Association of Long-term Outcomes and Survival With Multidisciplinary Salvage Treatment for Local and Regional Recurrence After Stereotactic Ablative Radiotherapy for Early-Stage Lung Cancer.
ABSTRACT: Importance:Stereotactic ablative radiotherapy (SABR) is first-line treatment for patients with early-stage non-small cell lung cancer (NSCLC) who cannot undergo surgery. However, up to 1 in 6 such patients will develop isolated local recurrence (iLR) or isolated regional recurrence (iRR). Little is known about outcomes when disease recurs after SABR, or about optimal management strategies for such recurrences. Objective:To characterize long-term outcomes for patients with iLR or iRR after SABR for early-stage NSCLC with the aim of informing treatment decision making for these patients with potentially curable disease. Design, Setting, and Participants:In this cohort study, a retrospective review was conducted of 912 patients prospectively enrolled in an institutional database at a tertiary cancer center from January 1, 2004, through December 31, 2014. Main Outcomes and Measures:Overall survival, progression-free survival, recurrence patterns, demographics, salvage techniques, patterns of salvage failure, and toxic effects. Results:Of the 912 patients in the study (456 women and 456 men; median age, 72 years [range, 46-91 years]), 756 (82.9%) had T1 tumors at initial diagnosis; 502 tumors (55.0%) were adenocarcinomas and 309 tumors (33.9%) were squamous cell carcinomas. Of 912 patients with early-stage I to II NSCLC who received definitive SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions), 102 developed isolated recurrence (49 with iLR and 53 with iRR), and 658 had no recurrence. Median times to recurrence after SABR were 14.5 months (range, 1.5-60.8 months) for iLR and 9.0 months (range, 1.9-70.7 months) for iRR; 39 of 49 patients (79.6%) with iLR and 48 of 53 patients (90.6%) with iRR underwent salvage with reirradiation, surgery, thermal ablation, or chemotherapy. Median follow-up times for patients with iLR or iRR were 57.2 months (interquartile range, 37.7-87.6 months) from initial SABR and 38.5 months (interquartile range, 19.9-69.3 months) from recurrence. Rates of overall survival at 5 years from initial SABR were no different between patients with iLR and salvage treatment (57.9%) and patients with no recurrence (54.9%; hazard ratio, 0.89; 95% CI, 0.56-1.43; P?=?.65) but were lower for patients with iRR and salvage treatment (31.1%; hazard ratio, 1.43; 95% CI, 1.00-2.34; P?=?.049). Patients receiving salvage treatment had longer overall survival than patients who did not (median, 37 vs 7 months after recurrence; hazard ratio, 0.40; 95% CI, 0.09-0.66; P?=?.006). Twenty-four of 87 patients (27.6%) who received salvage treatment for iLR or iRR subsequently developed distant metastases. No patient experienced grade 5 toxic effects after salvage treatment. Conclusions and Relevance:Life expectancy after salvage treatment for iLR was similar to that for patients without recurrence, but survival after salvage treatment for iRR was similar to that of patients with stage III NSCLC. Patients who received salvage treatment had significantly improved survival. Because salvage treatment for iLR or iRR was based on a consistent multidisciplinary approach, this may help in clinical decision making.
Project description:OBJECTIVES:Our goal was to evaluate stereotactic ablative radiotherapy (SABR) as a salvage option for isolated recurrence of NSCLC in the lung parenchyma after definitive treatment of stage I to III disease. METHODS:Patients who had histologically confirmed, positron emission tomography-staged, isolated NSCLC recurring locally or metastasis in the lung parenchyma (?3 cm, suitable for SABR) after previous definitive treatment were prospectively enrolled in this trial and treated with volumetric, image-guided SABR to 50 Gy in four fractions. Patients were then followed with computed tomography or positron emission tomography/computed tomography. Primary end points included the pattern of failure after salvage SABR, overall survival (OS), and progression-free survival (PFS). RESULTS:Fifty-nine patients with recurrent disease were treated with salvage SABR. The median age was 70 years (range 45-86 years), and the median follow-up time after salvage SABR was 58.3 months. Re-recurrence after salvage SABR developed in 19 patients (32%). Measuring from the date of salvage SABR, the estimated 5-year rates of local, regional, and distant failure were 5.2%, 10.3%, and 22.4%, respectively; the estimated PFS was 46.2% at 3 years and 41.1% at 5 years; and the OS rates were 63.5% at 3 years and 56.5% at 5 years. A high post-SABR neutrophil-to-lymphocyte ratio was found to predict poor survival. Grade 3 treatment-related adverse events developed in three patients (5%). No patient had a grade 4 or 5 event. CONCLUSION:Our study showed that salvage SABR provides excellent 5-year OS, local control, and PFS rates with minimal toxicity for patients with isolated NSCLC recurrence in the lung parenchyma. These results are striking and comparable to historically reported outcomes of patients with primary early-stage NSCLC treated with definitive SABR. SABR appears to be a very effective and safe salvage option for patients with isolated lung parenchyma recurrent disease after definitive treatment and should be considered along with surgery as a potential first-line option for patients with local lung parenchymal recurrent disease.
Project description:BACKGROUND:This study aimed to identify the factors that predict distant recurrence and survival outcome after patients with primary positive hormone receptor-positive (HR+) invasive breast cancer undergo complete excision for isolated local recurrence (ILR). METHODS:From January 2000 to December 2009, we performed a retrospective review of our database and identified 51 patients with HR + invasive breast cancer who underwent complete excision for ILR as a component of salvage therapy. The distant metastasis-free survival (DMFS) and overall survival (OS) from the time of ILR were calculated using the Kaplan-Meier method, and a Cox regression model was used for multivariate analysis. RESULTS:Of the 51 cases of ILR, 28 were of ipsilateral breast tumor recurrence and 23 were of chest wall recurrence. By receiver operating characteristic curve analyses, the cut-off time point for time to ILR was determined to be 29 months. According to time to ILR (?29 vs. >29 months) and primary tumor size (?2 vs. >2 cm), patients were divided into four risk groups as variables for analysis. On multivariate analysis, two independent prognostic factors for DMFS and OS after ILR were identified: risk groups (ILR?29 months with primary tumor size >2 cm vs. ILR>29 months with primary tumor size ? 2 cm, HR = 8.53 for DMFS and HR = 11.18 for OS) and primary tumor grade (2/3 vs. 1, HR = 6.10 for DMFS and 4.27 for OS). CONCLUSION:We demonstrated that poor DMFS and OS are associated with high risk group defined as short time to ILR (?29 months) with primary tumor size (>2 cm) and higher primary tumor grade (2/3) among patients with HR + invasive breast cancer treated with complete excision for ILR. Therapeutic strategies for ILR based on hormone therapy with new agents should be explored in future prospective studies, especially for patients with poor outcome.
Project description: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.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).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%]).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.Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.
Project description:Stereotactic ablative body radiotherapy (SABR) describes a radiotherapy (RT) technique where high doses of radiation are precisely delivered to an extracranial target within the body, using either a single fraction of RT or using multiple small numbers of fractions. SABR has now become the standard of care treatment for patients with early-stage non-small-cell lung cancer (NSCLC) for whom surgery is not appropriate. This systematic review considers the evidence supporting the use of SABR in early-stage NSCLC, reported toxicity rates, the use of SABR in centrally located NSCLC, the use of SABR as salvage therapy following surgery or RT, and future potential drug combinations with SABR.
Project description:<h4>Introduction</h4>Stereotactic body (or ablative) radiotherapy (SBRT/SABR) is now a guideline-recommended treatment for medically inoperable patients with peripherally-located, stage I non-small cell lung cancer (NSCLC), and for medically operable patients who decline surgery. The 5-year local failure rate after SBRT is about 10% and in highly selected patients, surgery has been used as a salvage therapy. We performed a systematic review to address the feasibility, safety, and outcome of salvage surgery for locally recurrent early stage NSCLC after SBRT.<h4>Methods</h4>A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. <i>PubMed, Embase</i> and <i>Cochrane databases</i> were searched and two authors independently assessed the articles. A total of seven eligible articles were identified.<h4>Results</h4>All seven articles were retrospective case series, representing a total of 47 patients. Surgery was completed in all patients. Where reported in sufficient detail, morbidity (four studies) was between 29 and 50% (series of two patients) and 90-day mortality (six studies) was between 0% (four studies) and 11% (<i>n</i> = 1, disease progression). Median (<i>n</i> = 5)/mean (<i>n</i> = 1) reported or calculated follow ups were 7-54.5/17.3 months. Median overall survival was reported in three studies and ranged between 13.6-82.7 months. Crude survival in three others was 2-35 months.<h4>Conclusion</h4>Limited, low-level evidence prevents firm conclusions, but based on the existing data, salvage surgery after local recurrence of NSCLC following SBRT appears technically feasible, with acceptable morbidity and mortality in appropriately selected and counselled patients who are fit enough and who accept the risks (level of evidence 4, strength of recommendation C).
Project description:A phase II trial was launched to evaluate if neoadjuvant stereotactic ablative radiotherapy (SABR) before surgery improves oncologic outcomes in patients with stage I non-small cell lung cancer (NSCLC). We report a mandated interim safety analysis for the first 10 patients who completed protocol treatment. Operable patients with biopsy-proven T1-2 N0 NSCLC were eligible. SABR was delivered using a risk-adapted fractionation (54Gy/3 fractions, 55/5 or 60/8). Surgical resection was planned 10 weeks later at a high-volume center (>200 lung cancer resections annually). Patients were imaged with dynamic positron emission tomography-computed tomography scans using 18F-fludeoxyglucose (18F-FDG-PET CT) and dynamic contrast-enhanced CT before SABR and again before surgery. Toxicity was recorded using CTCAE version 4.0. Twelve patients were enrolled between 09/2014 and 09/2015. Two did not undergo surgery, due to patient or surgeon preference; neither patient has developed toxicity or recurrence. For the 10 patients completing both treatments, median age was 70 (range: 54-76), 60% had T1 disease, and 60% had adenocarcinoma. Median FEV1 was 73% predicted (range: 54-87%). Median time to surgery post-SABR was 10.1 weeks (range: 9.3-15.6 weeks). Surgery consisted of lobectomy (n?=?8) or wedge resection (n?=?2). Median follow-up post-SABR was 6.3 months. After combined treatment, the rate of acute grade 3-4 toxicity was 10%. There was no post-operative mortality at 90 days. The small sample size included herein precludes any definitive conclusions regarding overall toxicity rates until larger datasets are available. However, these data may inform others who are designing or conducting similar trials.NCT02136355 . Registered 8 May 2014.
Project description:Importance:Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. Objective:To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). Design, Setting, and Participants:This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. Interventions:Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. Main Outcomes and Measures:The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. Results:A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P?=?.01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. Conclusions and Relevance:Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. Trial Registration:clinicaltrials.gov Identifier: NCT02045446.
Project description:BACKGROUND:Stereotactic ablative radiotherapy (SABR) shows a remarkable local control of non-small cell lung cancer (NSCLC) metastases, partially as a result of host immune status. However, the predictors of immune cells for tumor response after SABR are unknown. To that effect, we investigated the ability of pre-SABR immune cells in peripheral blood to predict early tumor response to SABR in patients with lung metastases from NSCLC. METHODS:This study included 70 patients with lung metastases from NSCLC who were undergoing SABR. We evaluated the early tumor response 1 month and 6 months after SABR in these patients following RECIST 1.1 guidelines. Pre-SABR peripheral CD8+ T cell count, CD8+CD28+ T-cell count, CD8+CD28- T-cell count, CD4+ T-cell count, and Treg-cell count were measured using flow cytometry. RESULTS:Increased CD8+CD28+ T-cell counts (14.43 ± 0.65 vs. 10.21 ± 0.66; P = 0.001) and CD4/Treg ratio (16.96 ± 1.76 vs. 11.91 ± 0.74; P = 0.011) were noted in 1-month responsive patients, compared with non-responsive patients. In univariate logistic analyses, high CD8+CD28+ T-cell counts (OR 0.12, 95% CI 0.03-0.48; P = 0.003), CD4/Treg ratio (OR 0.24, 95% CI 0.06-0.90; P = 0.035), and BED10 (OR 0.91, 95% CI 0.84-0.99; P = 0.032) predicted a 1-month tumor response to SABR. According to multivariate logistic analyses, the CD8+CD28+ T-cell count predicted a 1-month tumor response to SABR (OR 0.19, 95% CI 0.04-0.90; P = 0.037) independently. Furthermore, we confirmed the independent predictive value of the CD8+CD28+ T-cell count in predicting tumor response to SABR in 41 patients 6 months after treatment (OR 0.08, 95% CI 0.01-0.85; P = 0.039). CONCLUSIONS:A pre-SABR CD8+CD28+ T-cell count could predict early tumor response to SABR in patients with lung metastases from NSCLC. Larger, independently prospective analyses are warranted to verify our findings.
Project description:The incidence of early-stage non-small cell lung cancer (NSCLC) among older adults is expected to increase because of demographic trends and computed tomography-based screening; yet, optimal treatment in the elderly remains controversial. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort spanning 2001-2007, we compared survival outcomes associated with 5 strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic ablative radiation therapy (SABR), and observation.Treatment strategy and covariates were determined in 10,923 patients aged ? 66 years with stage IA-IB NSCLC. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for the 5 strategies. In a second exploratory analysis, propensity-score matching was used for comparison of SABR with other options.The median age was 75 years, and 29% had moderate to severe comorbidities. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SABR (1.1%). In Cox regression analysis with a median follow-up time of 3.2 years, SABR was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.38-0.63; referent is lobectomy). After 6 months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after SABR was similar to that after lobectomy (HR 0.71; 95% CI 0.45-1.12; referent is SABR). Conventional radiation and observation were associated with poor outcomes in all analyses.In this population-based experience, lobectomy was associated with the best long-term outcomes in fit elderly patients with early-stage NSCLC. Exploratory analysis of SABR early adopters suggests efficacy comparable with that of surgery in select populations. Evaluation of these therapies in randomized trials is urgently needed.