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Purpose: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC)., Patients and Methods: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cβ inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety., Results: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08)., Conclusion: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Cancer causes muscle mass loss, which is associated with a poor prognosis. Chemotherapy may also reduce muscle mass. We investigated skeletal muscle mass change during palliative chemotherapy for advanced gastric cancer (AGC) and its association with treatment outcomes. We retrospectively reviewed 111 consecutive AGC patients who underwent first-line palliative chemotherapy. Skeletal muscle area was measured before and after chemotherapy at the third lumbar vertebra level using computed tomography scans. We compared skeletal muscle index (SMI), body mass index (BMI), and body weight changes to chemotherapy response and survival. The 80 male and 31 female patients' median age was 65 (range 31-87) years, and 46.8% had sarcopenia at baseline. Median pre-chemotherapy to post-chemotherapy SMI, BMI, and body weight decreases were - 4.5 cm 2 /m 2 (- 11.3%) (P < 0.001); - 0.7 kg/m 2 (- 3.2%) (P < 0.001); and - 2.0 kg (- 3.5%) (P < 0.001), respectively. Median SMI decreases for patients with objective response, stable disease, and disease progression were - 4.0 cm 2 /m 2 (range - 20.1 ~ 9.5); - 4.5 cm 2 /m 2 (range - 19.8 ~ 0.8); and - 3.8 cm 2 /m 2 (range: - 17.6 ~ 0.1), respectively. Response to chemotherapy was not associated with SMI decrease (P = 0.463). In multivariable analysis, sarcopenia at baseline (HR 1.681; 95% CI 1.083-2.609, P = 0.021), decreased SMI (HR 1.620; 95% CI 1.041-2.520; P = 0.032) were significant poor prognostic factors for survival. Skeletal muscle mass decreased significantly during chemotherapy in AGC patients, but was not associated with chemotherapy response. Decreased SMI was a poor prognostic factor in AGC patients during first-line palliative chemotherapy.

Background: Older patients have increased risk of toxicity from chemotherapy. Current prediction tools do not provide information on cumulative risk., Methods: Patients aged ≥ 70 years with solid cancer were prospectively enrolled. A prediction model was developed for adverse events (AEs) ≥ Grade 3 (G3), based on geriatric assessment (GA), laboratory, and clinical variables., Results: 301 patients were enrolled (median age, 75 years). Median number of chemotherapy cycles was 4. During first-line chemotherapy, 53.8% of patients experienced AEs ≥ G3. Serum protein < 6.7 g/dL, initial full-dose chemotherapy, psychological stress or acute disease in the past 3 months, water consumption < 3 cups/day, unable to obey a simple command, and self-perception of poor health were significantly related with AEs ≥ G3. A predicting model with these six variables ranging 0-8 points was selected with the highest discriminatory ability (c-statistic= 0.646), which could classify patients into four risk groups. Predicted cumulative incidence of AEs ≥ G3 was discriminated according to risk groups., Conclusions: This prediction tool could identify the risk of AEs ≥ G3 after chemotherapy and provide information on the cumulative incidence of AEs in each cycle., Clinical Trial Id: WHO ICTRP number, KCT0001071.

Aim: Although targeting angiogenesis with vascular endothelial growth factor receptor (VEGFR) inhibitors has demonstrated efficacy in the treatment of renal cell carcinoma, primary, intrinsic resistance to the VEGFR inhibitor sunitinib is not fully understood in a subset of metastatic RCC (mRCC) patients., Methods: Between 2008 and 2012, a total of 134 patients with mRCC were treated with first-line sunitinib at one of six tertiary centers. Patients in whom progressive disease was the best response were classified as the intrinsic resistance group. Univariate and multivariate analyses were performed on the recognized baseline parameters., Results: Among 134 patients, 33 (25%) intrinsically resistant to sunitinib were identified. Multivariate logistic regression analyses revealed that the number of metastatic sites (OR = 3.6) and neutrophilia (OR = 7.4) were independently associated with development of intrinsic resistance. There were significant differences with regard to overall survival (P = 0.001) and progression-free survival (P < 0.0001) between the patients with and without intrinsic resistance., Conclusions: Intrinsic resistance to first-line sunitinib treatment is associated with a dismal prognosis in mRCC patients. Patients with known high-risk factors (poor performance, neutrophilia, elevated lactate dehydrogenase) and multiple metastatic sites including the liver may experience a limited benefit from sunitinib. Greater understanding of the underlying mechanism and molecular biomarkers for detecting intrinsically resistant disease is needed., (© 2016 John Wiley & Sons Australia, Ltd.)

Purpose: The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib-related skin effects (ERSEs)., Methods: This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to ≤ grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks., Results: Fifty-two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2%) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 ± 0.83 to 1.13 ± 0.89 and 1.52 ± 0.84 to 0.67 ± 0.90, respectively (p < 0.001). The most common reason for discontinuing the study was progression of cancer (37%)., Conclusions: Based on the results, the EGF ointment is effective for ERSEs, regardless of gender, age, type of tumor, and dosage of erlotinib. The EGF ointment evenly improved all kinds of symptoms of ERSEs., Clinical Trial Registration No: ClinicalTrials.gov identifier: NCT01593995.

Background: Gefitinib was compared with pemetrexed as second-line therapy in a clinically selected population previously treated with platinum-based chemotherapy., Methods: A phase 3 trial of gefitinib (250 mg/day) versus pemetrexed (500 mg/m(2) on day 1, every 3 weeks) was conducted in patients who had never smoked and who had advanced pulmonary adenocarcinoma treated with 1 previous platinum-based regimen. The primary endpoint was progression-free survival (PFS)., Results: A total of 135 patients were analyzed. The gefitinib group had significantly longer PFS compared with the pemetrexed group, with a median PFS time of 9.0 versus 3.0 months (P = .0006). The objective response rates were 58.8% and 22.4% for gefitinib and pemetrexed, respectively (P < .001). However, there was no statistically significant difference in overall survival between the 2 groups (22.2 vs 18.9 months; P = .37). The difference of PFS was increased in a subgroup analysis of 33 patients with activating epidermal growth factor receptor mutation (15.7 vs 2.9 months; hazard ratio, 0.3; 95% confidence interval, 0.13-0.72; P = .005), with numerical superiority of gefitinib in the 38 patients testing negative for epidermal growth factor receptor mutation (5.9 vs 2.7 months; P = .099). Both regimens were well tolerated. There were no significantly different changes in quality of life between the 2 groups, except that symptom scores for dyspnea and diarrhea favored the gefitinib and pemetrexed arms, respectively., Conclusions: Gefitinib showed superior efficacy to pemetrexed as second-line therapy in Korean never-smokers with pulmonary adenocarcinoma., (Copyright © 2012 American Cancer Society.)

Aim: We conducted this phase II study in an effort to evaluate the efficacy and safety of a gemcitabine single chemotherapy as a second-line treatment for biliary tract cancer (BTC) patients who evidenced disease progression after the administration of 5-fluorouracil (5-FU)-based palliative chemotherapy., Patients and Method: Patients treated previously with 5-FU-based palliative treatment as a BTC were enrolled in this study. Treatment consisted of gemcitabine at a dosage of 1,250 mg/m(2) administered intravenously over a 30-minute period on days 1 and 8 of each 21-day cycle until progression., Results: Between Feb. 2006 and July 2009, a total of 32 patients were assigned to treatment groups. 16 patients (50%) had cancers of intra-hepatic cholangiocarcinoma, 12 patients (37.5%) had gall bladder cancer, and 4 patients (12.5%) had extra-hepatic cholangiocarcinoma. In the 29 patients whose tumor responses were evaluated, two achieved a partial response, with an overall response rate of 6.9% (95% confidence interval [CI]: 0.0-16.7%). Six patients (20.7%) evidenced stable disease and 21 patients (72.4%) evidenced progression during the course of treatment. The median follow-up duration was 23.2 months (range: 3.0-53.1 months). The median time to progression (TTP) was 1.6 months (95% CI: 1.3-1.9 months), and the median overall survival (OS) time was 4.1 months (95% CI: 2.7-5.5 months). Poor performance status (ECOG 2) in patients was predictive of shorter TTP. Lower albumin levels (<3.5 g/dL) in patients were predictive of shorter TTP and OS., Conclusions: Despite first salvage chemotherapy in the phase II study for patients with 5-FU refractory BTC, the results in terms of RR, TTP, and OS were lower than expected. However, selected patients with good performance status and sufficient albumin levels may have derived some survival benefits from salvage chemotherapy.

Backgrounds: Cisplatin-based chemotherapy, in combination with fluoropyrimidines or taxanes, have demonstrated efficacy against advanced gastric cancer (AGC). This retrospective study was performed with the data obtained from our cancer chemotherapy registry and eight another cancer centers., Methods: In 2008, a total of 283 AGC patients were treated with cisplatin-based doublet chemotherapy in the first-line setting: capecitabine plus cisplatin (XP, n = 77), S-1 plus cisplatin (SP, n = 97), taxanes (docetaxel, paclitaxel) plus cisplatin (TP, n = 72), and 5-fluorouracil plus platinum (FP, n = 37). The primary endpoint of this study was overall survival (OS) and the secondary endpoints were safety, response rate and progression-free survival (PFS)., Results: The median age was 54 years with a range of 28-78 years and median delivered number of chemotherapy cycles were XP: 4, SP: 5, TP: 5 and FP: 5, respectively. Objective tumor responses (38%; 95% CI, 32-43%) were 40% for XP, 42% for SP, 36% for DP, and 24% for FP. The estimated median PFS was 4.5 months (95% CI, 3.6-5.4 months) and the median OS was 12.3 months (95% CI, 10.8-13.7 months). No statistically significant difference was found between each regimen used as first-line chemotherapy. At multivariate analysis, independent prognostic parameters for OS were prior gastrectomy, peritoneal dissemination, performance status and hemoglobin level, Conclusion: All of the cisplatin-based doublet chemotherapy regimens appear to be active as first-line chemotherapy for AGC. With better patient selection according to clinical parameters and molecular markers, clinical outcomes of AGC patients in first-line setting can be improved.

Many natural compounds have been shown to prevent cancer cell growth through the redox regulation of transcription factors. NF-kappaB, a redox transcription factor, has been implicated in the apoptotic cell death of several cancer cells. This study examined whether or nor 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyranone (DDMP) isolated from onions can modulate the activity of NF-kappaB, thereby induce the apoptotic cell death of colon cancer cells. Treatment with different DDMP concentrations (0.5-1.5 mg/mL) for various periods (0-48 h) inhibited the growth of colon cancer cells (SW620 and HCT116) followed by the induction of apoptosis in a dose dependent manner. It was also found that DDMP modulated tumor necrosis factor-alpha (TNF-alpha) and tetradeanoyl phorbol acetate (TPA)-induced NF-kappaB transcriptional and DNA binding activity. Moreover, DDMP suppressed the NF-kappaB target anti-apoptotic genes (Bcl-2), whereas it induced the expression of the apoptotic genes (Bax, cleaved caspase-3 and cleaved PARP). These results suggest that DDMP from onions inhibit colon cancer cell growth by inducing apoptotic cell death through the inhibition of NF-kappaB.

The clinical features and prognostic factor of lymphoma-associated hemophagocytic syndrome (LAHS), diagnosed according to World Health Organization classification, were investigated by reviewing the clinical records of 29 patients between September 1994 and September 2006. Compared with patients with T or natural killer (NK)/T cell LAHS, patients with B cell LAHS were older (p = 0.022), were less likely to exhibit disseminated intravascular coagulation (DIC; p = 0.011), and had less direct involvement of bone marrow (p = 0.03). Clinical response was achieved in 15 (65.2%) and complete remission (CR) was achieved in 4 (17%) of 23 patients who received chemotherapy. Four patients received high-dose chemotherapy and autologous stem cell transplantation (A-SCT), and three of these four patients showed CR. The median survival was 36 days (95%CI, 20.2-51.8). Univariate analysis showed that poor performance status (p = 0.028), T or NK/T cell lymphoma (p = 0.016), presence of jaundice (p = 0.063), the presence of DIC (p = 0.002), and poor clinical response to treatment (p < 0.001) predicted poor overall survival. These data suggest that the clinical features differ significantly between B cell LAHS and T or NK/T cell LAHS. Intensive treatment including high-dose chemotherapy and A-SCT should be investigated.