Evolving sociodemographic trends with survival analysis in lung carcinoma: 6-year insight from Regional Cancer Center (RCC) of North India

Blood-based biomarkers including systemic inflammation (SI) indicators or circulating factors (cytokines, chemokines, or growth factors) are associated with a poor prognosis for lung cancer patients. Collectively these biomarkers can predict the immune state of a patient. We wanted to define and compare the immune states of small cell and non-small cell lung cancer patients, in the hopes that the information gained could lead to overall improvements in patient care and outcomes. Specimens and data from 235 patients was utilized, 49 surgically resected non-small cell lung cancer (NSCLC) patients with no evidence of disease (DF), 135 advanced non-small cell lung cancer (NSCLC), 51 small cell lung cancer (SCLC). SI markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI) were determined from blood counts. Forty-seven plasma cytokines were measured using a multiplex bead-based assay. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox Proportional Hazards models. NSCLC patients had significantly high levels of SI markers than SCLC and DF patients, while NLR, PLR and SII were also higher in SCLC than DF patients. SI optimized marker values to differentiate SI value were; 6.04 (NLR), 320 (PLR), 1615 (SII), and 7.3 (SIRI). Elevated levels NLR (p<0.001), PLR (p<0.001), and SII (p = 0.018) were associated with a worse PFS and OS in NSCLC, while none of the markers were associated with PFS in SCLC patients. NSCLC patients with a poor outcome displayed heterogeneous immune states relative to systemic inflammation and circulating IL-6 markers. These groups could be distinguished based on the cytokines IL-8, TNFα, and IL-27. We identified heterogeneity of immune states in SCLC and NSCLC patients and in NSCLC patients with the poorest prognosis. This heterogeneity could be exploited to improve outcomes for these patients.

185 Background: The Patient Reported Outcome version of Common-Terminology-Criteria-for-Adverse-Events (PRO-CTCAE) and Edmonton Symptom Assessment System (ESAS) are validated tools that measure toxicities and symptoms in cancer patients. We compared the extent in which the presence and severity of toxicities and symptoms affected HUS in SCLC and NSCLC patients. Methods: Adult SCLC and NSCLC patients were recruited from the Princess Margaret Cancer Centre and surveyed cross-sectionally for clinico-demographic variables, EQ5D-5L, PRO-CTCAE and ESAS. HUS were estimated using EQ5D-5L. PRO-CTCAE toxicities include diarrhea, constipation, decreased appetite, nausea, vomiting, fatigue, neuropathy and rash. ESAS symptoms include pain, tiredness, drowsiness, appetite loss, nausea, shortness of breath, depression, anxiety and lack of well-being. These were combined to show frequency and average severity of toxicities/symptoms per patient. Univariable and multivariable linear regression analyses identified toxicity/symptom influencing HUS. Results: Of 75 SCLC and 150 NSCLC, 52% were male with median age of 65 years. The mean HUS was 0.76 (SCLC = 0.69; NSCLC = 0.79; p = 0.001). Compared to NSCLC, SCLC patients had a significantly higher number of toxicities (3.14 versus 1.33 using PRO-CTCAE, p &lt; 0.0001); symptoms (6.75 vs 5.45 using ESAS, p = 0.0003) and severity of toxicities/symptoms (PRO-CTCAE 0-4: 0.95 versus 0.35, p &lt; 0.0001; ESAS 0-10: 3.37 versus 2.04. p &lt; 0.0001). There were significant correlations between the average severity of toxicities/symptoms and HUS (p &lt; 0.0001) adjusted for age, histology, smoking pack years and performance status. For each increase in the average severity of toxicities, there was a corresponding mean drop of 0.03 in the HUS; for every increase in the average severity of symptoms, the drop was 0.04. These relationships were similar for both SCLC and NSCLC patients. Conclusions: Patient reported toxicities and symptoms have a significant impact on HUS in both SCLC and NSCLC patients. Early and aggressive management of such adverse events may be necessary to improve patients’ HRQoL.

146 Background: Kentucky has the highest incidence of lung cancer death and despite improvements in treatment and survival, some small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients remain untreated. We looked at factors preventing these patients from receiving necessary treatment. Methods: Data was collected from the Kentucky Cancer Registry (KCR) for SCLC and NSCLC patients from 2012-2015 and included race, gender, age at diagnosis, treatment history, insurance and overall survival. Treatment included any combination of surgery, radiation, chemotherapy or immunotherapy. Patient demographics were summarized based on treatment status and derived odds ratio (OR) and 95% confidence intervals (CI) were reported. Significant associations were assessed at the p &lt; 0.05 level. Results: KCR identified 2,992 SCLC and 13,975 NSCLC patients from 2012-2015. More NSCLC patients [3,608 (25.8%)] were untreated than SCLC patients [621 (20.8%), p &lt; 0.001], and untreated patients overall were more likely to be older, have more comorbidities (SCLC only), and have Medicare, Medicaid or no insurance. Stage at diagnosis was also a factor but differed based on histology. NSCLC stage III and stage IV patients had higher odds of being untreated compared to stage I (Stage III OR: 2.91, 95% CI: 2.57-3.28; Stage IV OR: 4.82, 95% CI: 4.29-5.41) where these odds in SCLC patients were non-significant (Stage III OR: 0.94, 95% CI: 0.56-1.55) or lower (Stage IV OR: 1.61, 95% CI: 1.01-2.55). SCLC patients also had lower odds of delayed treatment (defined as &gt; 4 weeks to treatment) in stage III and stage IV compared to stage I (Stage III OR: 0.33, 95% CI: 0.23-0.48; Stage IV OR: 0.27, 95% CI: 0.20-0.38). Conclusions: This study shows an overall significant number of untreated lung cancer patients with treatment being strongly associated with insurance status, histology and stage at diagnosis. SCLC patients are more likely to be treated than NSCLC, and advanced stage is less a factor in treating SCLC than NSCLC. The difference may be due to the more aggressive nature of SCLC with physicians feeling more urgency to treat SCLC given its rapid progression and chemotherapy sensitivity compared to NSCLC.

Integrin αvβ3 is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare αvβ3 levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer 68Ga-labeled dimerized-RGD (68Ga-RGD2). Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using 68Ga-RGD2.18F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker αvβ3 in NSCLC and SCLC lesions was analyzed by immunohistochemistry. The 18F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The 68Ga-RGD2 uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of 68Ga-RGD2 SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that αvβ3 integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression. The uptake of 68Ga-RGD2 in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower αvβ3 target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of αvβ3 also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of αvβ3 may potentially improve current applications of αvβ3-targeted therapy and diagnostic imaging in lung cancer.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Background: According to recent publications of our group, JUNB and CXCR4 were overexpressed in CTCs and DTCs isolated from breast cancer patients. This expression was related with patients’ clinical outcome. Current study investigates for the first time, the expression of JUNB and CXCR4 in CTCs from patients with Non-Small Cell Lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC). Methods: Forty four patients were enrolled in this study (30 NSCLC and 14 SCLC patients, before the initiation of 1st line treatment). ISET system was used for NSCLC patients' samples preparation, while the CTCs from SCLC patients were isolated using Ficoll density gradient. Triple immunofluorescence experiments were performed, using CK, JUNB, and CXCR4 antibodies. Results conducted using confocal laser scanning microscopy for NSCLC samples and the VyCAP system for SCLC samples. Results: Sixteen out of 30 NSCLC patients (53.33%), were positive for CTCs, while all SCLC patients harbored CK-positive cells. Most common phenotypes in CK-positive NSCLC patients were the [(CK+/JUNB+/CXCR4+): 50% (8/16patients)], [(CK+/JUNB+/CXCR4-): 43.75%, (7/16)] and the [(CK+/JUNB-/CXCR4-): 37.5% (6/16)]. Less frequent phenotype was the [(CK+/JUNB-/CXCR4+): 6.25%, (1/16)]. Analysis of the mean isolated CTCs/patient revealed that most of the isolated CTCs belonged to the (CK+/JUNB+/CXCR4+) phenotype (42.19%), while less frequent were the (CK+/JUNB+/CXCR4-): 33.13%, (CK+/JUNB-/CXCR4-): 18.44% and the (CK+/JUNB-/CXCR4+): 6.25% phenotypes. Survival analysis revealed that the presence of (CK+/JUNB+/CXCR4+) was related to poorer OS (cox regression: p=0.008) and PFS (Log Rank, p=0.014) All SCLC patients had detectable CTCs in their blood with 13 out of 14 of them having the (CK+/JUNB-/CXCR4-) phenotype (92.86%). The rest of CTC’s phenotypes (CK+/JUNB+/CXCR4+), (CK+/JUNB+/CXCR4-) and (CK+/JUNB-/CXCR4+) where found in 10 out of 14 patients (71.43%) each. Examination of the mean percentage of the total isolated CTCs/patient indicated that the (CK+/JUNB-/CXCR4-) phenotype was the most frequent (49.71%), while the percentages for the rest phenotypes were [(CK+/JUNB+/CXCR4-): 25.94%], [(CK+/JUNB-/CXCR4+): 12.65%] and (CK+/JUNB+/CXCR4+): 11.70%]. Conclusion: JUNB and CXCR4 were upregulated in CTCs from NSCLC and SCLC patients. However, in NSCLC the most frequent phenotype (CK+/JUNB+/CXCR4+) was also related to patients’ outcome, underlying the key role of these molecules in metastatic dissemination. Further examination will determine the role of this expression in all lung cancer subtypes. Acknowledge: This research has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH - CREATE - INNOVATE (project code: T2ΕΔΚ-01562). Citation Format: Argyro Roumeliotou, Evangelia Pantazaka, Anastasia Xagara, Thomas Makatsoris, Angelos Koutras, Vassilis Georgoulias, Athanasios Kotsakis, Galaktia Kallergi. Dr [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1966.

Surgical Assessment and Intraoperative Management of Mediastinal Lymph Nodes in Non-Small Cell Lung Cancer

The aim of this study was to examine the survival difference between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients with diabetes mellitus (DM) according to the first-line therapy. All patients with lung cancer diagnosed at our hospitals between April 1999 and March 2011 were retrospectively analyzed. The definition of DM was strictly determined and included fasting plasma glucose and HbA1c levels. The patients were divided into 2 groups: those with DM (DM group) and those without DM (non-DM group). For each treatment type, the survival of these 2 groups was evaluated. For NSCLC patients overall, the difference in survival between the DM group and the non-DM group was not significant (p = 0.112). However, in surgically treated NSCLC patients, the difference in survival between the 2 groups was significant (p = 0.022). In chemotherapy-treated NSCLC patients, the difference in survival between the 2 groups was not significant (p = 0.942). On the other hand, for SCLC patients overall, the difference in survival between the DM group and the non-DM group was significant (p = 0.012). In chemotherapy-treated SCLC patients, the difference in survival between the 2 groups was significant (p = 0.026). The influence of DM may differ between NSCLC and SCLC patients. At the current treatment level for unresectable NSCLC, the influence of DM might not be the same for NSCLC patients treated with surgery as for SCLC patients treated with chemotherapy. Elucidation of the mechanism by which hyperglycemia influences the progression of lung cancer will improve survival in lung cancer patients with DM.

Objective To investigate the serum levels and clinical significance of the angiogenic factor pleiotrophin (PTN) in patients with lung cancer. Methods Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of PTN in 57 patients with non-small cell lung cancer (NSCLC), 20 patients with small cell lung cancer (SCLC) and 12 healthy individuals, and their relationship with pathological stage and operation therapy foe NSCLC was explored. Results PTN expression was significantly lower in healthy individuals than that in SCLC (P<0.001) and NSCLC patients (P=0.003). PTN level was significantly higher in SCLC patients than that in NSCLC patients (P=0.010). High expression of PTN was identified as a moderately specific marker for lung carcinoma distinguished from healthy subjects with the area under the ROC curve (AUC) at 0.821(95%CI 0.730~0.913) (P<0.001). Additionally, PTN was identified as a lowly specific marker for NSCLC distinguished from healthy subjects with AUC at 0.794 (95%CI 0.684~0.904) (P=0.001). However, PTN was identified as a highly specific marker for SCLC distinguished from healthy subjects with AUC at 0.900 (95%CI 0.783~1.000) (P<0.001). The PTN level in NSCLC patients was significantly associated with clinical stage (P<0.001) and distant metastasis (P=0.019). No association was found between PTN and other clinic pathological features such as pathological type and lymphatic metastasis in NSCLC patients. Compared with NSCLC patients before opertion, PTN level in NSCLC patients after operation was significantly decreased(P<0.001). Conclusion PTN in serum has the important values of diagnosing lung cancer. Moreover, PTN in serum can be available to estimate condition and curative effects of NSCLC. Key words: Pleiotrophin; Bronchiogenic lung cancer; Diagnosis; Clinical significance

OA06.05 Impact of COVID-19 Pandemic on Proportion and Treatment Patterns for Stage I Non-small Cell Lung Cancer in the Netherlands

The medical costs associated with cancer treatment have increased rapidly in Japan; however, little data exist on actual costs, especially for end-of-life care. Therefore, this study aimed to examine the medical costs of lung cancer patients during the last 3 months before death and to compare the costs with those of initial anticancer treatment. We retrospectively evaluated all patients who died from lung cancer at the Japanese Red Cross Medical Center between 1 January 2008 and 31 August 2019. Patients were classified into three cohorts (2008-2011, 2012-2015 and 2016-2019) according to the year of death; the medical costs were evaluated for each cohort. Costs were then divided into outpatient and inpatient costs and calculated per month. Seventy-nine small cell lung cancer and 213 non-small cell lung cancer patients were included. For small cell lung cancer and non-small cell lung cancer patients, most end-of-life medical costs were inpatient costs across all cohorts. The median monthly medical costs for the last 3 months among both small cell lung cancer and non-small cell lung cancer patients did not differ significantly among the cohorts, but the mean monthly costs for non-small cell lung cancer tended to increase. The monthly medical costs for the last 3 months were significantly higher than those for the first year in SCLC (P=0.013) and non-small cell lung cancer (P<0.001) patients and those for the first 3 months in non-small cell lung cancer patients (P=0.005). The medical costs during the end-of-life period for lung cancer were high and surpassed those for initial treatment.

Local Treatment Improves Survival in NSCLC Patients With Synchronous Brain Oligometastases

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

Objective To explore the associations between genetic polymorphisms and haplotypes of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and patients with non small-cell lung cancer (NSCLC).Methods A total of 592 patients with NSCLC and 636 healthy controls were collected.After PCR amplification,TRAIL (G1525A/G1588A/CI595T) gene polymorphisms were detected by using direct sequencing.Haplotype analysis was also performed on all study subjects.Results Frequencies of variant allele (A) and genotype (GA + AA) in TRAIL G1525A were significantly lower in NSCLC patients than in healthy controls (both P＜0.01).Frequencies of variant allele (A) and (T) in TRAIL G1588A and C1595T were also significantly lower in NSCLC patients than those in the healthy controls (both P ＜ 0.01).In the further stratification analysis,frequencies of variant allele (T) and genotype (CT + TT) in TRAIL C1595T significantly differed between (stage Ⅰ + Ⅱ) and (stage Ⅲ + Ⅳ) NSCLC patients [47.89％ vs.58.80％,OR =2.710,95％ confidence interval (CI):1.598-4.596 ; 62.01％ vs.74.65％,OR =2.935,95 ％ CI:1.188-7.249,respectively,both P ＜ 0.05).Moreover,frequency of variant allele (A) in TRAIL G1525A was significantly higher in (stage Ⅲ+ Ⅳ) NSCLC patients than that in (stage Ⅰ + Ⅱ) NSCLC patients (47.54％ vs.40.75％,OR =1.318,95 ％ CI:1.658-1.047,P ＜ 0.05).In addition,TRAIL (G1525A/G1588A/C1595T) genes were found to be in a complete disequilibrium linkage in all study subjects.In contrast with healthy controls,frequency of AAT haplotype was significantly decreased (42.45％ vs.58.23％,95％ CI:1.525-2.824,P ＜0.01),wherease frequency of GAT haplotype was significantly increased in NSCLC patients (9.98％ vs.0.21％,95％ CI:0.015-0.059,P ＜0.01).Conclusion Genetic polymorphisms and haplotypes of TRAIL (G1525A/G1588A/C1595T) genes may be significantly correlated with the susceptibility to NSCLC in Chinese patients. Key words: Non small-cell lung cancer; Tumor necrosis factor; Gene polymorphism