Total-body Dynamic Imaging and Kinetic Modeling of 18F-AraG in Healthy Individuals and a Non-Small Cell Lung Cancer Patient Undergoing Anti-PD-1 Immunotherapy.

Immunotherapies, especially the checkpoint inhibitors such as anti-PD-1 antibodies, have transformed cancer treatment by enhancing immune system's capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging. 18F-AraG is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by non-invasive quantification of immune cell activity within tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of 18F-AraG, as a potential quantitative biomarker for immune response evaluation. Methods: The study consisted of 90-min total-body dynamic scans of four healthy subjects and one non-small cell lung cancer (NSCLC) patient, scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection were employed to analyze tracer kinetics in various organs. Additionally, seven sub-regions of the primary lung tumor and four mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess reliability of kinetic parameter estimation. Correlations of SUVmean, SUVR (tissue-to-blood ratio), and Logan plot slope KLogan with total volume-of-distribution VT were calculated to identify potential surrogates for kinetic modeling. Results: Strong correlations were observed between KLogan and SUVR values with VT, suggesting that they can be used as promising surrogates for VT, especially in organs with low blood-volume fraction. Moreover, the practical identifiability analysis suggests that the dynamic 18F-AraG PET scans could potentially be shortened to 60 minutes, while maintaining quantification accuracy for all organs-of-interest. The study suggests that although 18F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response post-therapy. While SUVmean showed variable changes in different sub-regions of the tumor post-therapy, the SUVR, KLogan, and VT showed consistent increasing trends in all analyzed sub-regions of the tumor with high practical identifiability. Conclusion: Our findings highlight the promise of 18F-AraG dynamic imaging as a non-invasive biomarker for quantifying the immune response to immunotherapy in cancer patients. The promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial.

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.

Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update.

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. See the Appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).

Nonsurgical Therapy for Early-Stage Lung Cancer.

Treatment options for medically inoperable, early-stage non-small cell lung cancer (NSCLC) include stereotactic ablative radiotherapy (SABR) and percutaneous image guided thermal ablation. SABR is delivered over 1-5 sessions of highly conformal ablative radiation with excellent tumor control. Toxicity is depending on tumor location and anatomy but is typically mild. Studies evaluating SABR in operable NSCLC are ongoing. Thermal ablation can be delivered via radiofrequency, microwave, or cryoablation, with promising results and modest toxicity. We review the data and outcomes for these approaches and discuss ongoing studies.

ASTRO Radiation Therapy Summary of the ASCO Guideline on Management of Stage III Non-Small Cell Lung Cancer.

PURPOSE: To develop a radiation therapy summary of recommendations on the management of locally advanced non-small cell lung cancer (NSCLC) based on the Management of Stage III Non-Small Cell Lung Cancer: American Society of Clinical Oncology Guideline, which was endorsed by the American Society for Radiation Oncology (ASTRO). METHODS: The American Society of Clinical Oncology, ASTRO, and the American College of Chest Physicians convened a multidisciplinary panel to develop a guideline based on a systematic review of the literature and a formal consensus process, that has been separately published. A new panel consisting of radiation oncologists from the original guideline as well as additional ASTRO members was formed to provide further guidance to the radiation oncology community. A total of 127 articles met the eligibility criteria to answer 5 clinical questions. This summary focuses on the 3 radiation therapy questions (neoadjuvant, adjuvant, and unresectable settings). RESULTS: Radiation-specific recommendations are summarized with additional relevant commentary on specific questions regarding the management of preoperative radiation, postoperative radiation, and combined chemoradiation. CONCLUSIONS: Patients with stage III NSCLC who are planned for surgical resection, should receive either neoadjuvant chemotherapy or chemoradiation. The addition of neoadjuvant treatment is particularly important in patients planned for surgery in the N2 or superior sulcus settings. Postoperatively, patients who did not receive neoadjuvant chemotherapy should be offered adjuvant chemotherapy. The use of postoperative radiation for completely resected N2 disease is not routinely recommended. Unresectable patients with stage III NSCLC should ideally be managed with combined concurrent chemoradiation using a platinum-based doublet with a standard radiation dose of 60 Gy followed by consolidation durvalumab in patients without progression after initial therapy. Patients who cannot tolerate a concurrent chemoradiation approach can be managed either by sequential chemotherapy followed by radiation or by dose-escalated or hypofractionated radiation alone.

Hypofractionation and SABR: 25 years of evolution in medical physics and a glimpse of the future.

As we were invited to write an article for celebrating the 50th Anniversary of Medical Physics journal, on something historically significant, commemorative, and exciting happening in the past decades, the first idea came to our mind is the fascinating radiotherapy paradigm shift from conventional fractionation to hypofractionation and stereotactic ablative radiotherapy (SABR). It is historically and clinically significant since as we all know this RT treatment revolution not only reduces treatment duration for patients, but also improves tumor control and cancer treatment outcomes. It is also commemorative and exciting for us medical physicists since the technology development in medical physics has been the main driver for the success of this treatment regimen which requires high precision and accuracy throughout the entire treatment planning and delivery. This article provides an overview of the technological development and clinical trials evolvement in the past 25 years for hypofractionation and SABR, with an outlook to the future improvement.

Four-Dimensional Computed Tomography Ventilation Image-Guided Lung Functional Avoidance Radiation Therapy: A Single-Arm Prospective Pilot Clinical Trial.

PURPOSE: The primary objective of this prospective pilot trial was to assess the safety and feasibility of lung functional avoidance radiation therapy (RT) with 4-dimensional (4D) computed tomography (CT) ventilation imaging. METHODS AND MATERIALS: Patients with primary lung cancer or metastatic disease to the lungs to receive conventionally fractionated RT (CFRT) or stereotactic body RT (SBRT) were eligible. Standard-of-care 4D-CT scans were used to generate ventilation images through image processing/analysis. Each patient required a standard intensity modulated RT plan and ventilation image guided functional avoidance plan. The primary endpoint was the safety of functional avoidance RT, defined as the rate of grade ≥3 adverse events (AEs) that occurred ≤12 months after treatment. Protocol treatment was considered safe if the rates of grade ≥3 pneumonitis and esophagitis were <13% and <21%, respectively for CFRT, and if the rate of any grade ≥3 AEs was <28% for SBRT. Feasibility of functional avoidance RT was assessed by comparison of dose metrics between the 2 plans using the Wilcoxon signed-rank test. RESULTS: Between May 2015 and November 2019, 34 patients with non-small cell lung cancer were enrolled, and 33 patients were evaluable (n = 24 for CFRT; n = 9 for SBRT). Median follow-up was 14.7 months. For CFRT, the rates of grade ≥3 pneumonitis and esophagitis were 4.2% (95% confidence interval, 0.1%-21.1%) and 12.5% (2.7%-32.4%). For SBRT, no patients developed grade ≥3 AEs. Compared with the standard plans, the functional avoidance plans significantly (P < .01) reduced the lung dose-function metrics without compromising target coverage or adherence to standard organs at risk constraints. CONCLUSIONS: This study, representing one of the first prospective investigations on lung functional avoidance RT, demonstrated that the 4D-CT ventilation image guided functional avoidance RT that significantly reduced dose to ventilated lung regions could be safely administered, adding to the growing body of evidence for its clinical utility.

The Role of Chemotherapy Plus Immune Checkpoint Inhibitors in Oncogenic-Driven NSCLC: A University of California Lung Cancer Consortium Retrospective Study.

Introduction: There is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population. Methods: We conducted a retrospective study at the five University of California National Cancer Institute-designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured. Results: A total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2/ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83-1.51; p = 0.472) and 0.86 (95% confidence interval: 0.60-1.24, p = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI. Conclusions: Our study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR-driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients.

Noninvasive Stereotactic Radiation for Refractory Ventricular Tachycardia After Failure of Cardiac Sympathetic Denervation.

Stereotactic body radiation therapy is a novel treatment option for refractory ventricular tachycardia. We present a case of ventricular tachycardia, with epicardial origin located in large inferior infarct scar, that recurred despite treatment with multiple antiarrhythmic drugs, catheter ablation, and cardiac sympathetic denervation. Stereotactic body radiation therapy safely and effectively terminated the arrhythmia. (Level of Difficulty: Advanced.).

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Inoperable Early-Stage Non-Small-Cell Lung Cancer: Stereotactic Ablative Radiotherapy and Rationale for Systemic Therapy.

Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable, early-stage non-small-cell lung cancer. SABR results in high rates of in-field tumor control, but among larger and more biologically aggressive tumors, regional and distant failures are problematic. Cytotoxic chemotherapy is rarely used in this patient population and the benefit is unclear. Alternative systemic therapy options with a milder side-effect profile are of considerable interest, and several randomized phase III trials are currently testing immune checkpoint inhibitors in this setting. We review the rationale, data, and ongoing studies evaluating systemic therapy in medically inoperable, early-stage non-small-cell lung cancer treated with SABR.

Detection of second primary lung cancers on surveillance imaging following stereotactic ablative radiotherapy for non-small cell lung cancer.

INTRODUCTION/BACKGROUND: Second primary lung cancers (SPLC) are common following non-small cell lung cancer (NSCLC) treatment. Development of SPLC following stereotactic ablative radiation therapy (SABR) may differ as compared to surgical cohorts. We report incidence of and outcomes for SPLC detected by surveillance imaging in a cohort of patients treated with SABR. MATERIALS/METHODS: Patients treated with SABR for node-negative NSCLC between February, 2007 to May, 2019 were retrospectively identified. Patient characteristics, frequency of surveillance imaging, development of SPLC, recurrence patterns, and survival were reviewed. Surveillance CT was performed Q3-4 month year 1, Q3-6 month year 2, Q6-12 month year 3-5, and Q12 month thereafter. Actuarial estimates of development of SPLC and overall survival (OS) were generated with competing risk analysis. RESULTS: We identified 134 patients treated with SABR with ≥6 months follow up. Eighteen (13.4%) developed a total of 21 SPLC at a median of 28.5 months (range 3.0-84.7 months) following SABR, 19 (90.5%) biopsy-proven. Twenty (95.2%) SPLC were detected by surveillance imaging. Three patients developed 2 metachronous SPLC. Three and 5 year SPLC estimates were 11.7% and 13.1%. Eighteen (85.7%) SPLC were treated with curative intent. Two and 3 year estimate of OS following detection of SPLC was 79.8% and 54.7%. CONCLUSION: SPLC were more common in our cohort than other published studies. Outcomes following surveillance detected SPLC are similar to those of de novo early stage lung cancers. The high frequency of SPLC in our cohort suggests further studies to refine overall surveillance in very high-risk populations are needed.

Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline.

PURPOSE: To provide evidence-based recommendations to practicing clinicians on management of patients with stage III non-small-cell lung cancer (NSCLC). METHODS: An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary oncology, community oncology, research methodology, and advocacy experts was convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 127 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed to address evaluation and staging workup of patients with suspected stage III NSCLC, surgical management, neoadjuvant and adjuvant approaches, and management of patients with unresectable stage III NSCLC.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

Prognostic Value of Computed Tomography and/or 18F-Fluorodeoxyglucose Positron Emission Tomography Radiomics Features in Locally Advanced Non-small Cell Lung Cancer.

INTRODUCTION: We investigated whether adding computed tomography (CT) and/or 18F-fluorodeoxyglucose (18F-FDG) PET radiomics features to conventional prognostic factors (CPFs) improves prognostic value in locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively identified 39 cases with stage III NSCLC who received chemoradiotherapy and underwent planning CT and staging 18F-FDG PET scans. Seven CPFs were recorded. Feature selection was performed on 48 CT and 49 PET extracted radiomics features. A penalized multivariate Cox proportional hazards model was used to generate models for overall survival based on CPFs alone, CPFs with CT features, CPFs with PET features, and CPFs with CT and PET features. Linear predictors generated and categorized into 2 risk groups for which Kaplan-Meier survival curves were calculated. A log-rank test was performed to quantify the discrimination between the groups and calculated the Harrell's C-index to quantify the discriminatory power. A likelihood ratio test was performed to determine whether adding CT and/or PET features to CPFs improved model performance. RESULTS: All 4 models significantly discriminated between the 2 risk groups. The discriminatory power was significantly increased when CPFs were combined with PET features (C-index 0.82; likelihood ratio test P < .01) or with both CT and PET features (0.83; P < .01) compared with CPFs alone (0.68). There was no significant improvement when CPFs were combined with CT features (0.68). CONCLUSION: Adding PET radiomics features to CPFs yielded a significant improvement in the prognostic value in locally advanced NSCLC; adding CT features did not.

A Dose-finding Study Followed by a Phase II Randomized, Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non-small-cell Lung Cancer: SWOG 1206 (8811).

BACKGROUND: We conducted a 2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer. PATIENTS AND METHODS: In the phase I part, patients were treated successively at 3 dose levels of veliparib (40, 80, and 120 mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin and paclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care. RESULTS: Of 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P = .20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively. CONCLUSION: Veliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.

Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline.

PURPOSE: The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy (RT) for small-cell lung cancer (SCLC). Because of the relevance of this topic to ASCO membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations. METHODS: The ASTRO guideline on RT for SCLC was reviewed for developmental rigor by methodologists. Then, an ASCO Expert Panel reviewed the content and the recommendations. RESULTS: The ASCO Expert Panel determined that the recommendations from ASTRO guideline on RT for SCLC, published in June 2020, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed ASTRO guideline on RT for SCLC with a few discussion points. RECOMMENDATIONS: Recommendations addressed thoracic radiotherapy for limited-stage SCLC, role of stereotactic body radiotherapy in stage I or II node-negative SCLC, prophylactic cranial radiotherapy, and thoracic consolidation for extensive-stage SCLC.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

Radiation and immunotherapy combinations in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a common and lethal malignancy. The recent development of immune checkpoint inhibitors has afforded a durable, dramatic treatment response for a subset of patients, but strategies to expand these benefits to a broader swath of patients are needed. Preliminary evidence suggests radiotherapy may modulate a patient's immune system, particularly when delivered in high doses over few fractions with conformal techniques, as with stereotactic ablative radiotherapy (SABR). Radiotherapy for advanced stage NSCLC has traditionally been administered with palliative intent. However, an emergence of data from retrospective studies and, more recently, prospective trials has indicated the potential of using stereotactic ablative radiotherapy (SABR), in combination with systemic immunotherapy agents have synergistic effect and may enhance survival. We review current evidence for synergy between radiation and immunotherapy in metastatic, locally advanced, and localized NSCLC and discuss ongoing studies.