Changes In Gross Tumor Volume Research Articles

Weekly assessment of volumetric and dosimetric changes during volumetric modulated arc therapy of locally advanced head and neck carcinoma: Implications for adaptive radiation therapy-A prospective study.

Chemoradiation in head and neck carcinoma (HNC) shows significant anatomical resulting in erroneous dose deposition in the target or the organ at risk (OAR). Adaptive radiotherapy (ART) can overcome this. Timing of significant target and OAR changes with dosimetric impact; thus, most suitable time and frequency of ART is unclear. This dosimetric study used prospective weekly non-contrast CT scans in 12 HNC patients (78 scans). OARs and TVs were manually contoured after registration with simulation scan. Dose overlay done on each scan without reoptimization. Dosimetric and volumetric variations assessed. Commonest site was oropharynx. Gross Tumor Volume (GTV) reduced from 47.5 ± 19.2 to 17.8 ± 10.7 cc. Nodal GTV reduced from 15.7 ± 18.8 to 4.7 ± 7.1 cc. Parotid showed mean volume loss of 35%. T stage moderately correlated with GTV regression. Maximum GTV changes occurred after 3 weeks. Best time to do single fixed interval ART would be by the end of 3 weeks.

Dosimetric Effect of Target Position Accuracy on Single-Isocenter Multiple Liver Metastases SBRT.

Purpose: To evaluate the dosimetric effects of intrafraction baseline shifts combined with rotational errors on Four-dimensional computed tomography-guided stereotactic body radiotherapy for multiple liver metastases (MLMs). Methods: A total of 10 patients with MLM (2 or 3 lesions) were selected for this retrospective study. Baseline shift errors of 0.5, 1.0, and 2.0 mm; and rotational errors of 0.5°, 1°, and 1.5°, were simulated about all axes. All of the baseline shifts and rotation errors were simulated around the planned isocenter using a matrix transformation of 6° of freedom. The coverage degradation of baseline shifts and rotational errors were analyzed according to the dose to 95% of the planning target volume (D95) and the volume covered by 95% of the prescribed dose (V95), and related changes in gross tumor volume were also analyzed. Results: At the rotation error of 0.5° and the baseline offset of less than 0.5 mm, the D95 and V95 values of all targets were >95%. For rotational errors of 1.0° (combined with all baseline shift errors), 36.3% of targets had D95 and V95 values of <95%. Coverage worsened substantially when the baseline shift errors were increased to 1.0 mm. D95 and V95 values were >95% for about 77.3% of the targets. Only 11.4% of the D95 and V95 values were >95% when the baseline shift errors were increased to 2.0 mm. When the rotational error was increased to 1.5° and baseline shift errors increased to 1.0 mm, the D95 and V95 values were >95% in only 3 cases. Conclusions: The multivariate regression model analysis in this study showed that the coverage of the target decreased further with reduced target volume, increasing the baseline drift, the rotation error, and the distance to the target.

KV-CBCT-Guided Daily Adaptation Improves Target Coverage and Spares Normal Tissue for Accelerated Partial Breast Irradiation

Linear accelerator based accelerated partial breast irradiation (APBI) in early-stage breast cancer necessitates a reduction in non-target breast tissue to decrease long term toxicity and adverse cosmetic outcome. In particular, lumpectomy cavity seromas may decrease in size and deform in shape during the course of short course APBI. Online adaptive RT (oART) offers considerable prospect for treating mobile targets through pendulous breast anatomy. However, there are limited studies outlining the methods and outcomes of CBCT-based oART for APBI. Here we present a retrospective, single institutional study analyzing the treatment process for patients receiving stereotactic kV-CBCT guided oART APBI. Fourteen patients were treated to 30 Gy in 5 fractions for a total of 70 fractions. Time between simulation and treatment, change in gross tumor volume (GTV), and differences in DVH metrics with adaption were analyzed. The Wilcoxon paired, non-parametric test was utilized to test for DVH metric differences between the scheduled plans (initial plans recalculated on daily CBCT anatomy) and treated plans, which were either the scheduled or adapted plan (initial plans re-optimized using daily anatomy), depending on the preference of the treating physician or physicist. Median (inter-quartile range) time from simulation to first treatment was 28 days (21-33 days). During this same time, GTV volume reduced to 72.5% (57.8-87.3%) of the simulation lumpectomy cavity volume. Adaptive treatments required 31.1 min (27.2-37.1 min) from start of CBCT to treatment session end. Table 1 summarizes differences between scheduled and treated plan metrics for 70 fractions, 62 (89%) of which were treated adaptively and 8 (11%) of which were treated using the scheduled plan. Significant improvement in prescription planning target volume coverage (p = 0.003), significant reduction in 5/6 organ-at-risk metrics evaluated (p ≤ 0.003), and significant improvement in conformity index and high dose spillage (p ≤ 0.001) were realized with adaption. Table 1: Scheduled versus treated plan metrics. APBI using oART decreased most organs at risk DVH metrics, improved plan quality metrics, and increased target coverage, justifying the use of kV-CBCT-guided oART for APBI.

Parametric Response Mapping of Co-Registered Ivim MRI and PET to Identify Radioresistant Sub-Volumes in Locally Advanced Cervical Carcinoma Undergoing CCRT

To investigate parametric response mapping (PRM) of co-registered positron emission tomography (PET) and intravoxel incoherent motion (IVIM) MRI in locally advanced cervical carcinoma patients to identify sub-volumes that may predict treatment response to adjuvant concurrent chemoradiation therapy (CCRT). Pre- and on-treatment (∼after four weeks of CCRT) diffusion weighted images (DWIs) MRI and pre-treatment PET were performed on 20 cervical cancer patients (median [range] age: 63 [41 to 85]; FIGO staging: 3 IIB, 1 IIIB, 10 IIIC1, 4 IIIC2, 2 IVA; histology: 11 squamous cell carcinoma, 4 endocervical adenocarcinoma; LN status: 4 negative, 16 positive). IVIM MRI maps were generated by Bayesian fitting of a two-compartment IVIM model to the DWIs to produce three-dimensional diffusion coefficient (D) and perfusion fraction (f). Three-dimensional IVIM D and f maps were co-registered to PET standardized uptake value (SUV) maps. Population means of PET SUV, IVIM D and f from pre-treatment scans were calculated to generate thresholds to identify low versus high metabolic (μSUV) regions, low versus high diffused (μD) regions as well as low versus high perfused (μf) regions, respectively. PRM maps were generated using voxel-wise joint histogram analysis to classify voxels within the tumor as highly metabolic and with low cellular density (SUV↑D↑), highly metabolic and with high cellular density (SUV↑D↓), metabolically inactive and with high cellular density (SUV↓D↓), or metabolically inactive and with low cellular density (SUV↓D↑) tissue based on the population mean thresholds. Similar PRM maps were generated using the joint histogram analysis with SUV and f. Summary statistics for these and other imaging parameters were calculated pre- and on-treatment. Univariate analysis was performed to determine relationships between relative change in gross tumor volume (ΔGTV) and pre-treatment imaging measurements. In tumors, on- versus pre-treatment tumor volume (p<.001) significantly decreased, while IVIM f (p = .002) and D (p = .03) significantly increased. Pre-treatment tumor volume (r = .45, p = .04) and PRM SUV↑D↓ (r = .65, p = .002) regions were positively related with ΔGTV, while pre-treatment IVIM D (r = -.64, p = .002), PRM SUV↓f↑ (r = -.52, p = .02) and PRM SUV↓D↑ (r = -.74, p<.001) regions were negatively related with ΔGTV. The latter PRM result suggests that larger regions of low cellular density (as represented by elevated D) + low metabolism result in a reduced change in tumor volume on-treatment, potentially representing a radioresistant sub-volume. PRM, generated from PET and IVIM MRI, was applied to patients with locally advanced cervical carcinoma and radioresistant sub-volumes were identified which may predict treatment response. The complementary information provided from PET and IVIM, combined using PRM, may assist in decision-making to individualize therapies, such as with image guided brachytherapy, to improve patient outcomes.

Reduction of tumor volume during radiotherapy in patients with small-cell lung cancer and its prognostic significance.

Several studies have reported the potential prognostic significance of tumor volume reduction ratio (VRR) induced by radiotherapy (RT) in patients with non-small-cell lung cancer. However, there are no data yet on the prognostic significance of volumetric shrinkage in patients with small-cell lung cancer (SCLC). This study aimed to demonstrate the correlation between tumor volume reduction ratio and treatment outcomes. The study included 61 patients with SCLC treated with fractionated RT of the primary tumor at our institution between 2013 and 2020. The relationship between volumetric changes in gross tumor volume (GTV) during radiotherapy and outcomes were analyzed and reported. The median radiation dose was 59.4 Gy (median fraction dose was 1.8 Gy). The median GTV before radiotherapy was 74 cm3, with amedian GTV reduction of 48%. There was ahigher VRR in patients receiving concurrent radiochemotherapy (p = 0.05). No volumetric parameters were identified as relevant predictors of outcome in the entire cohort. In multivariate analysis, only age had an impact on survival, while prophylactic whole-brain radiation influenced the progression-free survival significantly. Concurrent chemotherapy was associated with ahigher VRR than sequential chemotherapy. No significant impact of VRR on patients' outcome or survival was detected.

Automated tracking of morphologic changes in weekly magnetic resonance imaging during head and neck radiotherapy.

Anatomic changes during head and neck radiotherapy can impact dose delivery, necessitate adaptive replanning, and indicate patient-specific response to treatment. We have developed an automated system to track these changes through longitudinal MRI scans to aid identification and clinical intervention. The purpose of this article is to describe this tracking system and present results from an initial cohort of patients. The Automated Watchdog in Adaptive Radiotherapy Environment (AWARE) was developed to process longitudinal MRI data for radiotherapy patients. AWARE automatically identifies and collects weekly scans, propagates radiotherapy planning structures, computes structure changes over time, and reports important trends to the clinical team. AWARE also incorporates manual structure review and revision from clinical experts and dynamically updates tracking statistics when necessary. AWARE was applied to patients receiving weekly T2-weighted MRI scans during head and neck radiotherapy. Changes in nodal gross tumor volume (GTV) and parotid gland delineations were tracked over time to assess changes during treatment and identify early indicators of treatment response. N=91 patients were tracked and analyzed in this study. Nodal GTVs and parotids both shrunk considerably throughout treatment (-9.7±7.7% and -3.7±3.3% per week, respectively). Ipsilateral parotids shrunk significantly faster than contralateral (-4.3±3.1%vs. -2.9±3.3% per week, p=0.005) and increased in distance from GTVs over time (+2.7±7.2% per week, p<1×10-5 ). Automatic structure propagations agreed well with manual revisions (Dice=0.88±0.09 for parotids and 0.80±0.15 for GTVs), but for GTVs the agreement degraded 4-5weeks after the start of treatment. Changes in GTV volume observed by AWARE as early as one week into treatment were predictive of large changes later in the course (AUC=0.79). AWARE automatically identified longitudinal changes in GTV and parotid volumes during radiotherapy. Results suggest that this system may be useful for identifying rapidly responding patients as early as one week into treatment.

Intravoxel Incoherent Motion MRI and PET in Locally Advanced Cervical Carcinoma Undergoing Concurrent Chemoradiation Therapy

<h3>Purpose/Objective(s)</h3> Dynamic contrast enhanced (DCE) CT or MRI and FDG PET have been used to evaluate the impact of tumor perfusion and metabolism on the course and effectiveness of concurrent chemoradiation therapy (CCRT) for cervical cancer. Combining perfusion and metabolic measures allows better identification of radioresistant sub-volumes: however, use of contrast and additional dose are barriers to frequent dual perfusion-metabolic imaging. Here, we investigated a contrast-free, non-ionizing alternative to DCE: intravoxel incoherent motion (IVIM) MRI which provides both perfusion and diffusion measurements. Our objective was to evaluate changes of PET and IVIM parameters in cervical cancer patients before and during CCRT and to correlate these parameters and their changes with tumor volume response during CCRT. <h3>Materials/Methods</h3> Pre- and on-treatment IVIM scans were performed on 15 cervical cancer patients undergoing definitive chemoradiation (median [range] age: 66 [29 to 85]; FIGO: 1 IB1, 1 IIA, 3 IIB, 1 IIIB, 1 IIIC, 5 IIIC1, 2 IIIC2, 1 IVA; hist: 11 squamous cell carcinoma, 3 endocervical adenocarcinoma, 1 large cell neuroendocrine carcinoma), of whom 14 also underwent pre-treatment PET scans. The on-treatment MRI occurred generally during the last week or shortly after completing EBRT. Diffusion weighted images (DWIs) were acquired at 3T scanners using a free-breathing single shot spin echo planar imaging (EPI) sequence. IVIM MRI maps were generated by Bayesian fitting of a two-compartment IVIM model to the DWIs. Three-dimensional co-registered maps of PET standardized uptake value (SUV) and IVIM diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) were generated. Summary statistics (mean +/- standard deviation) for these and other imaging parameters were calculated pre- and on-treatment. Univariate analysis was performed to determine relationships between relative change in gross tumor volume (ΔGTV) and pre-treatment imaging measurements. <h3>Results</h3> In tumors, pre- versus on-treatment values significantly changed for the following parameters: ΔGTV (66.8 +/- 43.2 vs. 32.0+/-23.0 ml, p<.001) and D (0.00109 +/- 0.00023 vs. 0.00120 +/- 0.00026 mm²/s, p=.02). The perfusion fraction f increased and D* decreased, but not significantly (f: 0.127 +/- 0.022 vs. 0.154 +/- 0.057 %, p=.07, D*: 0.0137 +/- 0.0035 vs. 0.0133 +/- 0.0039 mm²/s, p=.6). Pre-treatment SUV_max (r=.76, p=.002) and SUV_mean (r=.70, p=.007) were positively related with ΔGTV, while pre-treatment f, D*, and D were negatively but not significantly related with ΔGTV (r=-.44, p=.1; D*: r=-.14, p=.6; D: r=-.12, p=.7). <h3>Conclusion</h3> Both perfusion fraction and diffusion coefficient IVIM increased in locally advanced cervical carcinoma patients undergoing CCRT – reflecting changes in the tumor microenvironment during treatment. These weak relationships observed here suggest a potential complementary role and motivating the combined use of these modalities for tumor characterization.

Assessment of Interfraction Change in Gross Tumor Volume of Anal Carcinoma Patients Undergoing Curative Chemoradiotherapy

<h3>Purpose/Objective(s)</h3> Radiation with concurrent chemotherapy (CRT) represents standard definitive therapy for anal cancer. CRT protocols result in excellent local control but are associated with significant acute and late morbidity. Adaptive planning techniques may allow for decrease in treatment volume and reduce toxicity. In this study, we used serial MRI scans to assess changes in gross tumor volume (GTV) during curative CRT. <h3>Materials/Methods</h3> Since 2019, we have instituted a REB-approved prospective registry study of de-escalated radiotherapy for patients undergoing CRT for anal cancer. Patients received a total dose of 45-63 Gy in 25-35 fractions with concurrent Capecitabine and a single dose of Mitomycin-C on day 1. In addition to pre-treatment (pre-tx) CT and MR simulation, patients also underwent MR simulation at fraction 11 (fx11) and fraction 21 (fx21). The GTV was contoured separately on individual axial T2 sequences. Median (inter-quartile-range) was used for descriptive statistics and the Mann-Whitney-Wilcoxon was used between groups of interfractional contours to determine statistically significant differences in tumor size between fractions. The Kruskal-Wallace test was used to determine significance between all 3 GTV volumes. P-values of <0.05 were considered statistically significant. <h3>Results</h3> A total of 24 patients were accrued. All patient completed RT without interruptions. All 24 had pre-tx MRI. During CRT course, 22 had a second MRI scan (fx11), and 19 had a third (fx21) scan. Table 1 shows the median (IQR) pre-tx GTV and the absolute and percent reduction in the GTV at fx11 and fx21 compared to pre-treatment GTV. Median (IQR) reduction in GTV between pre-tx and fx11 and fx21 MRI was 6.1cc (3.8-12.1) and 7.8cc (5.7-14.6), respectively. Median reduction in GTV between fx11 and fx21 was 2.9cc (1.3-6.6). After normalizing volumes as the percentage of pre-tx GTV, median (IQR) volume was 62.5% (51.6-69.7) (p<0.001) at fx11 and 43.6% (34.2-55.6) (p<0.001) at fx21. Based on Kruskal-Wallace test, overall change between GTVs at all 3 time points was found to be significant, p=0.042. <h3>Conclusion</h3> For patients undergoing CRT for anal cancer, there appears to be an early and significant reduction in the tumor volume over time. This study helps define planning adaptation parameters using serial MRI during CRT and will inform strategies to reduce normal tissue exposure

Effect of applicator removal from target volume for cervical cancer patients treated with Venezia high-dose-rate brachytherapy applicator.

PurposeThe volume of Venezia applicator with vaginal caps can be relatively large compared to target volumes. This study investigated the dosimetric and radiobiological effects of applicator volume removal for cervical cancer patients treated with Venezia (VZ) and tandem and split-ring (TSR) applicators used in the clinic.Material and methodsA total of 40 patients (101 plans) with stage IIA-IIIC cervical cancer were retrospectively reviewed. Thirty patients were treated with VZ and ten patients were treated with TSR. Applicators were contoured on planning CTs where target contours were involved. Applicator contours were subtracted from the target contours. External beam radiation therapy (EBRT) and brachytherapy doses were calculated in biologically equivalent doses in 2 Gy fractions (EQD2) and combined using full parameter addition for dose-volume histogram (DVH) parameters of composited dose. D90%, D50%, V100%, V150%, V200%, and tumor control probability (TCP) were evaluated and compared for targets after applicator exclusion.ResultsThe average volume changes in gross tumor volume (GTV), high-risk clinical target volume (HR-CTV), and intermediate-risk clinical target volume (IR-CTV) after VZ applicator exclusion were 1.4 ±1.5 cm3, 15.7 ±6.6 cm3, and 33.8 ±15.1 cm3, respectively. VZ exclusion resulted in significant changes (p < 0.05) in small volume parameters (D50%) and high-dose parameters (V150% and V200%) for HR-CTV and IR-CTV. Dosimetric impact of TSR exclusion on targets was not significant. There was no significant change in TCP after applicator exclusion.ConclusionsVenezia applicator with vaginal caps has significant impact on small volume and high-dose DVH parameters of the target. Applicator contour exclusion is recommended for dosimetric evaluation when Venezia applicator is used.

The Initial Step Towards Establishing a Quantitative, Magnetic Resonance Imaging-Based Framework for Response Assessment of Spinal Metastases After Stereotactic Body Radiation Therapy.

There are no established threshold values regarding the degree of growth on imaging when assessing response of spinal metastases treated with stereotactic body radiation therapy (SBRT). To determine a magnetic resonance imaging-based minimum detectable difference (MDD) in gross tumor volume (GTV) and its association with 1-yr radiation site-specific (RSS) progression-free survival (PFS). GTVs at baseline and first 2 post-SBRT scans (Post1 and Post2, respectively) for 142 spinal segments were contoured, and percentage volume change between scans calculated. One-year RSS PFS was acquired from medical records. The MDD was determined. The MDD was compared against optimal thresholds of GTV changes associated with 1-yr RSS PFS using Youden's J index, and receiver operating characteristic curves between timepoints compared to determine which timeframe had the best association. A total of 17 of the 142 segments demonstrated progression. The MDD was 10.9%. Baseline-Post2 demonstrated the best performance (area under the curve [AUC] 0.90). Only Baseline-Post2 had an optimal threshold>MDD at 14.7%. Due to large distribution of GTVs, volumes were split into tertiles. Small tumors (GTV<2 cc) had optimal thresholds of 42.0%, 71.3%, and 37.2% at Baseline-Post1 (AUC 0.81), Baseline-Post2 (AUC 0.89), and Post1-Post2 (AUC 0.77), respectively. Medium tumors (2≤GTV≤8.3 cc) all demonstrated optimal thresholds<MDD, with AUCs ranging from 0.65 to 0.84. Large tumors (GTV>8.3 cc) had 2 timepoints where optimal thresholds>MDD: Baseline-Post2 (13.3%; AUC 0.97) and Post1-Post2 (11.8%; AUC 0.66). Baseline-Post2 had the best association with RSS PFS for all tertiles. Given a MDD of 10.9%, for small GTVs, larger (>37%) changes were required before local failure could be determined, compared to 11% to 13% for medium/large tumors.

On-Treatment Changes in Gross Tumor Volume of Pediatric Parameningeal Rhabdomyosarcoma Treated With Upfront Proton Therapy

<h3>Purpose/Objective(s)</h3> To characterize the time trends of on-treatment morphologic change in pediatric parameningeal rhabdomyosarcoma treated with upfront proton therapy and examine the feasibility of identifying patients who may benefit from on-treatment CT/MRI to address significant changes. <h3>Materials/Methods</h3> We retrospectively analyzed 69 pretreatment and weekly on-treatment MRI as well as simulation and repeat CT acquired from 10 patients (aged 1 – 21 years) with parameningeal rhabdomyosarcoma, who were treated with chemotherapy and upfront proton therapy in a prospective trial. A radiation oncologist delineated GTV on each MRI by modifying the GTV contour from the initial simulation MRI (reference). Longitudinal changes in the volume and surface of GTV from the reference GTV were quantified to examine the feasibility of predicting the on-treatment behavior. The surface displacement was measured by the 90% Hausdorff distance. We investigated the association between the pattern grouping and the clinical need for repeat CT and/or replanning as well as potential image features of simulation CT in differentiating the groups. <h3>Results</h3> The median time was 6.5 days from the start of chemotherapy to CT/MR simulation (ranged -6 to 12 days) and 14 days from simulation to the start of proton therapy (ranged 6 to 21 days). Most (8/10) patients showed continuously decreasing trends in GTV from the simulation (slope, 0.13 – 0.88 %/day), except for two whose GTV reduced only after the start of proton therapy. The GTV reduction was > 20% in 6 patients, which occurred in 13 - 31 days from the simulation, while it was < 10% in the other 4 patients up to 38 days. Excluding a case with orbital involvement, all patients with early significant GTV reduction also showed a distinctively greater surface displacement (> 3 mm) than those in the other group (< 2 mm) at as early as 13 days from the simulation. Image features that most differentiated the group of significant reduction from the other group, was a lower mean HU intensity (70 ± 19 vs. 115 ± 40) and a higher inverse-elongation parameter (0.81 ± 0.05 vs. 0.63 ± 0.12), which suggested a potential relationship between the reduction with a lower occupancy of bony structures and a rounded shape. Among the 6 patients exhibiting significant GTV reduction, 5 received a repeat CT in 10 days from the start of proton therapy for replanning (n = 4) or plan verification (n = 1), whereas any repeat CT prescribed for the other group, on 21 - 23 days from the start of proton therapy, was solely for the scheduled boost phase simulation. <h3>Conclusion</h3> The early significant GTV change is common in pediatric parameningeal rhabdomyosarcoma receiving upfront proton therapy, which often needs repeat CT for dose recalculation and even adaptive replanning. Image features reflecting bone content and shape of the initial GTV appear promising for predicting the extent of GTV reduction.

Deformation driven Seq2Seq longitudinal tumor and organs-at-risk prediction for radiotherapy.

Radiotherapy presents unique challenges and clinical requirements for longitudinal tumor and organ-at-risk (OAR) prediction during treatment. The challenges include tumor inflammation/edema and radiation-induced changes in organ geometry, whereas the clinical requirements demand flexibility in input/output sequence timepoints to update the predictions on rolling basis and the grounding of all predictions in relationship to the pre-treatment imaging information for response and toxicity assessment in adaptive radiotherapy. To deal with the aforementioned challenges and to comply with the clinical requirements, we present a novel 3D sequence-to-sequence model based on Convolution Long Short-Term Memory (ConvLSTM) that makes use of series of deformation vector fields (DVFs) between individual timepoints and reference pre-treatment/planning CTs to predict future anatomical deformations and changes in gross tumor volume as well as critical OARs. High-quality DVF training data are created by employing hyper-parameter optimization on the subset of the training data with DICE coefficient and mutual information metric. We validated our model on two radiotherapy datasets: a publicly available head-and-neck dataset (28 patients with manually contoured pre-, mid-, and post-treatment CTs), and an internal non-small cell lung cancer dataset (63 patients with manually contoured planning CT and 6weekly CBCTs). The use of DVF representation and skip connections overcomes the blurring issue of ConvLSTM prediction with the traditional image representation. The mean and standard deviation of DICE for predictions of lung GTV at weeks 4, 5, and 6 were 0.83±0.09, 0.82±0.08, and 0.81±0.10, respectively, and for post-treatment ipsilateral and contralateral parotids, were 0.81±0.06 and 0.85±0.02. We presented a novel DVF-based Seq2Seq model for medical images, leveraging the complete 3D imaging information of a relatively large longitudinal clinical dataset, to carry out longitudinal GTV/OAR predictions for anatomical changes in HN and lung radiotherapy patients, which has potential to improve RT outcomes.

Prognostic impact of gross tumor volume during radical radiochemotherapy of locally advanced non-small cell lung cancer\u2014results from the NCT03055715 multicenter cohort study of the Young DEGRO Trial Group

BackgroundIn radical radiochemotherapy (RCT) of inoperable non-small-cell lung cancer (NSCLC) typical prognostic factors include T- and N-stage, while there are still conflicting data on the prognostic relevance of gross tumor volume (GTV) and particularly its changes during RCT. The NCT03055715 study of the Young DEGRO working group of the German Society of Radiation Oncology (DEGRO) evaluated the prognostic impact of GTV and its changes during RCT.MethodsA total of 21 university centers for radiation oncology from five different European countries (Germany, Switzerland, Spain, Belgium, and Austria) participated in the study which evaluated n = 347 patients with confirmed (biopsy) inoperable NSCLC in UICC stage III A/B who received radical curative-intent RCT between 2010 and 2013. Patient and disease data were collected anonymously via electronic case report forms and entered into the multi-institutional RadPlanBio platform for central data analysis. GTV before RCT (initial planning CT, GTV1) and at 40–50 Gy (re-planning CT for radiation boost, GTV2) was delineated. Absolute GTV before/during RCT and relative GTV changes were correlated with overall survival as the primary endpoint. Hazard ratios (HR) of survival analysis were estimated by means of adjusted Cox regression models.ResultsGTV1 was found to have a mean of 154.4 ml (95%CI: 1.5–877) and GTV2 of 106.2 ml (95% CI: 0.5–589.5), resulting in an estimated reduction of 48.2 ml (p < 0.001). Median overall survival (OS) was 18.8 months with a median of 22.1, 20.9, and 12.6 months for patients with high, intermediate, and low GTV before RT. Considering all patients, in one survival model of overall mortality, GTV2 (2.75 (1.12–6.75, p = 0.03) was found to be a stronger survival predictor than GTV1 (1.34 (0.9–2, p > 0.05). In patients with available data on both GTV1 and GTV2, absolute GTV1 before RT was not significantly associated with survival (HR 0–69, 0.32–1.49, p > 0.05) but GTV2 significantly predicted OS in a model adjusted for age, T stage, and chemotherapy, with an HR of 3.7 (1.01–13.53, p = 0.04) per 300 ml. The absolute decrease from GTV1 to GTV2 was correlated to survival, where every decrease by 50 ml reduced the HR by 0.8 (CI 0.64–0.99, p = 0.04). There was no evidence for a survival effect of the relative change between GTV1 and GTV2.ConclusionOur results indicate that independently of T stage, the re-planning GTV during RCT is a significant and superior survival predictor compared to baseline GTV before RT. Patients with a high absolute (rather than relative) change in GTV during RT show a superior survival outcome after RCT.

Cone-Beam-CT Guided Adaptive Radiotherapy for Locally Advanced Non-small Cell Lung Cancer Enables Quality Assurance and Superior Sparing of Healthy Lung.

PurposeTo evaluate the potential of cone-beam-CT (CB-CT) guided adaptive radiotherapy (ART) for locally advanced non-small cell lung cancer (NSCLC) for sparing of surrounding organs-at-risk (OAR).Materials and MethodsIn 10 patients with locally advanced NSCLC, daily CB-CT imaging was acquired during radio- (n = 4) or radiochemotherapy (n = 6) for simulation of ART. Patients were treated with conventionally fractionated intensity-modulated radiotherapy (IMRT) with total doses of 60–66 Gy (pPlan) (311 fraction CB-CTs). OAR were segmented on every daily CB-CT and the tumor volumes were modified weekly depending on tumor changes. Doses actually delivered were recalculated on daily images (dPlan), and voxel-wise dose accumulation was performed using a deformable registration algorithm. For simulation of ART, treatment plans were adapted using the new contours and re-optimized weekly (aPlan).ResultsCB-CT showed continuous tumor regression of 1.1 ± 0.4% per day, leading to a residual gross tumor volume (GTV) of 65.3 ± 13.4% after 6 weeks of radiotherapy (p = 0.005). Corresponding PTVs decreased to 83.7 ± 7.8% (p = 0.005). In the actually delivered plans (dPlan), both conformity (p = 0.005) and homogeneity (p = 0.059) indices were impaired compared to the initial plans (pPlan). This resulted in higher actual lung doses than planned: V20Gy was 34.6 ± 6.8% instead of 32.8 ± 4.9% (p = 0.066), mean lung dose was 19.0 ± 3.1 Gy instead of 17.9 ± 2.5 Gy (p = 0.013). The generalized equivalent uniform dose (gEUD) of the lung was 18.9 ± 3.1 Gy instead of 17.8 ± 2.5 Gy (p = 0.013), leading to an increased lung normal tissue complication probability (NTCP) of 15.2 ± 13.9% instead of 9.6 ± 7.3% (p = 0.017). Weekly plan adaptation enabled decreased lung V20Gy of 31.6 ± 6.2% (−3.0%, p = 0.007), decreased mean lung dose of 17.7 ± 2.9 Gy (−1.3 Gy, p = 0.005), and decreased lung gEUD of 17.6 ± 2.9 Gy (−1.3 Gy, p = 0.005). Thus, resulting lung NTCP was reduced to 10.0 ± 9.5% (−5.2%, p = 0.005). Target volume coverage represented by conformity and homogeneity indices could be improved by weekly plan adaptation (CI: p = 0.007, HI: p = 0.114) and reached levels of the initial plan (CI: p = 0.721, HI: p = 0.333).ConclusionIGRT with CB-CT detects continuous GTV and PTV changes. CB-CT-guided ART for locally advanced NSCLC is feasible and enables superior sparing of healthy lung at high levels of plan conformity.

MR-Guided Liver Stereotactic Body Radiotherapy (SBRT): To Adapt, or Not to Adapt?

Long-term disease-free survival is possible in liver oligometastatic cancer with ablative local treatment such as SBRT, however in some studies, long term local control remains an issue. Planning target volume (PTV) for tumors accounts for positional uncertainty, but not intra-fractional changes in tumor size, which are assumed to be negligible. Magnetic resonance imaging (MRI)-guided radiotherapy (MRgRT) to the liver using gadoxetate contrast allows for radiation oncologists to evaluate daily fractional dose to liver metastases and to adapt for anatomical variation. The purpose of this study is to determine the extent of gross tumor volume (GTV) changes between simulation and treatment start, as well as during each fraction of SBRT. Patients who underwent 5-fraction maximum inspiratory breath hold MR-guided liver SBRT for metastases were retrospectively screened for use of gadoxetate during simulation and at least the first treatment. An experienced radiation oncologist contoured the GTV on the MR planning scan and subsequent daily setup MRIs. Sørensen–Dice coefficients (DC) were calculated. Wilcoxon signed rank test was used to test significance of the median change in tumor volume using SPSS version 26.0. A total of 37 patients were treated with MR-guided SBRT for metastatic liver lesions, 20 of which had gadoxetate enhanced MRs for simulation and at least the first fraction of treatment. SBRT doses ranged from 40-80 Gy over 5 fractions. 17 out of 20 patients had all treatments using MRgRT (91 evaluable fractions). Median simulation GTV was 5.4 ml (R: 0.29-90.47 ml). From simulation to fraction 1, the mean DC was 0.78 (R: 0.55-.877). Mean DC for tumors treated solely using MRgRT for fractions 1 to 2, 2 to 3, 3 to 4, and 4 to 5 were 0.83, 0.82, 0.82, 0.79, 0.82, respectively. Following simulation, GTV volume was found to increase peaking at fraction 2 with a median 37% increase over simulation (95% CI: 20% to 59% increase, p<0.001) with a median absolute increase of 1.9 ml. Thereafter, volume decreased to a median of 17% (95% CI: -1%-25%) greater than simulation by the final fraction (p<0.01). At the time of the second fraction, 70% of tumors had increased by 20% over simulation volumes with 35% having a volume that was ≥ 50% larger than at the time of simulation. At the time of treatment completion, tumors had begun to regress and only 43% measured ≥ 20% larger than at the time of simulation. Volumes of GTVs visualized on initial gadoxetate enhanced MRI simulation demonstrated notable tumor volume changes throughout SBRT treatment. Potential causes for GTV changes include tumor growth, inflammation, treatment response, or radiation effects on gadoxetate distribution. These changes suggest there may be a role for daily adaptive radiation planning to improve plan coverage using MRgRT. In the absence of MR guidance, this study suggests the importance of minimizing the time to treatment and/or using a larger PTV margin to account for GTV changes.

Image-guidance triggered adaptive replanning of radiation therapy for locally advanced lung cancer: an evaluation of cases requiring plan adaptation.

Anatomic changes may occur during chemoradiation treatment for lung cancers, requiring adaptive replanning. Here we characterize these cases. We retrospectively studied lung cancer cases that underwent resimulation and adaptive replanning during 1/2016-3/2019. We compared first and second CT-simulation regarding tumor location, timing of change, tumor volume, anatomical alteration and change in simulation technique. We also compared dosimetric parameters between the plans, recorded local control, and overall survival outcomes. Out of 281 patients, 58 underwent replanning (20.6%). Histology included small cell (22.4%) and non-small cell (77.6%). Stage III was in 91.4%. Mean radiation dose of 59.4 Gray (Gy) (range 50-66Gy).Tumor location was peribronchial in 53.5%. Timing of replanning was in the first, second and final third of the treatment course in 26%, 43% and 31% respectively. Changes in gross tumor volume were observed in 74%; mean gross tumor volume was 276.7cc vs 192.7 cc (first vs second simulation, p = 0.001). Anatomical changes were identified in 35.4% including pleural fluid accumulation, atelectasis or pneumothorax alteration. Change in simulation technique was performed in 25.9%, including breath-hold or continuous positive airway pressure.Changes in dosimetric parameters when the same technique was used: lung V20Gy 26% (standard deviation, SD 7.6) vs 25.3% (SD 6.6) (p = 0.36), mean lung dose 15.1 Gy (SD 3.7) vs 14.7Gy (SD 3.3) (p = 0.23), heart V40Gy 10.2% (SD13) vs 7.2% (SD 9.8) (p = 0.037). When simulation technique changed: lung V20Gy 30.8% (SD 8.2) vs 27.3% (SD 8) (p = 0.012), mean lung dose 17.3 Gy (SD 4.4) vs 15.3 Gy (SD 3.8) (p = 0.007), heart V40Gy 11.1% (SD 14.7) vs 6.5% (SD 6.7) (p = 0.014).2 year local control was 60.7% (95% confidence interval, 34.5-79.2%), and median overall survival was 19.7 months. Adaptive replanning of radiation was performed in a fifth of locally advanced lung cancer patients. In most cases tumor volume decreased, or atelectasis resolved, causing mediastinal shifts, which, if unidentified and left uncorrected, may have led to local failure and increased toxicity. The heart V40Gy was reduced significantly in all cases, but significant reduction in lung doses was evident only if simulation technique was altered. In locally advanced lung cancer image-guidance with cone beam CT can detect significant mediastinal shifts and gross tumor volume changes that raise the need for adaptive replanning. Image guidance-triggered adaptive replanning should be added to the armament of advanced radiation treatment planning in locally advanced lung cancer.

Evaluation of the robustness of 3-dimensional conformal technique with MLC position control into the planning target volume in stereotactic body radiotherapy for lung cancer

The purpose of this study was to evaluate the robustness of 3-dimensional conformal technique with MLC position control into the planning target volume (PTV) in stereotactic body radiotherapy for lung cancer. Two techniques using fixed beams were compared; one technique involved setting the MLC position outside the PTV and was referred to as Plan “O.” Another technique involved setting the MLC position inside the PTV and was referred to as Plan “I.” Two tumor motions were simulated: (1) tumor motion on the internal target volume (ITV) boundary and (2) tumor motion on the PTV boundary. Ten-phase CT images that captured the tumor in respiratory motion were generated for 2 simulations. Then, 4-dimensional (4D) treatment planning was performed by using deformable image registration. The gross tumor volume (GTV) dose changes between the 4D accumulated dose and treatment planning dose were evaluated for Plan “O” and Plan “I,” respectively. For the simulation of tumor motion on the ITV boundary, the changes in GTV D50% were −0.10 ± 0.31% and −0.22 ± 0.26% (p < 0.05) for Plan “O” and Plan “I,” respectively. In the same manner, for the simulation of tumor motion on the PTV boundary, the changes in GTV D50% were −3.37 ± 2.16% and −3.68 ± 1.71% (p < 0.05). Our result suggested that the dose change would be negligible in a clinical situation where the tumor moves within the ITV margin for both techniques, while Plan “O” showed better robustness.

Tumor volume, circulating tumor cells, and cfDNA changes during radiotherapy in patients with head and neck cancer.

6062 Background: Head and neck (HN) cancer treatment response relies heavily on macroscopic clinical findings. Monitoring of circulating markers during treatment may improve detection of responders versus non-responders during radiotherapy (RT). Our work prospectively describes the changes in gross tumor volume (GTV), circulating tumor cell (CTC), and cell-free DNA (cfDNA) enumeration during RT. Methods: Patients with intact HN squamous cell carcinoma were enrolled in a prospective IRB-approved study. Pre-, after first RT, weekly in-, and post-RT blood samples were collected. Serial pre-, weekly in-, and post-RT magnetic resonance imaging (MRI) was obtained. Serial GTV measurements were recorded. CTC was enumerated using the FDA-approved CellSearch (Menarini Silicon Biosystems) system. Plasma were collected and cfNA from pre-, mid- and post-RT timepoints were isolated using the MagMAX Nucleic Acid Isolation Kit (Thermo Fisher Scientific), and cfDNA were quantified with Qubit high sensitivity dsDNA assay (Invitrogen). Results: 40 patients were eligible for analysis. Median age was 60 years and 36 were males. The median pre-RT GTV was 14.1cc (range 1.3 – 44.9cc). There was a median reduction of 81% in GTV by week 4 (p &lt; 0.0001). Of the 341 samples analyzed for CTC, 146 (43%) had detectable CTC. 7 patients had detectable pre-RT CTCs (1-3/7.5ml blood). There was no correlation between cancer stage, nodal status, and GTV with detection of CTC. After 1 fraction of RT, 14 patients had CTCs detected, including 11 who had no CTC detected prior. All patients had CTC detected at some point during RT except for 2 patients who had none. In week 4, with significant reduction in GTV, 25 (63%) had detectable CTC. 16 and 11 patients had detectable CTC in final week and post-RT timepoints. The cfDNA levels increased during RT, with its highest level in the final week of RT and lowest at post-RT time-point, inversely correlated with GTV. Conclusions: Our study showed that CTCs can be detected during RT, suggesting mobilization into peripheral circulation during RT with unknown viability. cfDNA kinetics during RT correlated with CTC release, and may indicate apoptotic change during RT. Combined cfDNA-CTC as an early marker of treatment response should be investigated further.

18F-FDG PET/CT in staging and delineation of radiotherapy volume for head and neck cancer.

The aim is to investigate the use of 18F-FDG (fluorine-18 fluorodeoxyglucose) PET/CT in head and neck cancer (HNC) staging and its effect on the therapeutic strategy and radiotherapy (RT) planning. One hundred patients with HNC were included. Primary tumor sites: 18% oral cavity, 20% oropharynx, 12% hypopharynx, 11% nasopharynx, 37% larynx, 2% paranasal sinuses. Patients were staged according to the American Joint Committee of Cancer 7th edition. Stage: 5% stage I, 7% stage II, 14% stage III, 61% stage IVA, 7% stage IVB and 6% stage IVC. A contrast-enhanced CT and a 18F-FDG PET/CT acquired under RT position were performed. Both exams were compared to analyze patients' staging reclassification. Changes in therapeutic strategy were analyzed. 18F-FDG PET/CT detected 6 distant metastases and treatment intention changed to palliative. Eight synchronous tumors were detected; one received palliative treatment. 18F-FDG PET/CT reclassified cTNM staging in 27patients. Tumor extension changed in 28 (14% up-staged; 14% down-staged), implying a change in GTV (Gross Tumor Volume) delineation. Nodal detection was reclassified in 47 patients: 8 patients down-staged (N2C to N2A/N2B/N1) and 2 were false positive. Nineteen patients were false negatives and 5 staged as N+(N1/N2A/N2B) turned out into N2C. These staging modifications imply adapting the nodal volume to be irradiated. 18F-FDG PET/CT reclassification was higher than 10% in almost all categories studied (cTNM, tumor extension and nodal disease) and detects more metastases and synchronous tumors than conventional studies, which has an impact on the therapeutic patient management and RT planning.

Changes in apparent diffusion coefficient radiomics features during dose-painted radiotherapy and high dose rate brachytherapy for prostate cancer.

Background and purposeDose escalation has improved cancer outcomes for patients with localized prostate cancer. Targeting subprostatic tumor regions for dose intensification may further improve outcomes. Apparent Diffusion Coefficient (ADC) maps may enable early radiation response assessment and dose adaptation. This study was a proof-of-principle investigation of early changes in ADC radiomics features for patients undergoing radiotherapy with dose escalation to the gross tumor volume (GTV).Materials and methodsFifty-nine patients were enrolled on a prospective tumor dose-escalation trial. Multi-parametric MRI was performed at baseline and week six, corresponding to the time of peak ADC change. GTV and prostate contours were deformably registered between baseline and week six T2-weighted images, and applied to ADC maps, to account for diminished image contrast post-EBRT and possible differences in prostate gland volume, shape, and orientation. A total of 101 radiomics features were tested for significant change post-EBRT using two-tailed Student’s t-test. All ADC features of the prostate and GTV volumes were correlated using Pearson’s coefficient (p < 0.00008, based on Bonferroni correction).ResultsADC feature extraction was insensitive to b = 0 s/mm2 exclusion, and to gradient non-linearity bias. GTV presented predominant changes in first-order features, particularly 10Percentile, and prostate volumes presented predominant changes in second-order features. Changes in both first and second-order features of GTV and prostate ROIs were strongly correlated.ConclusionsOur data confirmed significant changes in numerous GTV and prostate features assessed from ADC and T2-weighted images during radiotherapy; all of which may be potential biomarkers of early radiation response.