Prediction of Microscopic Metastases in Patients with Metachronous Oligo-Metastases after Curative Treatment of Non-Small Cell Lung Cancer: A Microsimulation Study.

Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and the 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with a high versus low risk of undetected metastases can be separated. Because there is no clinical data on undetected metastases available, a microsimulation model of the development and detection of metastases in 100,000 hypothetical stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for the unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with a different risk of undetectable metastases. We identified the size and number of detected oligo-metastases, as well as the presence of symptoms that are the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group, having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively. Currently, the model is based on a synthesis of the literature data and individual patient-level data that were not collected for the purpose of this study. Optimization and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such a validation study.

Cost-effectiveness of stereotactic body radiation therapy versus video assisted thoracic surgery in medically operable stage I non-small cell lung cancer: A modeling study.

OBJECTIVES: Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC. MATERIALS AND METHODS: Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses. RESULTS: Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations. CONCLUSION: Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

Salvage surgery for local failures after stereotactic ablative radiotherapy for early stage non-small cell lung cancer.

INTRODUCTION: The literature on surgical salvage, i.e. lung resections in patients who develop a local recurrence following stereotactic ablative radiotherapy (SABR), is limited. We describe our experience with salvage surgery in nine patients who developed a local recurrence following SABR for early stage non-small cell lung cancer (NSCLC). METHODS: Patients who underwent surgical salvage for a local recurrence following SABR for NSCLC were identified from two Dutch institutional databases. Complications were scored using the Dindo-Clavien-classification. RESULTS: Nine patients who underwent surgery for a local recurrence were identified. Median time to local recurrence was 22 months. Recurrences were diagnosed with CT- and/or 18FDG-PET-imaging, with four patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during two resections, requiring conversion from a thoracoscopic procedure to thoracotomy during one of these procedures. Three patients experienced complications post-surgery; grade 2 (N = 2) and grade 3a (N = 1), respectively. All resection specimens showed viable tumor cells. Median length of hospital stay was 8 days (range 5-15 days) and 30-day mortality was 0 %. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. CONCLUSIONS: Our experience with nine surgical procedures for local recurrences post-SABR revealed two grade IIIa complications, and a 30-day mortality of 0 %, suggesting that salvage surgery can be safely performed after SABR.

Patterns of Disease Recurrence after SABR for Early Stage Non-Small-Cell Lung Cancer: Optimizing Follow-Up Schedules for Salvage Therapy.

INTRODUCTION: Stereotactic ablative radiotherapy is a guideline-recommended treatment for early stage non-small-cell lung cancer. We report on incidence and salvage of local recurrences (LR) and second primary lung cancers (SPLC) in a large series of patients with long-term follow-up, to generate data for evidence-based follow-up regimens. METHODS: We excluded all patients with double tumors, TNM-stages other than T1-T2N0M0, biologically effective dose less than 100 Gy10 and previous treatment for the index tumor from our institutional database. LR was defined as recurrence in/adjacent to the planning target volume. A diagnosis of SPLC was determined using criteria described by Martini et al. RESULTS: The 855 patients included had a median follow-up of 52 months. Forty-six patients developed LR after a median of 22 months (range 7-87 months). Actuarial local control rates at 3 and 5 years were 92.4% and 90.9%, respectively. Fifty-four percent had isolated LR and 13% had LR in combination with regional recurrences. Ten patients underwent radical salvage treatment; surgery (N = 6), high-dose radiotherapy (N = 3), or chemoradiation (N = 1). Median overall survival following LR was 13 months, but it was 36 months in patients who underwent radical salvage. A SPLC was diagnosed in 79 patients, after a median interval of 34 months. Actuarial cumulative incidences of SPLC at 3 and 5 years were 11.7% and 16.7%, respectively. Radical salvage for SPLC was performed in 63 patients (80%). CONCLUSIONS: Both the timing of LR and persistent risk of SPLC serve as rationale for long-term follow-up using computed tomography scans in patients fit enough to undergo any radical treatment.

An evaluation of websites providing patient information on stereotactic body radiation therapy (SBRT) for stage I lung cancer in three Western European countries.

BACKGROUND: The use of stereotactic body radiation therapy (SBRT) for the treatment of stage I lung cancer has been associated with improvements in population-based survival in Western Europe. As patients are increasingly accessing the Internet for information on health-related topics, we evaluated the quality, usability and readability of online patient information about SBRT in three adjacent Western European countries. MATERIALS AND METHODS: We conducted a web search and analysis between May - June 2011. Thirteen key terms were entered into the Google search engine. We analyzed websites from the Netherlands, Germany and the United Kingdom, by using the DISCERN instrument, a tool designed to assess the quality of health information on treatment choices. In addition, websites' usability and readability were examined. RESULTS: We identified a total of 20 websites. None of the websites received an excellent or good quality rating and only two were rated as fair (both from the United Kingdom). DISCERN scores rated 55% (N = 11) of the websites as poor, and 35% (N = 7) as very poor. Dutch websites had the lowest scores. Five websites attained relatively high usability scores, and none had sufficient readability scores. CONCLUSIONS: Despite the fact that SBRT is widely used as a standard therapy in elderly patients with stage I NSCLC in the Netherlands, only limited high quality information is available on the Internet. Improvements in quality information available on the Internet are required in order to increase patient participation in decision-making.

Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer.

BACKGROUND: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.