Stage I-IIIB Non-small Cell Lung Cancer Research Articles

Utility of 18F-FDG uptake in predicting major pathological response to neoadjuvant immunotherapy in patients with resectable non‑small cell lung cancer

PurposeThe aim of present study was to investigate the efficiency of 18F-FDG uptake in predicting major pathological response (MPR) in resectable non-small cell lung cancer (NSCLC) patients with neoadjuvant immunotherapy. MethodsA total of 104 patients with stage I-IIIB NSCLC were retrospectively derived from National Cancer Center of China, of which 36 cases received immune checkpoint inhibitors (ICIs) monotherapy (I-M) and 68 cases with ICI combination therapy (I-C). 18F-FDG PET-CT scans were performed at baseline and after neoadjuvant therapy (NAT). Receiver‐operating characteristic (ROC) curve analyses were conducted and area under ROC curve (AUC) was calculated for biomarkers including maximum standardized uptake value (SUVmax), inflammatory biomarkers, tumor mutation burden (TMB), PD-L1 tumor proportion score (TPS) and iRECIST. ResultsFifty-four resected NSCLC tumors achieved MPR (51.9%, 54/104). In both neoadjuvant I-M and I-C cohorts, post-NAT SUVmax and the percentage changes of SUVmax (ΔSUVmax%) were significantly lower in the patients with MPR versus non-MPR (p < 0.01), and were also negatively correlated with the degree of pathological regression (p < 0.01). The AUC of ΔSUVmax% for predicting MPR was respectively 1.00 (95% CI: 1.00–1.00) in neoadjuvant I-M cohort and 0.94 (95% CI: 0.86–1.00) in I-C cohort. Baseline SUVmax had a statistical prediction value for MPR only in I-M cohort, with an AUC up to 0.76 at the threshold of 17.0. ΔSUVmax% showed an obvious advantage in MPR prediction over inflammatory biomarkers, TMB, PD-L1 TPS and iRECIST. Conclusion18F-FDG uptake can predict MPR in NSCLC patients with neoadjuvant immunotherapy.

Prognostic predictors of radical resection of stage I-IIIB non-small cell lung cancer: the role of preoperative CT texture features, conventional imaging features, and clinical features in a retrospectively analyzed

BackgroundTo investigate the value of preoperative computed tomography (CT) texture features, routine imaging features, and clinical features in the prognosis of non-small cell lung cancer (NSCLC) after radical resection.MethodsDemographic parameters and clinically features were analyzed in 107 patients with stage I-IIIB NSCLC, while 73 of these patients received CT scanning and radiomic characteristics for prognosis assessment. Texture analysis features include histogram, gray size area matrix and gray co-occurrence matrix features. The clinical risk features were identified using univariate and multivariate logistic analyses. By incorporating the radiomics score (Rad-score) and clinical risk features with multivariate cox regression, a combined nomogram was built. The nomogram performance was assessed by its calibration, clinical usefulness and Harrell’s concordance index (C-index). The 5-year OS between the dichotomized subgroups was compared using Kaplan–Meier (KM) analysis and the log-rank test.ResultsConsisting of 4 selected features, the radiomics signature showed a favorable discriminative performance for prognosis, with an AUC of 0.91 (95% CI: 0.84 ~ 0.97). The nomogram, consisting of the radiomics signature, N stage, and tumor size, showed good calibration. The nomogram also exhibited prognostic ability with a C-index of 0.91 (95% CI, 0.86–0.95) for OS. The decision curve analysis indicated that the nomogram was clinically useful. According to the KM survival curves, the low-risk group had higher 5-year survival rate compared to high-risk.ConclusionThe as developed nomogram, combining with preoperative radiomics evidence, N stage, and tumor size, has potential to preoperatively predict the prognosis of NSCLC with a high accuracy and could assist to treatment for the NSCLC patients in the clinic.

A Comprehensive Nomogram Combining CT Imaging with Clinical Features for Prediction of Lymph Node Metastasis in Stage I-IIIB Non-small Cell Lung Cancer.

The status of lymph node metastasis (LNM) is highly correlated with the recurrence and survival outcomes of patients with lung cancer. Thus, a tool that predicts LNM could benefit patient treatment and prognosis. The present study established a new radiomic model by combining computed tomography (CT) radiomic features and clinical parameters to predict the LNM status in patients with non-small cell lung cancer (NSCLC). Demographic parameters and clinical laboratory values were analyzed in 217 patients with stage I-IIIB NSCLC; 107 of the patients received CT scanning and radiomic characteristics were used for LNM assessment (76 in the training cohort and 31 in the validation cohort). The minimum redundancy maximum relevance (mRMR) and the least absolute shrinkage and selection operator (LASSO) regression model were used to select the most predictive features on the basis of the 76 patients in the training set. The value of the area under the receiver operator characteristic (ROC) curve (AUC) was adopted to determine the correlation between LN status and the radiomics signature in training cohorts and then validated in the 31 patients of validation set. The radiomics nomogram was analyzed using univariate and multivariate logistic regression. Decision curve analysis (DCA) was performed to evaluate the clinical utility of this model. This was a retrospective study. Five radiomic characteristics were significantly correlated with LNM in the two cohorts (P < 0.05). The radiomic nomogram that incorporated the above radiomic characteristics, the RDW, and the CT-based LN status had satisfactory discrimination and calibration in the training (AUC, 0.79; 95% CI 0.69-0.89) and validation cohorts (AUC, 0.70; 95% CI 0.50-0.89).The DCA showed that the developed nomogram had promising clinical utility. The developed nomogram, combined with preoperative radiomics evidence, the RDW, and the CT-based LN status, has the potential to preoperatively predict LNM with high accuracy and can facilitate the prediction of LN status for NSCLC patients.

Abstract 736: ctDNA detection in early stage non-small cell lung cancer

Abstract Introduction Overall survival of non-small-cell lung cancer (NSCLC) patients remains poor as patients are frequently diagnosed at late stage. The evaluation of circulating tumor DNA (ctDNA) has been shown to offer a non-invasive method for cancer detection. However, detection rates of ctDNA in patients with early stage cancers have been low. The distribution of ctDNA levels in this population is unknown, and the analytical requirements for a test to detect the majority of cancers cannot be defined. Methods The LUCID study (LUng cancer - CIrculating tumour DNA study) recruited 100 patients with stage I-IIIB NSCLC according to the TNM 7th edition and collected plasma samples before and after radical treatment by surgery or radiotherapy +/- chemotherapy with curative intent. To measure levels of ctDNA in patients with early stage disease and very low tumor burden we developed a method for INtegration of VAriant Reads (INVAR), which uses sequencing data across hundreds to thousands of tumor-mutated loci to detect ctDNA in plasma samples at high sensitivity. We applied INVAR to 90 of the patients from the LUCID study, where tumor sequencing data was available. To measure ctDNA in the remaining LUCID patients, we applied the InVision® amplicon-based plasma sequencing assay. Results Across the 100 patients, ctDNA signals were observed in 67% of samples obtained prior to treatment. ctDNA was detected in 66% of cases, with ctDNA levels as low as 9.1x10-6 (9 parts per million), at a detection threshold with 95% specificity. ctDNA was detected in 52% of 60 patients with stage I NSCLC and in 88% of 40 patients with stage II/III disease. Analyzing different histological subtypes, ctDNA was detected in 79% of squamous cell carcinomas and 60% of adenocarcinomas. We found a good agreement when comparing the ctDNA results obtained from INVAR and the InVision® assay. Conclusions Our findings suggest that an assay with sensitivity to below 10 parts per million may be able to detect ctDNA in as many as 2/3 of patients with early stage NSCLC prior to treatment, including the majority of adenocarcinoma cases. Additionally, patient-specific analysis of ctDNA has the potential to aid in longitudinal cancer monitoring and in detection of low tumor burden and minimal residual disease. We aim to apply this approach to serial samples obtained through the LUCID study to investigate its application in treatment management. Citation Format: Katrin Heider, Jonathan C. Wan, Davina Gale, Andrea Ruiz-Valdepenas, Florent Mouliere, James Morris, Nagmi R. Qureshi, Wendi Qian, Jerome Wulff, Nikolaos Demiris, Karen Howarth, Emma Green, Viona Rundell, Tim Eisen, Wendy Cooper, Christopher G. Smith, Charles Massie, Susan Harden, Doris M. Rassl, Robert C. Rintoul, Nitzan Rosenfeld. ctDNA detection in early stage non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 736.

Multifactorial risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer

Background and purposeA higher radiation dose to the heart is known to be associated with increased mortality in non-small cell lung cancer (NSCLC) patients. It is however unknown what the contribution of the heart dose is when other risk factors for mortality are also accounted for. Materials and methodsWe constructed and externally validated prediction models of mortality after definitive chemoradiotherapy for NSCLC. Models were developed in 145 stage I-IIIB NSCLC patients. Clinical (performance status, age, gross tumour volume (GTV) combining primary tumour and involved lymph nodes, current smoker) and dosimetric (mean lung (MLD) and heart (MHD) dose) variables were considered. Multivariable logistic regression models predicting 12 and 24 month mortality were built in 5-fold cross-validation. Discrimination and calibration was assessed in 3 external validation datasets containing 878 (via distributed learning), 127 and 96 NSCLC patients. ResultsThe best discriminating prediction models combined GTV, smoker and/or MHD: bootstrapping AUC (95% CI) of 0.74 (0.66–0.78) and 0.69 (0.55–0.74) at 12 and 24 months. At external validation, the 24 month mortality GTV-smoker-MHD model robustly showed moderate discrimination (AUC = 0.61–0.64 before and 0.64–0.65 after model update) with limited 0.01–0.07 improvement over a GTV-only model, and calibration slope (0.64–0.65). This model can identify patients for whom a MHD reduction may be useful (e.g. PPV = 77%, NPV = 52% (60% cut-off)). ConclusionsTumour volume is strongly related to mortality risk in the first 2 years after chemoradiotherapy for NSCLC. Modelling indicates that efforts to reduce cardiac dose may be relevant for small tumours and that smoking has an important negative association with survival.

Differential prognostic impact of platelet-derived growth factor receptor expression in NSCLC

Preclinical evidence suggests that stromal expression of platelet-derived growth factor receptors (PDGFRs) stimulates tumor development and diminishes intratumoral drug uptake. In non-small cell lung cancer (NSCLC), the clinical relevance of stromal PDGFR expression remains uncertain. Tumor specimens from 553 patients with primary operable stage I-IIIB NSCLC was obtained and tissue micro-arrays (TMA) were constructed (Norwegian cohort). Immunohistochemistry (IHC) was used to evaluate the expression of PDGFRα and -β in stromal cells and to explore their impact on patient survival. Results were validated in a non-related cohort consisting of TMAs of 367 stage I (A and B) NSCLC patients (Swedish cohort). High stromal PDGFRα expression was an independent predictor of increased survival in the overall populations and SCC (squamous cell carcinoma) subgroups of both investigated cohorts. PDGFRβ was an independent predictor of poor survival in the overall Norwegian cohort and an independent predictor of increased survival in the ADC (adenocarcinoma) subgroup of the Swedish cohort. Tumors displaying the combination PDGFRα-low/PDGFRβ-high exhibited inferior survival according to increasing stage in the Norwegian cohort. This study confirms that high stromal expression of PDGFRα is a predictor of increased survival in NSCLC. Further exploration of the prognostic impact of PDGFRβ and the relationship between PDGFRα and -β is warranted.

Abstract 1377: Improved ctDNA detection in early stage non-small-cell lung cancer

Abstract Overall survival of non-small-cell lung cancer (NSCLC) patients remains poor as patients are frequently diagnosed at a late stage. The evaluation of circulating tumour DNA (ctDNA) has been shown to offer a non-invasive method for detection of cancer. However, detection rates of ctDNA in patients with early stage cancers, including NSCLC, have been limited due to sampling and sensitivity issues. We developed a novel algorithm for INtegration of VAriant Reads (INVAR), which uses sequencing data across hundreds to thousands of tumour-mutated loci to detect ctDNA in plasma samples at high sensitivity. We applied this to a cohort of stage I-III NSCLC patients recruited in the LUCID study. LUCID is a prospective and observational study of 100 stage I-IIIB NSCLC who are planning to undergo radical treatment (surgery or radiotherapy +/- chemotherapy) with curative intent. Plasma samples were collected before and after treatment with curative intent. We analysed a total of 50 patients using patient specific-sequencing panels and detected ctDNA in 78% of cases before treatment, at ctDNA fractions as low as 1.7x10-5. For 17 of those patients staging information was available. Here, we detected ctDNA in 50% of stage I patients (split evenly between stages IA and B) and 100% of stage II and III patients. We also applied INVAR to whole exome and shallow whole genome sequencing data from plasma samples, and showed that this algorithm can be used to detect low ctDNA fractions in such data. Our findings highlight an opportunity to improve ctDNA detection in early stage NSCLC by using patient specific sequencing information. Additionally, our algorithm has the potential to aid in longitudinal cancer monitoring and is applicable to a variety of sequencing data types. We aim to apply this approach to serial samples obtained through the LUCID study to investigate its application in the treatment management. Citation Format: Katrin Heider, Jonathan C. Wan, Davina Gale, Florent C. Mouliere, Wendi Qian, Angels Kateb, Gail Doughton, Nicola Ramenatte, Ruth Tysoe, Christopher G. Smith, Doris M. Rassl, Susan Harden, Robert C. Rintoul, Charles Massie, Nitzan Rosenfeld. Improved ctDNA detection in early stage non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1377.

MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer.

Dendritic cell (DC) immunotherapy is an optimal cancer treatment, resulting in its emergence as a therapeutic choice; however, there are limited studies investigating dual antigen-pulsed DC immunotherapy in non-small cell lung cancer (NSCLC). In order to determine the effect of a recombinant melanoma-associated antigen (rMAGE-3) and recombinant Survivin (rSurvivin) peptide-pulsed DC immunotherapy in patients with NSCLC, the present clinical study was performed. DC immunotherapy was generated from the monocytes of patients with NSCLC and primed with rMAGE-3 and rSurvivin peptides. The present open-label, non-randomised study enrolled 16 patients with histologically confirmed stage I-IIIB NSCLC between December 2013 and October 2014. A prime immunotherapy (9.1×107 cells/dose) and a single boost (8.2×107 cells/dose) were administered 1 month apart intradermally and the patients were evaluated for immunological and clinical response. DC immunotherapy was well tolerated, with no serious adverse events. There was a single incidence of grade 1 fever, chills and fatigue. Out of the 16 patients enrolled, 11 patients showed stable disease and 5 showed disease progression. There was a significant increase in IFN-γ expression on day 60 vs. day 0 (P=0.048). An increasing trend in the mean cluster of differentiation (CD)4:CD8 values of day 30 and day 90 was observed, but this was not significant. The present study established that DCs primed with rMAGE-3 and rSurvivin may be used in NSCLC treatment. However, a larger study is required to address prominent issues, including secretion of immunosuppressive cytokines and mechanisms of tumour escape from immune surveillance. Several factors associated with the manufacturing and quality of immunotherapy also require standardisation.

LAG-3 in Non–Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival

BackgroundLymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor and a putative therapeutic target in non–small-cell lung cancer (NSCLC). We explored the prognostic effect of LAG-3+ tumor-infiltrating lymphocytes (TILs) in primary tumors and metastatic lymph nodes in NSCLC and its potential for inclusion in an immunoscore, supplementing the TNM classification. Materials and MethodsPrimary tumor tissue from 553 stage I-IIIB NSCLC patients and 143 corresponding metastatic lymph nodes were collected. The expression of LAG-3 was evaluated by immunohistochemistry on tissue microarrays. ResultsOn univariate analysis, LAG-3+ TILs in the intraepithelial and stromal compartments of primary tumors and in the intraepithelial and extraepithelial compartments of metastatic lymph nodes were associated with improved disease-specific survival (DSS). On multivariate analysis, stromal LAG-3+ TILs were a significant independent predictor of improved DSS (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.43-0.82; P = .002). Stromal LAG-3+ TILs did not have prognostic impact across all pathologic stages. In the metastatic lymph nodes, intraepithelial (HR, 0.61; 95% CI, 0.38-0.99; P = .049) and extraepithelial (HR, 0.54; 95% CI, 0.29-0.70; P < .001) LAG-3+ TILs were independently associated with favorable DSS. ConclusionLAG-3+ TILs are an independent positive prognostic factor in stage I-IIIB NSCLC. LAG-3 in metastatic lymph nodes is a candidate marker for an immunoscore in NSCLC.

In-vivo isolation of circulating tumor cells in non-small cell lung cancer patients by CellCollector.

In non-small cell lung cancer (NSCLC) circulating tumor cells (CTCs) can provide information on patient prognosis and treatment efficacy. Currently CTCs are mostly isolated in vitro from small volumes of patient blood samples. The aim of the study was to assess a medical device for in vivo isolation of CTCs directly from the blood of NSCLC patients. The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the CellCollector was mediated by an antibody directed against the epithelial cell adhesion molecule. There were 60 applications of the wire in 48 stage I-IIIB NSCLC patients and 12 non-cancer patients. The device was well tolerated in all applications without side effects. We obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with a median (range) of 13 (0-300) CTCs. In the non-cancer patients, no CTCs were detected. The safety and efficacy of an in vivo CTC detection method directly from the bloodstream of patients with NSCLC has been demonstrated. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients.

Prognostic value of blood-biomarkers related to hypoxia, inflammation, immune response and tumour load in non-small cell lung cancer – A survival model with external validation

AimImprove the prognostic prediction of clinical variables for non-small cell lung cancer (NSCLC), by selecting from blood-biomarkers, non-invasively describing hypoxia, inflammation and tumour load. MethodsModel development and validation included 182 and 181 inoperable stage I-IIIB NSCLC patients treated radically with radiotherapy (55.2%) or chemo-radiotherapy (44.8%). Least absolute shrinkage and selection operator (LASSO), selected from blood-biomarkers related to hypoxia [osteopontin (OPN) and carbonic anhydrase IX (CA-IX)], inflammation [interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP)], and tumour load [carcinoembryonic antigen (CEA), and cytokeratin fragment 21-1 (Cyfra 21-1)]. Sequent model extension selected from alpha-2-macroglobulin (α2M), serum interleukin-2 receptor (sIL2r), toll-like receptor 4 (TLR4), and vascular endothelial growth factor (VEGF). Discrimination was reported by concordance-index. ResultsOPN and Cyfra 21-1 (hazard ratios of 3.3 and 1.7) significantly improved a clinical model comprising gender, World Health Organization performance-status, forced expiratory volume in 1s, number of positive lymph node stations, and gross tumour volume, from a concordance-index of 0.66 to 0.70 (validation=0.62 and 0.66). Extension of the validated model yielded a concordance-index of 0.67, including α2M, sIL2r and VEGF (hazard ratios of 4.6, 3.1, and 1.4). ConclusionImprovement of a clinical model including hypoxia and tumour load blood-biomarkers was validated. New immunological markers were associated with overall survival. Data and models can be found at www.cancerdata.org (http://dx.doi.org/10.17195/candat.2016.04.1) and www.predictcancer.org.

Which field walking test should be used to assess functional exercise capacity in lung cancer? An observational study.

BackgroundThere is emerging evidence regarding the efficacy of exercise training to improve exercise capacity for individuals with non-small cell lung cancer (NSCLC). Cardiopulmonary exercise testing (CPET) is the gold standard measure of exercise capacity; however this laboratory test has limitations for use in research and clinical practice. Alternative field walking tests are the six-minute walk test (6MWT), incremental-shuttle walk test (ISWT) and endurance-shuttle walk test (ESWT); however there is limited information about their clinimetric properties in NSCLC. Aims: In NSCLC to determine the 1) criterion validity of the 6MWT, ISWT and ESWT against CPET; 2) construct validity of the 6MWT, ISWT and ESWT against measures of function, strength, respiratory function and health-related quality of life (HRQoL); and 3) clinical applicability of the tests.MethodsTwenty participants (40 % male, mean ± SD age 66.1 ± 6.5 years) with stage I-IIIb NSCLC completed the 6MWT, ISWT, ESWT and CPET within six months of treatment. Testing order was randomised. Additional measures included Eastern Cooperative Oncology Group Performance-Status (ECOG-PS, function), respiratory function, hand-grip dynamometry and HRQoL. Correlations and regression analyses were used to assess relationships.ResultsThe ISWT demonstrated criterion validity with a moderate relationship between ISWT distance and CPET peak oxygen consumption (r = 0.61, p = 0.007). Relationships between CPET and six minute walk distance (6MWD) (r = 0.24, p = 0.329) or ESWT time (r = 0.02, p = 0.942) were poor. Moderate construct validity existed for the 6MWD and respiratory function (forced vital capacity % predicted r = 0.53, p = 0.019; forced expiratory volume in the first second % predicted r = 0.55, p = 0.015). There were no relationships between the walking tests and measures of function, strength or HRQoL. The ESWT had a ceiling effect with 18 % reaching maximum time. No floor effects were seen in the tests. The mean ± SD time required to perform the individual 6MWT, ISWT and ESWT was 12.8 ± 2.5, 14.7 ± 3.7 and 16.3 ± 5.0 min respectively; in comparison to CPET which was 51.2 ± 12.7 min. Only one assessor was required to perform all field walking tests and no adverse events occurred.ConclusionsThe ISWT is a promising measure of functional exercise capacity in lung cancer. Findings need to be confirmed in a larger sample prior to translation into practice.

In vivo isolation of circulating tumor cells in non-small cell lung cancer (NSCLC) patients by a medical device.

10536 Background: Currently, circulating tumor cells (CTCs) are isolated in vitro from small limited volumes of blood samples. Furthermore, CTC results for NSCLC as a prognostic and stratification biomarker are scarce. The aim of the study was to assess a functionalized and structured medical wire (FSMW) for in vivo isolation of CTCs directly from the blood of NSCLC patients, and to compare it to the Cell Search method. Methods: The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the FSMW was mediated by an antibody directed against the epithelial cell adhesion molecule (EpCAM). To confirm the CTCs binding to the wire, the immunohistochemical staining against EpCAM as well as CD45 for negative cell selection was performed. There were 72 applications of the wire in 48 stage I-IIIB NSCLC patients (12 double applications) and 12 non cancer patients. Enumeration data was available for 34 NSCLC patients and 8 non cancer patients. For 34 patients, samples were also tested in the Cell Search system. Results: The device was well tolerated in all 72 applications without side effects. We obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with a median (range) of 13 (0-300) CTCs. The sensitivity was similar for early and late stage NSCLC patients. In the non-cancer patients, no CTCs were detected (100 % specificity). In 2 of 34 samples (5.8%), CTCs were detected by the Cell Search method. In all matched pairs, the FSMW detected the same number or more CTCs compared to the Cell Search method. Conclusions: Whilst well tolerated without side effects, the CTC detection rate of the FSMW in NSCLC patients was &gt;90%. In contrast, &lt;10% detection was obtained using the Cell Search analysis. No CTCs were detected in non-cancer patients. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. The method may also allow the molecular analysis of the CTCs, with the possibility of establishing more personalized treatment regiments.

A Randomized Phase II Trial of Two Regimens of Moderate Dose Chemoradiation Therapy for Patients with Non-small Cell Lung Cancer Not Suitable for Curative Therapy: Trans Tasman Radiation Oncology Study TROG 03.07

There are patients with stage I-III non-small cell lung cancer (NSCLC) who are not suitable for curative radical chemoradiation therapy. There are patients with an isolated solitary extracranial metastasis who have improved outcomes compared with those with cranial or multiple metastases. Patients of good performance status receiving moderate dose radiation therapy have improved survival. Two regimens of moderate dose chemoradiation therapy for such patients were compared in a randomized phase II trial. Patients were eligible if they had stage I-IIIB NSCLC, unsuitable for curative therapy, or stage IV with a PET-detected extracranial solitary metastasis. Patients were randomized to the following groups-arm A: 40 Gy/20 fractions/4 weeks with concurrent weekly vinorelbine 25 mg/m + cisplatin 20 mg/m or arm B: 30 Gy/15 fractions/3 weeks with concurrent weekly gemcitabine 200 mg. Primary end points were feasibility, response rates, and toxicity. Secondary end points were progression-free survival, overall survival, and quality of life. Eighty-four patients were randomized. Compliance was above 90% for both arms. The overall response rate was 51% in arm A and 38% in arm B (p = 0.147). Grade 3/4 toxicity in both arms was acceptable. There was no difference in median progression-free survival between the two arms (5.5 versus 5.0 months, p = 0.19). Patients in arm A had longer median survival but this did not reach statistical significance (13.1 versus 8.3 months, p = 0.25). No difference in quality of life was observed. Arm A was chosen for a future phase II comparison with radiation therapy alone as it demonstrated a response rate greater than 50%, and data suggested that arm A had superior survival to arm B.

Effects of Aerobic Training on Oxidative Status in Postsurgical Non-Small Cell Lung Cancer Patients: A Pilot Study

Background Oxidative stress is postulated to contribute to the initiation, promotion, and progression of non-small cell lung cancer (NSCLC). We investigated the effects of supervised, moderate-intensity aerobic training on urinary markers of oxidative status in patients with postsurgical NSCLC. Patients and Methods Sixteen patients with histologically confirmed stage I-IIIB NSCLC were recruited. Exercise training consisted of aerobic cycle ergometry sessions at 60 to ≥70% of baseline peak workload 20–45 min .d −1, 3 d .wk −1for 14 weeks. Oxidative status was assessed via four urinary F 2-isoprostanes isomers: iPF (2-alpha)-III, 2,3-dinor-iPF(2 alpha)-III, iPF (2-alpha)-VI, and 8,12-iso-iPF(2 alpha)-VI using liquid chromatography with tandem mass spectrometry detection. Peak oxygen consumption (VO2peak) was assessed using a maximal, incremental, cardiopulmonary exercise test with expired gas analysis. Results A composite index of all four F2-isoprostanes isomers increased from baseline to post-intervention by 32% (p = 0.08). Concerning individual isomers, iPF (2-alpha)-III increased by 0.09 (+55%; p = .010), iPF (2-alpha)-VI by 0.81 (+29%; p = 0.04), and 8,12-iso-iPF(2 alpha)-VI by 0.59 (+28%; p = 0.07) from baseline to postintervention. There was no change in 2,3-dinor-iPF(2 alpha)-III levels. VO2peak increased 1.1 mL.kg.-1min-1 (p = 0.14) and peak workload increased 10 Watts (p < .001). Change in VO2peak was not associated with change in markers of oxidative status. Conclusions Aerobic training was associated with significant increases in urinary measures of oxidative status in postsurgical NSCLC. The clinical implications of these findings are currently unknown. Further studies are required to elucidate the complex relationship between aerobic training, oxidative stress, tumor biology, and response to cytotoxic agents in mouse and human models of cancer.

Safety and feasibility of aerobic training on cardiopulmonary function and quality of life in postsurgical nonsmall cell lung cancer patients

A feasibility study examining the effects of supervised aerobic exercise training on cardiopulmonary and quality of life (QOL) endpoints among postsurgical nonsmall cell lung cancer (NSCLC) patients was conducted. Using a single-group design, 20 patients with stage I-IIIB NSCLC performed 3 aerobic cycle ergometry sessions per week at 60% to 100% of peak workload for 14 weeks. Peak oxygen consumption (VO(2peak)) was assessed using an incremental exercise test. QOL and fatigue were assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale. Nineteen patients completed the study. Intention-to-treat analysis indicated that VO(2peak) increased 1.1 mL/kg(-1)/min(-1) (95% confidence interval [CI], -0.3-2.5; P = .109) and peak workload increased 9 W (95% CI, 3-14; P = .003), whereas FACT-L increased 10 points (95% CI, -1-22; P = .071) and fatigue decreased 7 points (95% CI; -1 to -17; P = .029) from baseline to postintervention. Per protocol analyses indicated greater improvements in cardiopulmonary and QOL endpoints among patients not receiving adjuvant chemotherapy. This pilot study provided proof of principle that supervised aerobic training is safe and feasible for postsurgical NSCLC patients. Aerobic exercise training is also associated with significant improvements in QOL and select cardiopulmonary endpoints, particularly among patients not receiving chemotherapy. Larger randomized trials are warranted.

Reproducibility of “Intelligent” Contouring of Gross Tumor Volume in Non-Small Cell Lung Cancer on PET/CT Images Using a Standardized Visual Method

Reproducibility of “Intelligent” Contouring of Gross Tumor Volume in Non-Small Cell Lung Cancer on PET/CT Images Using a Standardized Visual Method

The accuracy of EUS-FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC

Optimal management of nonsmall cell lung cancer (NSCLC) depends on tissue diagnosis and accurate staging. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is minimally invasive and provides cytological confirmation of malignant mediastinal disease. The aim was to assess the accuracy of EUS-FNA in cases of enlarged mediastinal lymphadenopathy (LN) of unknown aetiology and in the staging of NSCLC. A total of 52 consecutive patients with stage I-IIIb NSCLC or enlarged mediastinal LN of unknown aetiology underwent EUS-FNA. Negative results were confirmed with a surgical procedure: mediastinoscopy, video-assisted thoracic surgery (VATS) or lobectomy with systematic mediastinal lymph node dissection. In total, 34 patients had EUS-FNA performed for diagnosis, whilst the remaining 18 had EUS-FNA for staging. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy (95% confidence interval) were 93% (77-99), 100% (78-100), 100% (87-100), 88% (63-99) and 95% (84-99), respectively. When EUS-FNA was used in patients with NSCLC, the sensitivity, specificity, PPV, NPV and accuracy were 92% (73-99), 100% (69-100), 100% (85-100), 83% (51-98) and 94% (80-99), respectively. For mediastinal LN of unknown aetiology, no malignant disease was missed. Endoscopic ultrasound-guided fine-needle aspiration is an accurate tool for assessing mediastinal lymph node involvement in nonsmall cell lung cancer and in the diagnosis of unexplained mediastinal lymphadenopathy. Endoscopic ultrasound-guided fine-needle aspiration is a minimally invasive procedure that can be used as an adjunct or alternative to mediastinoscopy.