D.B. Shultz

Early-Stage Non-Small Cell Lung Cancer: Quantitative Imaging Characteristics of (18)F Fluorodeoxyglucose PET/CT Allow Prediction of Distant Metastasis.

Purpose To identify quantitative imaging biomarkers at fluorine 18 ((18)F) positron emission tomography (PET) for predicting distant metastasis in patients with early-stage non-small cell lung cancer (NSCLC). Materials and Methods In this institutional review board-approved HIPAA-compliant retrospective study, the pretreatment (18)F fluorodeoxyglucose PET images in 101 patients treated with stereotactic ablative radiation therapy from 2005 to 2013 were analyzed. Data for 70 patients who were treated before 2011 were used for discovery purposes, while data from the remaining 31 patients were used for independent validation. Quantitative PET imaging characteristics including statistical, histogram-related, morphologic, and texture features were analyzed, from which 35 nonredundant and robust features were further evaluated. Cox proportional hazards regression model coupled with the least absolute shrinkage and selection operator was used to predict distant metastasis. Whether histologic type provided complementary value to imaging by combining both in a single prognostic model was also assessed. Results The optimal prognostic model included two image features that allowed quantification of intratumor heterogeneity and peak standardized uptake value. In the independent validation cohort, this model showed a concordance index of 0.71, which was higher than those of the maximum standardized uptake value and tumor volume, with concordance indexes of 0.67 and 0.64, respectively. The prognostic model also allowed separation of groups with low and high risk for developing distant metastasis (hazard ratio, 4.8; P = .0498, log-rank test), which compared favorably with maximum standardized uptake value and tumor volume (hazard ratio, 1.5 and 2.0, respectively; P = .73 and 0.54, log-rank test, respectively). When combined with histologic types, the prognostic power was further improved (hazard ratio, 6.9; P = .0289, log-rank test; and concordance index, 0.80). Conclusion PET imaging characteristics associated with distant metastasis that could potentially help practitioners to tailor appropriate therapy for individual patients with early-stage NSCLC were identified. (©) RSNA, 2016 Online supplemental material is available for this article.

Stereotactic Ablative Radiotherapy for Pulmonary Oligometastases and Oligometastatic Lung Cancer

An increasing body of experience suggests that oligometastasis represents a minimal metastatic state with the potential for cure or prolonged survival in selected patients treated with radical local therapy to all identified sites of disease. The main clinical scenarios managed by thoracic oncology specialists are pulmonary oligometastases from primary malignancies of other anatomic sites and primary lung cancer with oligometastases to lung or other organs. Surgery has been a mainstay of treatment in these situations, with remarkably favorable outcomes following pulmonary metastasectomy in well-selected patient cohorts. As with early stage lung cancer in patients who are medically inoperable, stereotactic ablative radiotherapy is emerging as a prominent local treatment option for oligometastatic disease. We review the role and clinical experience of stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer.

Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response.

Purpose: Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities. Experimental Design: Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non–small cell lung cancer (NSCLC)] and head and neck cancer patients. Results: LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8+ T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients. Conclusions: Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558–69. ©2014 AACR.

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non–Small Cell Lung Cancer

BACKGROUND Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables. METHODS Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided. RESULTS The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK. CONCLUSION The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

Imaging Features Associated With Disease Progression After Stereotactic Ablative Radiotherapy for Stage I Non–Small-Cell Lung Cancer

INTRODUCTION/BACKGROUND The aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC. PATIENTS AND METHODS Between March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax. RESULTS Ten patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases. CONCLUSION In our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.

Long-term outcomes of surgery followed by radiation therapy for minor salivary gland carcinomas.

Postoperative radiation therapy is often used in patients with high‐risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy.

To SABR or not to SABR? Indications and contraindications for stereotactic ablative radiotherapy in the treatment of early-stage, oligometastatic, or oligoprogressive non-small cell lung cancer.

Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for early-stage non-small cell lung cancer. Although direct comparisons from randomized trials are not available, rates of both primary tumor control and distant metastasis are similar between SABR and surgery. Overall survival is lower after SABR compared with surgery, largely reflecting that a primary selection criterion for SABR has been medical inoperability because of decreased cardiopulmonary function and other comorbidities that lead to decreased survival independent of non-small cell lung cancer. Survival outcomes between SABR and surgery are much more similar in propensity-matched cohorts. Newer potential indications for SABR include treatment of operable patients; of oligometastatic lung cancer, in which SABR has emerged as an alternative to metastasectomy; and of oligoprogressive lung cancer, an attractive concept especially as improved personalized systemic therapies emerge, and prospective trials are currently being conducted in these settings. Although toxicity in modern series is low, SABR is clearly capable of producing fatal complications, and understanding the risk factors and approaches for mitigating them has been emerging in recent years. Thus, appropriate patient selection is a vital, evolving, and controversial topic.

Vagal and recurrent laryngeal neuropathy following stereotactic ablative radiation therapy in the chest

PURPOSE To identify clinical and dosimetric factors associated with vagus nerve (VN) and recurrent laryngeal nerve (RecLN) injury following stereotactic ablative radiation therapy (SABR) in the chest. METHODS AND MATERIALS We examined the clinical courses and SABR plans of 67 patients treated for T1 or T2 non-small cell lung cancer of the upper right or left lung, including 2 who developed vocal cord paresis (VCP) following treatment. After developing a contouring atlas for the VN and RecLN in the thorax, dose to those structures was retrospectively determined for each patient, and we identified 12 patients whose treatment imparted significant dose to either nerve and who were assessable for more than 12 months follow-up. Biologically effective doses using linear-quadratic (LQ) and linear quadratic-linear (LQ-L) modeling were correlated with VN and RecLN toxicity. RESULTS Of 12 patients, 2 developed VCP. The first underwent repeat SABR and received a cumulative single fraction equivalent dose (alpha/beta = 3; SFED3) of 37.4 or 64.5 Gy to the VN and 13.7 or 15.3 Gy to the RecLN (by LQ or LQ-L modeling, respectively). This was the highest VN dose and fifth highest RecLN dose in the cohort. The second had rheumatoid arthritis and connective tissue disease and received a SFED3 of 16 Gy to the VN and 19.5 Gy to the RecLN (by both LQ and LQ-L modeling). This was in the upper tertile of VN and RecLN doses for the cohort. CONCLUSIONS Following SABR for non-small cell lung cancer, VCP was associated with high cumulative dose to the VN in 1 patient and a moderately high dose to the VN and RecLN in another patient with rheumatoid arthritis and connective tissue disease. Particularly in the setting of reirradiation or connective tissue disease, potential toxicity to the VN or RecLN should be considered.

A novel biomarker panel examining response to gemcitabine with or without erlotinib for pancreatic cancer therapy in NCIC Clinical Trials Group PA.3

Purpose NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples. Experimental Design Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fishers exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker. Results and Conclusion Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention. Trial Registration ClinicalTrials.gov NCT00040183