Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an abscopal effect although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This quadmodality approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy

An \u3cem\u3ein Vitro\u3c/em\u3e Assessment of Liposomal Topotecan Simulating Metronomic Chemotherapy in Combination with Radiation in Tumor-Endothelial Spheroids

Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare them to a fractionated low dose regimen of free TPT in tumor-endothelial spheroids (TES) with/without radiation exposure for a prolonged period of 10 days. Using confocal microscopy, TPT fluorescence was monitored to determine the accumulation of drug within TES. These studies showed TES, being more reflective of the in vivo tumor microenvironment, were more sensitive to LTPT in comparison to free TPT with radiation. More importantly, the response of TES to low-dose metronomic TPT with radiation was comparable to similar treatment with LTPT. This TES study suggests nanoparticle formulations designed for extended release of drug can simulate LDMC in vivo

Evaluation of Plan Quality and Treatment Efficiency for Single-Isocenter/Two-Lesion Lung Stereotactic Body Radiation Therapy

Purpose/objectives: To evaluate the plan quality and treatment delivery efficiency of single‐isocenter/two‐lesions volumetric modulated arc therapy (VMAT) lung stereotactic body radiation therapy (SBRT). Materials/methods: Eight consecutive patients with two peripherally located early stage nonsmall‐cell‐lung cancer (NSCLC) lung lesions underwent single‐isocenter highly conformal noncoplanar VMAT SBRT treatment in our institution. A single‐isocenter was placed between the two lesions. Doses were 54 or 50 Gy in 3 and 5 fractions respectively. Patients were treated every other day. Plans were calculated in Eclipse with AcurosXB algorithm and normalized to at least 95% of the planning target volume (PTV) receiving 100% of the prescribed dose. For comparison, two‐isocenter plans (isocenter placed centrally in each target) were retrospectively created. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D2cm were calculated. The normal lung V5, V10, V20, mean lung dose (MLD) and other organs at risk (OARs) doses were evaluated. Total number of monitor units (MUs), beam‐on time, and patient‐specific quality assurance (QA) results were recorded. Results: The mean isocenter to tumor distance was 6.7 ± 2.3 cm. The mean combined PTV was 44.0 ± 23.4 cc. There was no clinically significant difference in CI, HI, GD, GI, D2cm, and V20 including most of the OARs between single‐isocenter and two‐isocenter lung SBRT plans, evaluated per RTOG guidelines. However, for single‐isocenter plans as the distance between the lesions increased, the V5, V10, and MLD increased, marginally. The total number of MUs and beam‐on time was reduced by a factor of 1.5 for a single‐isocenter plan compared to a two‐isocenter plan. The single‐isocenter/two‐lesions VMAT lung SBRT QA plans demonstrated an accurate dose delivery of 98.1 ± 3.2% for clinical gamma passing rate of 3%/3 mm. Conclusion: The SBRT treatment of two peripherally located lung lesions with a centrally placed single‐isocenter was dosimetrically equivalent to two‐isocenter plans. Faster treatment delivery for single‐isocenter treatment can improve patient compliance and reduce the amount of intrafraction motion errors for well‐suited patients

Feasibility of Using Ring-Mounted Halcyon Linac for Single-Isocenter/Two-Lesion Lung Stereotactic Body Radiation Therapy

PURPOSE: To demonstrate the plan quality and delivery efficiency of volumetric-modulated arc therapy (VMAT) with the Halcyon Linac ring delivery system (RDS) in the treatment of single-isocenter/two-lesion lung stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Sixteen previously treated non-coplanar VMAT single-isocenter/two-lesion lung SBRT plans delivered with SBRT-dedicated C-arm TrueBeam Linac were selected. Prescribed dose was 50 Gy to each lesion over five fractions with treatment delivery every other day and AcurosXB algorithm as the final dose calculation algorithm. TrueBeam single-isocenter plans were reoptimized for Halcyon Linac with coplanar geometry. Both TrueBeam and Halcyon plans were normalized for identical combined target coverage and evaluated. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D2cm were compared. The normal lung V5Gy, V10Gy, V20Gy, mean lung dose (MLD), and dose to organs at risk (OAR) were evaluated. Treatment delivery parameters, including beam-on time, were recorded. RESULTS: Halcyon plans were statistically similar to clinically delivered TrueBeam plans. No statistical differences in target conformity, dose heterogeneity, or intermediate-dose spillage were observed (all, p \u3e 0.05). Halcyon plans, on average, demonstrated statistically insignificant reduced maximum dose to most adjacent OAR and normal lung. However, Halcyon yielded statistically significant lower maximal dose to the ribs (p = 0.041) and heart (p = 0.026), dose to 1 cc of ribs (p = 0.035) and dose to 5 cc of esophagus (p = 0.043). Plan complexity slightly increased as seen in the average increase of total monitor units, modulation factor, and beam-on time by 480, 0.48, and 2.78 min, respectively. However, the estimated overall treatment time was reduced by 2.22 min, on average. Mean dose delivery accuracy of clinical TrueBeam plans and the corresponding Halcyon plans was 98.9 ± 0.85% (range: 98.1%–100%) and 98.45 ± 0.99% (range: 97.9%–100%), respectively, demonstrating similar treatment delivery accuracy. CONCLUSION: SBRT treatment of synchronous lung lesions via single-isocenter VMAT on Halcyon RDS is feasible and dosimetrically equivalent to clinically delivered TrueBeam plans. Halcyon provides excellent plan quality and shorter overall treatment time that may improve patient compliance, reduce intrafraction movement, improve clinic efficiency, and potentially offering lung SBRT treatments for underserved patients on a Halcyon only clinic

Development of three-dimensional lung multicellular spheroids in air- and liquid-interface culture for the evaluation of anticancer therapeutics

Three-dimensional (3D) lung multicellular spheroids (MCS) in liquid-covered culture (LCC) and air-interface culture (AIC) conditions have both been developed for the evaluation of aerosol anticancer therapeutics in solution and aerosols, respectively. The MCS were formed by seeding lung cancer cells on top of collagen where they formed spheroids due to the prevalence of cell-to-cell interactions. LCC MCS were exposed to paclitaxel (PTX) in media whereas AIC MCS were exposed to dry powder PEGylated phospholipid aerosol microparticles containing paclitaxel. The difference in viability for 2D versus 3D culture for both LCC and AIC was evaluated along with the effects of the particles on lung epithelium via transepithelial electrical resistance (TEER) measurements. For LCC and AIC conditions, the 3D spheroids were more resistant to treatment with higher IC50 values for A549 and H358 cell lines. TEER results initially indicated a decrease in resistance upon drug or particle exposure, however, these values increased over the course of several days indicating the ability of the cells to recover. Overall, these studies offer a comprehensive in vitro evaluation of aerosol particles used in the treatment of lung cancer while introducing a new method for culturing lung cancer MCS in both LCC and AIC conditions

Design, Physicochemical Characterization, and Optimization of Organic Solution Advanced Spray-Dried Inhalable Dipalmitoylphosphatidylcholine (DPPC) and Dipalmitoylphosphatidylethanolamine Poly(Ethylene Glycol) (DPPE-PEG) Microparticles and Nanoparticles for Targeted Respiratory Nanomedicine Delivery as Dry Powder Inhalation Aerosols

Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 nm to 1.2 μm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation Impactor™ (NGI™) coupled with the HandiHaler® dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 μm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved

Fast Generation of Lung SBRT Plans with a Knowledge-Based Planning Model on Ring-Mounted Halcyon Linac

PURPOSE: To demonstrate fast treatment planning feasibility of stereotactic body radiation therapy (SBRT) for centrally located lung tumors on Halcyon Linac via a previously validated knowledge-based planning (KBP) model to support offline adaptive radiotherapy. MATERIALS/METHODS: Twenty previously treated non-coplanar volumetric-modulated arc therapy (VMAT) lung SBRT plans (c-Truebeam) on SBRT-dedicated C-arm Truebeam Linac were selected. Patients received 50 Gy in five fractions. c-Truebeam plans were re-optimized for Halcyon manually (m-Halcyon) and with KBP model (k-Halcyon). Both m-Halcyon and k-Halcyon plans were normalized for identical or better target coverage than clinical c-Truebeam plans and compared for target conformity, dose heterogeneity, dose fall-off, and dose tolerances to the organs-at-risk (OAR). Treatment delivery parameters and planning times were evaluated. RESULTS: k-Halcyon plans were dosimetrically similar or better than m-Halcyon and c-Truebeam plans. k-Halcyon and m-Halcyon plan comparisons are presented with respect to c-Truebeam. Differences in conformity index were statistically insignificant in k-Halcyon and on average 0.02 higher (p = 0.04) in m-Halcyon plans. Gradient index was on average 0.43 (p = 0.006) lower and 0.27 (p = 0.02) higher for k-Halcyon and m-Halcyon, respectively. Maximal dose 2 cm away in any direction from target was statistically insignificant. k-Halcyon increased maximal target dose on average by 2.9 Gy (p \u3c 0.001). Mean lung dose was on average reduced by 0.10 Gy (p = 0.004) in k-Halcyon and increased by 0.14 Gy (p \u3c 0.001) in m-Halcyon plans. k-Halcyon plans lowered bronchial tree dose on average by 1.2 Gy. Beam-on-time (BOT) was increased by 2.85 and 1.67 min, on average for k-Halcyon and m-Halcyon, respectively. k-Halcyon plans were generated in under 30 min compared to estimated dedicated 180 ± 30 min for m-Halcyon or c-Truebeam plan. CONCLUSION: k-Halcyon plans were generated in under 30 min with excellent plan quality. This adaptable KBP model supports high-volume clinics in the expansion or transfer of lung SBRT patients to Halcyon

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937

Introduction—RTOG-0937 is a randomized phase-II trial evaluating 1-year OS with PCI or PCI plus consolidative radiation therapy (cRT) to intra-thoracic disease and extracranial metastases for ED-SCLC. Methods—Patients with 1–4 extracranial metastases were eligible after CR or PR to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included PR vs CR after chemotherapy and 1 vs 2–4 metastases; age \u3c 65 vs ≥ 65 was added after an observed imbalance. PCI was 25GY/10 fractions. cRT was 45GY/15 fractions. To detect an OS improvement from 30% to 45% with a 34% hazard reduction (HR=0·66) under a 0.1 type-1 error (1-sided) and 80% power, 154 patients were required. Results—Ninety-seven patients were randomized between March, 2010 and February, 2015. Eleven patients were ineligible (nine PCI, two PCI+cRT), leaving 42 randomized to PCI and 44 to PCI+cRT. At planned interim analysis the study crossed the futility boundary for OS and was closed prior to meeting accrual target. Median follow-up was 9 months. One-year OS was not different between the groups: 60.1% [95% CI: 41.2–74.7%] for PCI and 50.8% [95% CI:34.0–65.3%] for PCI+cRT (p=0.21). Three and 12-month rates of progression were 53.3% and 79.6% for PCI, and 14.5% and 75% for PCI+cRT. Time to progression favored PCI+cRT, HR=0.53 (95% CI: 0.32–0.87, p=0.01). One-patient in each arm had Grade-4 therapy related toxicity and one had Grade-5 therapy related pneumonitis with PCI+cRT. Conclusions—OS exceeded predictions for both arms. Consolidative RT delayed progression but did not improve 1-year OS

Does physical activity modify the risk of obesity for type 2 diabetes: a review of epidemiological data

Obesity and physical inactivity are both risk factors for type 2 diabetes. Since they are strongly associated, it has been suggested that they might interact. In this study, we summarized the evidence on this interaction by conducting a systematic review. Two types of interaction have been discerned, statistical and biological interaction, which could give different results. Therefore, we calculated both types of interaction for the studies in our review. Cohort studies, published between 1999 and 2008, that investigated the effects of obesity and physical activity on the risk of type 2 diabetes were included. We calculated both biological and statistical interaction in these studies. Eight studies were included of which five were suitable to calculate interaction. All studies showed positive biological interaction, meaning that the joint effect was more than the sum of the individual effects. However, there was inconsistent statistical interaction; in some studies the joint effect was more than the product of the individual effects, in other studies it was less. The results show that obesity and physical inactivity interact on an additive scale. This means that prevention of either obesity or physical inactivity, not only reduces the risk of diabetes by taking away the independent effect of this factor, but also by preventing the cases that were caused by the interaction between both factors. Furthermore, this review clearly showed that results can differ depending on what method is used to assess interaction