A randomized phase III trial of stereotactic ablative radiotherapy for patients with up to 10 oligometastases and a synchronous primary tumor (SABR-SYNC): study protocol.

BACKGROUND: Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. METHODS: One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. DISCUSSION: SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. TRIAL REGISTRATION: Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Research productivity of RANZCR radiation oncology trainees from 2014 to 2023.

INTRODUCTION: The aim of this study was to describe the research productivity among RANZCR Radiation Oncology (RO) trainees. METHODS: Publicly available data on RO fellows, who were awarded the RANZCR fellowship between July 2014 and June 2023, was extracted from the RANZCR Annual Reports. Fellows who had qualified overseas and did not undertake full RANZCR training were excluded. A PubMed search was performed for publications by each fellow in the 5 years prior, and 6 months, after the estimated completion of training. Research productivity was defined as the number of first-author and any-author publications per trainee. RESULTS: In total, 168 eligible RO fellows were included in this study. 104 (62%) and 118 (70%) fellows had first-author and any-author publications during training, respectively. A total of 203 first-author and 308 unique any-author publications were identified, with mean first-author and any-author publications per trainee of 1.21 (SD = 2.37) and 2.02 (SD = 3.71), respectively. Trainee research was most commonly published in JMIRO (34% of first-author and 27% of any-author publications). There were significant differences in the number of first-author publications by gender (P = 0.04) and training jurisdictions (P = 0.03). There were also differences in the number of any-author publications by gender (P = 0.002) and training jurisdictions (P = 0.03). There was a significant increase in any-author publications over the 9-year study period (P = 0.005). CONCLUSION: This is the first study evaluating research productivity among RO fellows during training. We identified disparities in research productivity by gender and training jurisdictions. This offers opportunities to tailor efforts to better support a vibrant and productive research culture across the RO training program.

A multi-centre retrospective study of long-term outcomes of spinal re-irradiation with SABR.

INTRODUCTION: Stereotactic ablative body radiotherapy (SABR) is a highly conformal technique utilising a high dose per fraction commonly employed in the re-treatment of spinal metastases. This study sought to determine the safety and efficacy of re-irradiation with SABR to previously treated spinal metastases. METHODS: This was a retrospective analysis of patients at three Australian centres who have undergone spinal SABR after previous spinal radiotherapy to the same or immediately adjacent vertebral level. Efficacy was determined in terms of rates of local control, while safety was characterised by rates of serious complications. RESULTS: Thirty-three spinal segments were evaluated from 32 patients. Median follow-up for all patients was 2.6 years, and median overall survival was 4.3 years. Eleven of 33 (33.3%) treated spinal segments had local progression, with a local control rate at 12 months of 71.4% (95% C.I. 55.2%-92.4%). Four patients (16.7%) went on to develop cauda equina or spinal cord compression. Thirteen out of 32 patients (40.6%) experienced acute toxicity, of which 12 were grade 2 or less. Five out of 30 spinal (16.7%) segments with follow-up imaging had a radiation-induced vertebral compression fracture. There was one case of radiation myelitis which occurred in a patient who had mediastinal radiotherapy with a treatment field which overlapped their prior spinal radiation. CONCLUSION: The patients in this study experienced long median survival, durable tumour control and high rates of freedom from long-term sequelae of treatment. These results support the use of SABR in patients who progress in the spine despite previous radiotherapy.

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.

Management and outcomes of glioblastoma: 20-year experience in a single Australian institution.

INTRODUCTION: We aimed to evaluate the changing patterns in the management of glioblastoma (GBM) and impact on survival outcomes over a 20-year period. METHODS: This is a retrospective study of patients diagnosed with GBM between 2001 and 2020, who had radiation therapy (RT) in an Australian institution. The primary outcomes were changes in treatment modalities (including surgery, RT, and chemotherapy) over time and overall survival (OS). Multivariable Cox regressions were used to evaluate factors associated with OS, including age, sex, ECOG performance status, treatment modalities, treatment facility, and year of treatment. RESULTS: 1079 patients were included in this study. Thirty-five per cent of patients had gross total resection, increasing from 31% in 2001-2005 to 45% in 2016-2020 (P < 0.001). Sixty-four per cent of patients had ≥60 Gy RT, increasing from 57% in 2001-2005 to 66% in 2016-2020 (P < 0.001). Seventy-five per cent of patients had chemotherapy, increasing from 22% in 2001-2005 to 89% in 2016-2020 (P < 0.001). Treatment received varied based on patients' age and ECOG performance status. The median OS for the entire cohort was 13.0 months (95% CI = 12.0-13.7). Median OS in patients who had maximal treatment (i.e., gross total resection, ≥60 Gy RT and chemotherapy) was 20.6 months (95% CI = 17.3-22.8). In multivariable analyses, age, sex, treatment facility, extent of surgical resection, RT dose, and chemotherapy use were associated with OS. CONCLUSION: This is one of the largest Australian series on the management and outcomes of GBM spanning a 20-year period. We observed improvement in OS over time, which is likely associated with evolving treatment options over the study period.

Design, optimisation and standardisation of a high-dimensional spectral flow cytometry workflow assessing T-cell immunophenotype in patients with melanoma.

Objectives: Despite the success of immune checkpoint blockade, most metastatic melanoma patients fail to respond to therapy or experience severe toxicity. Assessment of biomarkers and immunophenotypes before or early into treatment will help to understand favourable responses and improve therapeutic outcomes. Methods: We present a high-dimensional approach for blood T-cell profiling using three multi-parameter cytometry panels: (1) a TruCount panel for absolute cell counts, (2) a 27-colour spectral panel assessing T-cell markers and (3) a 20-colour spectral panel evaluating intracellular cytokine expression. Pre-treatment blood mononuclear cells from patients and healthy controls were cryopreserved before staining across 11 batches. Batch effects were tracked using a single-donor control and the suitability of normalisation was assessed. The data were analysed using manual gating and high-dimensional strategies. Results: Batch-to-batch variation was minimal, as demonstrated by the dimensionality reduction of batch-control samples, and normalisation did not improve manual or high-dimensional analysis. Application of the workflow demonstrated the capacity of the panels and showed that patients had fewer lymphocytes than controls (P = 0.0027), due to lower naive CD4+ (P = 0.015) and CD8+ (P = 0.011) T cells and follicular helper T cells (P = 0.00076). Patients showed trends for higher proportions of Ki67 and IL-2-expressing cells within CD4+ and CD8+ memory subsets, and increased CD57 and EOMES expression within TCRγδ+ T cells. Conclusion: Our optimised high-parameter spectral cytometry approach provided in-depth profiling of blood T cells and found differences in patient immunophenotype at baseline. The robustness of our workflow, as demonstrated by minimal batch effects, makes this approach highly suitable for the longitudinal evaluation of immunotherapy effects.

Real-world data on patterns and outcomes of radiation therapy for brain metastases in a population-based cohort of lung cancer patients in Victoria.

INTRODUCTION: We evaluated real-world data on the patterns and outcomes of radiotherapy (RT) for brain metastases (BM) in a population-based cohort of patients with lung cancer (LC) in Victoria. METHODS: The Victorian Radiotherapy Minimum Data set (VRMDS) and the Victorian Cancer Registry (VCR) were linked to identify patients with LC who underwent RT for BM between 2013 and 2016. We determined: (i) proportion of patients treated with stereotactic radiosurgery (SRS); (ii) overall survival (OS); and (iii) 30-day mortality (30M) following RT for BM. RESULTS: Of the 1001 patients included in the study, 193 (19%) had SRS. There was no significant increase in SRS use over time - from 18% in 2013 to 21% in 2016 (P-trend = 0.8). In multivariate analyses, increased age (P = 0.03) and treatment in regional centres (P < 0.001) were independently associated with lower likelihood of SRS treatment. The median OS following RT for BM was 3.6 months. Patients who had SRS had better OS than those who did not have SRS (median OS 8.9 months vs. 3 months, P < 0.01). SRS use, age, sex and year of treatment were independently associated with OS in multivariate analyses. A total of 184 (18%) patients died within 30 days of RT for BM, and the proportion was higher in older (P = 0.001) and male patients (P = 0.004). CONCLUSION: One-in-five LC patients who received RT for BM had SRS. The improved OS with SRS is likely confounded by patient selection. It is important to reduce 30M by better selecting patients who may not benefit from RT for BM.

Persisting Gaps in Optimal Care of Stage III Non-small Cell Lung Cancer: An Australian Patterns of Care Analysis.

BACKGROUND: Wide variation exists globally in the treatment and outcomes of stage III patients with non-small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. MATERIALS AND METHODS: Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, public/private status of notifying institution, and multidisciplinary meeting discussion. RESULTS: A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were >75 years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. CONCLUSION: Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required.

Blood T-cell profiling in metastatic melanoma patients as a marker for response to immune checkpoint inhibitors combined with radiotherapy.

BACKGROUND: The addition of stereotactic ablative radiotherapy (SABR) to immune checkpoint inhibitors (ICIs) has the potential to significantly improve outcomes in the treatment of metastatic melanoma. We analysed peripheral blood immune cells of patients receiving combination SABR and ICI to detect the effect of treatment and identify potential biomarkers that predict outcome. METHODS: 24 polymetastatic melanoma patients participated in the SABR IMPACT trial, receiving standard dose immunotherapy with anti-PD-1 and/or anti-CTLA-4 and stereotactic ablative radiotherapy to one site. Comprehensive immunophenotyping of T-cells was performed with flow cytometry on blood samples from 13 patients at baseline and following the first 4 cycles of treatment. RESULTS: Following four cycles of immunotherapy and SABR, the proportion of naïve subsets were reduced within both the CD4 and CD8 T-cell lineages. Independently, SABR resulted in increased expression of PD-1 (p = 0.019) and ICOS (p = 0.046) on the CD8+ T-cells, accompanied by a reduction in regulatory T-cell frequencies (p = 0.048). A multivariate discriminant analysis revealed a baseline signature of lower levels of CD8+ naive T-cells and higher expression of TIM-3 on regulatory T-cells and memory T-cells better predicted response. CONCLUSION: The combination of immunotherapy and SABR changed the immunophenotype of blood T cells, with some shifts attributable to SABR. Importantly, we identified a T-cell signature at baseline that best predicted response. Validation of these findings in an independent cohort could confirm these as biomarkers at baseline or early during treatment, and whether these can be utilised to stratify patients for high or low intensity treatment to reduce toxicity.

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.

MArkerless image Guidance using Intrafraction Kilovoltage x-ray imaging (MAGIK): study protocol for a phase I interventional study for lung cancer radiotherapy.

INTRODUCTION: In radiotherapy, tumour tracking leads the radiation beam to accurately target the tumour while it moves in a complex and unpredictable way due to respiration. Several tumour tracking techniques require the implantation of fiducial markers around the tumour, a procedure that involves unnecessary risks and costs. Markerless tumour tracking (MTT) negates the need for implanted markers, potentially enabling accurate and optimal radiotherapy in a non-invasive way. METHODS AND ANALYSIS: We will perform a phase I interventional trial called MArkerless image Guidance using Intrafraction Kilovoltage x-ray imaging (MAGIK) to investigate the technical feasibility of the MTT technology developed at the University of Sydney (sponsor). 30 participants will undergo the current standard of care lung stereotactic ablative radiation therapy, with the exception that kilovoltage X-ray images will be acquired continuously during treatment delivery to enable MTT. If MTT indicates that the mean lung tumour position has shifted >3 mm, a warning message will be displayed to indicate the need for a treatment intervention. The radiation therapist will then pause the treatment, shift the treatment couch to account for the shift in tumour position and resume the treatment. Participants will be implanted with fiducial markers, which act as the ground truth for evaluating the accuracy of MTT. MTT is considered feasible if the tracking accuracy is <3 mm in each dimension for >80% of the treatment time. ETHICS AND DISSEMINATION: The MAGIK trial has received ethical approval from The Alfred Human Research Ethics Committee and has been registered with ClinicalTrials.gov with the Identifier: NCT04086082. Estimated time of first recruitment is early 2022. The study recruitment and data analysis phases will be performed concurrently. Treatment for all 30 participants is expected to be completed within 2 years and participant follow-up within a total duration of 7 years. Findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04086082; Pre-result.

Oesophageal IGRT considerations for SBRT of LA-NSCLC: barium-enhanced CBCT and interfraction motion.

BACKGROUND: To determine the optimal volume of barium for oesophageal localisation on cone-beam CT (CBCT) for locally-advanced non-small cell lung cancers (NSCLC) and quantify the interfraction oesophageal movement relative to tumour. METHODS: Twenty NSCLC patients with mediastinal and/or hilar disease receiving radical radiotherapy were recruited. The first five patients received 25 ml of barium prior to their planning CT and alternate CBCTs during treatment. Subsequent five patient cohorts, received 15 ml, 10 ml and 5 ml. Six observers contoured the oesophagus on each of the 107 datasets and consensus contours were created. Overall 642 observer contours were generated and interobserver contouring reproducibility was assessed. The kappa statistic, dice coefficient and Hausdorff Distance (HD) were used to compare barium-enhanced CBCTs and non-enhanced CBCTs. Oesophageal displacement was assessed using the HD between consensus contours of barium-enhanced CBCTs and planning CTs. RESULTS: Interobserver contouring reproducibility was significantly improved in barium-enhanced CBCTs compared to non-contrast CBCTs with minimal difference between barium dose levels. Only 10 mL produced a significantly higher kappa (0.814, p = 0.008) and dice (0.895, p = 0.001). The poorer the reproducibility without barium, the greater the improvement barium provided. The median interfraction HD between consensus contours was 4 mm, with 95% of the oesophageal displacement within 15 mm. CONCLUSIONS: 10 mL of barium significantly improves oesophageal localisation on CBCT with minimal image artifact. The oesophagus moves substantially and unpredictably over a course of treatment, requiring close daily monitoring in the context of hypofractionation.

Is SABR Cost-Effective in Oligometastatic Cancer? An Economic Analysis of the SABR-COMET Randomized Trial.

PURPOSE: The phase 2 randomized study SABR-COMET demonstrated that in patients with controlled primary tumors and 1 to 5 oligometastatic lesions, SABR was associated with improved progression-free survival (PFS) compared with standard of care (SoC), but with higher costs and treatment-related toxicities. The aim of this study was to assess the cost-effectiveness of SABR versus SoC in this setting. METHODS AND MATERIALS: A Markov model was constructed to perform a cost-utility analysis from the Canadian health care system perspective. Utility values and transition probabilities were derived from individual-level data from the SABR-COMET trial. One-way, 2-way, and probabilistic sensitivity analyses were performed. Costs were expressed in 2018 CAD. A separate analysis based on US payer's perspective was performed. An incremental cost-effectiveness ratio (ICER) at a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) was used. RESULTS: In the base case scenario, SABR was cost-effective at an ICER of $37,157 per QALY gained. This finding was most sensitive to the number of metastatic lesions treated with SABR (ICER: $28,066 per QALY for 2, increasing to $64,429 per QALY for 5), difference in chemotherapy use (ICER: $27,173-$53,738 per QALY), and PFS hazard ratio (HR) between strategies (ICER: $31,548-$53,273 per QALY). Probabilistic sensitivity analysis revealed that SABR was cost-effective in 97% of all iterations. Two-way sensitivity analysis demonstrated a nonlinear relationship between the number of lesions and the PFS HR. To maintain cost-effectiveness for each additional metastasis, the HR must decrease by approximately 0.047. The US cost analysis yielded similar results, with an ICER of $54,564 (2018 USD per QALY) for SABR. CONCLUSIONS: SABR is cost-effective for patients with 1 to 5 oligometastatic lesions compared with SoC.

Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial.

PURPOSE: The oligometastatic paradigm hypothesizes that patients with a limited number of metastases may achieve long-term disease control, or even cure, if all sites of disease can be ablated. However, long-term randomized data that test this paradigm are lacking. METHODS: We enrolled patients with a controlled primary malignancy and 1-5 metastatic lesions, with all metastases amenable to stereotactic ablative radiotherapy (SABR). We stratified by the number of metastases (1-3 v 4-5) and randomized in a 1:2 ratio between palliative standard-of-care (SOC) treatments (arm 1) and SOC plus SABR (arm 2). We used a randomized phase II screening design with a primary end point of overall survival (OS), using an α of .20 (wherein P < .20 indicates a positive trial). Secondary end points included progression-free survival (PFS), toxicity, and quality of life (QOL). Herein, we present long-term outcomes from the trial. RESULTS: Between 2012 and 2016, 99 patients were randomly assigned at 10 centers internationally. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16). Median follow-up was 51 months. The 5-year OS rate was 17.7% in arm 1 (95% CI, 6% to 34%) versus 42.3% in arm 2 (95% CI, 28% to 56%; stratified log-rank P = .006). The 5-year PFS rate was not reached in arm 1 (3.2%; 95% CI, 0% to 14% at 4 years with last patient censored) and 17.3% in arm 2 (95% CI, 8% to 30%; P = .001). There were no new grade 2-5 adverse events and no differences in QOL between arms. CONCLUSION: With extended follow-up, the impact of SABR on OS was larger in magnitude than in the initial analysis and durable over time. There were no new safety signals, and SABR had no detrimental impact on QOL.

Stereotactic Radiation Therapy Combined With Immunotherapy Against Metastatic Melanoma: Long-Term Results of a Phase 1 Clinical Trial.

PURPOSE: To determine the maximum tolerated dose (MTD) of stereotactic ablative radiation therapy (SABR) in combination with immunotherapy for the treatment of patients with metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy. METHODS: Metastatic melanoma patients with at least 2 metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3 + 3 design, patients were escalated through 3 SABR doses (10 Gy, 15 Gy, and 20 Gy) delivered at 3 different time points (with cycle 1, 2, or 3 of immunotherapy). Dose-limiting toxicities (DLT) were defined as grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or Cox regressions were used to assess the impact of SABR dose and timing on the progression free (PFS) and overall survival (OS) of this cohort. RESULTS: Twenty-four patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs; 1 DLT occurred at a SABR-treated site, and all patients received 15 Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10 Gy. The 2-year PFS was 21.9% (95% CI, 7.1%-41.8%) and 2-year OS was 49.6% (95% CI, 28.7%-67.6%). The median PFS for those receiving 10 Gy was numerically higher than for those receiving 15 Gy, 8.3 months versus 2.1 months (P = .38). The only treatment-related factor associated with both improved PFS (HR 0.08, P < .01) and OS (HR 0.008, P ≤ .01) was receiving SABR with cycle 3. SABR dose (PFS P = .17, OS P = .50) was not significant. CONCLUSIONS: SABR at 10 Gy can be safely combined with immunotherapy. SABR timing appears to influence efficacy more than dose and warrants consideration in research attempting to optimize synergism.

Stereotactic ablative radiotherapy for the comprehensive treatment of 1-3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial.

BACKGROUND: A recent randomized phase II trial evaluated stereotactic ablative radiotherapy (SABR) in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with a significant improvement in progression-free survival and a trend to an overall survival benefit, supporting progression to phase III randomized trials. METHODS: Two hundred and ninety-seven patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care [SOC] palliative-intent treatments), and the SABR arm (consisting of SOC treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (prostate, breast, or renal vs. all others), and disease-free interval (defined as time from diagnosis of primary tumor until first detection of the metastases being treated on this trial; divided as ≤2 vs. > 2 years). The primary endpoint is overall survival, and secondary endpoints include progression-free survival, cost effectiveness, time to development of new metastatic lesions, quality of life (QoL), and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. DISCUSSION: This study will provide an assessment of the impact of SABR on survival, QoL, and cost effectiveness to determine if long-term survival can be achieved for selected patients with 1-3 oligometastatic lesions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03862911. Date of registration: March 5, 2019.

Quality of Life Outcomes After Stereotactic Ablative Radiation Therapy (SABR) Versus Standard of Care Treatments in the Oligometastatic Setting: A Secondary Analysis of the SABR-COMET Randomized Trial.

PURPOSE: Randomized data assessing the longitudinal quality of life (QoL) impact of stereotactic ablative radiation therapy (SABR) in the oligometastatic setting are lacking. METHODS AND MATERIALS: We enrolled patients who had a controlled primary malignancy with 1 to 5 metastatic lesions, with good performance status and life expectancy >6 months. We randomized in a 1:2 ratio between standard of care (SOC) treatment (SOC arm) and SOC plus SABR to all metastatic lesions (SABR arm). QoL was measured using the Functional Assessment of Cancer Therapy-General. QoL changes over time and between groups were assessed with linear mixed modeling. RESULTS: Ninety-nine patients were randomized. Median age was 68 years (range, 43-89), and 60% were male. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16). Most patients (n = 92) had 1 to 3 metastases. Median follow-up was 26 months. Because of the previously reported inferior survival of the SOC arm, the time for attrition in QoL respondents to <10% of subjects was shorter in the SOC versus SABR arm (30 vs 42 months). In the whole cohort, QoL declined over time after randomization: There were significant declines in total Functional Assessment of Cancer Therapy-General score over time compared with baseline (P < .001) owing to declines in physical and functional subscales (both P < .001), with no declines in social and emotional subscales. However, the magnitudes of decline were small, and clinically meaningful changes were not seen at most time points. Comparison between arms showed no differences in QoL between the SABR and SOC arms in total score (P = .42) or in the physical (P = .98), functional (P = .59), emotional (P = .82), or social (P = .17) subscales. CONCLUSIONS: For patients with oligometastases, average QoL declines slowly over time regardless of treatment approach, although the changes are small in magnitude. The use of SABR, compared with SOC, was not associated with a QoL detriment.

Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4-10 metastatic cancer lesions. METHODS: One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. DISCUSSION: This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4-10 oligometastatic lesions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03721341 . Date of registration: October 26, 2018.