Alexander V. Louie

Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.

Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons

The use of stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is growing rapidly, particularly since it has become the recommended therapy for unfit patients in current European and North American guidelines. As three randomized trials comparing surgery and SABR closed prematurely because of poor accrual, clinicians are faced with a dilemma in individual patient decision-making. Radiation oncologists, in particular, should be aware of the data from comparative effectiveness studies that suggest similar survival outcomes irrespective of local treatment modality. The necessity of obtaining a pathological diagnosis, particularly in frail patients prior to treatment remains a challenge, and this topic was addressed in recent European recommendations. Awareness of the high incidence of a second primary lung cancer in survivors, as well as other competing causes of mortality, is needed. The challenges in distinguishing focal scarring from recurrence after SABR also need to be appreciated by multidisciplinary tumor boards. With a shift in focus toward patient-centered decision-making, clinicians will need to be aware of these new developments and communicate effectively with patients, to ensure that treatment decisions are reflective of patient preferences. Priorities for additional research in the area are proposed.

Inter and Intrafraction Uncertainty in Prostate Bed Image-Guided Radiotherapy

PURPOSE The goals of this study were to measure inter- and intrafraction setup error and prostate bed motion (PBM) in patients undergoing post-prostatectomy image-guided radiotherapy (IGRT) and to propose appropriate population-based three-dimensional clinical target volume to planning target volume (CTV-PTV) margins in both non-IGRT and IGRT scenarios. METHODS AND MATERIALS In this prospective study, 14 patients underwent adjuvant or salvage radiotherapy to the prostate bed under image guidance using linac-based kilovoltage cone-beam CT (kV-CBCT). Inter- and intrafraction uncertainty/motion was assessed by offline analysis of three consecutive daily kV-CBCT images of each patient: (1) after initial setup to skin marks, (2) after correction for positional error/immediately before radiation treatment, and (3) immediately after treatment. RESULTS The magnitude of interfraction PBM was 2.1 mm, and intrafraction PBM was 0.4 mm. The maximum inter- and intrafraction prostate bed motion was primarily in the anterior-posterior direction. Margins of at least 3-5 mm with IGRT and 4-7 mm without IGRT (aligning to skin marks) will ensure 95% of the prescribed dose to the clinical target volume in 90% of patients. CONCLUSIONS PBM is a predominant source of intrafraction error compared with setup error and has implications for appropriate PTV margins. Based on inter- and estimated intrafraction motion of the prostate bed using pre- and post-kV-CBCT images, CBCT IGRT to correct for day-to-day variances can potentially reduce CTV-PTV margins by 1-2 mm. CTV-PTV margins for prostate bed treatment in the IGRT and non-IGRT scenarios are proposed; however, in cases with more uncertainty of target delineation and image guidance accuracy, larger margins are recommended.

Adjuvant radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline

PURPOSE To provide guidance to physicians and patients with regard to the use of adjuvant external beam radiation therapy (RT) in locally advanced non-small cell lung cancer (LA NSCLC) based on available medical evidence complemented by consensus-based expert opinion. METHODS AND MATERIALS A panel authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors and Guidelines Subcommittee conducted 2 systematic reviews on the following topics: (1) indications for postoperative adjuvant RT and (2) indications for preoperative neoadjuvant RT. Practice guideline recommendations were approved using an a priori-defined consensus-building methodology supported by ASTRO and approved tools for the grading of evidence quality and the strength of guideline recommendations. RESULTS For patients who have undergone surgical resection, high-level evidence suggests that use of postoperative RT does not influence survival, but optimizes local control for patients with N2 involvement, and its use in the setting of positive margins or gross primary/nodal residual disease is recommended. No high-level evidence exists for the routine use of preoperative induction chemoradiation therapy; however, modern surgical series and a post-hoc Intergroup 0139 clinical trial analysis suggest that a survival benefit may exist if patients are properly selected and surgical techniques/postoperative care is optimized. CONCLUSIONS A consensus and evidence-based clinical practice guideline for the adjuvant radiotherapeutic management of LA NSCLC has been created addressing 2 important questions.

Management and Prognosis in Synchronous Solitary Resected Brain Metastasis from Non–Small-Cell Lung Cancer

BACKGROUND Reports in the medical literature have described cases of extended survival of patients with non-small-cell lung cancer (NSCLC) with solitary metastatic disease who have received aggressive treatment both to the brain metastasis and to the local/regional disease. The objective of this research is to analyze prognostic factors that predict for outcome in this unique patient population. PATIENTS AND METHODS A single-institution, retrospective chart review was performed on 35 patients with NSCLC and a synchronous solitary brain metastasis (SSBM) treated with craniotomy and whole-brain radiation therapy. Eight patients (22.9%) had chest surgery, 24 (68.6%) had chemotherapy, and 14 (40%) had thoracic radiation as part of their local management. Fourteen had stage I/II disease (42.9%), and 20 had stage III disease (57.1%). Mean age at diagnosis was 58.5 years. Eighteen patients (56.25%) had a brain metastasis < 3 cm, and 14 patients (43.75%) had a metastasis > 3 cm. RESULTS Median survival was 7.8 months, and at last follow-up, 3 patients (8.6%) were alive and well, 6 patients (17.1%) were alive and with disease, 24 patients (68.6%) had died of disease, and 2 patients (5.7%) had died of other causes. Univariate analysis demonstrated that lung surgery (P = .0033), primary lung treatment > 8 weeks after brain surgery (P = .0128), and stage I/II disease (P = .0467) were predictive of overall survival. CONCLUSION Survival remains poor for patients with NSCLC with an SSBM. However, patients with thoracic disease amenable to local resection should be considered for such therapy because a survival advantage could exist compared with patients with more locally advanced disease.

When Is a Biopsy-Proven Diagnosis Necessary Before Stereotactic Ablative Radiotherapy for Lung Cancer?: A Decision Analysis

BACKGROUND The practice of treating a solitary pulmonary nodule (SPN) suspicious for stage I non-small cell lung cancer (NSCLC) with stereotactic ablative radiotherapy (SABR) in the absence of pathology is growing. In the absence of randomized evidence, the appropriate prior probability threshold of lung cancer of when such a strategy is warranted can be informed using decision analysis. METHODS A decision tree and Markov model were constructed to evaluate the relative merits of surveillance, a PET scan-directed SABR strategy (without pathology), or a PET scan-biopsy-SABR strategy, when faced with an SPN at different prior probabilities for lung cancer. Diagnostic characteristics, as well as disease, treatment, and toxicity parameters, were extracted from the literature. Deterministic analysis and probabilistic sensitivity analyses were performed to inform the appropriate lung cancer prior probability threshold between treatment strategies. RESULTS In the reference case analysis, the prior probability threshold between surveillance and PET scan-biopsy-SABR was 17.0%; between PET scan-directed SABR and PET scan-biopsy-SABR, the threshold was 85.0%. The latter finding was confirmed on probabilistic sensitivity analysis (85.2%; 95% CI, 80.0% to 87.2%). This predicted lung cancer prior probability threshold was most sensitive to the diagnostic sensitivity of transthoracic biopsy (range, 77.2% to 94.0%) and the detection rate of false negatives on CT scan surveillance (range, 82.4% to 92.3%). CONCLUSIONS This model suggests that if there are concerns about morbidity related to biopsy for an SPN, a PET scan-directed SABR strategy is warranted when the prior probability of lung cancer exceeds a point estimate of 85%.

Detection of Local Cancer Recurrence After Stereotactic Ablative Radiation Therapy for Lung Cancer: Physician Performance Versus Radiomic Assessment

PURPOSE Stereotactic ablative radiation therapy (SABR) is a guideline-specified treatment option for early-stage lung cancer. However, significant posttreatment fibrosis can occur and obfuscate the detection of local recurrence. The goal of this study was to assess physician ability to detect timely local recurrence and to compare physician performance with a radiomics tool. METHODS AND MATERIALS Posttreatment computed tomography (CT) scans (n=182) from 45 patients treated with SABR (15 with local recurrence matched to 30 with no local recurrence) were used to measure physician and radiomic performance in assessing response. Scans were individually scored by 3 thoracic radiation oncologists and 3 thoracic radiologists, all of whom were blinded to clinical outcomes. Radiomic features were extracted from the same images. Performances of the physician assessors and the radiomics signature were compared. RESULTS When taking into account all CT scans during the whole follow-up period, median sensitivity for physician assessment of local recurrence was 83% (range, 67%-100%), and specificity was 75% (range, 67%-87%), with only moderate interobserver agreement (κ = 0.54) and a median time to detection of recurrence of 15.5 months. When determining the early prediction of recurrence within <6 months after SABR, physicians assessed the majority of images as benign injury/no recurrence, with a mean error of 35%, false positive rate (FPR) of 1%, and false negative rate (FNR) of 99%. At the same time point, a radiomic signature consisting of 5 image-appearance features demonstrated excellent discrimination, with an area under the receiver operating characteristic curve of 0.85, classification error of 24%, FPR of 24%, and FNR of 23%. CONCLUSIONS These results suggest that radiomics can detect early changes associated with local recurrence that are not typically considered by physicians. This decision support system could potentially allow for early salvage therapy of patients with local recurrence after SABR.

Systematic review of the cost-effectiveness of positron-emission tomography in staging of non--small-cell lung cancer and management of solitary pulmonary nodules.

Implementation of positron-emission tomography (PET) is variable depending on jurisdiction in part due to uncertainty about cost-effectiveness. Our objective was to perform a systematic review describing cost-effectiveness of PET in staging of non-small-cell lung cancer (NSCLC) and management of solitary pulmonary nodules (SPN). Systematic literature searches were conducted using separate search strategies for multiple databases. Our validity criteria included measurement of study quality by means of the validated Quality of Health Economic Studies (QHES) instrument. Metrics such as mean PET costs, median average cost savings per patient, incremental cost-effectiveness ratio based on life years saved and quality-adjusted life years were calculated. Eighteen studies met our inclusion criteria with average QHES scores > 75. Studies were primarily based on the national health insurance payer perspective from 10 different countries. Cost-effectiveness was assessed primarily using decision-tree modeling and sensitivity analysis to determine the effects of changing variables on expected cost and life expectancy. After adjusting for currency exchange rates and inflation to 2010 United States dollars, the mean cost of PET was

Systematic review of brain metastases prognostic indices

1478. The cost-effectiveness metrics used in these studies were variable depending on sensitivity and specificity of diagnostic tests used in the models, probability of malignancy, and baseline strategy. Despite observed study heterogeneity, the consensus of these studies conclude that the additional information gained from PET imaging in the staging of NSCLC and diagnosis of SPNs is worth the cost in context of proper medical indications.

Creation of RTOG compliant patient CT-atlases for automated atlas based contouring of local regional breast and high-risk prostate cancers

PURPOSE A variety of prognostic indices for patients with brain metastases have been published in the literature, to guide clinical decision-making and clinical trial stratification. The purpose of this investigation is to perform a systematic review of all primary and validation reports of such prognostic systems. An assessment of index operating characteristics and misclassification rates was performed to assist in highlighting the advantages and disadvantages of competing systems. METHODS AND MATERIALS A systematic review of the English language literature regarding primary and validation brain metastases prognostic indices was performed according to PRISMA guidelines. Clinical, treatment, statistical, and prognostic index classification details were abstracted and organized into tables. Receiver operator characteristic curves were created from available Kaplan-Meier curves using a novel digitization procedure. From these curves, various operating characteristics such as positive predictive value (PPV), negative predictive value (NPV), accuracy (ACC), likelihood ratio (LR), and area under the curve (AUC) were calculated. Additionally, the major misclassification rate (MMR), defined as good or poor risk patients misclassified into the opposite group, was calculated for all available receiver operator characteristic curves. RESULTS A total of 9 prognostic systems have been published in the medical literature. In terms of the poor prognostic group, observed ranges are as follow: for PPV (0.25-0.72), NPV (0.72-0.97), ACC (0.57-0.95), LR (1.54-16.4), AUC (0.64-0.90), and MMR (0.02-0.39). Similarly, ranges of PPV (0.52-0.96), NPV (0.31-0.77), ACC (0.41-0.74), LR (1.69-20), AUC (0.64-0.89), and MMR (0.00-0.19) were observed for the good prognostic group. CONCLUSIONS Operating characteristic and major misclassification analyses of all available prognostic index information demonstrated a range of results. As the ideal prognostic index has not yet been defined, further research into alternative approaches is warranted. Information contained within this report can serve as a benchmark for future investigations of existing and proposed prognostic indices.