetric parameters were log-transformed to normalize the distribution. Cox regression was used to identify dosimetric predictors for acute and late grade ≥2 GU toxicities. Logistic regression was used to identify dosimetric predictors for late MCIC in urinary, bowel and sexual QoL domains. Backward stepwise selection was used to identify significant dosimetric parameters. For GU toxicities and urinary QoL, three additional clinical factors (age, prostate volume and IPSS) were included in the final model as confounding factors. Receiver operating characteristics curve was used to identify cut-off for significant dosimetric parameters. The median follow-up for the cohort was 56 months (range: 39-78 months). The cumulative acute and late grade ³2 GU toxicities were 62% (37/60) and 57% (34/60) respectively. No bladder or urethra dosimetric parameter was associated with acute grade ≥2 GU toxicities. Bladder D0.5cc was significant predictor of late grade ≥2 GU toxicities in univariate model (P = 0.05), but not in multivariate model. Baseline IPSS score was the single strongest predictor for late grade ≥2 GU toxicities (HR = 1.9; 95% CI = 1.1-3.4; P = 0.03). For late QoL outcomes, there were 36% (21/58), 28% (16/58), and 29% (17/58) of patients with MCIC in urinary, bowel and sexual QoL domains respectively. Bladder V10Gy was associated with late urinary MCIC in multivariate model after adjusting for clinical confounders (HR = 2.6, 95% CI = 1.1-6.6; P = 0.04). 48% (14/29) and 24% (7/29) of patients with bladder V10Gy>13.9% and V10Gy≤13.9% respectively had late urinary MCIC. No rectum and penile bulb dosimetry parameters was identified to be associated with late bowel or sexual QoL. Using real life patient data from prospective clinical trials with medium term follow-up, we identified statistically significant bladder dosimetry parameter predictive of late urinary QoL. This finding could be useful to guide OAR dose constraints in prostate 2#SBRT trials.

Predicting Local Control with Dosimetric Parameters in Patients Receiving Individualized Stereotactic Ablative Radiotherapy for Lung Tumors

Stereotactic ablative radiotherapy (SABR) is an effective treatment option for lung tumors. The individualized lung tumor SABR (iSABR) trial was a phase II single-arm study that personalized lung tumor SABR dose and fractionation based on tumor size, location, and histology with very low rates of local recurrence (LR). A secondary analysis of this trial was conducted to assess for potential dosimetric predictors of LR, in order to help guide future clinical treatment planning. From 2011 to 2018, local, regional and distant recurrence data were prospectively collected from 204 patients (261 lung SABR treatments) enrolled in a prospective trial. Baseline characteristics and treatment details were evaluated. Dosimetric and treatment plan parameters were evaluated for their potential to predict LR, using logistic regression and chi-squared analyses. The majority of treated tumors were peripheral (71%, vs 29% central), primary lesions (76%, versus 24% metastatic), and of adenocarcinoma histology (67%, versus 13% squamous cell carcinoma and 19% other). The median follow-up was 24 months (range 2-95). Twenty-seven (10.3%) LRs occurred, with a median time to LR of 15 months (range 6-81 months). There were no significant associations between the overall cohort and the dosimetric parameters. However, for the multi-fraction cohort, an increased proportion of the PTV receiving 110% and 115% of the prescription dose were associated with lower LR (p = 0.01 and p = 0.01 respectively). Specifically for the 50 Gy in 4 fraction cohort, an increased D1cc, D0.03cc, as well as the proportion of the PTV receiving 110%, 115%, and 120% of the prescription dose were associated with lower LR (p < 0.001, p = 0.001, p = 0.003, p < 0.001, p = 0.004, respectively). There was no association of LR with prescription dose expressed as biologically effective dose using an alpha/beta of 10 Gy (BED10), D99%, or single- versus multi-fraction regimens. SABR for lung tumors using the individualized protocol on this trial showed excellent LR rates. We identified dosimetric parameters that were associated with LR, including V110% and V115% within the multi-fraction cohort, as well as the 50 Gy in 4 fraction cohort the D1cc, D0.03cc, and proportions of the PTV receiving 110%, 115%, and 120% of the prescription dose in the 50 Gy in 4 fraction cohort. Optimal thresholds for these parameters will be identified in further analyses. There did not appear to be an association with LR and BED10, D99%, or comparing single- vs multi-fraction regimens.

Potential Dosimetric Predictors of Patient-Reported Quality of Life for Head and Neck Cancer Following Chemoradiation IMRT

This study aims to identify both acute and late patient patient-reported salivary quality of life outcomes in patients with head and neck cancer treated with chemoradiation therapy on a prospective trial. A cohort of 40 patients with head and neck cancers were included in the study. All patients underwent concurrent chemoradiation therapy using IMRT delivery (1 patient on one Linac, 24 patients on a different Linac, and 15 on a helical delivery machine). All patients were asked to complete the University of Washington Quality of Life (UOW-QOL) questionnaire at baseline, immediately after treatment, as well as at 1 month, 3 months, 6 months, 12 month and 18 months post-treatment. For the salivary quality of life (QOL) outcome scores, the possible responses were scored on a discreet scale of 100, 70, 30, and 0, with 100 as normal and 0 as dysfunctional. Dosimetric endpoints achieved based on the treatment plan, such as maximum/mean/minimum doses, V30 (percent volume receiving 30 Gy dose), and Dy (dose received to y percent volume) were collected for the bilateral salivary glands, bilateral temporomandibular joint and bilateral submandibular glands. The associations between these dosimetric parameters and the corresponding salivary QOL scores at each time point were analyzed. A Wilcoxon test was performed to identify any differences in the dosimetry and salivary QOL scores among the four different responses. At short-term follow-up including 1- and 6-month, the distribution of the mean dose received by the right parotid was significantly different between the patients that reported a salivary QOL score of 30 and those that reported 100, with p-values of 0.007 for the 1-month comparison and 0.006 for the 6-month comparison. This was also seen for the V30, with p-values of 0.027 for the 1-month comparison and 0.013 for the 6-month comparison. At 3 months, the maximum dose received by the left temporomandibular joint was significantly different between the patients that reported 30 and those that reported 70, with a p-value of 0.038. At 6 months, the average dose distribution of the right submandibular gland received between the patients that reported a score of 30 and 100 was also significantly different, with a p-value of 0.006. At the long-term follow-up time points of 12 and 18 months, no significant differences were found. The significant differences seen in the data suggest that the dosimetry may have effects on patient reported salivary QOL at short-term follow-up but not long-term. This provides a new perspective into how a patient's QOL over a period of time could be affected by the amount of dose to critical organs. These results also serve as the basis for further investigation into the actual delivered dose, which could differ from the planned dose due to daily anatomic changes over the course of head and neck radiotherapy delivery. These daily volumetric and dosimetric changes may guide early adaptive treatment to improve patient-reported QOL outcomes.

Evidence-Based Multivariate Normal Tissue Complication Probability (NTCP) Study of Domain-Specific Cognitive Decline after Partial Brain RT

Beyond the hippocampus, there are no evidence-based dose constraints for eloquent brain structures which subserve memory and attention/processing speed. We performed a multivariate normal tissue complication probability analysis of post-RT neurocognitive decline, examining dosimetric predictors of eloquent brain regions. Data were analyzed from a prospective longitudinal clinical trial. Patients (n = 78) with primary brain tumors receiving fractionated RT complete a comprehensive neurocognitive evaluation and high-resolution volumetric and diffusion MRI at baseline and 6 months post-RT. Image processing using robust, validated automated segmentation parcellated individual WM tracts, cortical regions, and hippocampi. Well-validated neurocognitive tests including Delis-Kaplan Executive Function System and Wechsler Adult Intelligence Scale-IV coding (attention/processing), Boston Naming Test (language) and Hopkins Verbal Learning Test and Brief Visuospatial Memory Test (verbal/visuospatial memory) were assessed. Reliable change indices adjusted for practice effects (RCI-PE) were calculated for each patient between baseline and 6 months; a negative RCI-PE was scored as decline. Univariate logistic regression was performed with mean and max dose to structures of interest as well as clinical variables. Multivariate model building was performed using automated bootstrapped logistic regression, LASSO and random forest modeling. On univariate analysis mean and max dose to multiple regions of the corpus callosum (CC) were correlated with attention/processing speed decline; most significantly in WAIS coding, including Dmax to the anterior CC (p = 0.011) and central CC (p = 0.010), and Dmax and Dmean to the mid anterior CC (p = 0.006 and 0.010). Mean dose to the left fornix was associated with decline in memory (p = 0.023, cutoff 12.9 Gy), as were increasing age and both concurrent and adjuvant chemotherapy. On multivariate analysis for attention, automated bootstrapped logistic regression showed the most frequently selected variable was mean dose to the mid anterior CC. Performance at nested cross-validation by AUC was 0.80 (0.75-0.84); LASSO model performance by AUC was 0.76 (0.72-0.81) with Dmean to the mid anterior CC being the most frequent variable. The top five most important variables in the Random Forest as ranked by mean decrease in Gini coefficient were mean dose to mid anterior CC, all white matter, combined CC and max dose to CC and posterior CC. Model performance by AUC was 0.66 (0.60-0.71). Here, we present the first, to our knowledge, NTCP model for decline in attention/processing speed, along with dosimetric predictors of memory decline beyond the hippocampus. We found that after partial brain RT, dose to several ROIs significantly correlated with post-RT impairment. These data can guide future cognitive-sparing strategies for brain RT.

Dosimetric Predictors of Acute Diarrhea in Locally Advanced Rectal Cancer Patients Treated with Neoadjuvant Chemoradiation with Capecitabine and Irinotecan: A Discovery and Validation Study

Additional irinotecan can increase the pCR rate from 15% to 30% compared with capecitabine-based neoadjuvant chemoradiotherapy in locally advanced rectal cancer, while more acute diarrhea was induced and predictors of diarrhea have yet to be fully elucidated. In this analysis, we report the incidence of and factors associated with grade 3+ acute diarrhea in LARC patients treated with the CaplriRT regimen in the CinClare trial. We identified the dosimetric markers with a lasso-Cox risk scoring model tested on CaplriRT group patients in the CinClare trial at our institution from 2015 to 2017 (CinClare, NCT02605265), and then independently validated according to a predefined protocol in patients treated with neoadjuvant chemoradiation with capecitabine and irinotecan from 2019 to 2022 (NCT05688033). Clinical documentation and patient-reported outcomes were reviewed to determine grade 3+ acute diarrhea events. A total of 116 patients from Cinclare trial treated with CaplriRT regimen were used as a training cohort to obtain dosimetric prediction model and 168 patients were used for independent validation. The majority received 50 Gray (Gy) in 25 fractions with concurrent capecitabine and irinotecan. Median number of concurrent chemotherapy cycles received was 4 (IQR: 3-4). Seventeen (23.6%) patients treated with the CaplriRT regimen in the CinClare trial experienced grade 3+ acute diarrhea. Dosimetric predictors of acute diarrhea included peritoneal space volume receiving 25 Gy or greater (V25Gy). The single multivariate Cox regression, and receiver operating characteristic (ROC) curve analysis showed that the model had good predictive ability (p<0.05). It was also validated using the validation cohort. Patients with peritoneal space V25Gy>950 cm3 were associated with a higher risk of 3+ acute diarrhea compared with those without constraints of V25Gy (p = 0.002). Peritoneal space V25Gy as an important predictor of acute diarrhea during capecitabine and irinotecan neoadjuvant chemoradiation treatment. Peritoneal space V25Gy < 950 cm3 may reduce acute diarrhea toxicity.

Predictors of Low Anterior Resection Syndrome after Long-Course Chemoradiation for Locally Advanced Rectal Cancer

Low anterior resection syndrome (LARS) describes disordered bowel function including tenesmus, frequent, clustered, incomplete, urgent or incontinent bowel movements. The impact of clinical and radiation dosimetric factors on LARS score is unknown. We aimed to evaluate the radiation plans for patients who received long course chemoradiation (LC-CRT) to identify potential dosimetric predictors of LARS. We identified patients with rectal cancer treated with LC-CRT (50.4Gy in 28 fractions) at our institution from 2016-2020 who were alive and without disease. As a part of a larger patient-reported outcome survey, we obtained the Low Anterior Resection Syndrome Score (LARS) for patients without an ostomy at the time of the survey. We utilized clinical and dosimetric variables in a multivariate analysis including age at LC-CRT, body mass index, sex, distance of the tumor from the anal verge (AV), threatened mesorectal fascia (MRF) on staging imaging, T-stage, N-stage, receipt of surgery (vs non-operative management (NOM), radiation technique (3DCRT vs VMAT), mean dose and D0.03ccs for the anal canal (defined as 4cm from the anal verge) and D0.03cc, V30Gy and V45Gy for the small bowel loops. We then created a multiple linear regression model to predict LARS using P>.20 on univariate testing. Of 110 patients treated with preoperative LC-CRT and who did not have an ostomy, 57 responded (51.8%). The median [interquartile range (IQR)] interval from completion of LC-CRT to survey completion was 38.4 months [26.3-48.9]. Thirty-four patients (60%) were men, the median [IQR] BMI was 28 [24-31.9], the median [IQR] distance of the tumor to the anal verge was 7cm [5-10], 40 (70%) had T3 tumors, 7 (12%) had T4 tumors, 45 (79%) were N+. Forty-one patients (72%) had surgery following LC-CRT, and 16 (28%) had non-operative management. 3D conformal technique was used for 47 (82%) and VMAT used for 10 patients (18%). The median [IQR] LARS score was 32 [24-38] with 35 patients (61%) classified as Major LARS (LARS score = 30-42). On multiple linear regression modeling (Table), only receipt of surgery significantly predicted for higher (worse) LARS score. In our cohort, patients who received surgery after LC-CRT had a significantly higher LARS score. Of the dosimetric parameters tested, D0.03ccs was the best predictor and could potentially be significant with a larger number of patients. Further work is needed to improve bowel function and quality of life for patients treated with LC-CRT for rectal adenocarcinoma.

Assessment of Minimum Dose as a Strong Predictor of Local Failure after Spine SBRT

Stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). Even so, a wide range of dose-fractionation schemes are used in clinical practice. We seek to assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. From a large institutional database, spine SBRT treatments with subsequent imaging follow-up to assess local control were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, generally delivering 20-24 Gy in 1 fraction to the high dose volume and 16 Gy to the low dose volume (or 30-36 Gy and 24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. Statistical analyses included Cox proportional hazards analyses and the robust log-rank statistic for cut-point analysis. The cumulative incidence of local failure with death as a competing risk was considered as the primary endpoint. A total of 522 eligible spine SBRT treatments (68% single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95% confidence interval: 34.3-54.4). The cumulative incidence of local failure was 19.3% (15.3-23.2) at 1 year and 25.6% (21.1-29.9) at 2 years. Univariate analysis identified that the minimum dose (normalized for the prescription dose) was a strong predictor of local failure (p = 0.0093). Among patients treated with a single fraction, statistical significance was maintained (p = 0.024). No other dosimetric factors were predictive of local failure. In a cut point analysis, the log-rank statistic was maximized at 15.8 Gy minimum dose for single-fraction treatment (HR = 0.51, 95% CI: 0.34 - 0.75, p = 0.0009). Cumulative incidence of local failure was 15.1% (9.8-20.2) vs. 24.7% (17.2-31.5) at 1 year using this cut-off. Comparable local control was demonstrated with a minimum dose of 14 Gy (HR = 0.57, 95%: 0.37 - 0.87, p = 0.009), with reduced local control with lower minimum doses. Among a range of clinical factors assessed, only epidural and soft tissue involvement were predictive of local failure (HR = 1.80 and 1.98, respectively). Multivariable analyses incorporating soft tissue involvement, epidural extension, and multilevel disease confirmed the 15.8 Gy cutoff for single fraction cases (HR = 0.58, 95% CI: 0.38-0.88, p = 0.011). Spine SBRT offers favorable local control using a range of dose-fractionation schemes; however, minimum dose has a strong association with local control, unlike any other dosimetric factors tested. Furthermore, statistical significance was maintained even when considering epidural extension and potential limitations from dose to the spinal cord. Our data suggests that the minimum dose should be prioritized during treatment planning, ideally to at least 14 - 15.8 Gy for single fraction.

Dosimetric Predictors for Acute Esophagitis during Radiation Therapy for Lung Cancer: An Update of a Large Statewide Observational Study

Acute esophagitis remains a clinical challenge during the treatment of locally advanced non-small cell lung cancer (NSCLC). Here, we analyze the dosimetric and patient-level characteristics associated with acute grade 2+ and 3+ esophagitis in patients undergoing radiation therapy for NSCLC across a statewide consortium. Demographic, dosimetric, and acute toxicity data were prospectively collected for patients undergoing definitive radiation therapy +/- chemotherapy for stage II-III NSCLC from 2012-2022 across the Michigan Radiation Oncology Quality Consortium (MROQC). Logistic regression models were used to characterize the risk of grade 2+ and 3+ esophagitis as a function of dosimetric and clinical covariates. Multivariate regression models were fitted to predict the 50% risk of grade 2 esophagitis or 3% risk of grade 3 esophagitis at each dose value. Of 1760 patients evaluated, 84.2% had stage III disease and 85.3% received concurrent chemotherapy. 79.2% of patients had an ECOG performance status ≤1. Rates of acute grade 2+ and 3+ esophagitis were 48.4% and 2.2%, respectively. On multivariate analyses, performance status, mean esophageal dose and esophageal D2cc were significantly associated with grade 2+ and 3+ esophagitis. Concurrent chemotherapy was associated with grade 2+ but not grade 3+ esophagitis. Dose-response relationships were modeled for grade 2+ and 3+ esophagitis by mean esophageal dose and esophageal D2cc, stratified by performance status and/or receipt of concurrent chemotherapy. For all patients, mean esophageal dose of 29 Gy and esophageal D2cc of 61 Gy corresponded to a 3% risk of acute grade 3+ esophagitis. For patients receiving chemotherapy, mean esophageal dose of 22 Gy and esophageal D2cc of 49.5 Gy corresponded to a 50% risk of acute grade 2+ esophagitis. Performance status, concurrent chemotherapy, mean esophageal dose and esophageal D2cc are associated with acute esophagitis during definitive treatment of NSCLC. Models that quantitatively account for these factors can be useful in individualizing radiation plans. Mean esophageal dose of 29 Gy and esophageal D2cc of 61 Gy corresponded to a 3% risk of acute grade 3+ esophagitis and merit consideration as contemporary treatment planning constraints.

Predictive accuracy of machine learning for radiation-induced temporal lobe injury in nasopharyngeal carcinoma patients: a systematic review and meta-analysis.

Radiotherapy is a common treatment for nasopharyngeal carcinoma (NPC) but can cause radiation-induced temporal lobe injury (RTLI), resulting in irreversible damage. Predicting RTLI at the early stage may help with that issue by personalized adjustment of radiation dose based on the predicted risk. Machine learning (ML) models have recently been used to predict RTLI but their predictive accuracy remains unclear because the reported concordance index (C-index) varied widely from around 0.31 to 0.97. Therefore, a meta-analysis was needed. The PubMed, Web of Science, Embase, and Cochrane Library databases were searched from inception to November 2022. Studies that fully develop one or more ML risk models of RTLI after radiotherapy for NPC were included. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was used to assess the risk of bias in the included research. The primary outcome of this review was the C-index, specificity (Spe), and sensitivity (Sen). The meta-analysis included 14 studies with 15,573 NPC patients reporting a total of 72 prediction models. Overall, 94.44% of models were found to have a high risk of bias. Radiomics was included in 57 models, dosimetric predictors in 28, and clinical data in 27. The pooled C-index for ML models predicting RTLI was 0.77 [95% confidence interval (CI): 0.75-0.79] in the training set and 0.78 (95% CI: 0.75-0.81) in the validation set. The pooled Sen was 0.75 (95% CI: 0.69-0.80) in the training set and 0.70 (95% CI: 0.66-0.73) in the validation set and the pooled Spe was 0.78 (95% CI: 0.73-0.82) in the training set and 0.79 (95% CI: 0.75-0.82) in the validation set. Models with radiomics and clinical data achieved the most excellent discriminative performance, with a pooled C-index of 0.895. ML models can accurately predict RTLI at an early stage, allowing for timely interventions to prevent further damage. The kind of ML methods and the selection of predictors may influence the predictive accuracy.

Hypothyroidism following Radiotherapy for Head and Neck Cancer: A Systematic Review of the Literature and Opportunities to Improve the Therapeutic Ratio.

(1) Background: Radiotherapy (RT) is a central component for the treatment of many head and neck cancers. In this systematic review of the literature, we aimed to characterize and quantify the published evidence on RT-related hypothyroidism, including estimated incidence, clinical risk factors, and dosimetric parameters that may be used to guide clinical decision making. Furthermore, we aimed to identify potential areas of improvement in the prevention and clinical management of RT-induced hypothyroidism, including the role of modern advanced therapeutic techniques. (2) Methods: We conducted a systemic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed and Google Scholar were searched to identify original research articles describing the incidence, mechanism, dosimetry, treatment, or prevention of radiation-related hypothyroidism for adults receiving RT for the treatment of head and neck cancers. The snowball method was used to identify additional articles. For identified articles, we tabulated several datapoints, including publication date, patient sample size, estimated hypothyroidism incidence, cancer site/type, follow-up period, radiation modality and technique, use of multimodality therapy, method of thyroid function evaluation, and proposed dosimetric predictors of hypothyroidism. (3) Results: One hundred and eleven articles met inclusion criteria, reflecting a range of head and neck cancer subtypes. There was a large variation in the estimated incidence of RT-related hypothyroidism, with a median estimate of 36% (range 3% to 79%). Reported incidence increased in later publication dates, which was likely related to improved screening and longer follow up. There were a wide variety of predictive metrics used to identify patients at high risk of hypothyroidism, the most common of which were volumetric and mean dosimetrics related to the thyroid gland (Vxx%, Dmean). More recently, there has been increasing evidence to suggest that the thyroid gland volume itself and the volume of the thyroid gland spared from high-dose radiation (VSxx) may better predict thyroid function after RT. There were no identified studies investigating the role of advanced radiotherapeutic techniques such as MRI-guided RT or particle therapy to decrease RT-related hypothyroidism. Conclusions: Hypothyroidism is a common toxicity resulting from therapeutic radiation for head and neck cancer with recent estimates suggesting 40-50% of patients may experience hypothyroidism after treatment. Dosimetric predictive models are increasingly able to accurately identify patients at risk of hypothyroidism, especially those utilizing thyroid VS metrics. Further investigation regarding the potential for advanced radiotherapeutic therapies to decrease RT-induced thyroid dysfunction is needed.

Irradiation dose to the swallowing apparatus impacts nutritional status in head and neck cancer patients—results from the prospective randomized HEADNUT trial

PurposeTo investigate the influence of radiation dose to the swallowing muscles on the nutritional status in patients with head and neck cancer undergoing primary or adjuvant (chemo)radiotherapy (C)RT.MethodsBetween 2018 and 2020, 61 patients were prospectively randomized into the so-called HEADNUT trial (head and neck cancer patients undergoing nutritional intervention). Follow-up was continued until 2022. Contouring of the swallowing apparatus included the superior (scm), middle (mcm), and inferior constrictor muscle (icm), the cricopharyngeal muscle (cphm), and the esophageal inlet. Nutritional status was assessed by bioelectrical impedance analysis (BIA) at the beginning and the end of radiotherapy. The posttherapeutic nutritional status was evaluated by the BIA-derived fat-free mass index (FFMI; kg/m2). Malnutrition was assumed at FFMI values of < 15 (women) and < 17 (men) kg/m2. To find differences between dosimetric parameters in well- and malnourished patients, Mann–Whitney U test was used. To model the association between malnutrition and its potentially influencing variables, several logistic regression models were built.ResultsThe following parameters differed between well- and malnourished patients at the end of therapy: icm Dmean, V40Gy (%), V50Gy (%), and V60Gy (%), and sphm V40Gy (%). After entering these parameters into a multivariable logistic regression model (dosimetric model), icm Dmean (b = −0.12; Exp(b) = 0.88; 95% CI: 0.78–1.0; p = 0.06) and icm V40Gy (%; b = 0.06; Exp(b) = 1.07; 95% CI: 1–1.13; p = 0.04) proved to be independent dosimetric predictors of malnutrition. We only determined the cut-off value for predicting malnutrition for icm V40Gy (%) since it was the only parameter which met p < 0.05. The optimal cut-off value for the predictor V40Gy (%) based on the Youden Index was 85.6%. Another logistic regression model (dosimetric-clinical model) consisted of icm V40 (%) and the clinical parameters tumor localization, malnutrition before RT, gender, and combined chemotherapy. It was confirmed that both icm V40% (b = −1.9; Exp(b) = −2.7; 95% CI: 0.01–0.8; p = 0.03) and malnutrition at baseline (b = −1.9; Exp(b) = 4.4; 95% CI: 8.4–816.6; p = 0.0002) were independent predictors of subsequent malnutrition the end of RT.ConclusionEstablishment of a normal nutritional status before the start of RT and adherence to dose constraints for the swallowing apparatus may prevent malnutrition in head and neck cancer patients at the end of therapy. Specifically, we suggest an icm V40Gy (%) of more than 86% to be predictive for nutritional complications.

LMAP-20 EVIDENCE-BASED MULTIVARIATE NORMAL TISSUE COMPLICATION PROBABILITY (NTCP) STUDY OF DOMAIN-SPECIFIC COGNITIVE DECLINE AFTER PARTIAL BRAIN RT

Abstract Beyond the hippocampus, there are no evidence-based dose constraints for eloquent structures which subserve memory and attention/processing speed. We performed a multivariate normal tissue complication probability analysis of post-RT neurocognitive decline, examining dosimetric predictors of eloquent brain regions in a prospective longitudinal clinical trial. 78 patients with primary brain tumors receiving fractionated RT completed a comprehensive neurocognitive evaluation and high-resolution volumetric and diffusion MRI at baseline and 6 months post-RT. Image processing using validated automated segmentation parcellated individual white matter (WM) tracts, cortical regions, and hippocampi. Neurocognitive test performance was scored using reliable change indices adjusted for practice effects: negative scores indicate decline. Univariate logistic regression and multivariate model building were performed. On univariate analysis mean and max dose to multiple regions of the corpus callosum (CC) correlated with attention/processing speed decline including Dmax to anterior CC (p=0.011) and central CC (p=0.010), and Dmax/Dmean to mid-anterior CC (p=0.006 and 0.010). Dmean to left fornix was associated with memory decline (p=0.023), as were increasing age and chemotherapy. On multivariate analysis for attention, automated bootstrapped logistic regression showed the most frequently selected variable was Dmean to mid-anterior CC. Performance at nested cross-validation by AUC was 0.80 (0.75-0.84); LASSO model performance by AUC was 0.76 (0.72-0.81) with Dmean to the mid-anterior CC being the most frequent variable. The top five most important variables in Random Forest were Dmean to mid-anterior CC, all WM, combined CC and Dmax to CC and posterior CC. Model performance by AUC was 0.66 (0.60-0.71). We present the first, to our knowledge, multivariate NTCP model for decline in attention/processing speed, and dosimetric predictors of memory decline beyond the hippocampus. Dose to several eloquent ROIs significantly correlated with post-RT impairment. These data can guide future cognitive-sparing strategies for brain RT.

Explainable Artificial Intelligence to Identify Dosimetric Predictors of Toxicity in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Secondary Analysis of RTOG 0617

Dosimetric predictors of toxicity in patients treated with definitive chemoradiation for locally advanced non-small cell lung cancer are often identified through trial and error. This study used machine learning (ML) and explainable artificial intelligence to empirically characterize dosimetric predictors of toxicity in patients treated as part of a prospective clinical trial. A secondary analysis of the Radiation Therapy Oncology Group (RTOG) 0617 trial was performed. Multiple ML models were trained to predict grade ≥3 pulmonary, cardiac, and esophageal toxicities using clinical and dosimetric features. Model performance was evaluated using the area under the curve (AUC). The best performing model for each toxicity was explained using the Shapley Additive Explanation (SHAP) framework; SHAP values were used to identify relevant dosimetric thresholds and were converted to odds ratios (ORs) with confidence intervals (CIs) generated using bootstrapping to obtain quantitative measures of risk. Thresholds were validated using logistic regression. The best-performing models for pulmonary, cardiac, and esophageal toxicities, outperforming logistic regression, were extreme gradient boosting (AUC, 0.739), random forest (AUC, 0.706), and naive Bayes (AUC, 0.721), respectively. For pulmonary toxicity, thresholds of a mean dose >18 Gy (OR, 2.467; 95% CI, 1.049-5.800; P=.038) and lung volume receiving ≥20 Gy (V20) > 37% (OR, 2.722; 95% CI, 1.034-7.163; P=.043) were identified. For esophageal toxicity, thresholds of a mean dose >34 Gy (OR, 4.006; 95% CI, 2.183-7.354; P < .001) and V20 > 37% (OR, 3.725; 95% CI, 1.308-10.603; P=.014) were identified. No significant thresholds were identified for cardiac toxicity. In this data set, ML approaches validated known dosimetric thresholds and outperformed logistic regression at predicting toxicity. Furthermore, using explainable artificial intelligence, clinically useful dosimetric thresholds might be identified and subsequently externally validated.

The impact of local control on widespread progression and survival in oligometastasis-directed SBRT: Results from a large international database

PurposeWe investigated the impact of local control (LC) on widespread progression (WSP) and overall survival (OS) in patients treated to all extracranial oligometastases (OMs) at presentation to SBRT in this retrospective review across 6 international centers. Materials/MethodsRelationships between LC status of SBRT-directed OMs and OS and WSP (>5 new active/untreated lesions) were explored using Cox and Fine-Gray regression models, adjusting for radioresistant histology and pre-SBRT systemic therapy receipt. The association between LC and dosimetric predictors was analyzed with competing risk regression using death as a competing risk and across a wide range of simulated α/βratios. ResultsIn total, 1700 OMs in 1033 patients were analyzed, with 25.2% NSCLC, 22.7% colorectal, 12.8% prostate, and 8.1% breast histology. Patients who failed locally in any SBRT-directed OM within 6 mo were at 3.6-fold higher risk of death and 2.7-fold higher risk of WSP compared to those who remained locally-controlled (p < 0.001). Similar associations existed for each duration of LC investigated through 3 yrs post-SBRT. There was no significant difference in risk of WSP or death between patients who failed in a subset of SBRT-treated lesions vs. patients who failed in all lesions. Minimum dose (Dmin) to the GTV/ITV was most predictive of LC when compared to prescription dose, PTV Dmin, and PTV Dmax. Sensitivity analysis for achieving 1-yr LC > 95% found thresholds of 41.2 Gy and 55.2 Gy in 5 fractions for smaller (< 27.7 cc) and larger radioresistant lesions, respectively. ConclusionThis large multinational cohort suggests that the duration of LC following OM-directed SBRT strongly correlates with WSP and OS.

Dosimetric predictors of acute bowel toxicity after Stereotactic Body Radiotherapy (SBRT) in the definitive treatment of localized prostate cancer

Introduction SBRT is an increasingly popular treatment for localized prostate cancer, though considerable variation in technical approach is common and optimal dose constraints are uncertain. In this study, we sought to identify dosimetric and patient-related predictors of acute rectal toxicity. Methods Patients included in this study were treated with prostate SBRT on a prospective institutional protocol. Physician-graded toxicity and patient-reported outcomes were captured at one week, one month, and three months following SBRT. DVH data were extracted and converted into relative volume differential DVHs for NTCP modeling. Patient- and disease-related covariates along with NTCP model predictions were independently tested for significant association with physician-graded toxicity or a decline in bowel-related QoL. A multivariate model was constructed using forward selection, and significant parameter cutoff values were obtained with Fischer’s exact test to group patients by risk of developing physician-graded toxicity or detriments in patient-reported QoL. Results One hundred and three patients treated for localized prostate cancer with SBRT were included in our analysis. 52% of patients experienced a clinically significant decline in bowel-related QOL within 1 week of completion of treatment, while only 27.5% of patients developed grade 2+ physician-graded rectal toxicity. Sequential feature selection multivariate logistic regression identified rectal V22.5 Gy (p = 0.001) and D19% (p = 0.001) as independent predictors of clinically significant toxicity, while rectal V20Gy (p = 0.004) and D25.3% (p = 0.007) were independently correlated with physician-graded toxicity. Global multivariate step-wise logistic regression identified only D19% (p = 0.001) and V20Gy (p = 0.004) as independent predictors of acute bowel bother or physician-graded rectal toxicity respectively. Conclusions Moderate doses to large rectal volumes, D19% and V20Gy, were associated with an increased incidence of a clinically significant decrease in patient-reported bowel QOL and physician-scored grade 2+ rectal toxicity, respectively. These dosimetric parameters may help practitioners mitigate acute toxicity in patients treated with prostate SBRT.

Predictors of Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation Followed by Consolidative Durvalumab

PurposeIn patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab. Methods and MaterialsPatients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival. ResultsSixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% (P = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy (P = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively. ConclusionsThe modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed.

Evaluation of dosimetric predictors of toxicity after IMRT with concurrent chemotherapy for anal cancer

BackgroundThis study investigates the impact of dosimetric parameters on acute and late toxicity for patients with anal squamous cell carcinoma (SCC) treated with image-guided intensity modulated radiation therapy (IG-IMRT) and concurrent chemotherapy. Materials and MethodsPatients were enrolled in an observational cohort study between 2008 and 2013 (median follow-up 3.4 years). They were treated with standardized target and organ-at-risk (OAR) contouring, planning, and IG-IMRT. Radiotherapy dose, based on clinicopathologic features, ranged from 45 Gy to 63 Gy to gross targets and 27 Gy to 36 Gy to elective targets. Chemotherapy was concurrent 5-fluorouracil and mitomycin C (weeks 1&5). Toxicity was prospectively graded using NCI CTCAE v.3 and RTOG scales. Logistic regression was used to assess the association between dose/volume parameters (e.g small bowel V5) and corresponding grade 2 + and 3+ (G2+/3 + ) toxicities (e.g. diarrhea). ResultsIn total, 87 and 79 patients were included in the acute and late toxicity analyses, respectively. The most common acute G2 + toxicities were skin (dermatitis in 87 % [inguino-genital skin], 91 % [perianal skin]) and hematologic in 58 %. G2 + late anal toxicity (sphincter dysfunction), gastrointestinal toxicity, and skin toxicity were respectively experienced by 49 %, 38 %, and 44 % of patients. Statistically significant associations were observed between: G2 + acute diarrhea and small bowel V35; G2 + acute genitourinary toxicity and bladder D0.5cc; G2 + inguino-genital skin toxicity and anterior skin V35; G2 + perianal skin toxicity and posterior skin V15; G2 + anemia and lower pelvis bone V45. D0.5 cc was significantly predictive of late toxicity (G2 + anal dysfunction, intestinal toxicity, and inguino-genital/perianal dermatitis). Maximum skin toxicity grade was significantly correlated with the requirement for a treatment break. ConclusionStatistically significant dose-volume parameters were identified and may be used to offer individualized risk prediction and to inform treatment planning. Additional validation of the results is required.

ASO Visual Abstract: Clinical and Dosimetric Predictors for Postoperative Cardiopulmonary Complications in Patients with Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Chemoradiotherapy and Surgery.

ASO Visual Abstract: Clinical and Dosimetric Predictors for Postoperative Cardiopulmonary Complications in Patients with Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Chemoradiotherapy and Surgery.