Safety and Efficacy of HL301 In Radiation Pneumonitis in Patients With Unresectable Non-Small Cell Lung Cancer Receiving Curative Concurrent Chemoradiotherapy: A Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Phase 2a Clinical Trial.

PURPOSE: We aimed to investigate the safety and efficacy of HL301, a standardized combination product of 7 medicinal plants, in radiation pneumonitis in patients with unresectable non-small cell lung cancer undergoing curative concurrent chemoradiotherapy. METHODS AND MATERIALS: The target accrual was 87 and a total of 63 patients were enrolled due to poor accrual rate. We randomly assigned the 63 patients to receive a placebo (arm A), or 1200 mg HL301 (arm B), or 1800 mg HL301 (arm C). Patients received weekly paclitaxel and carboplatin concurrently with intensity-modulated radiation therapy at 60 to 66 Gy in conventional fractionation. Durvalumab was administered as a maintenance treatment according to standard clinical practice. HL301 was administered orally, daily for 12 weeks. The primary endpoint was incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy. RESULTS: The baseline characteristics of the patients were well balanced. The drug was tolerable with a compliance rate of 86.6%, 86.2%, and 88.8% in arms A, B, and C, respectively (P = .874). None of the patients experienced severe drug-related adverse events. No significant difference in the rate of adverse events were observed between the treatment arms. The incidence of grade ≥2 radiation pneumonitis at 24 weeks postchemoradiotherapy was 37.5% (95% CI, 18.5%-61.4%), 55.6% (95% CI, 33.7%-75.4%), and 52.4% (95% CI, 32.4%-71.7%) in arms A, B, and C, respectively (P = .535). CONCLUSIONS: This is the first exploratory clinical trial to test the safety and efficacy of HL301 in patients with non-small cell lung cancer. Safety and feasibility of HL301 were established but no signals of efficacy in reducing radiation pneumonitis was observed in this dose level.

Review: Mechanisms and perspective treatment of radioresistance in non-small cell lung cancer.

Radiotherapy is the major treatment of non-small cell lung cancer (NSCLC). The radioresistance and toxicity are the main obstacles that leading to therapeutic failure and poor prognosis. Oncogenic mutation, cancer stem cells (CSCs), tumor hypoxia, DNA damage repair, epithelial-mesenchymal transition (EMT), and tumor microenvironment (TME) may dominate the occurrence of radioresistance at different stages of radiotherapy. Chemotherapy drugs, targeted drugs, and immune checkpoint inhibitors are combined with radiotherapy to treat NSCLC to improve the efficacy. This article reviews the potential mechanism of radioresistance in NSCLC, and discusses the current drug research to overcome radioresistance and the advantages of Traditional Chinese medicine (TCM) in improving the efficacy and reducing the toxicity of radiotherapy.

Evaluation of quality of life in lung cancer patients receiving radiation and Viscum album L.: a real-world data study.

BACKGROUND: Lung cancer (LC) is associated with high mortality and poor quality of life (QoL). The disease as well as oncological treatments such as radiation and chemotherapy with adverse effects can impair the QoL of patients. Add-on treatment with extracts of Viscum album L. (white-berry European mistletoe, VA) has been shown to be feasible and safe and to improve the QoL of cancer patients. The aim of this study was to analyze the changes in QoL of LC patients being treated with radiation according to oncological guidelines and add-on VA treatment in a real-world setting. METHODS: A real-world data study was conducted using registry data. Self-reported QoL was assessed by the evaluation of the European Organization of Research and Treatment Health-Related Quality of Life Core Questionnaire scale (EORTC QLQ-C30). Adjusted multivariate linear regression analyses were performed to analyze factors associated with changes in QoL at 12 months. RESULTS: A total of 112 primary LC patients (all stages, 92% non-small-cell lung cancer, median age 70 (ICR: 63-75)), answered the questionnaires at first diagnosis and 12 months later. Assessment of 12 months changes in QoL revealed significant improvement of 27 points for pain (p = 0.006) and 17 points for nausea/vomiting (p = 0.005) in patients who received combined radiation and VA. In addition, significant improvements of 15 to 21 points for role (p = 0.03), physical (p = 0.02), cognitive (p = 0.04), and social functioning (p = 0.04) were observed in guideline treated patients receiving no radiation but add-on VA. CONCLUSIONS: Add-on VA therapy reveals supportive effects for the QoL of LC patients. Particularly in combination with radiation a significant reduction in pain and nausea/ vomiting has been observed. Trial registration The study received ethics approval and was retrospectively registered (DRKS00013335 on 27/11/2017).

Lack of Adherence to Guideline-Based Imaging Before Subsequent Radiation in Patients with Non-Small Cell Lung Cancer: Impact on Patient Outcomes.

Lung cancer is the leading cause of cancer death within the United States, yet prior studies have shown a lack of adherence to imaging and treatment guidelines in patients with lung cancer. This study evaluated the use of 18F-FDG PET/CT imaging before subsequent radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC), as recommended by National Comprehensive Cancer Network guidelines, and whether the use of this imaging modality impacts cancer-specific survival. Methods: This was a retrospective study of the National Cancer Institute's Surveillance, Epidemiology, and End Results program of Medicare-linked data in patients with NSCLC. Hazard ratios and 95% CIs for overall and cancer-specific survival were estimated for patients diagnosed between 2006 and 2015 who underwent either 18F-FDG PET/CT-based or CT-based imaging before subsequent RT. Results: Significant improvement in cancer-specific survival was found in patients who underwent 18F-FDG PET/CT imaging before subsequent RT, compared with those who underwent CT (hazard ratio, 1.43 [95% CI, 1.32-1.55; P < 0.0001]). Although the National Comprehensive Cancer Network recommends 18F-FDG PET/CT before subsequent RT, 43.6% of patients were imaged with CT alone. Conclusion: Many patients with NSCLC are not being imaged according to national guidelines before subsequent RT, and this omission is associated with a lower cancer-specific survival.

Adverse Events Following Limited Resection versus Stereotactic Body Radiation Therapy for Early Stage Lung Cancer.

Rationale: Approximately a quarter of patients with early stage lung cancer are not medically fit for lobectomy. Limited resection and stereotactic body radiation therapy (SBRT) have emerged as alternatives for these patients. Given the equipoise on the effectiveness of the two treatments, treatment-related adverse events (AEs) could have a significant impact on patients' decision-making and treatment outcomes. Objectives: To compare the AE profile between SBRT versus limited resection. Methods: Data were derived from a prospective cohort of patients with stage I-IIA non-small cell lung cancer who were deemed as high-risk for lobectomy recruited from five centers across the United States. Propensity scores and inverse probability weighting were used to compare the rates of 30- and 90-day AEs among patients treated with limited resection versus SBRT. Results: Overall, 65% of 252 patients underwent SBRT. After adjusting for propensity scores, there was no significant difference in developing at least one AE comparing SBRT to limited resection (odds ratio [OR]: 1.00; 95% confidence interval [CI]: 0.65-1.55 and OR: 1.27; 95% CI: 0.84-1.91 at 30 and 90 days, respectively). SBRT was associated with lower risk of infectious AEs than limited resection at 30 days (OR: 0.05; 95% CI: 0.01-0.39) and 90 days posttreatment (OR: 0.41; 95% CI: 0.17-0.98). Additionally, SBRT was associated with persistently elevated risk of fatigue (OR: 2.47; 95% CI: 1.34-4.54 at 30 days and OR: 2.69; 95% CI: 1.52-4.77 at 90 days, respectively), but significantly lower risks of respiratory AEs (OR: 0.36; 95% CI: 0.20-0.65 and OR: 0.51; 95% CI: 0.31-0.86 at 30 and 90 days, respectively). Conclusions: Though equivalent in developing at least one AE, we found that SBRT is associated with less toxicity than limited resection in terms of infectious and respiratory AEs but higher rates of fatigue that persisted up to 3 months posttreatment. This information, combined with data about oncologic effectiveness, can help patients' decision-making regarding these alternative therapies.

Secondary Infections After Diagnosis of Severe Radiation Pneumonitis (SRP) Among Patients With Non-Small Cell Lung Cancer: Pathogen Distributions, Choice of Empirical Antibiotics, and the Value of Empirical Antifungal Treatment.

PURPOSE: This study aimed to assess pathogen distributions and antimicrobial sensitivity characteristics in patients with non-small cell lung cancer (NSCLC) with severe radiation pneumonitis (SRP) and secondary infections. METHODS AND MATERIALS: Data from 1746 patients with NSCLC and SRP after thoracic radiation therapy from January 2009 to December 2020 were retrospectively analyzed. Pneumonia incidence, causative pathogens, and antibiotic resistance characteristics in patients with secondary lung infections were analyzed. Risk factors associated with mortality were identified through univariate and multivariate analyses. Antifungal drug efficacy and duration-related effects were assessed with Forest plots and receiver operating characteristic curves. RESULTS: Overall, 44.5% of patients with NSCLC and SRP (777 of 1746 patients) were diagnosed with secondary lung infections. In total, 899 bacterial strains were isolated from these patients, with Acinetobacter baumannii (n = 206; 27%), Klebsiella pneumonia (n = 200; 26.2%), and Pseudomonas aeruginosa (n = 104; 13.6%) being the most common. Carbapenem and cefoperazone-sulbactam resistance rates of 52.7% and 32.2%, 28.8% and 26.4%, and 23.7% and 20.2% were observed for these isolates, respectively. Infection-related deaths occurred in 22.4% of patients with SRP. Independent risk factors for infection-related death included poor performance status scores, inappropriate empirical antimicrobial treatment, bacteria/fungal coinfection, and lack of empirical antifungal treatment. Receiver operating characteristic curves showed that the cutoff value of empirical antifungal treatment duration was 9 (area under the curve: 0.819). CONCLUSIONS: For patients with SRP and secondary lung infections, appropriate empirical antimicrobial treatment could decrease infection-related mortality, and cefoperazone-sulbactam may be an appropriate antibacterial drug. Empirical antifungal treatment for a minimum of 9 days might contribute to better outcomes. Although this represents a promising treatment approach for patients with SRP and secondary lung infections before antibacterial susceptibility testing, further prospective validation is essential.

Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States (US). Among VHA patients, the rate of use of concurrent chemoradiation therapy (CCRT) among those with unresectable, stage III non-small cell lung cancer (NSCLC) is unknown. The objective was to report recent CCRT treatment patterns in VHA patients and identify characteristics associated with receipt of CCRT. METHODS: Using Department of Veteran Affairs (VA) Cancer Registry System data linked to VA electronic medical records, we determined rates of CCRT, sequential CRT (SCRT), radiation therapy (RT) only, chemotherapy (CT) only, and neither treatment. RESULTS: Among 4054 VHA patients who met study criteria, CCRT rates slightly increased from 44 to 50% between 2013 and 2017. Factors associated with decreased odds of CCRT receipt compared to any other treatment included increasing age (adjusted odds ratio [aOR] per 10 years = 0.67; 95% CI: 0.60-0.76) and Charlson-Deyo comorbidity score (aOR = 0.94; 95% CI: 0.91-0.97). White race was associated with increased odds of CCRT receipt (aOR = 1.24; 95% CI: 1.004-1.53). In a chart review sample of 200 patients, less than half (n = 85) had a documented reason for not receiving CCRT. Among these, 29% declined treatment, and 71% did not receive CCRT due to "not being a candidate" for reasons related to frailty or lung nodules being too far apart for radiation therapy. CONCLUSIONS: CCRT rates among VHA patients with unresectable, stage III NSCLC slightly increased from 2013 to 2017; however in 2017, only half were receiving CCRT. Older patients and those with multiple comorbidities were less likely to receive CCRT and even when controlling for these factors, non-white patients were less likely to receive CCRT.

Multiblock Discriminant Analysis of Integrative 18F-FDG-PET/CT Radiomics for Predicting Circulating Tumor Cells in Early-Stage Non-small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy.

PURPOSE: The main objective of the present study was to integrate 18F-FDG-PET/CT radiomics with multiblock discriminant analysis for predicting circulating tumor cells (CTCs) in early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic body radiation therapy (SBRT). METHODS: Fifty-six patients with stage I NSCLC treated with SBRT underwent 18F-FDG-PET/CT imaging pre-SBRT and post-SBRT (median, 5 months; range, 3-10 months). CTCs were assessed via a telomerase-based assay before and within 3 months after SBRT and dichotomized at 5 and 1.3 CTCs/mL. Pre-SBRT, post-SBRT, and delta PET/CT radiomics features (n = 1548 × 3/1562 × 3) were extracted from gross tumor volume. Seven feature blocks were constructed including clinical parameters (n = 12). Multiblock data integration was performed using block sparse partial least squares-discriminant analysis (sPLS-DA) referred to as Data Integration Analysis for Biomarker Discovery Using Latent Components (DIABLO) for identifying key signatures by maximizing common information between different feature blocks while discriminating CTC levels. Optimal input blocks were identified using a pairwise combination method. DIABLO performance for predicting pre-SBRT and post-SBRT CTCs was evaluated using combined AUC (area under the curve, averaged across different blocks) analysis with 20 × 5-fold cross-validation (CV) and compared with that of concatenation-based sPLS-DA that consisted of combining all features into 1 block. CV prediction scores between 1 class versus the other were compared using the Wilcoxon rank sum test. RESULTS: For predicting pre-SBRT CTCs, DIABLO achieved the best performance with combined pre-SBRT PET radiomics and clinical feature blocks, showing CV AUC of 0.875 (P = .009). For predicting post-SBRT CTCs, DIABLO achieved the best performance with combined post-SBRT CT and delta CT radiomics feature blocks, showing CV AUCs of 0.883 (P = .001). In contrast, all single-block sPLS-DA models could not attain CV AUCs higher than 0.7. CONCLUSIONS: Multiblock integration with discriminant analysis of 18F-FDG-PET/CT radiomics has the potential for predicting pre-SBRT and post-SBRT CTCs. Radiomics and CTC analysis may complement and together help guide the subsequent management of patients with ES-NSCLC.

Case report of visual biofeedback-driven, magnetic resonance-guided single-fraction SABR in breath hold for early stage non-small-cell lung cancer.

Stereotactic ablative body radiation therapy (SABR) is a well-established alternative to surgery for early stage non-small-cell lung cancer (NSCLC). While SABR is typically delivered in 3 to 5 fractions, randomized trials have shown single-fraction SABR to be a reasonable alternative. We present the case of a 66-year-old male with history of cholangiocarcinoma who was subsequently diagnosed with peripheral early stage NSCLC and treated in mid-inspiration breath hold (BH) to 34 Gy in 1 fraction on a magnetic resonance (MR)-guided linear accelerator, with treatment delivery completed in 17 minutes. Visual biofeedback was utilized to maximize patient compliance with appropriate depth of inspiration BH and improve overall treatment delivery time efficiency. The benefits of single- vs multifraction SABR and unique advantages of MR guidance that are particularly well-suited for single-fraction SABR are reviewed.

MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC.

BACKGROUND: The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as "self", evade the surveillance of the immune system, and accumulate to the tumor sites actively. RESULTS: Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate-an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. CONCLUSIONS: These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

High-dose Radiotherapy for Oligo-progressive NSCLC Receiving EGFR Tyrosine Kinase Inhibitors: Real World Data.

BACKGROUND/AIM: Local ablative treatments for oligo-progressive, EGFR mutated non-small cell lung cancer (mut-NCSLC) may improve long-term disease control and survival. We analyzed the efficacy of hypo-fractionated, high-dose radiation therapy (HDRT), in association with prolonged EGFR tyrosine kinase inhibitors (TKI) in oligo-progressive, EGFR mutant-NSCLC. PATIENTS AND METHODS: Progression-free survival-1 (PFS-1, date from initiation of TKI therapy until oligo-progression or death), and progression-free survival-2 (PFS-2, date of focal progression until further progression or death) were evaluated. RESULTS: Thirty-six patients were analyzed. The median PFS 1 was 12.5 months. HDHRT consisted of intensity-modulated RT and stereotactic RT in 23 (64%) and 13 (36%) patients respectively. The median PFS 2 was 6.3 months. Overall survival was 38.7 months. CONCLUSION: Hypo-fractionated HDRT plus TKI therapy, is associated with a significant prolongation of disease control (overall PFS: 18.8 months), with manageable side effects. These real-world data support the use of local ablative approaches in oligo-progressive EGFR mut-NSCLC.

Stereotactic body radiation therapy for early-stage non-small-cell lung cancer in octogenarians and older: an alternative treatment.

Surgery is the standard modality for early-stage I-II non-small-cell lung cancer (NSCLC). Generally, patients who are >80 years old tend to have more comorbidities and inferior physical status than younger patients. Stereotactic body radiation therapy (SBRT) may provide an alternative treatment for this group of patients. Here, we report our experience using SBRT to in the management of early-stage NSCLC in patients >80 years old. Patients aged ≥80 years old who were diagnosed with early-stage NSCLC and treated with definitive lung SBRT from January 2000 to January 2018 were retrospectively analysed. Local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), cancer-specific survival (CSS), progression-free survival (PFS), overall survival (OS) and treatment-related toxicities were analysed for patients >80 years old. A total of 153 patients were included, with a median age of 85 years (range, 80-94). The median follow-up period and OS was 39.8 months (range, 10-101 months) and 76 months, respectively. The 3-year OS, PFS, CSS, RRFS and LRFS were 65.3, 58.0, 75.7, 73.9 and 85.3%, respectively. Radiation pneumonitis grade 0-1, grade 2, grade 3 and grade 4 was observed in 135 (88.2%), 13 (8.5%), 4 (2.61%) and 1 (0.6%) patient(s), respectively. On multivariate analyses, tumor size, pretreatment C-reactive protein (CRP) value, histology and pretreatment physical state were significantly associated with OS. Definitive lung SBRT appears to have high LRFS and OS without causing high-grade radiation-related toxicities in early-stage NSCLC patients who were >80 years old.

Enhancing Targeted Cancer Treatment by Combining Hyperthermia and Radiotherapy Using Mn-Zn Ferrite Magnetic Nanoparticles.

Radiotherapy (RT) is a major treatment method for non-small-cell lung cancer (NSCLC), and development of new treatment modality is now critical to amplify the negative effects of RT on tumors. In this study, we demonstrated a nanoparticle-loaded block copolymer micellar system for cancer hyperthermia treatment (HT) that can be used for synergistic therapy under alternating magnetic field (AMF) and radiation field. Block copolymer micelles (polyethylene glycol-block-polycaprolactone, or PEG-PCL) containing hyaluronic acid (HA) and Mn-Zn ferrite magnetic nanoparticles (MZF) were fabricated via a two-step preparation. HA-modified Mn-Zn ferrite magnetic nanoparticles (MZF-HA) can be enriched in CD44 highly expressing tumor cells, such as A549 (human lung adenocarcinoma cell line), through an active targeting mechanism via receptor-ligand binding of HA and CD44 (HA receptor). MZF can generate thermal energy under an AMF, leading to a local temperature increase to approximately 43 °C at tumor sites for mild HT, and the increased tumor oxygenation can enhance the therapeutic effect of RT. In vitro experiments show that MZF-HA is able to achieve excellent specific targeting performance toward A549 cells with excellent biocompatibility as well as enhanced therapy performance under HT and RT in vitro by apoptosis flow cytometry. In the A549 subcutaneous tumor xenografts model, MRI confirms the enrichment of MZF-HA in tumor, and hypoxia immunohistochemistry analysis (IHC) proved the increased tumor oxygenation after HT. Furthermore, the tumor volume decreases to 49.6% through the combination of HT and RT in comparison with the 58.8% increase of the untreated group. These results suggest that the application of MZF-HA is able to increase the therapeutic effect of RT on A549 and can be used for further clinical NSCLC treatment evaluation.

Implantation of 125I radioactive seeds via c-TBNA combined with chemotherapy in an advanced non-small-cell lung carcinoma patient.

BACKGROUND: The critical management of advanced non-small-cell lung carcinoma (NSCLC), especially when complicated by severe airway stenosis, is difficult and often leads to high clinical risks and medical costs. CASE PRESENTATION: A 51-year-old previously healthy male was admitted to the Department of Respiratory and Critical Care Medicine, Taizhou People's Hospital, in November 2018 for haemoptysis and difficulty breathing during a 15-d period. Following admission, chest computed tomography (CT) showed a large mass in the left hilum with atelectasis in the left upper lobe and obstructive pneumonia in the left lower lobe. Bronchoscopy revealed that the lesions occurred in the distal segment of the left main trachea, with occlusion of the left upper bronchus and significant narrowing of the lower bronchus. A basal mucosal biopsy of the lump tissue was performed after haemostasis treatment with sub-plasma coagulation (APC), and squamous lung carcinoma was confirmed. Following the final diagnosis, the patient was successfully treated with implantation of 125I radioactive seeds via transbronchial needle aspiration (c-TBNA) combined with chemotherapy. CONCLUSION: We believe that implantation of 125I radioactive seeds via c-TBNA is an effective treatment for patients with advanced lung cancer and those presenting with severe and mixed main bronchus stenosis.

Cost-Effectiveness Analysis of Upfront SBRT for Oligometastatic Stage IV Non-Small Cell Lung Cancer Based on Mutational Status.

OBJECTIVES: Current National Comprehensive Cancer Network (NCCN) guidelines support systemic therapy based on mutational status in stage IV non-small cell lung cancer (NSCLC), with stereotactic body radiation therapy (SBRT) reserved for oligoprogression. We aimed to evaluate the cost-effectiveness of the routine addition of SBRT to upfront therapy in stage IV NSCLC by mutational subgroup. MATERIALS AND METHODS: A Markov state transition model was constructed to perform a cost-effectiveness analysis comparing SBRT plus maintenance therapy with maintenance therapy alone for oligometastatic NSCLC. Three hypothetical cohorts were analyzed: epidermal growth factor receptor or anaplastic lymphoma kinase mutation-positive, programmed death ligand-1 expressing, and mutation-negative group. Clinical parameters were obtained largely from clinical trial data, and cost data were based on 2018 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness to pay threshold of $100,000 per QALY gained. RESULTS: SBRT plus maintenance therapy was not cost-effective at a $100,000/QALY gained threshold, assuming the same survival for both treatments, resulting in an incremental cost effectiveness ratio of $564,186 and $299,248 per QALY gained for the epidermal growth factor receptor or anaplastic lymphoma kinase positive and programmed death ligand-1 positive cohorts, respectively. Results were most sensitive to the cost of maintenance therapy. A large overall survival gain with SBRT could potentially result in upfront SBRT becoming cost-effective. For the mutation-negative cohort, upfront SBRT was nearly cost-effective, costing $128,424 per QALY gained. CONCLUSION: Adding SBRT to maintenance therapy is not a cost-effective strategy for oligometastatic NSCLC compared with maintenance therapy alone for mutation-positive groups. However, this should be validated via randomized trials.

ß-Apopicropodophyllin functions as a radiosensitizer targeting ER stress in non-small cell lung cancer.

AIMS: In this study, we examined whether ß-apopicropodophyllin (APP) could act as a radiosensitizer in non-small cell lung cancer (NSCLC) cells. MAIN METHODS: The in vitro radiosensitizing activity of APP was demonstrated with clonogenic assay, immunoblotting, Annexin V-Propidium iodide (PI) assay, BrdU incorporation, detection of mitochondrial ROS/intracellular of H2O2, mitochondrial membrane potential detection, and performing of isolation of mitochondrial and cytosolic fractions. The in vivo radiosensitizing activity of APP was determined in xenografted mice with co-treatment of APP and IR based on measurement of tumor volumes and apoptotic cell death. KEY FINDINGS: The results of a clonogenic assay indicated that a combination of APP and γ-ionizing radiation (IR) inhibits cell growth and increases cell death in NSCLC cells. Several signal transduction pathways were examined for their potential involvement in the apparent radiosensitization effect of APP, as assessed by immunoblotting analyses and mitochondrial potential determination in vitro. Treatment of NCI-H460 cells with 15 nM APP and NCI-H1299 cells with 10 nM APP yielded dose-enhancement ratios of 1.44 and 1.24, respectively. Enhanced ER stress, disrupted mitochondrial membrane potential, and increased reactive oxygen species (ROS) were observed in cells co-treated with APP and IR, and this was followed by the cytosolic release of cytochrome c and consequent activation of caspase-3 and -9. Notably, inhibition of JNK, which prevents caspase activation, blocked the APP/IR-induced activations of ER stress and apoptotic cell death. In NCI-H460 or NCI-H1299 cell-xenografted mice, APP/IR treatment delayed the time it took tumors to reach a threshold size by 22.38 and 16.83 days, respectively, compared with controls, to yield enhancement factors of 1.53 and 1.38, respectively. SIGNIFICANCE: APP has a radiosensitizing function derived from its ability to induce apoptotic cell death via activation of ER stress, disruption of mitochondrial membrane potential, and induction of the caspase pathway.

Sanyang Xuedai enhances the radiosensitivity of human non-small cell lung cancer cells via increasing iNOS/NO production.

OBJECTIVE: In this research, we aimed at finding out how San Yang Xue Dai (SYKT) promotes the radiosensitivity of non-small cell lung cancer (NSCLC) cell line NCI-H460. METHODS: Survival rate of NSCLC cells (A549, NCI-H460, NCI-H1650 and NCI-H1975) after the SYKT treatment or irradiation (IR) was calculated by the MTT assay. The radiosensitization of SYKT (0.5 g/mL and 1.0 g/mL) on cell line NCI-H460 and the radioresistant cell line NCI-H460R was studied by MTT assay and clone formation assay. The protein expression levels of iNOS, Cyclin B1 and CDC2 were determined by western blot, and the expression of NO was measured by Griess method. Finally, cell cycle and apoptotic rate of NSCLC cell line NCI-H460 were accessed by flow cytometry assay. BrdU staining was also applied to detect the cell proliferation after IR with or without SYKT treatment. RESULTS: The IC10 value of SYKT for NCI-H460 cells was 1.03 g/mL. After 1.0 g/mL SYKT treatment, the radiosensitivity of NCI-H460R cells was enhanced. The level of iNOS in the cells was found decreased after IR. We also found that SYKT could enhance iNOS and NO expressions while inhibit cyclin B1 and CDC2 expressions in radiation resistant cells. Combining ß-irradiation with SYKT caused cell cycle arrest in G2/M phase and increased cell apoptosis. CONCLUSION: SYKT resensitized radioresistant NCI-H460R cells via increasing cell apoptosis and cell cycle arrest. This was due to an elevated NO level caused by accumulating iNOS and effects of SYKT on radiosensitization of NSCLC should be further investigated in clinical application.

Combination Strategies Using EGFR-TKi in NSCLC Therapy: Learning from the Gap between Pre-Clinical Results and Clinical Outcomes.

Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long-term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo. Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies. However, a significant gap still exists when applying pre-clinical results to clinical scenarios, which hinders the development and use of these strategies. This article is a literature review analysing the rationalities and controversies in the transition from pre-clinical investigation to clinical practice associated with various combination strategies. It also highlights clues and challenges regarding future combination therapeutic options in NSCLC treatment.

Standardization of radiation therapy dose for locally advanced non-small cell lung cancer through changes to a lung cancer clinical pathway in a large, integrated comprehensive cancer center network.

PURPOSE: The results of Radiation Therapy Oncology Group (RTOG) 0617, which randomized patients with stages IIIA/IIIB non-small cell lung cancer (NSCLC) to definitive chemoradiation therapy to 60 Gy versus 74 Gy, demonstrated a detrimental survival impact with high-dose radiation therapy. We evaluated the impact of changes to a provider-driven clinical pathway (CP) guiding management of NSCLC on practice throughout our cancer center network. METHODS AND MATERIALS: In 2001, we implemented a CP for management of stage IIIA/IIIB NSCLC with definitive chemoradiation therapy. In 2013, the CP for NSCLC was amended (amendment 1) to allow a dose range of 60 to 74 Gy. The CP was amended (amendment 2) in January 2016 to specify a dose range of 60 to 70 Gy. Higher doses were considered off-pathway and subject to peer review. Data from decisions entered from 2012 to 2016 were obtained. RESULTS: From 2012 until publication of RTOG 0617 in February 2015, the median prescription dose was 66 Gy delivered in 1.8 to 2.1 Gy fractions. Doses ≤66 Gy were prescribed for 52% of patients. From February 2015 to September 2016, the median prescription dose was 60 Gy, and 91% of prescription doses were ≤66 Gy. After amendment 2, 99% of decisions were ≤66 Gy. Dose ≤66 Gy was associated with treatment following publication of 0617 (P < .001) and treatment after amendment 2 (P < .001). On multivariable analysis, treatment after amendment 2 was associated with dose ≤66 Gy (odds ratio, 9.9; 95% confidence interval, 5.2-19.0; P < .001). The percentage of lung receiving 20 Gy was lower following publication of 0617 (P < .001). There was no difference in the percentage of heart receiving 40 Gy. CONCLUSIONS: CPs eliminate variations in practice that lead to inferior outcomes. Recognizing that our CP for definitive treatment of patients with locally advanced NSCLC allowed heterogeneous dose prescriptions, we modified the CP based on the publication of RTOG 0617. We found that the CP was a tool to ensure patients receive evidence-based care across a large cancer center network.

Radiotherapy for brain metastases near the end of life in an integrated health care system.

BACKGROUND: To examine radiotherapy (RT) patterns-of-care and utilization at the end of life (EOL) among non-small cell lung cancer (NSCLC) patients with brain metastasis (BrM) in an integrated health care system. METHODS: Central tumor registry identified 5,133 patients diagnosed with NSCLC from 2007-2011. BrM were determined by imaging. Patient and clinical characteristics were obtained by chart abstraction. In addition to abstracted variables, graded prognostic assessment (GPA) score of 0-1 was derived by collected data and tested as a predictor of death within 14 or 30 days of RT. RESULTS: On NSCLC presentation, 10% harbored BrM while 7% developed BrM thereafter. Of 900 BrM patients, 15% were not referred for RT, with median time to death of 21 days. Median time to death for 5% not recommended RT was 48 days. Among those receiving brain RT, 11.9% died within 14 days and 23.3% (cumulatively) died within 30 days of treatment. Over 50% with GPA score 0-1 received RT, 11% within 14 days and 21% within 30 days of death; median survival of GPA score 0-1 patients was 49 days. GPA score 0-1 independently predicted for death within 30 days of RT receipt. CONCLUSIONS: BrM are common in NSCLC, and most patients are referred for brain RT. A surprising proportion of patients received treatment near the EOL, as 23% died within 30 days of RT. GPA score of 0-1 predicted for death within 30 days of treatment. RT referral, recommendation, and timing should be better tailored to life expectancy, and additional benchmarks for quality of care are needed.