Cornelis J.A. Haasbeek

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

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.

Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis.

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 with (18)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.

Stage I–II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis

BACKGROUND Video-assisted thoracoscopic surgery (VATS) lobectomy and stereotactic ablative radiotherapy (SABR) are both used for early-stage non-small-cell lung cancer. We carried out a propensity score-matched analysis to compare locoregional control (LRC). PATIENTS AND METHODS VATS lobectomy data from six hospitals were retrospectively accessed; SABR data were obtained from a single institution database. Patients were matched using propensity scores based on cTNM stage, age, gender, Charlson comorbidity score, lung function and performance score. Eighty-six VATS and 527 SABR patients were matched blinded to outcome (1:1 ratio, caliper distance 0.025). Locoregional failure was defined as recurrence in/adjacent to the planning target volume/surgical margins, ipsilateral hilum or mediastinum. Recurrences were either biopsy-confirmed or had to be PET-positive and reviewed by a tumor board. RESULTS The matched cohort consisted of 64 SABR and 64 VATS patients with the median follow-up of 30 and 16 months, respectively. Post-SABR LRC rates were superior at 1 and 3 years (96.8% and 93.3% versus 86.9% and 82.6%, respectively, P = 0.04). Distant recurrences and overall survival (OS) were not significantly different. CONCLUSION This retrospective analysis found a superior LRC after SABR compared with VATS lobectomy, but OS did not differ. Our findings support the need to compare both treatments in a randomized, controlled trial.

Outcomes of Stereotactic Ablative Radiotherapy for Centrally Located Early-Stage Lung Cancer

Introduction: 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. Methods: 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. Results: 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). Conclusions: 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.

Outcomes of stereotactic ablative radiotherapy for central lung tumours: A systematic review

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.

75 Years Outcomes After Stereotactic Radiotherapy

BACKGROUND The number of patients aged > or =75 years who present with a stage I nonsmall cell lung cancer (NSCLC) is increasing. Elderly patients often have significant comorbidity and may be unfit for surgery. Furthermore, surgery in the elderly is associated with increased mortality and morbidity. In this study, the authors evaluated the outcomes of stereotactic radiotherapy (SRT) in elderly patients. METHODS Since 2003, 203 tumors in 193 patients aged > or =75 years were treated using SRT (118 T1 tumors, 85 T2 tumors). The median patient age was 79 years, 80% of patients were considered medically inoperable, and 20% of patients declined surgery. The median Charlson comorbidity score was 4, and severe chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease Class III or greater) was present in 25% of patients. Risk-adapted SRT schemes were used with the same total dose of 60 grays in 3 fractions (33%), 5 fractions (50%), or 8 fractions (17% of patients), depending on the patients risk for toxicity. RESULTS SRT was well tolerated, and all but 1 patient completed treatment. Survival rates at 1 year and 3 years were 86% and 45%, respectively. Survival was correlated with performance score (P = .001) and pre-SRT lung function (P = .04). The actuarial local control rate at 3 years was 89%. Acute toxicity was uncommon, and late Radiation Therapy Oncology Group grade > or =3 toxicity was observed in <10% of patients. CONCLUSIONS SRT achieved high local control rates with minimal toxicity in patients aged > or =75 years despite their significant medical comorbidities. These results indicated that more active diagnostic and therapeutic approaches are justified in elderly patients and that SRT should be considered and discussed as a curative treatment alternative.The number of patients aged ≥75 years who present with a stage I nonsmall cell lung cancer (NSCLC) is increasing. Elderly patients often have significant comorbidity and may be unfit for surgery. Furthermore, surgery in the elderly is associated with increased mortality and morbidity. In this study, the authors evaluated the outcomes of stereotactic radiotherapy (SRT) in elderly patients.

Curative treatment of Stage I non-small-cell lung cancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review.

OBJECTIVES Patients with severe chronic obstructive pulmonary disease (COPD) have a high risk of lung cancer and of postsurgical complications. We studied outcomes after stereotactic body radiotherapy (SBRT) in patients with severe COPD, as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, and performed a systematic review of the literature on outcomes after SBRT or surgery in these patients. METHODS A single-institution cohort of 176 patients with COPD GOLD III-IV and Stage I non-small-cell lung cancer (NSCLC) treated with SBRT was evaluated. A systematic review identified studies reporting outcomes after SBRT or surgery for Stage I NSCLC in patients with GOLD III-IV or a predicted postoperative forced expiratory volume in 1 second (FEV1) of ≤40%. RESULTS In the single-institution cohort, median follow-up was 21 months and median overall survival (OS) was 32 months. Actuarial 3-year local control was 89%, and 1- and 3-year OS were 79% and 47%, respectively. COPD severity correlated with OS (p = 0.01). The systematic review identified four other studies (two surgical, two SBRT, n = 196 patients). SBRT studies were published more recently and included older patients than surgical studies. Mean 30-day mortality was 0% post-SBRT and 10% after surgery. Local or locoregional control was high (≥89%) after both treatments. Post-SBRT, actuarial OS was 79-95% at 1 year and 43-70% at 3 years. Postsurgical actuarial OS was 45-86% at 1 year and 31-66% at 3 years. CONCLUSIONS SBRT and surgery differ in risk of 30-day mortality in patients with severe COPD. Despite the negative selection of SBRT patients, survival at 1 and 3 years is comparable between the two treatments.

Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial

BackgroundStereotactic 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.MethodsAfter 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.DiscussionThis 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.Trial registrationClinicaltrials.gov identifier: NCT01446744

Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: comparison with a contemporaneous cohort with pathologically proven disease.

INTRODUCTION As a finding of benign disease is uncommon in Dutch patients undergoing surgery after a clinical diagnosis of stage I NSCLC, patients are also accepted for stereotactic ablative radiotherapy (SABR) without pathology. We studied outcomes in patients who underwent SABR after either a pathological (n=209) or clinical diagnosis (N=382). MATERIALS AND METHODS Five hundred and ninety-one patients with a single pulmonary lesion underwent SABR after either a pathological- or a clinical diagnosis of stage I NSCLC based on a (18)FDG-PET positive lesion with CT features of malignancy. SABR was delivered to a total dose of 60Gy in 3, 5 or 8 fractions, and outcomes were compared between groups with and without pathological diagnosis. RESULTS Patients with pathology had significantly larger tumor diameters (p<.001) and higher predicted FEV1% values (p=.025). No significant differences were observed between both groups in overall survival (p=.99) or local control (p=.98). Regional and distant recurrence rates were also similar. CONCLUSIONS In a population with a low incidence of benign (18)FDG-PET positive lung nodules, clinical SABR outcomes were similar in large groups of patients with or without pathology. The survival benefits reported after the introduction of SABR are unlikely to be biased by inclusion of benign lesions.

Incidence and Risk Factors for Chest Wall Toxicity After Risk-Adapted Stereotactic Radiotherapy for Early-Stage Lung Cancer

Introduction: High local control rates are reported after stereotactic ablative body radiotherapy (SABR) in stage I non-small cell lung cancer. Toxicity is uncommon, but few reports on long-term follow-up are available. We studied the incidence of chest wall pain (CWP) and rib fractures in patients with long-term follow-up. Methods: Between 2003 and 2009, 500 patients (530 tumors) underwent SABR using risk-adapted fractionation schemes, consisting of three fractions of 20 Gy, five fractions of 12 Gy, or eight fractions of 7.5 Gy. Toxicity data were collected in a prospective database and scored using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Chest wall volumes receiving doses of 30, 40, 45, and 50 Gy (V30 Gy-V50 Gy) and maximum dose in 2 cm3 of chest wall (D2 ml) were determined for patients with CWP or rib fractures (n = 57). Results: With a median follow-up of 33 months, the 3-year overall survival and local control rates were 53.1% and 90.4%, respectively. CWP developed in 11.4% of patients and was severe (grade 3) in 2.0%. Rib fractures were observed in eight patients (1.6%), accompanied by CWP in seven of these patients. On multivariate analysis, patients with CWP had larger treatment volumes and shorter tumor-chest wall distances, whereas patients with rib fractures had larger tumor diameters and treatment volumes. Grade 3 CWP and rib fractures were associated with larger volumes of chest wall receiving doses of 30 to 50 Gy and rib fractures specifically with a higher maximum dose in the chest wall. Conclusions: Severe (grade 3) chest wall toxicity is uncommon after risk-adapted SABR and manifests in 2% or fewer of patients.