Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Upfront Versus Delayed Systemic Therapy in Patients With Oligometastatic Cancer Treated With SABR in the Phase 2 SABR-5 Trial.

PURPOSE: The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS: The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS: A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS: Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.

Four-dimensional treatment planning strategies for dynamic tumor tracking.

INTRODUCTION: Dynamic tumor tracking (DTT) is a motion management technique where the radiation beam follows a moving tumor in real time. Not modelling DTT beam motion in the treatment planning system leaves an organ at risk (OAR) vulnerable to exceeding its dose limit. This work investigates two planning strategies for DTT plans, the "Boolean OAR Method" and the "Aperture Sorting Method," to determine if they can successfully spare an OAR while maintaining sufficient target coverage. MATERIALS AND METHODS: A step-and-shoot intensity modulated radiation therapy (sIMRT) treatment plan was re-optimized for 10 previously treated liver stereotactic ablative radiotherapy patients who each had one OAR very close to the target. Two planning strategies were investigated to determine which is more effective at sparing an OAR while maintaining target coverage: (1) the "Boolean OAR Method" created a union of an OAR's contours from two breathing phases (exhale and inhale) on the exhale phase (the planning CT) and protected this combined OAR during plan optimization, (2) the "Aperture Sorting Method" assigned apertures to the breathing phase where they contributed the least to an OAR's maximum dose. RESULTS: All 10 OARs exceeded their dose constraints on the original plan four-dimensional (4D) dose distributions and average target coverage was V100% = 91.3% ± 2.9% (ranging from 85.1% to 94.8%). The "Boolean OAR Method" spared 7/10 OARs, and mean target coverage decreased to V100% = 87.1% ± 3.8% (ranging from 80.7% to 93.7%). The "Aperture Sorting Method" spared 9/10 OARs and the mean target coverage remained high at V100% = 91.7% ± 2.8% (ranging from 84.9% to 94.5%). CONCLUSIONS: 4D planning strategies are simple to implement and can improve OAR sparing during DTT treatments. The "Boolean OAR Method" improved sparing of OARs but target coverage was reduced. The "Aperture Sorting Method" further improved sparing of OARs and maintained target coverage.

Markerless dynamic tumor tracking (MDTT) radiotherapy using diaphragm as a surrogate for liver targets.

PURPOSE: To assess the feasibility of using the diaphragm as a surrogate for liver targets during MDTT. METHODS: Diaphragm as surrogate for markers: a dome-shaped phantom with implanted markers was fabricated and underwent dual-orthogonal fluoroscopy sequences on the Vero4DRT linac. Ten patients participated in an IRB-approved, feasibility study to assess the MDTT workflow. All images were analyzed using an in-house program to back-project the diaphragm/markers position to the isocenter plane. ExacTrac imager log files were analyzed. Diaphragm as tracking structure for MDTT: The phantom "diaphragm" was contoured as a markerless tracking structure (MTS) and exported to Vero4DRT/ExacTrac. A single field plan was delivered to the phantom film plane under static and MDTT conditions. In the patient study, the diaphragm tracking structure was contoured on CT breath-hold-exhale datasets. The MDTT workflow was applied until just prior to MV beam-on. RESULTS: Diaphragm as surrogate for markers: phantom data confirmed the in-house 3D back-projection program was functioning as intended. In patients, the diaphragm/marker relative positions had a mean ± RMS difference of 0.70 ± 0.89, 1.08 ± 1.26, and 0.96 ± 1.06 mm in ML, SI, and AP directions. Diaphragm as tracking structure for MDTT: Building a respiratory-correlation model using the diaphragm as surrogate for the implanted markers was successful in phantom/patients. During the tracking verification imaging step, the phantom mean ± SD difference between the image-detected and predicted "diaphragm" position was 0.52 ± 0.18 mm. The 2D film gamma (2%/2 mm) comparison (static to MDTT deliveries) was 98.2%. In patients, the mean difference between the image-detected and predicted diaphragm position was 2.02 ± 0.92 mm. The planning target margin contribution from MDTT diaphragm tracking is 2.2, 5.0, and 4.7 mm in the ML, SI, and AP directions. CONCLUSION: In phantom/patients, the diaphragm motion correlated well with markers' motion and could be used as a surrogate. MDTT workflows using the diaphragm as the MTS is feasible using the Vero4DRT linac and could replace the need for implanted markers for liver radiotherapy.

Monte Carlo Modeling of Dynamic Tumor Tracking on a Gimbaled Linear Accelerator.

Purpose and Aim: The Vero4DRT (Brainlab AG) linear accelerator is capable of dynamic tumor tracking (DTT) by panning/tilting the radiation beam to follow respiratory-induced tumor motion in real time. In this study, the panning/tilting motion is modeled in Monte Carlo (MC) for quality assurance (QA) of four-dimensional (4D) dose distributions created within the treatment planning system (TPS). Materials and Methods: Step-and-shoot intensity-modulated radiation therapy plans were optimized for 10 previously treated liver patients. These plans were recalculated on multiple phases of a 4D computed tomography (4DCT) scan using MC while modeling panning/tilting. The dose distributions on each phase were accumulated to create a respiratory-weighted 4D dose distribution. Differences between the TPS and MC modeled doses were examined. Results: On average, 4D dose calculations in MC showed the maximum dose of an organ at risk (OAR) to be 10% greater than the TPS' three-dimensional dose calculation (collapsed cone [CC] convolution algorithm) predicted. MC's 4D dose calculations showed that 6 out of 24 OARs could exceed their specified dose limits, and calculated their maximum dose to be 4% higher on average (up to 13%) than the TPS' 4D dose calculations. Dose differences between MC and the TPS were greatest in the beam penumbra region. Conclusion: Modeling panning/tilting for DTT has been successfully modeled with MC and is a useful tool to QA respiratory-correlated 4D dose distributions. The dose differences between the TPS and MC calculations highlight the importance of using 4D MC to confirm the safety of OAR doses before DTT treatments.

In-vivo quality assurance of dynamic tumor tracking (DTT) for liver SABR using EPID images.

PURPOSE: To assess dynamic tumor tracking (DTT) target localization uncertainty for in-vivo marker-based stereotactic ablative radiotherapy (SABR) treatments of the liver using electronic-portal-imaging-device (EPID) images. The Planning Target Volume (PTV) margin contribution for DTT is estimated. METHODS: Phantom and patient EPID images were acquired during non-coplanar 3DCRT-DTT delivered on a Vero4DRT linac. A chain-code algorithm was applied to detect Multileaf Collimator (MLC)-defined radiation field edges. Gold-seed markers were detected using a connected neighbor algorithm. For each EPID image, the absolute differences between the measured center-of-mass (COM) of the markers relative to the aperture-center (Tracking Error, (ET )) was reported in pan, tilt, and 2D-vector directions at the isocenter-plane. PHANTOM STUDY: An acrylic cube phantom implanted with gold-seed markers was irradiated with non-coplanar 3DCRT-DTT beams and EPID images collected. Patient Study: Eight liver SABR patients were treated with non-coplanar 3DCRT-DTT beams. All patients had three to four implanted gold-markers. In-vivo EPID images were analyzed. RESULTS: Phantom Study: On the 125 EPID images collected, 100% of the markers were identified. The average ± SD of ET were 0.24 ± 0.21, 0.47 ± 0.38, and 0.58 ± 0.37 mm in pan, tilt and 2D directions, respectively. Patient Study: Of the 1430 EPID patient images acquired, 78% had detectable markers. Over all patients, the average ± SD of ET was 0.33 ± 0.41 mm in pan, 0.63 ± 0.75 mm in tilt and 0.77 ± 0.80 mm in 2D directions The random 2D-error, σ, for all patients was 0.79 mm and the systematic 2D-error, Σ, was 0.20 mm. Using the Van Herk margin formula 1.1 mm planning target margin can represent the marker based DTT uncertainty. CONCLUSIONS: Marker-based DTT uncertainty can be evaluated in-vivo on a field-by-field basis using EPID images. This information can contribute to PTV margin calculations for DTT.

Should organs at risk (OARs) be prioritized over target volume coverage in stereotactic ablative radiotherapy (SABR) for oligometastases? a secondary analysis of the population-based phase II SABR-5 trial.

BACKGROUND AND PURPOSE: Stereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). METHODS: This single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. Theprotocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. RESULTS: 549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86-0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93-0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69-0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and 'other' (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. CONCLUSION: PTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning.

Stereotactic Ablative Radiation Therapy for Colorectal Liver Metastases.

INTRODUCTION: Stereotactic Ablative Radiation Therapy (SABR) is a therapeutic option for patients with inoperable oligometastatic colorectal carcinoma (CRC). Given the scarcity of prospective data on outcomes of SABR for metastatic CRC, this study aims to review SABR outcomes and determine predictive factors of local control (LC) and survival in patients with liver metastases from CRC. MATERIALS AND METHODS: A retrospective review of SABR for CRC liver metastases between 2011 and 2019 was undertaken. Endpoints included LC, overall survival (OS), progression-free survival (PFS) and time to restarting systemic therapy. Univariate (UVA) and multivariable analyses (MVA) were performed to identify predictive factors. RESULTS: Forty-eight patients were identified. The total number of tumors treated was 58. Median follow-up was 26.6 months. LC at 1, 2 and 3 years was 92.7%, 80.0%, and 61.2% respectively. Median time to local failure was 40.0 months (95% CI 31.8-76.1 months). Median OS was 31.9 months (95% CI 20.6-40.0 months). OS at 1, 2, and 3 years was 79.2%, 61.7%, and 44.9% respectively. Thirty-three patients (69%) restarted systemic therapy after completion of SABR. Median time to restarting chemotherapy was 11.0 months (95% CI 7.1-17.6 months). Systemic therapy free survival at 1, 2, and 3 years was 45.7%, 29.6%, and 22.6% respectively. On MVA, inferior LC was influenced by GTV volume ≥40 cm3 (HR: 3.805, 95% CI 1.376-10.521, P = .01) and PTV D100% BED <100 Gy10 (HR 2.971, 95% CI 1.110-7.953; P = .03). Inferior OS was associated with PTV volume ≥200 cm3 (HR 5.679, 95% CI 2.339-13.755; P < .001). CONCLUSION: SABR is an effective therapeutic option for selected patients with CRC liver metastases providing acceptable LC within the first 2 years. In many cases, it provides meaningful chemotherapy-free intervals. Higher biological effective doses are required to enhance LC.

Treatment With Stereotactic Ablative Radiotherapy for Up to 5 Oligometastases in Patients With Cancer: Primary Toxic Effect Results of the Nonrandomized Phase 2 SABR-5 Clinical Trial.

Importance: After the publication of the landmark SABR-COMET trial, concerns arose regarding high-grade toxic effects of treatment with stereotactic ablative body radiotherapy (SABR) for oligometastases. Objective: To document toxic effects of treatment with SABR in a large cohort from a population-based, provincial cancer program. Design, Setting, and Participants: From November 2016 to July 2020, 381 patients across all 6 cancer centers in British Columbia were treated in this single-arm, phase 2 trial of treatment with SABR for patients with oligometastatic or oligoprogressive disease. During this period, patients were only eligible to receive treatment with SABR in these settings in trials within British Columbia; therefore, this analysis is population based, with resultant minimal selection bias compared with previously published SABR series. Interventions: Stereotactic ablative body radiotherapy to up to 5 metastases. Main Outcomes and Measures: Rate of grade 2, 3, 4, and 5 toxic effects associated with SABR. Findings: Among 381 participants (122 women [32%]), the mean (SD; range) age was 68 (11.1; 30-97) years, and the median (range) follow-up was 25 (1-54) months. The most common histological findings were prostate cancer (123 [32%]), colorectal cancer (63 [17%]), breast cancer (42 [11%]), and lung cancer (33 [9%]). The number of SABR-treated sites were 1 (263 [69%]), 2 (82 [22%]), and 3 or more (36 [10%]). The most common sites of SABR were lung (188 [34%]), nonspine bone (136 [25%]), spine (85 [16%]), lymph nodes (78 [14%]), liver (29 [5%]), and adrenal (15 [3%]). Rates of grade 2, 3, 4, and 5 toxic effects associated with SABR (based on the highest-grade toxic effect per patient) were 14.2%; (95% CI, 10.7%-17.7%), 4.2% (95% CI, 2.2%-6.2%), 0%, and 0.3% (95% CI, 0%-0.8%), respectively. The cumulative incidence of grade 2 or higher toxic effects associated with SABR at year 2 by Kaplan-Meier analysis was 8%, and for grade 3 or higher, 4%. Conclusions and Relevance: This single-arm, phase 2 clinical trial found that the incidence of grade 3 or higher SABR toxic effects in this population-based study was less than 5%. Furthermore, the rates of grade 2 or higher toxic effects (18.6%) were lower than previously published for SABR-COMET (29%). These results suggest that SABR treatment for oligometastases has acceptable rates of toxic effects and potentially support further enrollment in randomized phase 3 clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02933242.

Predictors of Early Polymetastatic Relapse After SABR for up to 5 Oligometastases: A Secondary Analysis of the Phase II SABR-5 Trial.

PURPOSE: A subset of patients with oligometastatic cancer experience early widespread cancer dissemination and do not benefit from metastasis-directed therapy such as SABR. This study aimed to identify factors associated with early polymetastatic relapse (PMR). METHODS AND MATERIALS: The SABR-5 trial was a single arm phase 2 study conducted at all 6 regional cancer centers across British Columbia (BC), Canada. SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastatic lesions (total, progressing, or induced) received SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2 and life expectancy ≥6 months. This secondary analysis evaluated factors associated with early PMR, defined as disease recurrence within 6 months of SABR, which is not amenable to further local treatment. Univariable and multivariable analyses were performed using binary logistic regression. The Kaplan-Meier method and log-rank tests assessed PMR-free survival and differences between risk groups, respectively. RESULTS: Between November 2016 and July 2020, 381 patients underwent treatment on SABR-5. A total of 16% of patients experienced PMR. Worse performance status (Eastern Cooperative Oncology Group 1-2 vs 0; hazard ratio [HR] = 2.01, P = .018), nonprostate/breast histology (HR = 3.64, P <.001), and oligoprogression (HR = 3.84, P <.001) were independent predictors for early PMR. Risk groups were identified with median PMR-free survival ranging from 5 months to not yet reached at the time of analysis. Rates of 3-year overall survival were 0%, 53% (95% confidence interval [CI], 48-58), 77% (95% CI, 73-81), and 93% (95% CI, 90-96) in groups 1 to 4, respectively (P <.001). CONCLUSIONS: Four distinct risk groups for early PMR are identified, which differ significantly in PMR-free survival and overall survival. The group with all 3 risk factors had a median PMR-free survival of 5 months and may not benefit from local ablative therapy alone. This model should be externally validated with data from other prospective trials.

Progression-Free Survival and Local Control After SABR for up to 5 Oligometastases: An Analysis From the Population-Based Phase 2 SABR-5 Trial.

PURPOSE: Despite increasing utilization of SABR for oligometastatic cancer, prospective outcomes are lacking. The purpose of this study was to determine progression-free survival (PFS), local control (LC), and prognostic factors from the population-based phase 2 SABR-5 trial. METHODS AND MATERIALS: The SABR-5 trial was a single-arm phase 2 study with the primary endpoint of toxicity, conducted at the 6 regional cancer centers across British Columbia (BC), Canada, during which time SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced oligometastatic disease) underwent SABR to all lesions. Patients were 18 years of age or older, had an Eastern Cooperative Oncology Group score of 0 to 2, and had life expectancy ≥ 6 months. The secondary outcomes of PFS and LC are presented here. RESULTS: Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). Median PFS was 15 months (95% confidence interval [CI], 12-18). LC at 1 and 3 years were 93% (95% CI, 91-95) and 87% (95% CI, 84-90), respectively. On multivariable analysis, increasing tumor diameter (hazard ratio [HR], 1.09; P < .001), declining performance status (HR, 2.13; P < .001), disease-free interval <18 months (HR, 1.52; P = .003), 4 or more metastases at SABR (HR, 1.48; P = .048), initiation or change in systemic treatment (HR, 0.50; P < .001), and oligoprogression (HR, 1.56; P = .008) were significant independent predictors of PFS. Tumor diameter (sub-hazard ratio [SHR], 1.28; P < .001), colorectal histology (SHR, 4.33; P = .002), and "other" histology (SHR, 3.90; P < .001) were associated with worse LC. CONCLUSIONS: In this population-based cohort including patients with genuine oligometastatic, oligoprogressive, and induced oligometastatic disease, the median PFS was 15 months and LC at 3 years was 87%. This supports ongoing efforts to randomize patients in phase 3 trials, even outside the original 1 to 5 metachronous oligometastatic paradigm.

A novel carbon-fibre adjustable reusable accessory (CARA) for supine breast positioning to reduce toxicity in breast adjuvant radiotherapy: a study protocol for a multicentre phase III randomized controlled trial.

BACKGROUND: A novel device for supine positioning in breast radiotherapy for patients with large or pendulous breasts has been developed and tested in phase II studies. This trial is designed to assess the efficacy of the device to reduce skin toxicity and unwanted normal tissue dose in comparison to the current clinical standard for supine breast support during breast radiotherapy. METHODS: Patients at high risk for moist desquamation, having infra-mammary fold or lateral ptosis, will be randomized into two arms. Patients in the control arm will receive breast radiotherapy with supine positioning using current standard of care. Patients in the experimental arm will be positioned supine with the novel device. The primary endpoint is the incidence of moist desquamation in the infra-mammary fold. We hypothesize a 20% reduction (from 50 to 30%) in the rate of moist desquamation in the study arm versus the control arm. For 80% power, two-tailed α = 0.05 and 10% loss to follow up, 110 patients will be assigned to each arm. The proportion of patients experiencing moist desquamation in the two arms will be compared using logistic regression adjusting for brassiere cup size, skin fold size, body mass index, smoking status, and dose fractionation schedule. An unadjusted comparison will also be made using the chi-square test, or Fisher's exact test, if appropriate. Secondary endpoints include dose-volume statistics for the lung and heart, skin dose and clinical parameters including setup time, reproducibility, and staff experience with setup procedures. Patient-reported pain, skin condition interference with sleep and daily activities, and comfort during treatment are also secondary endpoints. DISCUSSION: Based on results from earlier phase II studies, it is expected that the device-enabled elimination of infra-mammary fold should reduce toxicity and improve quality of life for this patient population. Earlier studies showed reduction in dose to organs at risk including lung and heart, indicating potential for other long-term benefits for patients using the device. This study is limited to acute skin toxicity, patient-reported outcomes, and clinical factors to inform integration of the device into standard breast radiotherapy procedures. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04257396 . Registered February 6 2020.

Determining Planning Priorities for SABR for Oligometastatic Disease: A Secondary Analysis of the SABR-COMET Phase II Randomized Trial.

PURPOSE: SABR may improve survival in patients with oligometastases, but for some lesions, safe delivery of SABR may require a reduction in delivered dose or target coverage. This study assessed the association between target coverage compromise and oncologic and survival outcomes. METHODS AND MATERIALS: Patients with a controlled primary malignancy and 1 to 5 oligometastases were randomized (1:2) between standard of care (SOC) treatment and SOC plus SABR. In patients receiving SABR, the target dose coverage was reduced to meet organ at risk (OAR) constraints, if necessary. The D99 value (minimum dose received by the hottest 99% of the planning target volume [PTV]) was used as a measure of PTV coverage for each treatment plan, and the relationship between the coverage compromise index (CCI, defined as D99/prescription dose) and patient outcomes was assessed. RESULTS: Sixty-two patients in the SABR arm had dosimetric information available and a total of 109 lesions were evaluated. The mean CCI per lesion was 0.96 (95% CI, 0.56-1.61). Of the 109 lesions evaluated, 29.4% (n = 32) required coverage compromise (CCI <0.9). Adrenal metastases required coverage compromise in 100% of analyzed lesions (n = 7). CCI was not significantly associated with lesional control, adverse events, overall survival (OS), or progression-free survival (PFS). CONCLUSIONS: Target compromise was required in a substantial minority of cases, but PTV coverage was not associated with OS, progression-free survival, or lesional control. This suggests that OAR constraints used for SABR treatments in the oligometastatic setting should continue to be prioritized during planning.

Thecal Sac Contouring as a Surrogate for the Cauda Equina and Intracanal Spinal Nerve Roots for Spine Stereotactic Body Radiation Therapy (SBRT): Contour Variability and Recommendations for Safe Practice.

PURPOSE: To present interobserver variability in thecal sac (TS) delineation based on contours generated by 8 radiation oncologists experienced in spine stereotactic body radiation therapy and to propose contouring recommendations to standardize practice. METHODS AND MATERIALS: In the setting of a larger contouring study that reported target volume delineation guidelines specific to sacral metastases, 8 academically based radiation oncologists with dedicated spine stereotactic body radiation therapy programs independently contoured the TS as a surrogate for the cauda equina and intracanal spinal nerve roots. Uniform treatment planning simulation computed tomography datasets fused with T1, T2, and T1 post gadolinium magnetic resonance imaging for each case were distributed to each radiation oncologist. All contours were analyzed and agreement was calculated using both Dice similarity coefficient and simultaneous truth and performance level estimation with kappa statistics. RESULTS: A fair level of simultaneous truth and performance level estimation agreement was observed between practitioners, with a mean kappa agreement of 0.38 (range, 0.210.55) and the mean Dice similarity coefficient (± standard deviation, with range) was 0.43 (0.36 ± 0.1 to -0.53 ±0.1). Recommendations for a reference TS contour, accounting for the variations in practice observed in this study, include contouring the TS to encompass all the intrathecal spinal nerve roots, and caudal to the termination of the TS, the bony canal can be contoured as a surrogate for the extra thecal nerves roots that run within it. CONCLUSIONS: This study shows that even among high-volume practitioners, there is a lack of uniformity when contouring the TS. Further modifications may be required once dosimetric data on nerve tolerance to ablative doses, and pattern of failure analyses of clinical data sets using these recommendations, become available. The contouring recommendations were designed as a guide to enable consistent and safe contouring across general practice.

Implementation of Single-Fraction Lung Stereotactic Ablative Radiotherapy in a Multicenter Provincial Cancer Program During the COVID-19 Pandemic.

Background During the novel coronavirus disease 2019 (COVID-19) pandemic, cancer centers considered shortened courses of radiotherapy to minimize the risk of infectious exposure of patients and staff members. Amidst a pandemic, the process of implementing new treatment approaches can be particularly challenging in larger institutions with multiple treatment centers. We describe the implementation of single-fraction (SF) lung stereotactic ablative radiotherapy (SABR) in a multicenter provincial cancer program. Materials and Methods British Columbia, Canada has a provincial cancer program with six geographically distributed radiotherapy centers serving a population of 5.1 million, over 944,735 square kilometers. In March 2020, provincial mitigation strategies were developed in case of reduced access to radiotherapy due to the COVID-19 pandemic. SF lung SABR was identified by the provincial lung radiation oncology group as a mitigation measure supported by high-quality randomized evidence that could provide comparable outcomes and toxicity to existing fractionated SABR protocols. A working group consisting of radiation oncologists and medical physicists reviewed the medical literature and drafted consensus guidelines that were reviewed by a group of center representatives as a component of provincial lung radiotherapy mitigation strategic planning. Individual centers were encouraged to implement SF lung SABR as their resources and staffing would allow. Centers were then surveyed about barriers to implementation. Results On March 24, 2020, a working group was created and consensus guidelines for SF lung SABR were drafted. The final version was approved and distributed by the working group on March 26, 2020. The provincial lung radiotherapy mitigation strategy group adopted the guidelines for implementation on April 1, 2020. Implementation was completed at the first center on April 27, 2020. Barriers to implementation were identified at five of six centers. Two centers in regions with disproportionately high COVID-19 cases described inadequate staffing as a barrier to implementation. One center encountered delays due to pre-scheduled commissioning of new treatment techniques. Three centers cited competing priorities as reasons for delay. As of May 2021, two centers had active SF lung SABR programs in place, three centers were in the process of implementation, and one center had no immediate plans for implementation due to ongoing resource issues. Conclusion SF lung SABR was adopted by a provincial cancer program within weeks of conception through rapid communication during the development of COVID-19 pandemic mitigation strategies for radiotherapy. Although consensus guidelines were written and approved in an expedited timeframe, the completion of implementation by individual centers was variable due to differences in resource allocation and staffing among the centers. Strong organizational structures and early identification of potential barriers may improve the efficiency of implementing new treatment initiatives in large multicenter radiotherapy programs.

Development of a physical geometric phantom for deformable image registration credentialing of radiotherapy centers for a clinical trial.

PURPOSE: This study aimed to develop a physical geometric phantom for the deformable image registration (DIR) credentialing of radiotherapy centers for a clinical trial and tested the feasibility of the proposed phantom at multiple domestic and international institutions. METHODS AND MATERIALS: The phantom reproduced tumor shrinkage, rectum shape change, and body shrinkage using several physical phantoms with custom inserts. We tested the feasibility of the proposed phantom using 5 DIR patterns at 17 domestic and 2 international institutions (21 datasets). Eight institutions used the MIM software (MIM Software Inc, Cleveland, OH); seven used Velocity (Varian Medical Systems, Palo Alto, CA), and six used RayStation (RaySearch Laboratories, Stockholm, Sweden). The DIR accuracy was evaluated using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). RESULTS: The mean and one standard deviation (SD) values (range) of DSC were 0.909 ± 0.088 (0.434-0.984) and 0.909 ± 0.048 (0.726-0.972) for tumor and rectum proxies, respectively. The mean and one SD values (range) of the HD value were 5.02 ± 3.32 (1.53-20.35) and 5.79 ± 3.47 (1.22-21.48) (mm) for the tumor and rectum proxies, respectively. In three patterns evaluating the DIR accuracy within the entire phantom, 61.9% of the data had more than a DSC of 0.8 in both tumor and rectum proxies. In two patterns evaluating the DIR accuracy by focusing on tumor and rectum proxies, all data had more than a DSC of 0.8 in both tumor and rectum proxies. CONCLUSIONS: The wide range of DIR performance highlights the importance of optimizing the DIR process. Thus, the proposed method has considerable potential as an evaluation tool for DIR credentialing and quality assurance.

Four-dimensional dose calculations for dynamic tumour tracking with a gimbal-mounted linear accelerator.

PURPOSE: In this study we present a novel method for re-calculating a treatment plan on different respiratory phases by accurately modeling the panning and tilting beam motion during DTT (the "rotation method"). This method is used to re-calculate the dose distribution of a plan on multiple breathing phases to accurately assess the dosimetry. METHODS: sIMRT plans were optimized on a breath hold computed tomography (CT) image taken at exhale (BHexhale ) for 10 previous liver stereotactic ablative radiotherapy patients. Our method was used to re-calculate the plan on the inhale (0%) and exhale (50%) phases of the four-dimensional CT (4DCT) image set. The dose distributions were deformed to the BHexhale CT and summed together with proper weighting calculated from the patient's breathing trace. Subsequently, the plan was re-calculated on all ten phases using our method and the dose distributions were deformed to the BHexhale CT and accumulated together. The maximum dose for certain organs at risk (OARs) was compared between calculating on two phases and all ten phases. RESULTS: In total, 26 OARs were examined from 10 patients. When the dose was calculated on the inhale and exhale phases six OARs exceeded their dose limit, and when all 10 phases were used five OARs exceeded their limit. CONCLUSION: Dynamic tumor tracking plans optimized for a single respiratory phase leave an OAR vulnerable to exceeding its dose constraint during other respiratory phases. The rotation method accurately models the beam's geometry. Using deformable image registration to accumulate dose from all 10 breathing phases provides the most accurate results, however it is a time consuming procedure. Accumulating the dose from two extreme breathing phases (exhale and inhale) and weighting them properly provides accurate results while requiring less time. This approach should be used to confirm the safety of a DTT treatment plan prior to delivery.

Monte Carlo simulation of 6-MV dynamic wave VMAT deliveries by Vero4DRT linear accelerator using EGSnrc moving sources.

The commissioning and benchmark of a Monte Carlo (MC) model of the 6-MV Brainlab-Mitsubishi Vero4DRT linear accelerator for the purpose of quality assurance of clinical dynamic wave arc (DWA) treatment plans is reported. Open-source MC applications based on EGSnrc particle transport codes are used to simulate the medical linear accelerator head components. Complex radiotherapy irradiations can be simulated in a single MC run using a shared library format combined with BEAMnrc "source20." Electron energy tuning is achieved by comparing measured vs simulated percentage depth doses (PDDs) for MLC-defined field sizes in a water phantom. Electron spot size tuning is achieved by comparing measured and simulated inplane and crossplane beam profiles. DWA treatment plans generated from RayStation (RaySearch) treatment planning system (TPS) are simulated on voxelized (2.5 mm3 ) patient CT datasets. Planning target volume (PTV) and organs at risk (OAR) dose-volume histograms (DVHs) are compared to TPS-calculated doses for clinically deliverable dynamic volumetric modulated arc therapy (VMAT) trajectories. MC simulations with an electron beam energy of 5.9 MeV and spot size FWHM of 1.9 mm had the closest agreement with measurement. DWA beam deliveries simulated on patient CT datasets results in DVH agreement with TPS-calculated doses. PTV coverage agreed within 0.1% and OAR max doses (to 0.035 cc volume) agreed within 1 Gy. This MC model can be used as an independent dose calculation from the TPS and as a quality assurance tool for complex, dynamic radiotherapy treatment deliveries. Full patient CT treatment simulations are performed in a single Monte Carlo run in 23 min. Simulations are run in parallel using the Condor High-Throughput Computing software1 on a cluster of eight servers. Each server has two physical processors (Intel Xeon CPU E5-2650 0 @2.00 GHz), with 8 cores per CPU and two threads per core for 256 calculation nodes.

International consensus recommendations for target volume delineation specific to sacral metastases and spinal stereotactic body radiation therapy (SBRT).

BACKGROUND AND PURPOSE: To interrogate inter-observer variability in gross tumour volume (GTV) and clinical target volume (CTV) delineation specific to the treatment of sacral metastases with spinal stereotactic body radiation therapy (SBRT) and develop CTV consensus contouring recommendations. MATERIALS AND METHODS: Nine specialists with spinal SBRT expertise representing 9 international centres independently contoured the GTV and CTV for 10 clinical cases of metastatic disease within the sacrum. Agreement between physicians was calculated with an expectation minimisation algorithm using simultaneous truth and performance level estimation (STAPLE) and with kappa statistics. Optimised confidence level consensus contours were obtained using a voxel-wise maximum likelihood approach and the STAPLE contours for GTV and CTV were based on an 80% confidence level. RESULTS: Mean GTV STAPLE agreement sensitivity and specificity was 0.70 (range, 0.54-0.87) and 1.00, respectively, and 0.55 (range, 0.44-0.64) and 1.00 for the CTV, respectively. Mean GTV and CTV kappa agreement was 0.73 (range, 0.59-0.83) and 0.59 (range, 0.41-0.70), respectively. Optimised confidence level consensus contours were identified by STAPLE analysis. Consensus recommendations for the CTV include treating the entire segment containing the disease in addition to the immediate adjacent bony anatomic segment at risk of microscopic extension. CONCLUSION: Consensus recommendations for CTV target delineation specific to sacral metastases treated with SBRT were established using expert contours. This is a critical first step to achieving standardisation of target delineation practice in the sacrum and will serve as a baseline for meaningful pattern of failure analyses going forward.

Cardiac death after breast radiotherapy and the QUANTEC cardiac guidelines.

BACKGROUND: Breast/chest wall irradiation (RT) increases risk of cardiovascular death. International Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines state for partial heart irradiation a "V25Gy <10% will be associated with a <1% probability of cardiac mortality" in long-term follow-up after RT. We assessed whether women treated with breast/chest wall RT 10-years ago who died of cardiovascular disease (CVD) violated QUANTEC guidelines. MATERIALS/METHODS: A population-based database identified all cardiovascular deaths in women with early-stage breast cancer <80 years, treated with adjuvant breast/chest wall RT from 2002 to 2006. Ten-year rate of cardiovascular death was calculated using a Kaplan-Meier method. Patients were matched on a 2:1 basis with controls that did not die of CVD. For left-sided cases, the heart and left anterior descending (LAD) artery were retrospectively delineated. Dose-volume histograms were calculated, and heart V25Gy compared to QUANTEC guidelines. RESULTS: 5249 eligible patients received breast/chest wall RT from 2002 to 2006: 76 (1.4% at 10-years) died of CVD by June 2015. Forty-two patients received left-sided RT (1.7% CVD death at 10-years), 34 right-sided RT (1.3% at 10-years). Heart V25Gy did not exceed 10% in any left-sided cases. No cardiac dosimetry parameter distinguished left-sided cases from controls. CONCLUSIONS: QUANTEC guidelines were not violated in any patient that died of CVD after left-sided RT. The risk of radiation induced cardiac death at 10-years appears to be very low if MHD is <3.3 Gy and maximum LAD dose (EQD23 Gy) is <45.4 Gy. Further studies are needed to evaluate heart and LAD constraints in the CT-planning era.