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.
Approximately two-thirds of patients with early-stage non-small-cell lung cancer (NSCLC) in The Netherlands currently undergo surgical resection. As an increasing number of fit patients have elected ...to undergo stereotactic ablative radiotherapy (SABR) in recent years, we studied outcomes after SABR in patients with potentially operable stage I NSCLC.
In an institutional prospective database collected since 2003, 25% of lung SABR cases (n = 177 patients) were found to be potentially operable when the following patients were excluded: those with (1) synchronous lung tumors or other malignancy, (2) prior high-dose radiotherapy/pneumonectomy, (3) chronic obstructive pulmonary disease with a severity score of 3-4 according to the Global initiative for Obstructive Lung Disease classification. (4) a performance score of ≥3, and (5) other comorbidity precluding surgery. Study patients included 101 males and 76 females, with a median age of 76 years old, 60% of whom were staged as T1 and 40% of whom were T2. Median Charlson comorbidity score was 2 (range, 0-5). A SABR dose of 60 Gy was delivered using a risk-adapted scheme in 3, 5, or 8 fractions, depending on tumor size and location. Follow-up chest computed tomography scans were obtained at 3, 6, and 12 months and yearly thereafter.
Median follow-up was 31.5 months; and median overall survival (OS) was 61.5 months, with 1- and 3-year survival rates of 94.7% and 84.7%, respectively. OS rates at 3 years in patients with (n = 59) and without (n = 118) histological diagnosis did not differ significantly (96% versus 81%, respectively, p = 0.39). Post-SABR 30-day mortality was 0%, while predicted 30-day mortality for a lobectomy, derived using the Thoracoscore predictive model (Falcoz PE et al. J Thorac Cardiovasc Surg 2007;133:325-332), would have been 2.6%. Local control rates at 1 and 3 years were 98% and 93%, respectively. Regional and distant failure rates at 3 years were each 9.7%. Toxicity was mild, with grade ≥3 radiation pneumonitis and rib fractures in 2% and 3%, respectively.
Patients with potentially operable disease who underwent primary SABR had a median OS that exceeded 5 years. This finding supports ongoing randomized clinical trials comparing surgery and SABR in cases of operable stage I NSCLC.
Abstract Background and purpose Stereotactic ablative radiotherapy (SABR) has improved the survival for medically inoperable patients with peripheral early-stage non-small cell lung cancer (NSCLC). ...We performed a systematic review of outcomes for central lung tumours. Material and methods The systematic review was performed following PRISMA guidelines. Survival outcomes were evaluated for central early-stage NSCLC. Local control and toxicity outcomes were evaluated for any centrally-located lung tumour. Results Twenty publications met the inclusion criteria, reporting outcomes for 563 central lung tumours, including 315 patients with early-stage NSCLC. There was heterogeneity in the planning, prescribing and delivery of SABR and the common toxicity criteria used to define toxicities (versions 2.0–4.0). Tumour location (central versus peripheral) did not impact overall survival. Local control rates were ⩾85% when the prescribed biologically equivalent tumour dose was ⩾100 Gy. Treatment-related mortality was 2.7% overall, and 1.0% when the biologically equivalent normal tissue dose was ⩽210 Gy. Grade 3 or 4 toxicities may be more common following SABR for central tumours, but occurred in less than 9% of patients. Conclusions Post-SABR survival for early-stage NSCLC is not affected by tumour location. SABR achieves high local control with limited toxicity when appropriate fractionation schedules are used for central tumours.
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.
Summary Background The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy ...(SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. Methods Eligible patients in the STARS and ROSEL studies were those with clinical T1–2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749 ; ROSEL: NCT00687986 ). Findings 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0–47·3) for the SABR group and 35·4 months (18·9–40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85–100) in the SABR group compared with 79% (64–97) in the surgery group (hazard ratio HR 0·14 95% CI 0·017–1·190, log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74–100) in the SABR group and 80% (65–97) in the surgery group (HR 0·69 95% CI 0·21–2·29, log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three 10% chest wall pain, two 6% dyspnoea or cough, and one 3% fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3–4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four 15% patients), chest pain (four 15% patients), and lung infections (two 7%). Interpretation SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. Funding Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.
High local control rates can be achieved using stereotactic radiotherapy in Stage I non-small-cell lung cancer (NSCLC), but reports have suggested that toxicity may be of concern. We evaluated early ...clinical outcomes of "risk-adapted" fractionation schemes in patients treated in a single institution.
Of 206 patients with Stage I NSCLC, 81% were unfit to undergo surgery and the rest refused surgery. Pathologic confirmation of malignancy was obtained in 31% of patients. All other patients had new or growing 18F-fluorodeoxyglucose positron emission tomography positive lesions with radiologic characteristics of malignancy. Planning four-dimensional computed tomography scans were performed and fractionation schemes used (3 x 20 Gy, 5 x 12 Gy, and 8 x 7.5 Gy) were determined by T stage and risk of normal tissue toxicity.
Median overall survival was 34 months, with 1- and 2-year survivals of 81% and 64%, respectively. Disease-free survival (DFS) at 1 and 2 years was 83% and 68%, respectively, and DFS correlated with T stage (p = 0.002). Local failure was observed in 7 patients (3%). The crude regional failure rate was 9%; isolated regional recurrence was observed in 4%. The distant progression-free survival at 1 and 2 years was 85% and 77%, respectively. SRT was well tolerated and severe late toxicity was observed in less than 3% of patients.
SRT is well tolerated in patients with extensive comorbidity with high local control rates and minimal toxicity. Early outcomes are not inferior to those reported for conventional radiotherapy. In view of patient convenience, such risk-adapted SRT schedules should be considered treatment of choice in patients presenting with medically inoperable Stage I NSCLC.
Use of stereotactic body radiation therapy (SBRT) is increasing in patients with localized prostate cancer, but concerns about early and late gastrointestinal (GI) and genitourinary (GU) toxicity ...exist after moderately or extremely hypofractionated radiation therapy schemes. Magnetic resonance guided radiation therapy (MRgRT) was clinically introduced in 2014. MrgRT allows for SBRT delivery with smaller uncertainty margins and permits daily adaptive planning. A phase 2 study in patients with localized prostate cancer was performed to study early GI and GU toxicity after SBRT using MRgRT.
One hundred one patients with clinical stage T1-3bN0M0 prostate cancer were enrolled in this prospective phase 2 study. All but 4 patients had intermediate- or high-risk prostate cancer, and 82.2% received adjuvant hormonal treatment. MRgRT was delivered in 5 fractions of 7.25 Gy to the target volume using daily plan adaptation with simultaneous relative sparing of the urethra to a dose of 6.5 Gy per fraction. Early toxicity was studied using both clinician- (Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group) and patient-reported outcome measurements (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, Quality of Life Questionnaire PR25, and International Prostate Symptom Scoring).
The maximum cumulative grade ≥2 early GU and GI toxicity measured by any symptom at any study time point was 23.8% and 5.0%, respectively. No early grade 3 GI toxicity was observed. Early grade 3 GU toxicity was 0% and 5.9% according to the Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group and scoring systems, respectively, as a result of different grading of radiation cystitis. The low incidence of early GI toxicity was confirmed by patient-reported outcome data. GU grade ≥2 toxicity peaked to 19.8% at the end of MRgRT, followed by a return to the baseline average score at 3-month follow-up.
This prospective study of MRgRT in patients with localized prostate cancer observed a low incidence of early GI and GU toxicity, both in clinician- and patient-reported outcome measurements.
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. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.
After stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy.
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 oligometastatic disease, and will inform the design of a possible phase III study.
The use of stereotactic ablative radiotherapy (SABR) in centrally located early-stage lung tumors has been associated with increased toxicity. We studied outcomes after delivery of risk-adapted SABR ...of central tumors.
SABR was delivered in eight fractions of 7.5 Gy to 63 such patients between 2003 and 2009. Of these, 37 patients had a tumor at a central hilar location, whereas 26 patients had tumors abutting the pericardium or mediastinal structures. Survival outcomes were compared with patients with peripheral tumors treated during the same time period using fewer fractions of SABR.
Median follow-up was 35 months. Late grade III toxicity was limited to chest wall pain (n = 2) and increased dyspnoea (n = 2). No grade IV/V toxicity was observed, but grade V toxicity could not be excluded with certainty in nine patients who died of cardiopulmonary causes. Distant metastases were the predominant cause of death; cardiovascular deaths were not associated with a paracardial tumor location. No significant differences in outcomes were observed between these 63 patients and 445 other SABR patients treated for peripheral early-stage lung tumors. Three-year local control rates were 92.6% and 90.2% (p = 0.9). Three-year overall survival rates were 64.3% and 51.1% with median survival rates of 47 and 36 months, in favor of the group of patients with central tumors (p = 0.09).
Use of risk-adapted SABR delivered in eight fractions of 7.5 Gy did not result in excess toxicity for centrally located early-stage lung tumors, and clinical outcomes were comparable with those seen for peripheral lesions.
•Delivery of single-fraction SABR to lung tumors on a 0.35T MR-linac resulted in a 3-year local control rate of 97%.•Only 1 patient (2%) developed grade ≥3 toxicity, which was chest wall ...pain.•MR-guided SABR delivered using repeated breath-holds and with automatic beam gating, achieves good tumor control and low toxicity.
Magnetic resonance imaging (MR)-guided radiotherapy permits continuous intrafraction visualization and use of automatic triggered beam delivery, with use of smaller planning target volumes (PTV). We report on long-term clinical outcomes following MR-guided single fraction (SF) lung SABR on a 0.35 T linac.
Details of patients treated with SF-SABR for lung tumors were accessed from an ethics approved institutional database. A breath-hold 3D MR simulation scan was performed using a true FISP sequence, followed by a breath-hold 3D CT scan. The gross tumor volume (GTV) was first contoured on the breath-hold CT scan, which was then compared with contours on the 3D MR scan, before the GTV was finalized. SABR plans used step-and-shoot IMRT beams to a PTV derived by adding a 5 mm margin to the breath-hold GTV, and a 3 mm gating window was used. SABR was delivered during repeated breath-holds, using automatic beam gating with continuous visualization of the GTV in a sagittal MR plane.
Between 2018-2022, 50 consecutive patients were treated, and 69% had a primary non-small cell lung cancer. Median PTV was 11.2 cc (range 3.9-53.5); 80% of GTV’s were located ≤2.5cm from the chest wall. Prescribed doses were 34Gy (in 58%), 30Gy (32%), or between 20-28Gy (10%). After a median follow-up of 18.1 months (95% CI 12.8-23.5), the 2-year survival was 82% (89% for primary NSCLC and 62% for metastases). After a median follow-up of 16.1 months (95% CI 11.2-21.1), local recurrences developed in 2 patients (4%). The 3-year local control rate was 97%, and just 1 patient developed grade ≥3 toxicity (chest wall pain).
MR-guided SF-SABR delivery to lung tumors on a 0.35 T linac, using repeated breath-holds with automatic beam gating, achieves good tumor control and low toxicity.
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