Five-Fraction High-Conformal Ultrahypofractionated Radiotherapy for Primary Tumors in Metastatic Breast Cancer.

PURPOSE: To report on the local control and toxicity of 5-fraction, high-conformal ultrafractionated radiation therapy (RT) for primary tumors in patients with metastatic breast cancer (MBC) who did not undergo planned surgical intervention. METHODS: We retrospectively reviewed 27 patients with MBC who underwent 5-fraction high-dose ultrafractionated intensity-modulated RT for their primary tumors between 2017 and 2022 at our institution. A median dose of 66.8 Gy (range, 51.8-83.6 Gy) was prescribed to the gross tumor, calculated in 2-Gy equivalents using an α/ß ratio of 3.5, along with a simultaneous integrated boost of 81.5%. The primary endpoint of this study was local control. RESULTS: The median tumor size and volume were 5.1 cm and 112.4 cm3, respectively. Treatment was generally well tolerated, with only 15% of the patients experiencing mild acute skin toxicity, which resolved spontaneously. The best infield response rate was 82%, with the objective response observed at a median time of 10.8 months post-RT (range, 1.4-29.2), until local progression or the last follow-up. At a median follow-up of 18.3 months, the 2-year local control rate was 77%. A higher number of prior lines of systemic therapy was significantly associated with poorer 2-year local control (one-two lines, 94% vs three or more lines, 34%; p = 0.004). Post-RT, 67% of the patients transitioned to the next line of systemic therapy, and the median duration of maintaining the same systemic therapy post-RT was 16.3 months (range, 1.9-40.3). CONCLUSION: In our small dataset, 5-fraction, high-conformal ultrahypofractionated breast RT offered promising 2-year local control with minimal toxicity. Further studies are warranted to investigate the optimal dose and role in this setting.

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.

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.

Beyond PACIFIC: Real-World Outcomes of Adjuvant Durvalumab According to Treatment Received and PD-L1 Expression.

Adjuvant durvalumab after chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). A post hoc exploratory analysis of PACIFIC revealed no OS benefit in the PD-L1 < 1% subgroup. This retrospective analysis assesses the real-world impact of durvalumab on OS according to PD-L1 tumor proportion score (TPS). Patients with stage III, unresectable NSCLC treated by CRT, with available PD-L1 TPS, from 1 March 2018 to 31 December 2020, at BC Cancer, British Columbia, Canada were included. Patients were divided into two groups, CRT + durvalumab and CRT alone. OS and PFS were analyzed in the PD-L1 ≥ 1% and <1% subgroups. A total of 134 patients were included in the CRT + durvalumab group and 117, in the CRT alone group. Median OS was 35.9 months in the CRT + durvalumab group and 27.4 months in the CRT alone group [HR 0.59 (95% CI 0.42-0.83), p = 0.003]. Durvalumab improved OS in the PD-L1 ≥ 1% [HR 0.53 (95% CI 0.34-0.81), p = 0.003, n = 175], but not in the <1% subgroup [HR 0.79 (95% CI 0.44-1.42), p = 0.4, n = 76]. This retrospective study demonstrates a statistically significant improvement in OS associated with durvalumab after CRT in PD-L1 ≥ 1%, but not PD-L1 < 1% NSCLC. Variables not accounted for may have biased the survival analysis. A prospective study would bring more insight.

Mathematical prediction with pretreatment growth rate of metastatic cancer on outcomes: implications for the characterization of oligometastatic disease.

Background: Oligometastatic disease (OMD) represents an indolent cancer status characterized by slow tumor growth and limited metastatic potential. The use of local therapy in the management of the condition continues to rise. This study aimed to investigate the advantage of pretreatment tumor growth rate in addition to baseline disease burden in characterizing OMDs, generally defined by the presence of ≤ 5 metastatic lesions. Methods: The study included patients with metastatic melanoma treated with pembrolizumab. Gross tumor volume of all metastases was contoured on imaging before (TP-1) and at the initiation of pembrolizumab (TP0). Pretreatment tumor growth rate was calculated by an exponential ordinary differential equation model using the sum of tumor volumes at TP-1 and TP0 and the time interval between TP-1. and TP0. Patients were divided into interquartile groups based on pretreatment growth rate. Overall survival, progression-free survival, and subsequent progression-free survival were the study outcomes. Results: At baseline, median cumulative volume and number of metastases were 28.4 cc (range, 0.4-1194.8 cc) and 7 (range, 1-73), respectively. The median interval between TP-1 and TP0 was -90 days and pretreatment tumor growth rate (×10-2 days-1) was median 4.71 (range -0.62 to 44.1). The slow-paced group (pretreatment tumor growth rate ≤ 7.6 ×10-2 days-1, the upper quartile) had a significantly higher overall survival rate, progression-free survival, and subsequent progression-free survival compared to those of the fast-paced group (pretreatment tumor growth rate > 7.6 ×10-2 days-1). Notably, these differences were prominent in the subgroup with >5 metastases. Conclusion: Pretreatment tumor growth rate is a novel prognostic metric associated with overall survival, progression-free survival, and subsequent progression-free survival among metastatic melanoma patients, especially patients with >5 metastases. Future prospective studies should validate the advantage of disease growth rate plus disease burden in better defining OMDs.

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.

A Comparison of 2 Disease Burden Assessment Methods (3D Volume Versus the Number of Lesions) for Prognostication of Survival in Metastatic Melanoma: Implications for the Characterization of Oligometastatic Disease.

PURPOSE: Oligometastatic disease (OMD), generally defined by the presence of ≤5 metastatic lesions, represents an intermediate state between localized and widespread metastatic disease. This study aimed to question the conventional definition of OMD and assess the significance of the total volume and loci of metastases in characterizing OMD using an unselected metastatic melanoma cohort. METHODS AND MATERIALS: We identified 86 consecutive patients with metastatic melanoma who received pembrolizumab monotherapy from 2015 to 2020. We retrospectively contoured the gross tumor volumes of all metastatic lesions on baseline and follow-up imaging. The number, total volume, and loci information of metastases was collected. The primary endpoint was overall survival. A density histogram plot was used for tumor characteristic descriptions, and classification analysis using the decision tree and random forest methods was performed to determine the optimal combination of prognostic factors in the clinical setting. RESULTS: A total of 2728 gross tumor volumes were delineated. On baseline imaging, the median number and total volume of metastases was 7 (interquartile range, 3-17) and 28.4 cc (interquartile range, 8.4-88.78), respectively. The lymph node was the most common metastatic site (n = 46, 54%), followed by the lungs (n = 32, 37%), liver (n = 23, 27%), and bones (n = 21, 24%). Two-year overall survival rates of patients with 1 to 5, 6 to 10, 11 to 20, and >20 metastases were 58%, 47%, 31%, and 14%, respectively, and with ≤10, 11 to 30, 31 to 130, and >130 cc of metastatic volume were 64%, 43%, 33%, and 25%, respectively. K-adaptive partitioning revealed that the optimal cutoff was 20 and 37.9 cc. Decision tree and random forest analyses revealed that volume and loci (brain and liver metastases) were the most important factors (Harrell's C-index, 0.78). CONCLUSIONS: The OMD state could represent a continuous spectrum of disease burden instead of a binary phenomenon. We propose integrating the volumetric and spatial information of metastases into the characterization of OMD and the stratification tool of clinical trials in the metastatic setting, although external validation studies are needed.

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.

Stereotactic Radiation for the Comprehensive Treatment of Oligometastases (SABR-COMET): Extended Long-Term Outcomes.

PURPOSE: Long-term randomized data assessing the effect of ablative therapies in patients with oligometastases are lacking. The Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastases (SABR-COMET) randomized phase 2 trial was originally designed with 5 years of follow-up, but the trial was amended in 2016 to extend follow-up to 10 years. Herein we report oncologic outcomes beyond 5 years. METHODS AND MATERIALS: Patients were eligible if they had a controlled primary tumor and 1 to 5 metastases, with all metastases amenable to SABR. Patients were randomized in a 1:2 ratio between palliative standard-of-care treatment (control arm) versus SABR to all metastases plus standard of care (SABR arm). The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), toxicity, quality of life (using the Functional Assessment of Cancer Therapy: General [FACT-G]), and time to new metastases. RESULTS: Ninety-nine patients were randomized between 2012 and 2016 (n = 33 in arm 1 vs n = 66 in arm 2). Primary tumor sites included lung (n = 18), breast (n = 18), colon (n = 18), prostate (n = 16), and other (n = 29). Eight-year OS was 27.2% in the SABR arm versus 13.6% in the control arm (hazard ratio, 0.50; 95% confidence interval, 0.30-0.84; P = .008). Eight-year PFS estimates were 21.3% versus 0.0%, respectively (hazard ratio, 0.45; 95% confidence interval, 0.28-0.72; P < .001). Rates of grade ≥ 2 acute or late toxic effects were 30.3% versus 9.1% (P = .019), with no new grade 3 to 5 toxic effects. FACT-G quality of life scores declined over time in both arms, but there were no differences in quality of life scores between arms. The use of systemic therapy overall was similar between arms, but patients in the SABR arm were less likely to require cytotoxic chemotherapy (33.3% vs 54.6%, respectively, P = .043). CONCLUSIONS: SABR achieved durable improvements in OS and PFS, with no new major toxicity signals with extended follow-up. A minority of patients randomized to the SABR arm (21.3%) achieved > 5 years of survival without recurrence.

Comparison of 2-Weekly Versus 4-Weekly Durvalumab Consolidation for Locally Advanced NSCLC Treated With Chemoradiotherapy: A Brief Report.

Introduction: Durvalumab 10 mg/kg every 2 weeks for 1 year after chemoradiation has improved overall survival (OS) in unresectable stage III NSCLC. Subsequently, a 20 mg/kg 4-weekly regimen was approved. The study goal was to compare the efficacy and toxicity of the two regimens. Methods: All patients with NSCLC treated with curative-intent chemoradiation followed by durvalumab from March 1, 2018 to December 31, 2020 at BC Cancer, British Columbia, Canada were included in this retrospective review. Durvalumab dosing schedule, toxicity, progression, and OS were collected. Comparisons between treatment groups were made using chi-square and independent t tests. Kaplan-Meier curves and log-rank test were used to analyze OS. Results: A total of 152 patients were included in the 2-weekly group and 53 patients in the 4-weekly group. The median follow-up was 19.7 months and 12.0 months, respectively. The median OS was not reached, but 12-month survival rates were 88.4% versus 85.2% (p = 0.55). Toxicity profiles were similar in terms of sites and severity. Conclusions: There was no significant difference in efficacy or toxicity between the 2-weekly and 4-weekly durvalumab in this cohort of patients with advanced NSCLC previously treated with curative-intent chemoradiation.

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.

Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicentre, randomised, controlled, phase 2/3 trial.

BACKGROUND: Conventional external beam radiotherapy is the standard palliative treatment for spinal metastases; however, complete response rates for pain are as low as 10-20%. Stereotactic body radiotherapy delivers high-dose, ablative radiotherapy. We aimed to compare complete response rates for pain after stereotactic body radiotherapy or conventional external beam radiotherapy in patients with painful spinal metastasis. METHODS: This open-label, multicentre, randomised, controlled, phase 2/3 trial was done at 13 hospitals in Canada and five hospitals in Australia. Patients were eligible if they were aged 18 years and older, and had painful (defined as ≥2 points with the Brief Pain Inventory) MRI-confirmed spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0-2, a Spinal Instability Neoplasia Score of less than 12, and no neurologically symptomatic spinal cord or cauda equina compression. Patients were randomly assigned (1:1) with a web-based, computer-generated allocation sequence to receive either stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions or conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions using standard techniques. Treatment assignment was done centrally by use of a minimisation method to achieve balance for the stratification factors of radiosensitivity, the presence or absence of mass-type tumour (extraosseous or epidural disease extension, or both) on imaging, and centre. The primary endpoint was the proportion of patients with a complete response for pain at 3 months after radiotherapy. The primary endpoint was analysed in the intention-to-treat population and all safety and quality assurance analyses were done in the as-treated population (ie, all patients who received at least one fraction of radiotherapy). The trial is registered with ClinicalTrials.gov, NCT02512965. FINDINGS: Between Jan 4, 2016, and Sept 27, 2019, 229 patients were enrolled and randomly assigned to receive conventional external beam radiotherapy (n=115) or stereotactic body radiotherapy (n=114). All 229 patients were included in the intention-to-treat analysis. The median follow-up was 6·7 months (IQR 6·3-6·9). At 3 months, 40 (35%) of 114 patients in the stereotactic body radiotherapy group, and 16 (14%) of 115 patients in the conventional external beam radiotherapy group had a complete response for pain (risk ratio 1·33, 95% CI 1·14-1·55; p=0·0002). This significant difference was maintained in multivariable-adjusted analyses (odds ratio 3·47, 95% CI 1·77-6·80; p=0·0003). The most common grade 3-4 adverse event was grade 3 pain (five [4%] of 115 patients in the conventional external beam radiotherapy group vs five (5%) of 110 patients in the stereotactic body radiotherapy group). No treatment-related deaths were observed. INTERPRETATION: Stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions was superior to conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions in improving the complete response rate for pain. These results suggest that use of conformal, image-guided, stereotactically dose-escalated radiotherapy is appropriate in the palliative setting for symptom control for selected patients with painful spinal metastases, and an increased awareness of the need for specialised and multidisciplinary involvement in the delivery of end-of-life care is needed. FUNDING: Canadian Cancer Society and the Australian National Health and Medical Research Council.

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.