The rate of lung cancer metastasis to the bone is high and skeletal-related events (SREs) decrease the quality of life in many patients. Recently, it was found that a subgroup of patients with non-small cell lung cancer (NSCLC) have specific mutations in the EGFR (epidermal growth factor receptor) gene. We assessed the SREs in advanced lung adenocarcinoma patients that evaluated EGFR mutations in whom bone metastasis was present.We retrospectively investigated the clinical records of 377 patients with advanced NSCLC. Patients were evaluated for the presence of EGFR mutations, bone metastases, the incidence of SREs, and treatment history before the first SRE.A total of 78 patients who were evaluated for EGFR mutations had bone metastasis from lung adenocarcinoma. The most frequent site of bone metastasis was the spine (36.2%). SREs occurred in 37 patients (47.4%), the most common of which was bone radiotherapy (41.0%). Significant differences were not observed in the sites of bone metastases or the patterns of SREs between patients with and without EGFR mutations. The median time from bone metastasis to the first SRE was 5.8 months in all of the subjects, history of EGFR-tyrosine kinase inhibitor (TKI) treatment was significantly associated with longer median time to first SRE (14.2 months vs 1.3 months, p < 0.0001), and the median time to first SRE of patients with PS 0-1 was longer (8.5 months vs 0.9 months, p = 0.0023).We found that SRE patterns have no difference between EGFR mutation positive and negative, and that the time from bone metastasis to the first SRE was longer in advanced lung adenocarcinoma patients with good PS and history of EGFR-TKI treatment.
7334 Background: Gefinitib is an orally active, selective epidermal growth factor receptor thyrosine kinase inhibitor, which has shown efficacy in non-small cell lung cancer patients in phaseI and IIstudies. The result of phaseII trials (IDEALI and IDEALII) showed a response rate of 10–20% and overall disease-related symptom improvement rate of approx,40%. Significant factor for response were female gender and histological adenocarcinoma. Factors associated with efficacy of gefinitib were retrospectively analyzed in patients with lung adenocarcinoma who treated with gefinitib in our institute. Methods: Patients were received gefinitib from October 1998 to March 2003. They were categorized by age, gender, clinical stage, tumor differentiation, performance status (PS), number and response of prior chemotherapy, smoking history, and disease control. We examined whether there are the relationship between categories and, disease control and overall survival. Results: A total of 47 patients (median age, 63 years; range 24–85) were reviewed. The patients included 28 males and 19 females, and two patients had stage IIIB disease, 45 patients had stage IV disease. Tumor differentiation included 20 poor differentiations, 13 moderate differentiations, 5 well differentiations and 9 unknowns. Overall response rate and disease control rate was 14.8% and 31.9% respectively (CR 0 PR 7 SD 8). Estimated median survival time was 8.5 months. Significant correlation was found between gender and disease control. Significant predictive factors for improved survival included better PS (p=<0.01), disease controlled by gefinitib (p=<0.01) and well or moderately differentiation (p=0.04). Conclusions: To evaluate the furthermore, we conducted not only clinical characteristics but also biomarker that is EGFR, p-EGFR, p-AKT, p-ERK and HER2. These peptides are now evaluated by using IHC, and we will present the result of this study at 2004 ASCO meeting. No significant financial relationships to disclose.
6112 Background: The number of elderly NSCLC patients is increasing all over the world. Actual age and ECOG PS is not always efficient to select "fit-elderly" for chemotherapy. We integrated the data from two phase III trial (JCOG0207, JCOG0803/WJOG4307L) and evaluated 4 CGA items as well as age and PS to determine whether they would predict survival, response and toxicities. Methods: Eligibility criteria of both trials included histologically or cytologically proven NSCLC; stage III/IV; age 70 or more; ECOG PS of 0-1; unfit for bolus cisplatin; no prior treatment; adequate organ function. Patients were randomized to receive either weekly docetaxel (D) or D plus cisplatin (DP) in J0207, and either 3-weekly D or DP in J0803/W4307L. This study included all eligible pts for whom all of 4 CGA items (Activity of Daily Living [ADL], Instrumental Activity of Daily Living [IADL], Mini-Mental State Examination [MMSE], Geriatric Depression Scale [GDS-15]) were assessed before treatment. Primary endpoint was overall survival (OS). Survival curves are estimated by Kaplan-Meier method and multivariate analysis for OS adjusting baseline factors were performed by using stratified Cox regression model. Results: This analysis included 331 pts (J0207/J0803-W4307L: 105/226) in total. The result of multivariate analysis for OS was shown in the table. After adjusting baseline factors, MMSE as well as sex and PS was significantly associated with OS. None of the CGA items were associated with response and toxicities. Conclusions: It is not actual age but MMSE and PS that is useful for predicting prognosis of elderly pts. MMSE should be taken into consideration to determine the indication of chemotherapy for elderly pts. [Table: see text]
e14606 Background: Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-amino-anthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we performed a PK/PD study of AMR in patients with lung cancer treated with AMR alone or the combination of AMR + cisplatin (CDDP). Methods: AMR was given at a dose of 30 or 40 mg/m 2 on days 1 to 3. Plasma samples were collected at pretreatment, 24 hours after the 1 st injection (day 2), and 24 hours after the 3 rd injection (day 4). Plasma concentrations of AMR, AMR-OH, and CDDP were determined by HPLC and AAS. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid E max model. Results: A total of 35 patients with a median age of 65 years (range 40–78), including 10 with small cell lung cancer (SCLC), 23 with non-small cell lung cancer (NSCLC), 1 with thymic cancer, and 1 with neuroblastoma were enrolled. A total of 107 plasma samples were available for study. Mean concentrations of AMR on day 2, AMR on day 4, AMR-OH on day 2, and AMR-OH on day 4 were 8.52ng/mL+4.63, 16.55ng/mL+11.92, 7.28 ng/mL+3.56 SD, and 13.35ng/mL+5.56 (mean ± SD), with significant increase from day 2 to day 4 for both AMR (p<0.0001) and AMR-OH (p<0.0001). Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (p=.018, p=.012, and p=.025). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (p = .081). No relationships were observed between drug concentrations and responses. The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients with co-administration with CDDP using a sigmoid E max model. Conclusions: The plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. Assessment of plasma concentration of AMR-OH at one time point might enable prediction of hematological toxicities. No significant financial relationships to disclose.
Computed tomography (CT)-guided needle biopsy is a well-established and dependable procedure for the diagnosis of pulmonary lesions. Some tissue biopsy samples have loose cohesion and disintegrate into tiny pieces before formalin fixation. The purpose of this study was to assess the association between the fresh macroscopic appearance of samples obtained using CT-guided needle biopsy and the clinicopathological features of non-small cell lung cancer (NSCLC).A total of 111 patients who underwent CT-guided lung needle biopsy at Osaka City University Hospital between May 2009 and May 2013 were enrolled. Macroscopic appearance was categorized as either loose or tight cohesion. Samples were evaluated using Azan staining to detect collagen fibers. The staining intensity was multiplied by the percentage of positive cells, and the specimen was categorized as having either low (<100) or high expression ( ≥100). Univariate and multivariate logistic regression models were used to evaluate significant covariates for tumor metastasis.In the cohort of 111 patients, the diagnostic rates in loose and tight cohesions were 82.6% and 87.5%, respectively (p=0.509). In 60 patients diagnosed with NSCLC, Azan staining of collagen fibers was positive in 93.5% of the samples with tight cohesion and 28.6% of the samples with loose cohesion (p<0.001). In the multivariate logistic regression models, distant metastasis was significantly associated with loose cohesion (p=0.026).These results suggest that the macroscopic appearance of CT-guided biopsy samples correlates with tumor metastasis in NSCLC.
Objectives: We conducted a clinical phase II study to evaluate the modified weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimen in pretreated patients with advanced non–small cell lung cancer (NSCLC). Materials and Methods: This multicenter single-arm phase II study enrolled patients with advanced NSCLC who had previously received >1 chemotherapy regimen. Patients received nab-paclitaxel at 80 mg/m 2 on days 1, 8, and 15 (21-d cycle). The primary endpoint was the investigator-assessed overall response rate (ORR). Secondary endpoints included overall survival, progression-free survival (PFS), disease control rate, and safety. The planned enrollment was 30 patients according to a Simon 2-stage minimax design. Results: Thirty patients were enrolled between November 2015 and August 2017. Seventeen patients (56.7%) had received >2 regimens. The ORR was 23.3% (95% confidence interval [CI], 8.2%-38.4%), meeting the primary objective of the study. Median PFS was 5.7 months (95% CI, 3.4-9.0 mo), and median overall survival was 12.6 months (95% CI, 8.7-20.8 mo). The median number of treatment cycles was 4 (range, 1 to 20) over the entire study period, and median dose intensity was 63.6 mg/m 2 /wk (range, 45.7 to 100.0 mg/m 2 /wk). No new safety signals were reported; the most common grade ≥3 adverse events were neutropenia (56.7%), leukopenia (23.3%), and infection (10.0%). No cases of febrile neutropenia were observed. Conclusions: Nab-paclitaxel monotherapy with a dose and schedule suitable for outpatients showed high ORR, long median PFS, and acceptable toxicity for patients with previously treated NSCLC. This dosage method may be useful for selected patients.
Multiple primary lung cancers (MPLCs) occur in common carcinogenetic risks such as lifestyle, biological aging, immune responses, hormones, and metabolism. Although MPLCs harbor various genetic profiles within the same individuals, differences in the tumor microenvironment (TME) are unclear. We investigated the impact of genetic aberrations, non-intrinsic factors, and pathological subtypes on tumor immunity. In total, 73 surgically resected specimens from 32 patients with MPLC were analyzed. PD-L1 expression in tumor cells (TCs) and immune cells (ICs), CD3-positive tumor-infiltrating lymphocytes (TILs), CD8/CD3 ratios, and FOXP3-positive TILs that compose TMEs were evaluated by immunohistochemistry and classified on a score of 0–2. 38 tumors were sequenced for somatic mutations in 409 cancer-associated genes. Females and never or light smokers had a higher incidence of PD-L1-negative tumors and a higher concordance rate. PD-L1 positivity in TCs and ICs was significantly less frequent in EGFR-mutated than in wild-type tumors. Differences in the score of TMEs were observed between the KRAS-mutated-only tumor and the KRAS and TP53-co-mutated tumors, and between the KRAS-mutated-only tumor and the KRAS and STK11-co-mutated tumors. Significantly more FOXP3-high TILs were observed in invasive pathological subtypes than in non-invasive ones. Comparing TMEs among MPLCs revealed that non-smokers or light smokers and females were unlikely to express PD-L1 regardless of tumor site and confirmed that the EGFR mutations and co-occurring KRAS and STK11 or TP53 mutations were associated with TME. Pathological subtypes may impact the efficacy of immune therapy due to their potential correlations with regulatory T cells.
Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC.Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated.Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041).RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.
