GTV Volume Research Articles

Evaluation of early regression index as response predictor in cervical cancer: A retrospective study on T2 and DWI MR images

Background and PurposeEarly Regression Index (ERITCP) is an image-based parameter based on tumor control probability modelling, that reported interesting results in predicting pathological complete response (pCR) after pre-operative chemoradiotherapy (CRT) in rectal cancer. This study aims to evaluate this parameter for Locally Advanced Cervical Cancer (LACC), considering not only T2-weighted but also diffusion-weighted (DW) Magnetic Resonance (MR) images, comparing it with other image-based parameters such as tumor volumes and apparent coefficient diffusion (ADC). Materials and MethodsA total of 88 patients affected by LACC (FIGO IB2-IVA) and treated with CRT were enrolled. An MRI protocol consisting in two acquisitions (T2-w and DWI) in two times (before treatment and at mid-therapy) was applied.Gross Tumor Volume (GTV) was delineated and ERITCP was calculated for both imaging modalities. Surgery was performed for each patient after nCRT: pCR was considered in case of absence of any residual tumor cells. The predictive performance of ERITCP, GTV volumes (calculated on T2-w and DW MR images) and ADC parameters were evaluated in terms of area (AUC) under the Receiver Operating Characteristic (ROC) curve considering pCR and two-years survival parameters as clinical outcomes. ResultsERITCP and GTV volumes calculated on DW MR images (ERIDWI and Vmid_DWI) significantly predict pCR (AUC = 0.77 and 0.75 respectively) with results superior to those observed considering T2-w MR images or ADC parameters. Significance was also reported in the prediction of 2-years local control and disease free-survival. ConclusionThis study identified ERITCP and Vmid as good predictor of pCR in case of LACC, especially if calculated considering DWI. Using these indicators, it is possible to early identify not responders and modifying the treatment, accordingly.

Redefine the Role of Spot-Scanning Proton Beam Therapy for the Single Brain Metastasis Stereotactic Radiosurgery.

PurposeTo explore the role of using Pencil Beam Scanning (PBS) proton beam therapy in single lesion brain stereotactic radiosurgery (SRS), we developed and validated a dosimetric in silico model to assist in the selection of an optimal treatment approach among the conventional Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Proton Therapy (IMPT) and Spot-scanning Proton Arc (SPArc).Material and MethodsA patient’s head CT data set was used as an in silico model. A series of targets (volume range from 0.3 cc to 33.03 cc) were inserted in the deep central and peripheral region, simulating targets with different sizes and locations. Three planning groups: IMPT, VMAT, and SPArc were created for dosimetric comparison purposes and a decision tree was built based on this in silico model. Nine patients with single brain metastases were retrospectively selected for validation. Multiple dosimetric metrics were analyzed to assess the plan quality, such as dose Conformity Index (CI) (ratio of the target volume to 100% prescription isodose volume); R50 (ratio of 50% prescription isodose volume to the target volume); V12Gy (volume of brain tissue minus GTV receiving 12 Gy), and mean dose of the normal brain. Normal tissue complication probability (NTCP) of brain radionecrosis (RN) was calculated using the Lyman-Kutcher-Burman (LKB) model and total treatment delivery time was calculated. Six physicians from different institutions participated in the blind survey to evaluate the plan quality and rank their choices.ResultsThe study showed that SPArc has a dosimetric advantage in the V12Gy and R50 with target volumes > 9.00 cc compared to VMAT and IMPT. A significant clinical benefit can be found in deep centrally located lesions larger than 20.00 cc using SPArc because of the superior dose conformity and mean dose reduction in healthy brain tissue. Nine retrospective clinical cases and the blind survey showed good agreement with the in silico dosimetric model and decision tree. Additionally, SPArc significantly reduced the treatment delivery time compared to VMAT (SPArc 184.46 ± 59.51s vs. VMAT: 1574.78 ± 213.65s).ConclusionThe study demonstrated the feasibility of using Proton beam therapy for single brain metastasis patients utilizing the SPArc technique. At the current stage of technological development, VMAT remains the current standard modality of choice for single lesion brain SRS. The in silico dosimetric model and decision tree presented here could be used as a practical clinical decision tool to assist the selection of the optimal treatment modality among VMAT, IMPT, and SPArc in centers that have both photon and proton capabilities.

Causal relation between heart irradiation and survival of lung cancer patients after radiotherapy

IntroductionIn a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT. MethodNSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency. ResultsDaily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors. ConclusionOur results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted.

Calculation of set-up margin in frameless stereotactic radiotherapy accounting for translational and rotational patient positing error.

Rotation corrected set-up margins in stereotactic radiotherapy (SRT). This study aimed to calculate the rotational positional error corrected set-up margin in frameless SRT. 6D setup errors for the steriotactic radiotherapy patients were converted to 3D translational only error mathematically. Setup margins were calculated with and without considering the rotational error and compared. A total of 79 patients of SRT each received >1 fraction (3-6 fractions) incorporated in this study. Two cone-beam computed tomography (CBCT) scans were acquired for each session of treatment, before and after the robotic couch-aided patient position correction using a CBCT. The postpositional correction set-up margin was calculated using the van Herk formula. Further, a planning target volume_R (PTV_R) (with rotational correction) and PTV_NR (without rotational correction) were calculated by applying the rotation corrected and uncorrected set-up margins on the gross tumor volumes (GTVs). Statistical Analysis Used: General. A total of 380 sessions of pre- (190) and post (190) table positional correction CBCT was analyzed. Posttable position correction mean positional error for lateral, longitudinal, and vertical translational and rotational shifts was (x)-0.01 ± 0.05 cm, (y)-0.02 ± 0.05 cm, (z) 0.00 ± 0.05 cm, and (θ) 0.04° ± 0.3°, (Φ) 0.1° ± 0.4°, (Ψ) 0.0° ± 0.4°, respectively. The GTV volumes show a range of 0.13 cc-39.56 cc, with a mean volume of 6.35 ± 8.65 cc. Rotational correction incorporated postpositional correction set-up margin the in lateral (x), longitudinal (y) and vertical (z) directions were 0.05 cm, 0.12 cm, and 0.1 cm, respectively. PTV_R ranges from 0.27 cc to 44.7 cc, with a mean volume of 7.7 ± 9.8 cc. PTV_NR ranges from 0.32 cc to 46.0 cc, with a mean volume of 8.1 ± 10.1 cc. The postcorrection linear set-up margin matches well with the conventional set-up margin of 1 mm. Beyond a GTV radius of 2 cm, the difference between PTV_NR and PTV_R is ≤2.5%, hence not significant.

Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety.

Simple SummaryWe present the early results of a novel partial bulky-tumor irradiation using carbon ions and protons. This approach explores the radiation-induced bystander and abscopal effects in patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments including radio-chemotherapy. Early tumor response, symptom relief and minimal toxicity suggest that the partial bulky-tumor irradiation was an effective, safe and well tolerated treatment. Abscopal effects elucidate an immunogenic pathway contribution.Background: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. Methods: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30–45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. Results: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. Conclusions: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment—otherwise previously impossible.

DEHART: Dose-Escalated Hypofractionated Adaptive Radiation Therapy with Atezolizumab for Head and Neck Cancers

<h3>Purpose/Objective(s)</h3> To determine the maximum-tolerated dose (MTD) of Dose-Escalated Hypofractionated Adaptive Radiation Therapy (DEHART) delivered with concurrent atezolizumab (Genentech) in patients with locally advanced or <i>de novo</i> metastatic head and neck squamous cell carcinomas (HNSCCs). (ClinicalTrials.Gov Identifier NCT04477759) We hypothesize that using DEHART we will be able to safely deliver ablative radiation doses for HNSCC in 15 fractions. <h3>Materials/Methods</h3> This is an NIH-funded (R21 CA256144-01) Phase I dose-escalation trial to determine the MTD of weekly adapted MR-guided radiation therapy delivered using the DEHART regimen with concurrent atezolizumab for patients with locoregionally advanced or <i>de novo</i> metastatic HNSCCs. Eligible patients are 18 years or older including all patients presenting with <i>de novo</i> metastatic HNSCC or patients presenting with localized AJCC 8^th edition T3-T4 N0-N3, T0-T4 N1-N3 HNSCC who meet at least one of the following criteria: 1) they are not candidates for concurrent bolus cisplatin; 2) they refuse concurrent cisplatin-based chemoradiation; 3) they have unresected or unresectable oral cavity cancer; or 4) they have recurrent disease after definitive surgical resection. DEHART is a novel adaptive MR-guided radiation regimen in which the gross tumor volume (GTV) plus a 3 mm PTV margin receives the experimental dose (50 Gy, 55 Gy or 60 Gy) in 15 fractions, a 1 cm anatomically-confined margin on the GTV plus a 3 mm PTV margin receives 45 Gy in 15 fractions, and elective lymph node basins plus a 3 mm PTV margin receives 40 Gy in 15 fractions. On fractions 6 and 11 of radiation, the GTV volume is adapted based on MR-documented tumor regression. All patients are treated on a linear accelerator. All patients receive the DEHART radiation regimen with concurrent and adjuvant monthly atezolizumab for 1 year. Atezolizumab (1680 mg) is delivered on the first day of radiation and every 4 weeks thereafter for up to 1 year after treatment. The primary endpoint of the study is the MTD of DEHART determined using a modified Time-To-Event Continual Reassessment Methodology (TITE-CRM). The MTD is the radiation dose at which there is a 30% rate of dose-limiting toxicity (DLT) up to 12 months after completion of radiation therapy. DLTs include an inability to complete radiation within 30 days of starting radiation deemed not to be related to disease progression and any Grade 4+ toxicity probably or definitely related to treatment with radiation and/or atezolizumab. Secondary study endpoints include locoregional control, overall survival, and patient quality-of-life as measured by the MD Anderson Symptom Inventory for Head and Neck (MDASI-HN) and the MD Anderson Dysphagia Inventory (MDADI-HN). <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Predicting personalised and progressive adaptive dose escalation to gross tumour volume using knowledge-based planning models for inoperable advanced-stage non-small cell lung cancer patients treated with volumetric modulated arc therapy

Objectives. Increased radiation doses could improve local control and overall survival of lung cancer patients, however, this could be challenging without exceeding organs at risk (OAR) dose constraints, especially for patients with advanced-stage disease. Increasing OAR doses could reduce the therapeutic ratio and quality of life. It is therefore important to investigate methods to increase the dose to target volume without exceeding OAR dose constraints. Methods. Gross tumour volume (GTV) was contoured on synthetic computerised tomography (sCT) datasets produced using the Velocity adaptive radiotherapy software for eleven patients. The fractions where GTV volume decreased compared to that prior to radiotherapy (reference plan) were considered for personalised progressive dose escalation. The dose to the adapted GTV (GTVAdaptive) was increased until OAR doses were affected (as compared to the original clinical plan). Planning target volume (PTV) coverage was maintained for all plans. Doses were also escalated to the reference plan (GTVClinical) using the same method. Adapted, dose-escalated, plans were combined to estimate accumulated dose, D99 (dose to 99%) of GTVAdapted, PTV D99 and OAR doses and compared with those in the original clinical plans. Knowledge-based planning (KBP) model was developed to predict D99 of the adapted GTV with OAR doses and PTV coverage kept similar to the original clinical plans; prediction accuracy and model verification were performed using further data sets. Results. Compared to the original clinical plan, the dose to GTV was significantly increased without exceeding OAR doses. Adaptive dose-escalation increased the average D99 to GTVAdaptive by 15.1Gy and 8.7Gy compared to the clinical plans. The KBP models were verified and demonstrated prediction accuracy of 0.4% and 0.7% respectively. Conclusion. Progressive adaptive dose escalation can significantly increase the dose to GTV without increasing OAR doses or compromising the dose to microscopic disease. This may increase overall survival without increasing toxicities.

Adaptive dose escalated radiotherapy in oropharyngeal cancers: a treatment planning feasibility study

BackgroundA significant proportion of patients with poor prognosis squamous cell cancer of the oropharynx relapse loco-regionally despite radical (chemo)radiotherapy. If a predictive biomarker for disease control can be identified during treatment then individualised and adaptive treatment strategies may be employed. The aim of this study is to assess the feasibility of adaptive and dose-escalated RT to the gross tumour volume without increasing surrounding planning target volume doses and maintaining clinically acceptable organs at risk doses.Materials and methodsTwenty representative patients with poor prognosis locally advanced OPSCC who were known to have relapsed post RT, were re-planned retrospectively using Eclipse TPS v15.5, RapidPlan™ and multi-criteria optimisation. In our centre, PTV65 is treated with 65 Gy in 30 fractions while areas at risk of containing microscopic disease (PTV54) are treated synchronously to 54 Gy in 30 fractions. The original clinical plans were re-optimised to act as controls (Group I). These plans were split into two plans of 15 fractions each, with the latter 15 fractions used to escalate the dose to the GTV to 73 Gy (Group II) and 82 Gy (Group III). Plan sums were created for the total 30 fractions to record plan evaluation parameters along with assessments of plan deliverability.ResultsFor all groups, the dose coverage at D98% and D50% for the PTVs were comparable. The D2% dose levels for PTV65-GTV increased. All dose levels associated with PTV54 remained largely unaffected by the dose escalation regimens. Conformity indices for PTV65 and PTVAll (PTV65 plus PTV54) reveal comparable target volume coverage across all three groups. Despite the GTV being escalated by 12.3% and 26.2% in groups II and III, the volume of GTV receiving > 84 Gy was considerably less than 1.75 cc. While OAR doses increased for the escalated groups, these increases were not clinically significant.ConclusionThis planning feasibility study exploring RapidPlan™ combined with multi-criteria optimisation has demonstrated that doses to the GTV may be escalated without increasing PTV65-GTV, PTV54 or OAR doses considerably, suggesting an interventional clinical trial using this approach would be feasible.

Survival benefits for non-small cell lung cancer patients treated with adaptive radiotherapy

IntroductionTumor match and adaptive radiotherapy based on on-treatment imaging increases the precision of RT. This allows a reduction of treatment volume and, consequently, of the dose to organs at risk. We investigate the clinical benefits of tumor match and adaptive radiotherapy for a cohort of non-small cell lung cancer patients (NSCLC). MethodsIn 2013, tumor match and adaptive radiotherapy based on daily cone-beam CT scans was introduced to ensure adaption of the radiotherapy treatment plan for all patients with significant anatomical changes during radiotherapy. Before 2013, the daily cone-beam CT scans were matched on the vertebra and anatomical changes were not evaluated systematically. To estimate the effect of tumor match and adaptive radiotherapy, 439 consecutive NSCLC patients treated with definitive chemo-radiotherapy (50–66 Gy/25–33 fractions, 2010–2018) were investigated retrospectively. They were split in two groups, pre-ART (before tumor match and adaptive radiotherapy, 184 patients), and ART (after tumor match and adaptive radiotherapy, 255 patients) and compared with respect to clinical, treatment-specific and dosimetric variables (χ2 tests, Mann Whitney U tests), progression, survival and radiation pneumonits (CTCAEv3). Progression-free and overall survival as well as radiation pneumonitis were compared with log-rank tests. Hazard ratios were estimated from Cox proportional hazard regression. ResultsNo significant differences in stage (p = 0.36), histology (p = 0.35), PS (p = 0.12) and GTV volumes (p = 0.24) were observed. Concomitant chemotherapy was administered more frequently in the ART group (78%) compared to preART (64%), p < 0.001. Median[range] PTV volumes decreased from 456 [71;1262] cm3 (preART) to 270 [31;1166] cm3 (ART), p < 0.001, thereby significantly reducing mean doses to lungs (median, preART 16.4 [1.9;24.7] Gy, ART 12.1 [1.7;19.4] Gy, p < 0.001) and heart (median, preART 8.0 [0.1;32.1] Gy, ART 4.4 [0.1;33.9] Gy, p < 0.001). The incidence of RP at nine months decreased significantly with ART (50% to 20% for symptomatic RP (≥G2), 21% to 7% for severe RP (≥G3), 6% to 0.4% for lethal RP (G5), all p < 0.001). The two-year progression free survival increased from 22% (preART) to 30% (ART), while the overall survival increased from 43% (preART) to 56% (ART). The median overall survival time increased from 20 (preART) to 28 months (ART). ConclusionTumor match and adaptive radiotherapy significantly decreased radiation pneumonitis, while maintaining loco-regional control. Further, we observed a significantly improved progression-free and overall survival.

Interstitial 125I Brachytherapy as a Salvage Treatment for Refractory Cervical Lymph Node Metastasis of Thoracic Esophageal Squamous Cell Carcinoma After External Irradiation With a CT-Guided Coplanar Template-Assisted Technique: A Retrospective Study.

Purpose: To analyze the outcome and prognosis of patients with refractory cervical lymph node metastasis of thoracic esophageal squamous cell carcinoma after external irradiation, who underwent interstitial 125I brachytherapy as a salvage treatment with a CT-guided coplanar template-assisted technique. We also want to compare the dosimetry of 3D printed coplanar template-assisted interstitial 125I brachytherapy preoperative and postoperative, and to explore the accuracy of this technology. Material and methods: We retrospectively collected and analyzed the results of 32 patients with refractory cervical lymph node metastasis of thoracic esophageal squamous cell carcinoma after external irradiation, who underwent interstitial 125I brachytherapy as a salvage treatment with a CT-guided coplanar template-assisted technique from January 2012 to December 2017. Results: The actual D90 were 114 to 240 Gy, and the median postoperative dosimetry assessment was 177.5 Gy. The local control rates at 3, 6, 9, and 12 months were 87.5%, 59.38%, 40.63%, and 31.25%, respectively. The median local control time was 7.5 months. The median overall survival time was 10.5 months (95% CI, 8.9-13.4), and the survival rates of 1- and 2-year, respectively, were 43.75% and 9.38%. There were 36 lesions in 32 patients. By performing a paired t-test analysis, there was no significant difference in D90, D100, V100, V150, V200, GTV volume, CI, EI, and HI between preoperative and postoperative (P > .05). Conclusions: Interstitial 125I brachytherapy can be used as a salvage treatment for patients with refractory cervical lymph node metastasis of thoracic esophageal squamous cell carcinoma after external irradiation. With the auxiliary function of 3D printed coplanar template, the main dosimetry parameters verified after the operation can meet the requirements of the preoperative plan with good treatment accuracy.

Radiotherapy and high bilirubin may be metformin like effect on lung cancer via possible AMPK pathway modulation.

Life expectancy of cancer patients determine the regimen of treatment. There is no feasible marker that determines the survival other than the stage of the disease or other patients related factors. Bilirubin can be a revealing marker for these. The effect of bilirubin may be due to the fact that the genetic and biochemical processes of bilirubin also modulate the tumour microenvironment. Radiotherapy and bilirubin can produce an effect similar to metformin via AMPK pathway. This analysis was performed retrospectively in a cohort of 80 patients with a diagnosis of locoregional lung cancer with bilirubin levels in the accepted range. Receiver operating characteristic curve (ROC) analysis was performed to determine the optimal cut-off points. Pre-treatment serum total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL) levels and tumour volumes in the prognosis of the patients were investigated. The cut-off points for serum TBIL, DBIL and IBIL were 0.565 mg/dL, 0.105 mg/dL and 0.415 mg/dL,respectively. High TBIL 47.5 %, high DBIL and high IBIL were observed in 45 % of the entire patient population. The overall survival was three times longer in the high TBIL group than in the low TBIL group (OS; Hazard Ratio (HR), 0.33; 95% CI 0.16-0.70; p <0.001), locoregional free survival (LRFS; HR, 0.44; 95% CI 0.27-0.71; p <0.001) and distant metastasis-free survival (DMFS; HR, 0.44; 95% 0.25-0.80; p < 0.001). Similarly, high DBIL and high IBIL levels have been associated with longer OS, LRFS, and DMFS with significant differences. In addition, in the survival analysis of the cohort stratified with gross tumour volume (GTV) 128.5cc and TBIL 0.565 cut-off values; In the comparison of high TBIL and low TBIL groups, a significantly longer OS was observed in the high TBIL group in the patients with a GTV volume greater than128.5cc (p <0.001). Plasma bilirubin level at the time of diagnosis affects the survival of the patients independent of cancer stage and tumour volume. Possible additive interactions of radiotherapy and bilirubin are discussed with their pathophysiological mechanisms (Tab. 2, Fig. 7, Ref. 26).

MET-6 Neoadjuvant fractionated stereotactic radiotherapy followed by piecemeal resection for metastatic brain tumor

BACKGROUND: Large brain metastases which require resection are treated with surgery followed by whole brain radiation therapy or postoperative stereotactic radiosurgery (SRS). Recently a novel strategy using neoadjuvant stereotactic radiosurgery (Na-SRS) followed by surgery was reported, demonstrating lower rates of postoperative leptomeningeal dissemination (LMD) and symptomatic radiation necrosis (RN). We treated with neoadjuvant fractionated stereotactic radiotherapy (Na-fSRT) followed by surgery for large brain metastasis with piecemeal resection. METHODS: Twelve patients received Na-fSRT followed by surgery between July 2019 and April 2021. Na-fSRT dose was based on lesion size and was standard dosing. Surgery generally followed within 7 days after radiotherapy. RESULTS: The mean age was 68 years (51–79). Sixteen men and five women. Mean follow-up period was 8.5 months (1–24.9). Primary were lung; 10 (NSCLC; 9, SCLC (recurrence); 1), esophagus; 3, colon; 2, melanoma; 2, kidney; 2 (recurrence1), uterus body; 1, and liver; 1. The median maximum tumor diameter was 3.6 cm (2.6–4.9). Median PTV, GTV volume were 21.7ml, 15.5ml, respectively. The median fSRT dose was 30Gy/5fr, and the median time from fSRT to surgery was 4 days (1–7). As preoperative adverse event, intracranial hypertension and partial seizure grade 2 (CTCAE ver.5) were occurred, but controlled with steroid and osmotic diuretics and anticonvulsant. Grade 3 and more adverse events were not occurred. Gross total removal was performed in 95.2%. Event cumulative incidence as follows: cavity local recurrence 4.8% (subtotal removal case); distant brain failure 33%; LMD 4.8%; and symptomatic RN 0%. The median intracranial progression free survival was 7 months, and median overall survival was 8.4 months. CONCLUSIONS: Na-fSRT followed by piecemeal resection is safety and feasible, and may have therapeutic value for deep large brain metastasis and eloquent lesion. Further prospective investigations in multi-institutional settings are warranted.

Proton therapy with a fixed beamline for skull-base chordomas and chondrosarcomas: outcomes and toxicity

AimThis study presents an analysis (efficacy and toxicity) of outcomes in patients with skull-base chordomas or chondrosarcomas treated with a fixed horizontal pencil proton beam.BackgroundChordomas (CAs) and chondrosarcomas (CSAs) are rare tumours that are usually located near the base of the skull and very close to the brain's most critical structures. Proton therapy (PT) is often considered the best radiation treatment for these diseases, but it is still a limited resource. Active scanning PT delivered via a fixed pencil beamline might be a promising option.MethodsThis is a single-centre experience describing the results of proton therapy for 31 patients with CA (n = 23) or CSA (n = 8) located near the base of the skull. Proton therapy was utilized by a fixed pencil beamline with a chair to position the patient between May 2016 and November 2020. Ten patients underwent resection (32.2%), 15 patients (48.4%) underwent R2 resection, and 6 patients had unresectable tumours (19.4%). In 4 cases, the tumours had been previously irradiated. The median PT dose was 70 GyRBE (relative biological efficacy, 1.1) [range, 60 to 74] with 2.0 GyRBE per fraction. The mean GTV volume was 25.6 cm3 [range, 4.2–115.6]. Patient demographics, pathology, treatment parameters, and toxicity were collected and analysed. Radiation-induced reactions were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0.ResultsThe median follow-up time was 21 months [range, 4 to 52]. The median overall survival (OS) was 40 months. The 1- and 2-year OS was 100%, and the 3-year OS was 66.3%. Four patients died due to non-cancer-related reasons, 1 patient died due to tumour progression, and 1 patient died due to treatment-related injuries. The 1-year local control (LC) rate was 100%, the 2-year LC rate was 93.7%, and the 3-year LC rate was 85.3%. Two patients with CSA exhibited progression in the neck lymph nodes and lungs. All patients tolerated PT well without any treatment interruptions. We observed 2 cases of ≥ grade 3 toxicity, with 1 case of grade 3 myelitis and 1 case of grade 5 brainstem injury.ConclusionTreatment with a fixed proton beam shows promising disease control and an acceptable toxicity rate, even the difficult-to-treat subpopulation of patients with skull-base chordomas or chondrosarcomas requiring dose escalation.

Short-Course Palliative Radiotherapy Combined With Immunotherapy for Recurrent/Advanced/Metastatic Head and Neck Cancer

To evaluate tumor response rates in patients treated with a combination of palliative short-course radiotherapy (SCRT) and immune checkpoint inhibitor immunotherapy (IO) in patients with recurrent, advanced or metastatic (R/A/M) head and neck cancer (HNC).We reviewed the medical records of patients treated with short-course palliative intent radiation therapy (RT) (hypofractionated RT in 4-5 fractions) for R/A/M HNC between 2014-2020. Patient, disease, and treatment factors were abstracted from the medical record. Patients were categorized as having been treated with combined immunotherapy and radiotherapy (IO+RT) if the RT was given after at least 1 cycle of IO with at least 1 cycle of IO afterward. Treated gross tumor volume (GTV) was measured prior to and after RT and percent change in GTV volume from baseline to best overall response (BOR) was calculated. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.In total, 19 patients were treated with SCRT, 7 of whom were treated with combined IO+RT. Primary site included oral cavity (n = 6), larynx/hypopharynx (5), oropharynx (3), sinonasal (2), cutaneous (2), and thyroid (1). Squamous cell histology was most frequent (16/19) with the other 3 comprised of sinonasal intestinal-type adenocarcinoma, mucosal melanoma, and Hürthle cell carcinoma. Disease status included 6 patients with a recurrence, 6 were metastatic, 3 locally advanced/incurable, and 3 recurrent/metastatic. Prior treatments included RT (n = 9) and chemotherapy (6); ECOG performance status was 1-2 in 13 patients and 3-4 in 6 patients. Seventeen patients were treated with "quad-shot" radiotherapy (14.4-14.8 Gy in 4 fractions delivered twice daily) and 2 were treated with 20 Gy in 5 fractions. Median (range) number of IO cycles given pre- and post-RT were 7 (1-11) and 2 (1-21), respectively. Of the 17 evaluable patients for treatment response, 13 patients responded or were stable while 4 had progression. Median pre-RT target volume in the RT cohort was 37.2 (6.14-486.21) cc and 145.28 (24.21-219.51) cc in the IO+RT cohort. Median post-RT target volume in the RT cohort was 28.00 (17.23, 57.630 cc and 58.44 (0.00, 246.56) cc in the IO+RT cohort. Median change in target volume in RT cohort was -42% (range: -100, 259) cc and -54% (-100, 12) cc in the IO+RT cohort. 1-year PFS and OS were 5% and 21%, respectively. 1-year OS was numerically higher for IO+RT patients (43% v. 8%, P = 0.13).In this select cohort of patients with R/A/M HNC, combined IO+SCRT was feasible and showed an improved tumor response as evidenced by greater decrement in post-treatment tumor volume. An ongoing clinical trial (NCT04454489) aims to prospectively evaluate the potential benefit of combined quad-shot radiotherapy with Pembrolizumab to improve response rates to IO alone.

Adaptive Lung Radiotherapy in the Era of Immunotherapy: A Single Center Retrospective Review

<h3>Purpose/Objective(s)</h3> Treatment with concurrent chemoradiation and immune checkpoint inhibition (ICI) in patients (pts) with locally advanced or stage III/IV non-small lung cancer (NSCLC) is associated with improved PFS and OS. However, treatment is limited by the development of pneumonitis and esophagitis, toxicities associated with both chemoradiation and ICIs. <h3>Materials/Methods</h3> We conducted a single center retrospective review of pts with locally advanced or stage III/IV NSCLC who received chemoradiation with concurrent or subsequent ICI. Pts were excluded if the relevant structure contours were missing or if the tumor location was not matched by both groups. Pneumonitis and esophagitis were assessed with CTACE V5. <h3>Results</h3> From 2015-2020, 49 pts were identified and 25 were included in the analysis. One patient was excluded due absent contours. Ten pts were adapted and 15 were non-adaptive controls. Mean age at onset was 728 years, 12F, 13 M; 13 adenocarcinoma, 9 squamous, 3 poorly differentiated; mean BMI 28.3 6.1, 1 IIB, 9 IIIA, 15 IIIB; 4 T1, 6 T2, 9 T3, 6 T4; 1 LLL, 8 LUL, 4 RLL, 12 RUL. Twenty and 77.7% of pts in the adaptive group had pneumonitis and esophagitis respectively, while 20% and 80% in the non-adapted group had pneumonitis and esophagitis respectively. Due to the number of DVH parameters sampled, bivariate analysis was performed; values with <i>P</i> < 0.05 were included for multiple regression analysis. Wilcoxon Rank Sum test was performed for the GTV of adapted and non-adaptive pts with <i>P</i> = 0.0213, indicating a significant difference between the GTV sizes of the adaptive pts (346.2 +/- 284.3 cm³) and non-adapted (153.1 +/-103.1 cm³). Multiple regression analysis was performed for esophagitis vs. plan adaptation (<i>P</i> = 0.58) adjusting for covariates of BMI (<i>P</i> = 0.14), age at onset (<i>P</i> = 0.019), and esophagus dose max (<i>P</i> = 0.07), did not distinguish a difference in toxicity between pts. Multiple regression analysis of pneumonitis vs. plan adaptation (<i>P</i> = 0.64) adjusting for covariates of both lung dose max (<i>P</i> = 0.28), R lung volume (<i>P</i> = 0.67), BMI (<i>P</i> = 0.23), and age at onset (<i>P</i> = 0.74) did not demonstrate a significant difference in toxicity between the adapted and non-adaptive pts. <h3>Conclusion</h3> Both the adaptive and non-adaptive groups had statistically equivalent toxicities; however, GTV volumes between the 2 groups were significantly different in size. By using adaptive therapy techniques, pts with large tumor sizes can be treated with an equivalent level of toxicity to patients with smaller tumors treated with traditionally.

Application of Silicone-Filled Vaginal Spacers for Pediatric Proton Therapy

Tissue spacers, including vaginal wall spacers, are used in a number of cancer diagnoses including soft tissue sarcomas, prostate cancer, cervical and uterine cancers. In proton therapy, the benefit of tissue spacers can be even greater as the device can serve as a beam stopper where protons reach their end of range in the material of the spacer instead of adjacent tissues.Commercially available hollow vaginal spacers which come in sizes ranging from 1.46 cm to 3.65 cm in diameter were filled with air-free silicone in a custom-made vacuum chamber. Two adolescent patients with pelvic soft tissue sarcomas receiving proton therapy were CT-simulated with and without a vaginal spacer. The relative stopping power of silicone was measured in a water tank to estimate the water equivalent thickness from 1.56 cm to 3.91 cm used in the treatment planning system for dosimetric comparisons. The dosimetric advantages of the silicone-filled vaginal spacer were investigated in three different dosimetric scenarios: (1) no vaginal spacer, (2) hollow vaginal spacer, (3) silicone-filled vaginal spacer in terms of plan quality and sparing of contralateral vaginal wall during primary and boost phases for two patients.While the target coverages remained comparable for the phase I (CTV, Rx = 36 Gy) and the phase II (GTV, Rx = 59.4 Gy), the dose distributions of ipsilateral and contralateral vaginal walls varied across these scenarios. After the phase II, the dosimetric sparing of contralateral vaginal wall was chiefly achieved in the patient A as the mean dose was 8.4 Gy with the silicone-filled spacer, and 17.1 Gy with hollow spacer, and 30.8 Gy with no spacer. However, due to the size and location of the tumor relative to the vagina, the sparing of contralateral vaginal was not observed in the patient B. While the patient A had a unilateral tumor with smaller GTV volume (23.3 cc) irradiated by straight lateral and posterior beams, the patient B had bilaterally located larger GTV volume (342.2 cc) covered by two posterior oblique beams.The study suggested that when the vagina is adjacent but located distal to the tumor, a significant dose reduction can be achieved with the insertion of a silicon-filled vaginal spacer.

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.

The Utility of Stereotactic Body Radiotherapy for Pelvic Recurrences After Prior Radiation Therapy

Patients with locally recurrent colorectal cancer represent a particular clinical challenge as these patients often present with unresectable disease and a history of prior pelvic radiotherapy. While options are therefore limited, radiation is usually the only local therapy available. The purpose of this study was to analyze the efficacy and outcomes associated with treating recurrent colorectal cancer using stereotactic body radiation therapy (SBRT) in patients who have been previously irradiated to the pelvis.We identified 23 patients with recurrent rectal (n = 20, 87%) or colon (n = 3, 13%) adenocarcinoma who were treated with SBRT in the Department of Radiation Oncology at Stanford University from June 2009 to November 2019. In total, 11 males and 12 females were included in this study with a median age of 53 years old (range: 25-76). All 23 patients had a history of surgical resection and at least one course of radiation therapy to disease in the pelvis before SBRT treatment to the pelvis for recurrent cancer, of which 8 patients (35%) received two prior radiotherapy courses and 1 patient (4%) received three prior courses. Data collection included tumor staging and grading, radiation treatment details, and follow up information to determine toxicities and survival outcomes. Time to events were calculated from the completion of SBRT. Toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.Median time to follow up was 91 months (range: 36-237). Median GTV and PTV volumes for tumor treated using SBRT were 79.9 and 136.5 cm3, respectively. Median SBRT dose was 40 Gy (range: 30 - 50). Median PTV mean dose was 41.8Gy. The median cumulative biological effective dose (BED) was 145 Gy (range: 72.0-254.4). Overall, 22 patients received 5 fractions of treatment and one patient received 4 of the 5 planned fractions due to deteriorating condition related to disease. Median time to overall survival (OS) was 125 months (range: 61-194) and median progression free survival (PFS) was 82 months (range: 57-142). The 3- and 5-year rate of local failure was 4.4% and 17.4%, respectively. Of the 23 patients in this cohort, there were 6 patients (26%) with grade 2 acute toxicities, including 3 patients (13%) with increased pain, and 6 patients (26%) with late grade 2 or 3 toxicities, including 3 patients (13%) with grade 3 neuropathy. There was no grade 3 or 4 acute, or grade 4 late toxicities reported. On univariate analysis, no factors were significantly predictive of OS, PFS, or toxicity.SBRT to previously irradiated areas of the pelvis was effective in controlling unresectable pelvic recurrences of colorectal cancer following previous radiation. While treatment was generally well-tolerated, pelvic pain was the most common acute toxicity, and neuropathy was the most common late toxicity. Further investigation is needed to improve the toxicity profile and optimize the therapeutic ratio.

Impact of Tumor Dosimetry on Clinical Outcomes after Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma

We hypothesized that escalated biological effective dose (BED) via stereotactic body radiation therapy (SBRT) would improve outcomes for patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC).A retrospective review was performed on consecutive patients who received pancreas SBRT from June 2009 to June 2020, were non-metastatic at the time of SBRT, received neoadjuvant chemotherapy, and had available gross tumor volume (GTV) dosimetry. Variables of interest included: age, gender, tumor location (body/tail vs head/neck), chemotherapy type (5-fluorouracil-based vs gemcitabine-based), AJCC V8 stage, pre- and post-radiotherapy (RT) CA19-9, GTV D95, and GTV V55-40 Gy. GTV volume variables were analyzed as continuous (cont) and as binary (+) functions. All patients with BRPC at diagnosis were analyzed by a logistic regression model for variables that predicted a higher likelihood of undergoing surgical resection (Model A). A second model of all patients (BRPC and LAPC) unable to undergo surgery was constructed by Cox regression analysis investigating variables that predicted for improved overall survival (OS), progression free survival (PFS), time to loco-regional failure (TTLRF), and time to distant failure (TTDF; Model B). All clinical time points were calculated from the end of SBRT and data analysis was performed in SAS with backward elimination variable selection.A total of 365 patients had a median follow up from SBRT of 12.1 months and 251 patients (69%) were diagnosed with BRPC. Model A composed of 200 BRPC patients (56% resected) with 3 clinical variables: chemotherapy (P = .39), AJCC stage (OR 0.54, P = 0.01), post-RT CA19-9 (OR 0.27, P = < 0.001); and 3 dosimetric variables: GTV D95 (OR 3.81, P = 0.03), GTV V40+ (OR 2.52, P = 0.07), and GTV V40cont (OR 0.98, P = 0.03). Model B included 168 patients (51% BRPC) unable to undergo surgery. In this group, 5-fluorouracil-based chemotherapy was associated with improved OS (HR 0.51, P = < 0.001), PFS (HR 0.48, P = < 0.001), TTLRF (HR 0.47, P = 0.004), and TTDF (HR 0.54, P = 0.006). GTV V40+ was significantly associated with improved PFS (HR 0.59, P = 0.005) and TTLRF (HR 0.58, P = 0.036), but not with OS (HR 1.06, P = 0.78) or TTDF (HR 0.68, P = 0.113). Pre-RT CA19-9 was associated with worse OS (HR 1.43, P = 0.010) and TTLRF (HR 1.59, P = 0.022). The proportion of patients receiving 5-flurouracil-based chemo and achieving GTV V40+ was evenly distributed across the cohort (χ2 = 0.55, P = 0.45).In the largest series of pancreatic cancer SBRT to date, dose-escalated tumor coverage specifically to 40 Gy (BED10 = 72 Gy) increases the likelihood of surgical resection in patients with upfront BRPC and is associated with improved PFS that is driven by improvement in loco-regional disease control for unresected patients. These data may help to inform the evolving landscape on the use of neoadjuvant and definitive radiotherapy in pancreatic cancer.

Tumor Volume Predicts for Pathological Complete Response in Rectal Cancer Patients Treated With Neoadjuvant Chemoradiation

<h3>Purpose/Objective(s)</h3> Currently, neoadjuvant chemoradiation (CRT) followed by total mesorectal excision is a standard treatment for patients with stage II and III rectal cancer. However, non-operative management of rectal cancer is an emerging approach to allow patients to preserve their anal sphincter. Factors that may help identify patients most likely to have a pathological complete response (pCR) would be helpful for physicians and patients considering a non-operative approach. <h3>Materials/Methods</h3> A total of 377 patients from our institution who had clinical stage II or III rectal cancer treated with neoadjuvant chemoradiation were included in the analysis. Patients were grouped based on their pCR status. Clinical parameters including overall stage, gross tumor volume (GTV), and radiation dose were analyzed by univariate and multivariate analysis, with pCR being the dependent variable. A Receiver Operator Characteristic (ROC) curve was generated in order to identify a tumor volume cutoff with the highest sensitivity for predicting pCR. <h3>Results</h3> The cohort had a median age at diagnosis of 61 years, 68% were male, and 85% presented with stage III disease. 68 of the 377 patients (18%) included in our analysis achieved pCR. A tumor volume of < 18.7 cc is highly sensitive (90%) for predicting pCR. Additionally, on multivariate analysis, a GTV of < 18.7 cc (odds ratio (OR) = 3.1, 95% confidence interval (CI) = 1.613-6.356, <i>P</i> = 0.001) was significantly associated with an increased rate of pCR. Overall stage (<i>P</i> = 0.026) was also significantly associated with pCR, while prescribed dose (<i>P</i> = 0.45) did not appear to impact pCR rates. <h3>Conclusion</h3> Our analysis identified a GTV volume of < 18.7 cc as a strong predictor for pCR in stage II and III rectal cancer patients receiving neoadjuvant chemoradiation, which will be helpful in identifying potential candidates for non-operative management.