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Purpose: To determine if the radiomic features on CT can predict progression-free survival (PFS) in epidermal growth factor receptor (EGFR) mutant adenocarcinoma patients treated with first-line EGFR tyrosine kinase inhibitors (TKIs) and to identify the incremental value of radiomic features over conventional clinical factors in PFS prediction., Methods: In this institutional review board-approved retrospective study, pretreatment contrast-enhanced CT and first follow-up CT after initiation of TKIs were analyzed in 48 patients (M:F = 23:25; median age: 61 years). Radiomic features at baseline, at 1st first follow-up, and the percentage change between the two were determined. A Cox regression model was used to predict PFS with nonredundant radiomic features and clinical factors, respectively. The incremental value of radiomic features over the clinical factors in PFS prediction was also assessed by way of a concordance index., Results: Roundness (HR: 3.91; 95% CI: 1.72, 8.90; P = 0.001) and grey-level nonuniformity (HR: 3.60; 95% CI: 1.80, 7.18; P<0.001) were independent predictors of PFS. For clinical factors, patient age (HR: 2.11; 95% CI: 1.01, 4.39; P = 0.046), baseline tumor diameter (HR: 1.03; 95% CI: 1.01, 1.05; P = 0.002), and treatment response (HR: 0.46; 95% CI: 0.24, 0.87; P = 0.017) were independent predictors. The addition of radiomic features to clinical factors significantly improved predictive performance (concordance index; combined model = 0.77, clinical-only model = 0.69, P<0.001)., Conclusions: Radiomic features enable PFS estimation in EGFR mutant adenocarcinoma patients treated with first-line EGFR TKIs. Radiomic features combined with clinical factors provide significant improvement in prognostic performance compared with using only clinical factors.

Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI-resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues. Results We identified that EGFR TKI-resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell-transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 43× greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced hypermutation was frequent in the branches toward small-cell transformation. Conclusion EGFR TKI-resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI-treated LADCs is informative in predicting small-cell transformation.

Introduction: The International Association for the Study of Lung Cancer recently proposed new M descriptors for the next edition of the TNM classification for NSCLC, subdividing the current M1b category into two subcategories: M1b, which indicates a solitary extrathoracic metastasis in a single organ, and M1c, which indicates multiple extrathoracic metastasis. The purpose of this study was to validate the prognostic value of the newly proposed M descriptors in an independent cohort with multivariate and subgroup analysis., Methods: A total of 1024 patients in a consecutive lung cancer database who had stage IV NSCLC treated between 2011 and 2014 were analyzed. Newly proposed M staging was used for classification and comparison of survival. Adjustment for other clinical covariates and subgroup analysis was conducted., Results: According to the newly proposed M descriptors, 262 patients (25.6%), 152 patients (14.8%), and 610 patients (59.6%) were classified into the subgroups M1a, M1b, and M1c, respectively. The median overall survival times were 22.5, 17.8, and 13.6 months for the M1a, M1b, and M1c groups, respectively (p < 0.001). After adjustment for other covariates, Cox proportional hazards regression revealed statistically significantly shorter overall survival for the M1b group than for the M1a group (hazard ratio = 1.30; 95% confidence interval: 1.03-1.65, p = 0.03) and for the M1c than the M1b group (hazard ratio = 1.57; 95% confidence interval: 1.28-1.93, p < 0.001). These differences showed a consistent tendency regardless of pathologic and molecular subtypes., Conclusions: The newly proposed M descriptors have prognostic value in patients with stage IV NSCLC., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Our study aimed to determine the predictive and prognostic values of the serum neuron-specific enolase (NSE) level in patients who had non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and who had been treated with EGFR-tyrosine kinase inhibitors (TKIs)., Materials and Methods: We retrospectively analyzed 151 patients who had NSCLC harboring EGFR mutations and had received either gefitinib or erlotinib as first-line treatment between 2005 and 2014. The serum NSE level was measured before initiation of EGFR-TKI treatment., Results: Of the 151 patients, 92 (60.9%) had elevated NSE levels (> 16.3 ng/mL). Patients with elevated NSE levels showed significantly shorter progression-free survival (PFS) after EGFR-TKI treatment than those with normal NSE levels (median PFS, 10.5 months vs. 15.4 months; P = .034). Multivariate analysis demonstrated that elevated NSE levels (hazard ratio [HR], 1.656; P = .017), CNS metastasis at diagnosis (HR, 1.567; P = .037), and male gender (HR, 1.840; P = .005) were independent predictive factors for short PFS. A significant difference in overall survival (OS) was observed between patient groups with elevated and normal NSE levels (median OS, 17.0 months vs. 29.1 months; P < .001), and serum NSE level remained an independent prognostic factor for OS in multivariate analysis (HR, 2.671; P < .001)., Conclusion: Patients with elevated serum NSE levels have significantly shorter PFS and OS. The NSE level is both a predictive marker of EGFR-TKI treatment and a prognostic marker in EGFR-mutant NSCLC patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: MET amplification, protein expression, and splice mutations at exon 14 are known to cause dysregulation of the MET/HGF pathway. Our study aimed to confirm the relationship among MET amplification, protein expression, and mutations in pulmonary adenocarcinoma., Materials and Methods: MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH) were evaluated in 316 surgically resected lung adenocarcinomas. Patients were divided into 4 groups (IHC-negative/FISH-negative, IHC-negative/FISH-positive, IHC-positive/FISH-negative, and IHC-positive/FISH-positive), and 15-20 tumors in each group were randomly selected for mutation analyses to find splice mutations at exon 14., Results: An IHC score of 0-3 was found in 168 (53.2%), 71 (22.5%), 59 (18.7%), and 18 (5.7%) tumors, respectively. The mean gene copy number (GCN) was 3.56; MET FISH positivity was detected in 123 (38.9%) samples, and 26 (8.2%) of them were gene amplifications. MET amplification were significantly associated with the IHC score (P<0.001, χ(2) test). Splice mutations were identified in only 2 (2.9%) of 70 cases. One had a MET IHC score of 2 and negative FISH without amplification; The other had a MET IHC score of 0 and positive FISH without amplification. MET IHC or FISH results were not prognostic indicators of overall survival in multivariate analysis., Conclusion: There is a significant relationship between MET amplification and protein expression, and selection of tumors with amplification using IHC was effective. However, because of its rarity, a selection strategy for mutated tumors is implausible using IHC or FISH., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: While several prognostic models have been presented in NSCLC patients with brain metastasis, none of these models have included molecular markers as an index. The aim of our study was to evaluate the prognostic value of EGFR mutations and to integrate these EGFR mutations into the prognostic index in NSCLC patients with brain metastasis., Materials and Methods: We analyzed retrospectively 292 lung adenocarcinoma patients with brain metastasis. Clinico-pathological features and overall survival (OS) were compared between patients with EGFR mutations and patients with EGFR wild type. EGFR mutation status was integrated with lung specific graded prognostic assessment (GPA) score., Results: Among 292 patients, EGFR mutation status was tested in 183 patients. One hundred and five patients (57.4%) had EGFR activating mutations, 14 (7.7%) had EGFR non-activating mutations and 64 (35.0%) had EGFR wild type. OS was significantly longer in patients with EGFR activating mutations than in those with EGFR wild type patients (20.4 vs. 10.1 months, p = 0.002). However, patients with EGFR non-activating mutations did not show superior OS compared with EGFR wild type patients (14.6 vs. 10.1 months, p = 0.83). Multivariate analysis revealed that the presence of EGFR activating mutation is an independent positive prognostic factor for OS (adjusted hazard ratio 0.56, p = 0.002)., Conclusions: EGFR activating mutations have a prognostic role in lung adenocarcinoma patients with brain metastasis that is independent of other known prognostic factors. The frequency of EGFR mutation was higher than expected. The presence of EGFR activating mutations should be included as an index in the prognostic models for lung adenocarcinoma patients with brain metastasis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: We sought to evaluate the clinical and pathological characteristics of patients with non-small-cell lung cancer (NSCLC) that harbored a ROS1 rearrangement., Methods: Four hundred fifty-one Korean patients with resected NSCLC (the resected group) were examined for ROS1 rearrangements using a tissue microarray and ROS1 fluorescence in situ hybridization and analyzed for clinical and pathological features. Sixty-four patients with advanced pulmonary adenocarcinoma with no known oncogenic aberrations (the advanced group) were also screened for ROS1 rearrangements., Results: Of the 451 consecutive patients from the resected group, ROS1 rearrangements were detected in eight cases (1.8%). In the advanced group, an additional eight patients (12.5%) were identified as harboring ROS1 rearrangements. ROS1 rearrangement was detected exclusively in adenocarcinomas and occurred more frequently in women than in men. With the exception of one patient with an EGFR deletion mutation in exon 19, ROS1-positive adenocarcinomas in all patients revealed no alterations in ALK, EGFR, KRAS, or MET genes. Most ROS1-rearranged tumors showed solid and papillary patterns., Conclusions: ROS1 rearrangements were detected in 1.8% of patients with resected NSCLC and were detected exclusively in adenocarcinomas, which is similar to the frequency detected in non-Asian patients. We suggest that ROS1 screening in adenocarcinoma patients with no known oncogenic aberrations is an effective strategy to find ROS1 rearrangements in NSCLC.

Background: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is markedly sensitive to the ALK inhibitor crizotinib. However, acquired resistance to crizotinib is inevitable through several mechanisms. Therefore, this study was conducted to identify genetic alterations associated with crizotinib resistance., Methods: Tumor samples were derived from seven ALK-positive NSCLC patients who showed acquired resistance to crizotinib, and these patients were analyzed for ALK, EGFR, and KRAS mutations and ALK and EGFR gene amplifications. In vitro cytotoxicity of crizotinib and ALK downstream signals were compared between crizotinib-naive and -resistant NSCLC cells., Results: After a median duration of 6 months (range, 4-12 months), seven ALK-positive NSCLC patients developed acquired resistance to crizotinib. Three patients harbored secondary ALK mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Of note, one patient displayed ALK gene copy number gain (4.1-fold increase compared with the pre-crizotinib specimen) and EGFR L858R mutation with high polysomy. The amphiregulin concentration was high in the supernatant fluid from five patients with malignant pleural effusion (116.4-18934.0 pg/ml). SNU-2535 cells derived from a patient who harbored the G1269 mutation were resistant to crizotinib treatment similar to H3122 CR1 cells. L1196M and G1269A mutant clones were less sensitive to crizotinib and ALK downstream signals were ineffectively suppressed in these clones., Conclusions: Genetic changes associated with crizotinib resistance are heterogeneous in ALK-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance.

Background: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors., Methods: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136., Findings: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group., Interpretation: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment., Funding: Boehringer Ingelheim Inc., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: This study compared the efficacy of pemetrexed in patients with anaplastic lymphoma kinase (ALK)-positive versus ALK-negative (epidermal growth factor receptor [EGFR] mutant or wild type [WT] for both ALK and EGFR) non-small cell lung cancer (NSCLC)., Methods: Patients with advanced NSCLC who received second-line pemetrexed and beyond between March 2007 and April 2010 were screened for EGFR mutations and ALK rearrangements at Seoul National University Hospital. The clinical and in vitro efficacy of pemetrexed was evaluated for each genotypic group., Results: Ninety-five NSCLC patients were genotyped as follows: 43 (45%) EGFR mutation, 15 (16%) ALK translocation, and 37 (39%) WT. The overall response rate was superior in ALK-translocated patients compared with EGFR mutant or WT patients (46.7 versus 4.7 versus 16.2%, p = 0.001). ALK-positive patients showed longer time to progression than EGFR mutant or WT patients (9.2 versus 1.4 versus 2.9 months, p = 0.001). ALK positivity alone was a significant predictor for overall response rate (hazard ratio [HR] = 0.07, 95% confidence interval [CI]: 0.01-0.32; p = 0.001) and time to progression (HR = 0.44, 95% CI: 0.24-0.80; p = 0.007). ALK positivity remained independently significant regardless of treatment line (HR = 0.43, 95% CI: 0.24-0.77; p = 0.005). Thymidylate synthase mRNA levels in ALK-positive cells were significantly lower compared with control cells (p < 0.05)., Conclusion: Pemetrexed is an effective treatment in patients with ALK-positive NSCLC. ALK positivity was independently predictive of pemetrexed efficacy in NSCLC patients.

Introduction: The purpose of this study was to analyze the clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase (ALK)-positive advanced pulmonary adenocarcinoma and to devise an effective screening strategy to identify such patients., Methods: We screened advanced pulmonary adenocarcinoma patients to identify ALK-positive cases. The presence of ALK rearrangements was confirmed by fluorescence in situ hybridization., Results: Of the 221 screened patients, 45 demonstrated ALK rearrangements, and these individuals were younger than the ALK-negative patients (p < 0.001). The proportion of never smokers and light smokers was found not to differ according to the ALK status (p = 0.537). Epidermal growth factor receptor (EGFR) mutations and ALK rearrangements were found to be mutually exclusive. Thyroid-transcription factor-1 (TTF-1) expression was observed in all ALK-positive tumors for which immunohistochemistry data were available. The objective response rate and progression-free survival to first-line platinum-based chemotherapy showed no significant differences between ALK-positive and ALK-negative patients. On the other hand, no patient with ALK-positive tumors achieved objective tumor responses to EGFR tyrosine kinase inhibitors (TKIs). ALK rearrangements were not found among individuals who had EGFR mutations, an objective response to a previous EGFR TKI treatment or TTF-1-negative tumors., Conclusion: The clinical outcomes of platinum-based chemotherapy were found not to differ according to the ALK status. Both smokers and never/light smokers should be candidates for ALK screening. We suggest that the exclusion of patients with activating EGFR mutations, an objective response to previous EGFR TKIs, or TTF-1-negative tumors from ALK screening could be an effective enrichment strategy for ALK-positive cases.

Objective: The purpose of our study was to define the prognostic impact of increased copies of epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma patients receiving adjuvant chemotherapy after surgery., Methods: The study included 95 adenocarcinoma patients who received curative resection for non-small cell lung cancer. Patients received adjuvant chemotherapy composed of paclitaxel and carboplatin. We performed fluorescent in situ hybridization on tissue microarray in duplicate to detect EGFR copy number change., Results: The EGFR fluorescent in situ hybridization result was available in 93 patients with a positive rate of 32.6%. EGFR copy number change did not correlate with age, gender or smoking history. However, EGFR copy number gain was related to high tumor standardized uptake value at diagnosis (P = 0.042). An increase in EGFR copy number was a negative prognostic factor in terms of disease-free survival (median disease-free survival not reached versus 23.6 months, P = 0.037) and overall survival (median overall survival 74.6 versus 43.5 months, P = 0.032). An increase in EGFR copy number was independently related to short disease-free survival in multivariate analysis (hazard ratio 2.039, P = 0.025)., Conclusions: EGFR copy number gain is associated with aggressive tumor biology and is a poor prognostic factor for tumor relapse in resected lung adenocarcinoma patients receiving adjuvant chemotherapy of paclitaxel and carboplatin.

This study was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in patients with advanced pulmonary adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations and to explore the molecular factors affecting the efficacy of gefitinib. Tumor tissue, derived from either the original tumor or the metastatic or recurrent site was taken from chemo-naïve pts with advanced (stage IIIB, IV, and recurrent) pulmonary adenocarcinoma. Tumor genomic DNA underwent direct sequencing for EGFR exons 18, 19, 20, and 21. Patients with EGFR mutations received 250 mg of gefitinib daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and tolerability. Out of 147 screened patients, 45 pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (29 pts, 64%) and L858R point mutation in exon 21 (15 pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR was 53.3% (95% CI, 38.6-67.9) and disease control rate (DCR) including stable disease was 86.7%. The median progression free survival (PFS) was 398 days and the median overall survival (OS) was 819 days. Treatment was well tolerated. Grade 3/4 adverse events (AEs) were reported by 6 patients and treatment-related Grade 3 AEs by 3 patients. There were no treatment-related Grade 4 AEs. Exploratory subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in patients with exon 19 deletions than those with L858R (62.1% vs 33.3%; P=0.0705 and 96.6% vs 66.7%; P=0.0062, respectively). All 4 patients with progressive disease had a L858R mutation. No secondary resistant mutations such as T790M mutation or insertions in exon 20 were found in those patients. In addition, OS was significantly better in patients with exon 19 deletions than those with L858R (24-month OS rate was 72.1% vs 32.0%, P=0.0148). Gefitinib as the first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations was effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in patients with the exon 19 deletion mutations (ClinicalTrials.gov number, NCT00344773)., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The activity of erlotinib after gefitinib failure in non-small cell lung cancer patients with all four favorable clinical factors including female, never smoker, Asian, and adenocarcinoma histology for tyrosine kinase inhibitors (TKIs) is not well known. Treatment efficacy of erlotinib (150mg daily) after progression on gefitinib (250mg daily) was analyzed in patients exhibiting the four clinically favorable factors. Sixteen consecutive female, never smoker, Korean (Asian), adenocarcinoma patients who received erlotinib after gefitinib failure were analyzed. The disease control rate for gefitinib was 68.8% (95% CI, 0.44-0.86) while the disease control rate for erlotinib following gefitinib failure was 25.0% (95% CI, 0.10-0.50) comprised of one partial response and three stable disease patients. The median progression free survival was 6.3 months for gefitinib treatment and 1.7 months for erlotinib treatment following gefitinib failure. The efficacy of erlotinib after progression on gefitinib is unsatisfactory in patients with four favorable clinical factors for TKIs. Novel treatment approaches such as the use of irreversible TKIs or anti-cMET agents for those patients are warranted.

Background: The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified FOLFOX-6) in patients with advanced gastric cancer (AGC), as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin., Methods: Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m2). Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC., Results: The overall response rate (RR) was 43.8%. Median time to progression (TTP) and overall survival (OS) were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp) in TS-3'UTR (55.0% vs. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, p = 0.034), and C/A or A/A in XPD156 (52.0% vs. 26.1% in C/C, p = 0.038). The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, p = 0.032)., Conclusion: Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial.

This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel/cisplatin chemotherapy in patients with metastatic or recurrent gastric cancer that had failed 5-fluorouracil/platinum-based chemotherapy. Thirty-two patients with documented progression on or within 6 months after discontinuing 5-fluorouracil/platinum-based chemotherapy were enrolled. As a second-line treatment, paclitaxel (145 mg/m(2)) and cisplatin (60 mg/m(2)) was administered on day 1 every 3 weeks. Among 32 patients enrolled, 8 (25%) responded partially to paclitaxel/cisplatin, 8 (25%) had stable disease, and 14 (44%) had progressive disease. Two patients (6%) were not evaluable. The median time to progression (TTP) and overall survival for all patients were 2.9 months and 9.1 months, respectively. The most common hematologic toxicity was anemia (47%). Grade 3 neutropenia developed in three patients (9%), but no other grade 3/4 hematologic toxicity occurred. The most common non-hematologic toxicities were emesis (31%) and peripheral neuropathy (38%). Three cases (9%) of grade 3/4 emesis and 2 cases (6%) of grade 3 peripheral neuropathy developed. In conclusion, low-dose paclitaxel and cisplatin chemotherapy showed moderate activity with favorable toxicity profiles. However, relatively short TTP of this regimen warrants the development of more effective paclitaxel-based regimens other than combination with cisplatin in these patients as second-line therapies.

Primary adenocarcinoma of the nonpigmented ciliary epithelium (NPCE) is a very rare disease and the majority of acquired cases were treated by enucleation. We report the case of a 19-year-old man who had an adenocarcinoma arising from the NPCE. The tumor was found incidentally due to changed pupil shape. An excisional biopsy was performed and histopathological examination showed primary adenocarcinoma of the NPCE with a positive resection margin. Because of the positive resection margin and to save the eye, radiotherapy rather than enucleation was performed, followed by chemotherapy. Two years after the diagnosis, the patient continues to be followed up without evidence of relapse or cataract change. Our case suggests that adjunctive radiotherapy should be considered as a sight-saving treatment modality for primary malignant tumors of the NPCE.

Background: Clinical predictors including Asian, female, adenocarcinoma and never-smoker and epidermal growth factor mutation are associated with gefitinib responsiveness in non-small-cell lung cancer. Direct comparison between clinical predictors and EGFR mutation for their predictive power has not been reported., Patients and Methods: For 120 Korean NSCLC patients treated with gefitinib, we have analyzed EGFR mutational status in exons 18, 19 and 21. Patients were grouped according to the number of clinical predictors (female, adenocarcinoma and never-smoker). Response rate (RR), time-to-progression (TTP) and overall survival (OS) were analyzed. Multivariate analysis was performed to investigate which approach yielded better prediction., Results: RRs according to number of clinical predictors were 0: 3.4%, 1: 17.1%, 2: 29.4% and 3: 33.3% (p=0.002). Patients with gefitinib-sensitive EGFR mutation showed 61.9% RR compared with 12.1% in the remaining patients (p<0.001). RRs were higher in patients with the EGFR mutations regardless of the number of clinical predictors. In multivariate analysis, gefitinib-sensitive EGFR mutation showed higher odds ratio of response (9.6, 95% confidence interval [CI] 3.2-28.7) compared with number of clinical predictors (1.7, 95% CI 1.1-2.7). Hazard ratio (HR) of TTP was also better in gefitinib-sensitive EGFR mutation (0.24, 95% CI 0.12-0.47) than number of clinical predictors (0.83, 95% CI 0.69-0.99). Only gefitinib-sensitive EGFR mutation was associated with improved OS (HR 0.25, 95% CI 0.12-0.52)., Conclusion: EGFR mutation should be analyzed whenever possible for effective prediction of objective benefit from gefitinib in NSCLC patients with one or more clinical predictors.

Background: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer., Methods: Chemotherapy-naïve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting., Results: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%)., Conclusions: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-naïve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.

Because of unsatisfactory treatment results with 5-fluorouracil-based palliative combination chemotherapy for advanced gastric cancer, the evaluation of new effective and well-tolerated regimens is needed. We conducted a multi-center, late phase II trial to evaluate the efficacy and safety of Genexol (a paclitaxel formulation) combined chemotherapy with cisplatin in patients with previously untreated metastatic or unresectable measurable gastric adenocarcinoma. All patients were between 18 and 75 years of age, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and had an adequate baseline major organ function. Genexol 175 mg/m(2) was administered as a 3-h infusion, followed by cisplatin 75 mg/m(2) as an intravenous infusion day 1, once every 3 weeks. Thirty-six patients were enrolled from 7 hospitals between November 2002 and April 2003. Of these, 33 patients were assessable for efficacy and 35 for toxicity. Based on an intent-to-treat analysis, 16 patients (46%) achieved a partial response, 7 (20%) stable disease, and 10 (29%) progressed, giving an overall response rate of 46% (95% CI, 29% to 63%). The median duration of response was 7.1 months (95% CI, 6.3 to 7.9 months), and the median time to progression and overall survival were 4.9 months (95% CI, 3.2 to 6.6 months) and 13.8 months (95% CI, 10.8 to 16.8 months), respectively. The major toxicity was neutropenia, with grade 3/4 intensity in 10 patients (29%). However, no febrile neutropenia occurred, and non-hematologic toxicity was usually mild. Grade 3/4 toxicities included nausea (9% of the patients), vomiting (9%), peripheral neuropathy (9%), alopecia (9%), and myalgia (6%). In conclusion, the combination of Genexol and cisplatin was found to be an active and relatively well-tolerated regimen for the treatment of advanced gastric carcinoma.

Objective: The effectiveness of capecitabine, an oral fluoropyrimidine carbamate, is well documented in previously untreated metastatic colorectal cancer patients (overall response rate: 25%). However, its efficacy in patients with metastatic colorectal cancer refractory to 5-fluorouracil/leucovorin (5-FU/LV) has not been determined. This study was performed to evaluate the efficacy and to identify the side-effects of capecitabine in patients with metastatic colorectal cancer showing progression despite 5-FU/LV-based combination chemotherapy., Methods: Fifty-one metastatic colorectal cancer patients who showed progressive disease in 5-FU/LV-containing regimens (median: two regimes) were treated with capecitabine 1,250 mg/m(2) twice daily (days 1-14 repeated every 3 weeks)., Results: Only one partial response was observed (response rate: 2%). Twenty-seven patients (53%) showed stable disease after two cycles. The median time to disease progression of either a partial response or stable disease was 3.4 months. Hand-foot syndrome was the main toxicity of capecitabine and occurred in 35% of cases (grade 3 or 4 in 6%). The median number of cycles administered was two and the relative dose intensity of capecitabine was 80%., Conclusion: The response rate to capecitabine was low in metastatic colorectal cancers that were refractory to 5-FU/LV-containing chemotherapy. However, disease stabilization was seen in a significant number of patients.

Objective: To compare the efficacy of intrathecal methotrexate single therapy with three-drug combination therapy in patients with leptomeningeal carcinomatosis., Methods: Fifty-five patients who had pathologically proven leptomeningeal carcinomatosis of a solid tumor were evaluated in terms of pathological response. Group M (n = 29) received methotrexate 15 mg and group MHA (n = 26) received methotrexate 15 mg, hydrocortisone 15 mg/m(2) and ara-C 30 mg/m(2) twice a week intrathecally until a cytological response was obtained., Results: Primary sites of the tumor were the lung (n = 33), breast (n = 13) and stomach (n = 5). The pathology of 45 patients was adenocarcinoma. The cytological response rate to intrathecal chemotherapy was significantly higher in the MHA group than in the M group (38.5 vs 13.8%, P = 0.036). The median survival was 18.6 weeks in the MHA arm and 10.4 weeks in the M arm (P = 0.029)., Conclusion: Combination intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone showed more favorable effects than methotrexate single therapy for leptomeningeal carcinomatosis in solid tumors.

Objective: The aim of the present study was to confirm the efficacy and tolerability of docetaxel 75 mg/m(2) in a population of Korean patients with advanced gastric cancer., Methods: Patients with metastatic or locally recurrent gastric cancer received docetaxel 75 mg/m(2) by intravenous infusion every 3 weeks. Objective response rate was the primary endpoint., Results: Forty-five patients were enrolled. Most showed adenocarcinomas of the gastric antrum and/or body of the stomach. All showed metastases and two-thirds retained the primary tumour. Forty-four patients received at least one docetaxel infusion ('treated' population), with 40 patients evaluable for response. A total of 159 cycles (median three cycles) were administered, with mean duration of treatment 10.9 weeks. The objective response rate in the treated population was 15.9% (17.5% in the per protocol population), with stable disease in 25.0% of patients and progressive disease in 50.0%. Grade 3-4 neutropenia occurred in 36 (81.8%) patients and 36.1% of cycles. However, febrile neutropenia occurred in only two (4.5%) patients and 1.3% of cycles. Grade 3 anorexia, experienced by two patients (4.5%) and during 1.9% of cycles, was the most frequent non-haematological adverse event possibly or probably related to docetaxel. No grade 4 non-haematological events occurred., Conclusion: This study suggests that docetaxel 75 mg/m(2) is active in metastatic or locally recurrent adenocarcinoma with a low incidence of grade 3-4 adverse events. Docetaxel warrants further study in combination regimens for advanced gastric cancer.

Abstract: Background: We sought to identify the relationship between response to previous systemic treatment and the efficacy of subsequent pemetrexed therapy in advanced non-small cell lung cancer (NSCLC). Patients and methods: Two hundred and fifty clinical stage IIIB or IV NSCLC patients treated with pemetrexed as a second-line or further-line treatment between April 2007 and June 2008 were analyzed retrospectively. Prior therapies were divided into four types (gemcitabine-based [G], paclitaxel-based [P], docetaxel-based [D], and EGFR tyrosine kinase inhibitor [I]). Objective response rates (ORR) and progression-free survivals (PFS) for pemetrexed therapy were analyzed according to the response outcome with each previous treatment. Results: The ORR of pemetrexed therapy was higher for patients who had achieved partial response with previous [G] therapy than others (15.0% vs. 4.3%, p =0.02). In addition, median PFS for pemetrexed therapy was greater for responders to [G] than for nonresponders (3.0 months vs. 1.7 months, p =0.004). The longer PFS for responders to [G] was also shown in the analysis among patients with squamous cell carcinoma (3.2 months vs. 1.7 months, p =0.056). By univariate analyses, the variables of the responder to [G] therapy, female, adenocarcinoma, never smoking status, and ECOG performance status of 0–1 were good predictive factors for pemetrexed therapy in terms of PFS. Multivariate analysis revealed that only response to [G] had statistical significance (hazard ratio=0.62, p =0.006). Conclusion: Response outcome to prior [G] therapy might predict the efficacy of subsequent pemetrexed therapy in advanced NSCLC. [Copyright &y& Elsevier]