Summary Background Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of medically inoperable early stage non-small-cell lung cancer (NSCLC). Because patterns of late ...disease recurrence after SABR are not well characterised, we aimed to assess these outcomes in a cohort of patients with NSCLC. Methods Patients with18 F-fluorodeoxyglucose (18 F-FDG)-PET confirmed stage 1–2 NSCLC who were treated with SABR at the VU University Medical Center (Amsterdam, Netherlands) were identified from an institutional database. SABR doses were 54–60 Gy, delivered in three to eight once-daily fractions, depending on tumour size and location. Clinical follow-up and CT scans were done at 3, 6, and 12 months, then yearly thereafter.18 F-FDG-PET restaging was only done when clinically indicated. Initial sites of recurrence were classified as local, regional, and distant, and were differentiated from second primary tumours in the lung at multidisciplinary tumour board review. Findings Between April 4, 2003, and Dec 5, 2011, 676 patients were treated with SABR and were eligible for assessment of recurrence. The median follow-up was 32·9 months (IQR 14·9–50·9 months). 124 (18%) of 676 patients had disease recurrence. Actuarial 2-year rates of local, regional, and distant recurrence were 4·9% (95% CI 2·7–7·1), 7·8% (5·3–10·3), and 14·7% (11·4–18·0), respectively. Corresponding 5-year rates were 10·5% (95% CI 6·4–14·6), 12·7% (8·4–17·0), and 19·9% (14·9–24·6), respectively. Of the 124 recurrences, 82 (66%) were distant recurrences and 57 (46%) were isolated distant recurrences. Isolated locoregional recurrences occurred in the remaining 42 patients with disease recurrence (34%), 35 (83%) of whom did not develop subsequent distant recurrence. The median times to local, regional, and distant recurrence were 14·9 months (95% CI 11·4–18·4), 13·1 months (7·9–18·3), and 9·6 months (6·8–12·4), respectively. New pulmonary lesions characterised as second primary tumours in the lung developed in 42 (6%) of 676 patients at a median of 18·0 months (95% CI 12·5–23·5) after SABR. Interpretation Late recurrences after SABR are infrequent and two distinct patterns account for most cases. The predominant pattern is out-of-field, isolated distant recurrence presenting early, despite initial PET staging. A third of patients develop isolated locoregional recurrence; for these patients standardised follow-up is important to ensure that appropriate salvage treatments are considered. Funding None.
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.
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.
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.
Clinicaltrials.gov identifier: NCT03721341 . Date of registration: October 26, 2018.
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.
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.
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.
Clinicaltrials.gov identifier: NCT03862911. Date of registration: March 5, 2019.
Abstract Background and purpose Early detection of local recurrences following stereotactic ablative radiotherapy (SABR) for lung cancer may allow for curative salvage treatment, but recurrence can ...be difficult to distinguish from fibrosis. We studied the clinical performance of CT imaging high-risk features (HRFs) for detecting local recurrence. Materials and methods Patients treated with SABR for early stage lung cancer between 2003 and 2012 who developed pathology-proven local recurrence ( n = 12) were matched 1:2 to patients without recurrences ( n = 24), based on baseline factors. Serial CT images were assessed by blinded radiation oncologists. Previously reported HRFs were (1) enlarging opacity at primary site; (2) sequential enlarging opacity; (3) enlarging opacity after 12-months; (4) bulging margin; (5) loss of linear margin and (6) air bronchogram loss. Results All HRFs were significantly associated with local recurrence ( p < 0.01), and one new HRF was identified: cranio-caudal growth ( p < 0.001). The best individual predictor of local recurrence was opacity enlargement after 12-months (100% sensitivity, 83% specificity, p < 0.001). The odds of recurrence increased 4-fold for each additional HRF detected. The presence of ⩾3 HRFs was highly sensitive and specific for recurrence (both >90%). Conclusion The systematic assessment of post-SABR CT images for HRFs enables the accurate prediction of local recurrence.
Randomized data assessing the longitudinal quality of life (QoL) impact of stereotactic ablative radiation therapy (SABR) in the oligometastatic setting are lacking.
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.
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.
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.
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.
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.
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.
Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.
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.
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.
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.
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.
IntroductionIn 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 analysisWe 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 disseminationThe 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 numberNCT04086082; Pre-result.
BackgroundEmerging 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.MethodsOne 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.DiscussionSABR-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 registrationClinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).
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