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Purpose: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. Materials and Methods: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of =50.4 Gy were defined as the non-boost group, while =54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. Results: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). Conclusion: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC). Materials and Methods Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity. Results Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin. Conclusion The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity. [ABSTRACT FROM AUTHOR]

Background: With a 15% incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and is a poor prognostic factor. Immune checkpoint inhibitors (ICIs) as salvage therapy have modest activity in BTC. Objectives: There are limited data on the efficacy of ICIs according to KRAS mutation in BTC. We evaluated the efficacy of ICIs in BTC patients with or without KRAS mutations. Design: Retrospective observational study. Methods: We conducted molecular profiling in BTC patients who received ICIs as salvage therapy. The expression of programmed death ligand 1 (PD-L1) on tumor cells was assessed using immunohistochemistry. The TruSight™ Oncology 500 assay from Illumina was used as a cancer panel. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to KRAS mutation and PD-L1 expression. Results: A total of 62 patients were included in this analysis. The median age was 68.0years; 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% received fluoropyrimidine plus oxaliplatin (FOLFOX) before ICI. The median number of lines of prior chemotherapy was 2.5. The KRAS mutation was found in 13 patients (19.1%), and 28 patients (45.2%) showed 1% or more of tumor cells out of visible tumor cells positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS with ICI were 5.6 [interquartile range (IQR): 3.3–8.0] and 3.8 (IQR: 3.0–4.5) months, respectively. There were no statistically significant differences in PFS with ICIs according to KRAS mutation (mutant type versus wild type) and PD-L1 expression (positive versus negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS compared with patients with KRAS mutation and PD-L1 negativity (10.1 versus 2.6months, 푝=0.047). This finding was not shown in patients with wild-type KRAS. Conclusion: Our analysis suggested that PD-L1 expression might be a useful biomarker for ICIs in BTC patients with KRAS mutation but not in those with wild-type KRAS. [ABSTRACT FROM AUTHOR]

Background/Aim: Biliary tract cancer (BTC) has a poor prognosis due to its highly invasive and metastatic potential. Ataxia-telangiectasia mutated (ATM) is a key regulator of DNA damage response and an emerging therapeutic target; however, the association between the expression of ATM and the prognosis in advanced BTC is unknown. We aimed to identify the relationship between ATM expression, clinicopathological characteristics, and survival outcomes in patients with advanced BTC. Patients and Methods: We analyzed 113 patients with advanced BTC who received first-line gemcitabine and platinum. Results: The tumor location was intrahepatic cholangiocarcinoma (IHCCC) in 43 patients, extrahepatic cholangiocarcinoma (EHCCC) in 49, and gallbladder (GB) cancer in 21 patients. Fifty-four patients (47.8%) exhibited loss of ATM protein expression. The overall response rate (ORR) of ATM loss and intact ATM was 13.3% and 19.6%, respectively. In a subgroup analysis, EH-CCC patients with ATM loss tended to have improved PFS after platinum-based chemotherapy compared to those with intact ATM (7.9 vs. 6.2 months, respectively; p=0.050). Conclusion: We demonstrated that ATM loss could be a prognostic marker after platinum-based chemotherapy in patients with advanced EH-CCC. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the efficacy and safety of avelumab, an anti--PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. Materials and Methods In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥ 1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for micro-satellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1. Results The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSIH and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in four and two patients, respectively, with no treatment-related deaths. Conclusion Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to investigate the role of carcinoembryonic antigen (CEA) levels in improving the performance of magnetic resonance imaging (MRI) for the prediction of pathologic response after the neoadjuvant chemoradiation (NCRT) for patients with rectal cancer. Materials and Methods We retrospectively reviewed the medical records of 524 rectal cancer patients who underwent NCRT and total mesorectal excision between January 2009 and December 2014. The performances of MRI with or without CEA parameters (initial CEA and CEA dynamics) for prediction of pathologic tumor response grade (pTRG) were compared by receiver-operating characteristic analysis with DeLong's method. Cox regression was used to identify the independent factors associated to pTRG and disease-free survival (DFS) after NCRT. Results The median follow-up was 64.0 months (range, 3.0 to 113.0 months). On multivariate analysis, poor tumor regression grade on MRI (mrTRG; p < 0.001), initial CEA (p < 0.001) and the mesorectal fascia involvement on MRI before NCRT (mrMFI; p=0.054) showed association with poor pTRG. The mrTRG plus CEA parameters showed significantly improved performances in the prediction of pTRG than mrTRG alone. All of mrTRG, mrMFI, and initial CEA were also identified as independent factors associated with DFS. The initial CEA further discriminated DFS in the subgroups with good mrTRG or that without mrMFI. Conclusion The CEA parameters significantly improved the performance of MRI in the prediction of pTRG after NCRT for patients with rectal cancer. The DFS was further discriminated by initial CEA level in the groups with favorable MRI parameters. [ABSTRACT FROM AUTHOR]

Purpose Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, apoptosis, and anti-angiogenesis. This phase II trial evaluated the efficacy and toxicity profile of conventional XELOX and bevacizumab chemotherapy plus simvastatin in metastatic colorectal cancer patients (MCRC). Materials and Methods Patients with MCRC received first-line XELOX in 3-week treatment cycles of intravenous xaliplatin 130 mg/m² plus bevacizumab 7.5 mg/kg (day 1), followed by oral capecitabine 1,000 mg/m² twice daily (day 1-14). Simvastatin 80 mg tablets were taken orally once daily every day during the period of chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, duration of response, overall survival (OS), time to progression, and toxicity. Results From January 2014 to April 2015, 60 patients were enrolled and 55 patients were evaluable for tumor response. The median follow-up duration was 30.1 months (range, 28.5 to 31.7 months). The median PFS was 10.4 months (95% confidence interval [CI], 9.6 to 11.1). The median OS of all patients was 19.0 months (95% CI, 11.9 to 26.0). The disease-control rate and overall response rate were 88.3% (95% CI, 74 to 96) and 58.3% (95% CI, 44 to 77), respectively, by intent-to-treat protocol analysis. There was one complete response and 34 partial responses. One patient experienced grade 3 creatine kinase elevation and liver enzyme elevation. Conclusion Based on the current study, the addition of 80 mg simvastatin to XELOX and bevacizumab showed comparable clinical efficacy in patients with MCRC as first-line chemotherapy and did not increase toxicity. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to compare prognostic differentiation performances of the 7th and the 8th edition of American Joint Committee on Cancer (AJCC) staging system for gastric cancer (GC) patients. Materials and Methods A total of 1,633 GC patients who underwent curative D2 resection followed by adjuvant chemotherapy alone (CA) or concurrent chemo-radiotherapy (CCRT) from 2004 to 2013 were included. Concordance index (c-index) was applied to compare the discriminatory ability. Results In the 8th edition, migration of stage was detected in 248 patients (15.2%). Among them, 121 patients were up-staged while 127 patients were down-staged. Overall, there was no statistically significant difference in the discriminatory ability between the 7th and 8th editions. The new edition of staging system, however, showed a trend of better prognostic performance not only in recurrence-free survival (c-index=0.734; 95% confidence interval [CI], 0.706 to 0.762 in the 7th edition vs. c-index=0.740; 95% CI, 0.712 to 0.768 in the 8th edition; p=0.14), but also in overall survival (c-index=0.717; 95% CI, 0.688 to 0.745 in the 7th edition vs. c-index=0.722; 95% CI, 0.694 to 0.751 in the 8th edition; p=0.19), especially in stage III. This finding was repeated in the subgroup analysis regardless of adjuvant CA or CCRT. Conclusion Generally, the 8th edition of AJCC staging system had failed to show a superior discriminatory ability for curatively D2 resected GC patients than the 7th edition, although there was a trend of better prognostic performance of the new edition, regardless of adjuvant treatment method. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to discuss the roles of radiation and chemotherapy as adjuvant treatment in patients with staged IB GC who were enrolled in the adjuvant chemoradiotherapy in stomach tumors (ARTIST) trial. Materials and Methods: Among the 458 patients who were enrolled in the ARTIST trial, 99 had stage IB disease. The patients were randomly assigned to receive either adjuvant chemoradiotherapy with capecitabine plus cisplatin (XP, n=50) or chemoradiotherapy (XPRT, n=49). Survival analyses were performed in accordance with the AJCC 2010 staging system. Results: According to the AJCC 2010 system, stage migration from IB to II occurred in 71% of the patients; 98% of the T2 N0 cases were reclassified as T3 N0, and 42% of the T1 N1 cases were reclassified as T1 N2. When comparing survival outcomes between the XPRT and XP arms for stage IB cancer (AJCC 2002), no significant difference in 5-year disease-free survival (DFS) between the 2 arms was found. (median 5-year DFS, not reached, P=0.256). The patients classified as having stage IB cancer (AJCC 2002) and reclassified as having stage II cancer (AJCC 2010) exhibited worse prognoses than those who remained in stage IB, although the difference was not statistically significant (5-year DFS rate, 83% vs. 93%). When we compared 5-year DFS in 70 patients with stage II (AJCC 2010), the addition of radiotherapy to XP chemotherapy did not show better outcome than XP alone (P=0.137). Conclusions: The role of adjuvant chemoradiotherapy in the treatment of stage IB GC (AJCC 2002) warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose Although chemotherapy is recommended by various guidelines for advanced biliary tract cancer (BTC), the evidence supporting its use over best supportive care (BSC) is limited. The aim of this study was to investigate the survival benefit of chemotherapy over that of BSC in advanced BTC patients. Materials and Methods Advanced BTC patients with a good performance status (Eastern Cooperative Oncology Group [ECOG] 0-2) were eligible for the study. Data were retrospectively collected from four tertiary cancer centers and analyzed using propensity score matching (PSM). Of the 604 patients enrolled, 206 received BSC and 398 received chemotherapy. PSM analysis was performed using the following variables: age, ECOG status, carcinoembryonic antigen (CEA) level, white blood cell level, albumin level, total bilirubin level, and aspartate aminotransferase level. The sample size of each group was 164 patients after PSM. Median survival was compared between the two groups by using the Kaplan-Meier method, and prognostic factors were investigated using Cox proportional regression analysis. Results In post-PSM analysis, the respective median survival for the chemotherapy and BSC groups was dependent on the following prognostic factors: total population, 12.0 months vs. 7.5 months (p=0.001); locally advanced disease, 16.7 months vs. 13.4 months (p=0.490); cancer antigen 19-9 ὄ 100 IU/mL, 12.7 months vs. 10.6 months (p=0.330); and CEA 3.4 ng/mL, 17.1 months vs. 10.6 months (p=0.052). Conclusion Chemotherapy improved overall survival of patients with advanced BTC who had a good performance status. However, this survival benefit was not observed in BTC patients with locally advanced disease or with lower tumor marker. Individualized approach is needed for initiation of palliative chemotherapy in advanced BTC. [ABSTRACT FROM AUTHOR]

Purpose: Hematotoxicity following anti-cancer treatment is known to be related to treatment efficacy in several malignancies. The purpose of this study was to examine the hematologic parameters related to the tumor response and survival in patients treated with curative surgery following preoperative chemoradiotherapy (CRT) for rectal cancer. Materials and Methods: Four hundred eighteen patients with rectal cancer who underwent preoperative CRT and curative surgery were analyzed, retrospectively. The main clinical factors and blood cell counts before and after CRT were investigated with respect to their relationships with tumor downstaging and patient survival. Results: The post-CRT leukocyte count was significantly different between the tumor downstaging group and the nondownstaging group (median, 4740/uL vs. 5130/uL; p = 0.013). Multivariate analysis showed that histological grade, circumferential extent, and post-CRT leukocyte count were related to tumor downstaging. In addition, histological grade, post-CRT leukocyte count, and tumor downstaging were related to disease-free survival. The 5-year disease-free survival and overall survival in patients with post-CRT leukocyte count ≤3730/uL, which is the cut-off value derived from the receiver operation characteristic (ROC) curve analysis, were significantly higher than those with higher counts (88.0% vs. 71.6%, p = 0.001; 94.4% vs. 84.1%, p = 0.024). Conclusion: Post-CRT leukocyte count of ≤3730/uL could be regarded as a good prognostic factor for tumor response and survival in rectal cancer patients treated with preoperative CRT. [ABSTRACT FROM AUTHOR]

In patients with refractory cancer, the effect of additional chemotherapy is very limited. Targeted agents for molecular pathways associated with cancer cell progression and survival have emerged as attractive options in several cancer types. The current pilot study assessed the efficacy and safety of sirolimus in patients with refractory cancer with PIK3CA mutation/amplification. Refractory cancer patients with PIK3CA mutation/amplification were enrolled, irrespective of tumor-types. Enrolled patients received a daily dose of 1 mg sirolimus and one cycle defined as 28 days. An assessment of the efficacy and safety of sirolimus was performed. Overall, 4 patients were enrolled between October 2014 and April 2015. The median of 2.5 cycles of sirolimus was administered. Three patients had advanced gastric cancer and one had advanced cholangiocarcinoma. The overall response rate was 0%, three patients (75%) had stable disease following one cycle and one patient (25%) received sirolimus for 4 cycles without disease progression. The median progression free survival was 1.9 months [95% confidence interval (CI), 0.3-3.5 months], and the median overall survival was 3.6 months (95% CI, 0.4-6.8 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 1 nausea was reported in one patient each. There were no treatment-associated mortalities. Sirolimus had modest efficacy and a tolerable toxicity-profile in patients with refractory cancer with PIK3CA mutation/amplification. [ABSTRACT FROM AUTHOR]

Purpose Retrospective studies have demonstrated that cell-free circulating tumor DNA (ctDNA) hotspot testing predicts matched therapy response to first- and second-line therapies in patients with advanced non-small-cell lung cancer (NSCLC). However, no prospective outcomes studies have evaluated ctDNA-guided matched therapy decision making on the basis of comprehensive plasma genomic testing including all four major classes of alterations. Here, we report the clinical utility of this approach in advanced solid tumor cancers. Patients and Methods We conducted a multiple parallel cohort, open-label, clinical trial using ctDNA-guided matched therapy when tissue was insufficient or unobtainable for next-generation sequencing. Plasma-based digital sequencing identified point mutations in 70 genes and indels, fusions, and copy number amplifications in selected genes. Patients with prespecified targetable alterations in metastatic NSCLC, gastric cancer (GC), and other cancers were matched to several independent targeted agent trials at a tertiary academic center. Results Somatic alterations were detected in 59 patients with GC (78%), and 25 patients (33%) had targetable alterations (ERBB2, n = 11; MET, n = 5; FGFR2, n = 3; PIK3CA, n = 6). In NSCLC, 62 patients (85%) had somatic alterations, and 34 (47%) had targetable alterations (EGFR, n = 29; ALK, n = 2; RET, n = 1; ERBB2, n = 2). After confirmation of ctDNA findings on tissue (to meet trial eligibility criteria), 10 patients with GC and 17 patients with NSCLC received molecularly matched therapy. Response rate and disease control rate were 67% and 100%, respectively, in GC and 87% and 100%, respectively, in NSCLC. Response was independent of targeted alteration variant allele fraction in NSCLC (P = .63). Conclusion To our knowledge, this is the first prospective feasibility study of comprehensive ctDNA-guided treatment in advanced GC and lung cancers. Response rates in this interim analysis are similar to those in tissue-based targeted therapy studies. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to confirm the efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors (GISTs) reported in the GRID phase III trial in Korean patients. Materials and Methods Fifty-seven Korean patients with advanced GIST who experienced both imatinib and sunitinib failure were enrolled in the management access program between December 2012 and November 2013 and treated with regorafenib (160 mg orally once daily in a 3 weeks on /1 week off). Results None of the patients achieved a complete or partial response while 25 patients (44%) showed stable disease for ≥ 12 weeks. With a median follow-up of 12.7 months (range, 0.2 to 27.6 months), the median progression-free survival and overall survival were 4.5 months (95% confidence interval [CI], 3.8 to 5.3) and 12.9 months (95% CI, 8.1 to 17.7), respectively. Interestingly, 15 patients (26%) experienced an exacerbation of their cancer-related symptoms (abdominal pain in eight and abdominal distension in five) during the rest period for regorafenib, but all were ameliorated upon the resumption of regorafenib. The most common grade 3 or 4 adverse event was a hand-foot skin reaction (25%). The regorafenib dose was reduced in 44 patients (77%) due to toxicity, which manifested mainly as a handfoot skin reaction (n=31). Conclusion This study confirmed the efficacy and safety of regorafenib for advanced GIST after imatinib and sunitinib failure in Korean patients. Considering the exacerbation of the cancer-related symptoms observed during the rest periods, further exploration of the continuous dosing schedule of regorafenib is warranted in future clinical trials. [ABSTRACT FROM AUTHOR]

Background: We designed a single-arm, open-label phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy (#NCT02449538).Methods: Everolimus was administered orally at a daily dose of 10 mg continuously (28-day cycles). Treatment was continued until progression of the disease or intolerable toxicity was observed. Based on Simon's two-stage optimal design, 10 patients were treated with everolimus during the first stage.Results: The median age of the patients was 55.5 years (range, 42-72), and the median Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2 (range, 1-2). Most of the patients (50.0%) had gastric cancer (GC) as the site of their primary tumor followed by colorectal cancer (CRC), pancreatic cancer, and cholangiocarcinoma. Patients received everolimus as a third-line (3 patients), fourth-line (4 patients), fifth-line (1 patient) or sixth-line (2 patients) treatment. Complete or partial responses were not observed in any of the patients. Four patients showed stable disease, resulting in a disease control rate of 40%. The median PFS was 1.6 months (95% CI, 0.8-2.4 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 2 diarrhea and stomatitis were reported in one patient each. There were no treatment-related deaths. There was less than one response out of the 10 initial patients during the first stage, and the study did not progress to the second stage.Conclusions: The study did not meet its primary objective of demonstrating the anti-tumor activity of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. Further investigation using other genomic candidates and new-generation mTOR inhibitors is warranted in patients with treatment-refractory cancer.Trial Registration: # NCT02449538 , April 2015. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer (GBC) patients who have undergone R0 resection. Materials and Methods: Clinical data were collected on 441 consecutive patients who underwent R0 resection for stage I-III GBC. Eligible patients were classified into adjuvant therapy and surveillance only groups. Propensity score matching (PSM) between the two groups was performed, adjusting clinical factors. Results: In total, 84 and 279 patients treated with adjuvant therapy and followed up with surveillance only, respectively, were included in the analysis. Before PSM, the 5-year relapse-free survival (RFS) rate was lower in the adjuvant therapy group than in the surveillance only group (50.8% vs. 74.8%, p < 0.001), although there was no statistically significant difference in the 5-year overall survival (OS) rate (66.2% vs. 79.5%, p=0.089). After the PSM, baseline characteristics became comparable and there were no differences in the 5-year RFS (50.8% vs. 64.8%, p=0.319) and OS (66.2% vs. 70.4%, p=0.703) rates between the two groups. Conclusion: The results suggest that fluoropyrimidine-based adjuvant therapy is not indicated in stage I-III GBC patients who have undergone R0 resection. [ABSTRACT FROM AUTHOR]

Purpose: In the Adjuvant Chemoradiotherapy in Stomach Tumors (ARTIST) trial, we investigated whether chemoradiotherapy after D2 gastrectomy reduces the rate of recurrence. Recently, the ratio of metastatic lymph nodes to examined lymph nodes (N ratio) has been proposed as an independent prognostic factor in gastric cancer (GC). The aim of this study was to investigate the relationship between the metastatic N ratio and prognosis of GC after curative D2 surgery. Materials and Methods: We retrospectively reviewed the data of 458 ARTIST patients who underwent D2 gastrectomy followed by adjuvant chemotherapy (XP, n=228) or chemoradiotherapy (XPRT, n=230). The disease-free survival (DFS) rates of patients were used to evaluate the influence of N ratio on the treatment outcome. To achieve this, 4 different N ratio categories (0%, 1%~9%, 10%~25%, and >25%) were compared on the basis of their influence on the treatment outcome. Results: On multivariate analysis, the N ratio remained an independent prognostic factor for DFS. The hazard ratios (HRs) for the N ratio categories of 0%, 1%~9%, 10%~25%, and >25% were 1, 1.061, 1.202, and 3.571, respectively. In patients having N ratio >25%, the 5-year DFS rates were 55% and 28% for the XPRT and XP arms, respectively (HR, 0.527; 95% confidence interval, 0.307~0.904; P=0.020). Conclusions: In patients with curatively resected GC, the N ratio was independently associated with DFS. Although this finding warrants further investigation in future prospective studies, the benefit of chemoradiotherapy for D2 resected GC appears to be more beneficial in cancers having N ratios >25%. [ABSTRACT FROM AUTHOR]

Purpose While the Trastuzumab for Gastric Cancer (ToGA) trial demonstrated the efficacy and safety of trastuzumab-based chemotherapy in HER2-positive metastatic gastric cancer, the overall survival (OS) benefit was not found in Asian and diffuse-type cancer patients. The aim of the study is to investigate predictive markers for trastuzumab-based chemotherapy. Materials and Methods Data of patients with HER2-positive gastric cancer treated with trastuzumab-based chemotherapy were analyzed retrospectively. Results A total of 168 Asian patients were included. The median age was 60 years (range, 27 to 85 years) and the male:female ratio was 118 (70.2%):50 (29.8%). Fourteen (8.3%), 63 (37.5%), 75 (44.6%), and 11 (6.5%) patients had well, moderately, poorly-differentiated tubular adenocarcinoma and signet ring cell carcinoma, respectively. With 14 complete responses and 73 partial responses, the response rate was 50.6%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI], 8.7 to 11.7), and the median OS was 18.5 months (95% CI, 16.4 to 50.6). Next, we investigated the effect of poorly-differentiated histology (PDH, poorly-differentiated tubular adenocarcinoma+signet ring cell carcinoma) on clinical outcomes. The median PFS (8.9 months vs. 11.5 months, p=0.16) was slightly inferior in PDH patients, and the median OS was significantly shorter in PDH patients (14.6 months vs. 19.0 months, p=0.025). Conclusion While subset analysis of the ToGA trial demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asians and patients with PDH, our data may suggest that even in Asian patients and patients with PDH, trastuzumab-based chemotherapy could be associated with improved clinical outcomes in patients with HER2-positive gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose: A prospective phase II trial was conducted to evaluate the effectiveness and toxicity of regional hyperthermia and whole liver irradiation (WLI) for numerous chemorefractory liver metastases from colorectal cancer. Materials and Methods: Enrolled patients had numerous chemorefractory hepatic metastases from colorectal cancer. Five sessions of hyperthermia and seven fractions of 3-gray WLI were planned. Health-related quality of life (HRQoL) was determined using the Korean version of the European Organization for Research and Treatment of Cancer quality of life questionnaire C-30 and the Functional Assessment of Cancer Therapy-Hepatobiliary version 4.0. Objective and pain response was evaluated. Results: A total of 12 patients consented to the study and the 10 who received WLI and hyperthermia were analyzed. WLI was completed as planned in nine patients and hyperthermia in eight. Pain response was partial in four patients and stable in four. Partial objective response was achieved in three patients (30.0%) and stable disease was seen in four patients at the 1-month follow-up. One patient died 1 month after treatment because of respiratory failure related to pleural metastasis progression. Other grade III or higher toxicities were detected in three patients; however, all severe toxicities were related to disease progression rather than treatment. No significant difference in HRQoL was noted at the time of assessment for patients who were available for questionnaires. Conclusion: Combined WLI and hyperthermia were well tolerated without severe treatment-related toxicity with a promising response from numerous chemorefractory hepatic metastases from colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: KRAS mutations are common in colorectal cancer (CRC). The role of KRAS mutation status as a prognostic factor remains controversial, and most large population-based cohorts usually consist of patients with non-metastatic CRC. We evaluated the impact of KRAS mutations on the time to recurrence (TTR) and overall survival (OS) in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy.Methods: Patients who underwent curative resection for primary and synchronous metastases were retrospectively collected in a single institution during a 6 year period between January 2008 and June 2014. Patients with positive surgical margins, those with known BRAF mutation, or those with an unknown KRAS mutation status were excluded, and a total of 82 cases were identified. The pathological and clinical features were evaluated. Patients' outcome with KRAS mutation status for TTR and OS were investigated by univariate and multivariate analysis.Results: KRAS mutations were identified in 37.8% of the patients and not associated with TTR or OS between KRAS wild type and KRAS mutation cohorts (log-rank p = 0.425 for TTR; log-rank p = 0.137 for OS). When patients were further subdivided into three groups according to mutation subtype (wild-type vs. KRAS codon 12 mutation vs. KRAS codon 13 mutation) or amino acid missense mutation type (G > A vs. G > T vs. G > C), there were no significant differences in TTR or OS. Mutational frequencies were significantly higher in patients with lung metastases compared with those with liver and ovary/bladder metastases (p = 0.039), however, KRAS mutation status was not associated with an increased risk of relapsed in the lung.Conclusions: KRAS mutation was not associated with TTR or OS in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Chromogranin A (CgA) has been considered to be valuable not only in the diagnosis but also in monitoring the disease response to treatment. However, only a few studies have been published on this issue. We purposed to evaluate whether biochemical response using plasma CgA level is reliable in concordance with the clinical response of grade 1-3 nonfunctiong gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Materials and Methods: Between March 2011 and September 2013, a total of 27 cases in 18 patients were analysed, clinically and radiologically while serial CgA tests were also conducted during treatment. Tumor responses were defined by both Response Evaluation Criteria in Solid Tumors (RECIST) criteria ver. 1.1 and biochemical criteria based on the CgA level. Results: Among the 27 cases analysed, no difference in the basal CgA level was observed with regard to gender, primary tumor site, tumor grade (World Health Organization classification), liver metastasis, number of metastatic site, and line of chemotherapy. The overall response rate (RR) by RECIST criteria ver. 1.1 was six out of the 27 cases (22.2%) and eight out of the 27 cases (29.6%) for biochemical RR. The overall concordance rates of the response based on RECIST and biochemical criteria were 74%. In grades 1 and 2 GEP-NETs (n=17), the concordance rate of the disease control was 94.1%. There was a significant difference for progression-free survival (PFS) between responders and non-responder in accordance to biochemical criteria (35.73 months vs. 5.93 months, p=0.05). Conclusion: This study revealed that changes of the plasma CgA levels were associated with tumour response. Additionally, biochemical response based on serial CgA may be a predictive marker for PFS in GEP-NETs. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib. Methods: This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %. Results: Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p = 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p = 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p < 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p < 0.01) and OS (10.7 vs. 5.8 months, p < 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p < 0.01). Conclusions: ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated. [ABSTRACT FROM AUTHOR]

Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the appropriateness of prophylactic inguinal nodal irradiation (PINI), we analyzed patterns of failure in anal cancer patients who were inguinal node-negative at presentation and did not receive PINI. Materials and Methods: We retrospectively reviewed the records of 33 anal cancer patients treated by definitive concurrent chemoradiation therapy (CCRT) between 1994 and 2013. Radiotherapy consisted of a total dose of 44-45 Gy (22-25 fractions in 5 weeks) on the whole pelvis, anus, and perineum. Except inguinal lymphadenopathy was present at initial diagnosis, the entire inguinal chain was not included in the radiation field. In other words, there was no PINI. Results: The median follow-up duration was 50 months (range, 4 to 218 months). Median survival and progression-free survival (PFS) were 57 months (range, 10 to 218 months) and 50 months (range, 4 to 218 months), respectively. Among the survival, the median follow-up duration was 51 months (range, 12 to 218 months). The 5-year overall survival and PFS rates were 93.4% and 88.8%, respectively. Although none of the patients received inguinal node irradiation for prophylactic purposes, there was no inguinal recurrence. Conclusion: Treatment of anal cancer by omitting PINI might be considered in selected patients with clinically uninvolved inguinal nodes. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib. Methods: This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %. Results: Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p = 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p = 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p < 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p < 0.01) and OS (10.7 vs. 5.8 months, p < 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p < 0.01). Conclusions: ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated. [ABSTRACT FROM AUTHOR]

Purpose: Capecitabine is known to increase mean corpuscular volume (MCV). To define the incidence of capecitabine-induced macrocytosis and its association with chemotherapy outcomes, we investigated data of 89 patients with advanced gastric cancer (AGC) who were enrolled in a randomized chemotherapy trial involving capecitabine. Materials and Methods: Chemotherapy-naïve AGC patients were treated with capecitabine (1,000 mg/m²/day on days 1-14) plus cisplatin (75 mg/m² on day 1), with or without epirubicin (50 mg/m² on day 1). Complete blood counts including MCV were measured at baseline and on day 1 of each 3-week chemotherapy course. Macrocytosis was defined as a MCV increase > 10 fL from baseline. Multivariate Cox proportional hazards models were used for analysis of the impact of clinical and MCV values on chemotherapy outcomes. Results: At baseline, the mean MCV was 88.2 fL (normal range, 80 to 100 fL). During chemotherapy, MCV increased in a dose-dependent manner with a mean increase of 11.3 fL. MCV elevation after capecitabine treatment in 74 patients (90%) and 44 patients (42%) developed macrocytosis. Results: of multivariate analysis showed that development of macrocytosis was independent of baseline hemoglobin level, liver metastasis, performance status, or liver function. The number of chemotherapy cycles showed strong association with development of macrocytosis and hematologic adverse events. In addition, a significant association was observed between macrocytosis and clinical response or survival. Conclusion: Macrocytosis developed with more frequent and prolonged use of capecitabine. It is possible that association with treatment outcomes warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: To determine the prognostic and predictive value of liver volume in colorectal cancer patients with unresectable liver metastases. Materials and Methods: Sixteen patients received whole liver radiotherapy (WLRT) between January 1997 and June 2013. A total dose of 21 Gy was delivered in 7 fractions. Results: The median survival time after WLRT was 9 weeks. In univariate analysis, performance status, serum albumin and total bilirubin level, liver volume and extrahepatic metastases were associated with survival. The mean liver volume was significantly different between subgroups with and without pain relief (3,097 and 4,739 mL, respectively; p = 0.002). Conclusion: A larger liver volume is a poor prognostic factor for survival and also a negative predictive factor for response to WLRT. If patients who are referred for WLRT have large liver volume, they should be informed of the poor prognosis and should be closely observed during and after WLRT. [ABSTRACT FROM AUTHOR]

Although gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to those in western countries. However, there are currently no Korean multidisciplinary guidelines for gastric cancer. Experts from related societies developed guidelines de novo to meet Korean circumstances and requirements, including 23 recommendation statements for diagnosis (n=9) and treatment (n=14) based on relevant key questions. The quality of the evidence was rated according to the GRADE evidence evaluation framework: the evidence levels were based on a systematic review of the literature, and the recommendation grades were classified as either strong or weak. The applicability of the guidelines was considered to meet patients' view and preferences in the context of Korea. The topics of the guidelines cover diagnostic modalities (endoscopy, endoscopic ultrasound, and radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, and radiotherapy), and pathologic evaluation. An external review of the guidelines was conducted during the finalization phase. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to utilize the proteomics-based Collaborative Enzyme Enhanced Reactive (CEER) immunoassay to investigate protein tyrosine phosphorylations as diagnostic markers in gastric cancers (GCs). Experimental Design: Protein lysates from fresh-frozen 434 advanced stage GCs were analyzed for phosphorylation of HER1, HER2, p95HER2, HER3, cMET, IGF1R and PI3K. The pathway activation patterns were segregated based on the tumor HER2 status. Hierarchical clustering was utilized to determine pathway coactivations in GCs. Prognostic value of pathway activation patterns was determined by correlating disease-free survival times of the various GC subgroups using Kaplan-Meier survival analysis. CEER was also used to determine the presence of tyrosine phosphorylated signaling cascades in circulating tumor cells (CTCs) and ascites tumor cells (ATCs). Results: Utilizing a novel diagnostics immunoassay, CEER, we demonstrate the presence of p95HER2 and concomitantly activated signaling pathways in GC tumor tissues, CTCs and ATCs isolated from GC patients for the first time. p95HER2 is expressed in ∼ 77% of HER2(+) GCs. Approximately 54% of GCs have an activated HER1, HER2, HER3, cMET or IGF1R and demonstrate a poorer prognosis than those where these receptor tyrosine kinases (RTKs) are not activated. Hierarchical clustering of RTKs reveals co-clustering of phosphorylated HER1:cMET, HER2:HER3 and IGF1R-PI3K. Coactivation of HER1 with cMET renders GCs with a shorter disease-free survival as compared to only cMET activated GCs. Conclusions: Our study highlights the utility of a novel companion diagnostics technology, CEER that has strong implications for drug development and therapeutic monitoring. CEER is used to provide an increased understanding of activated signaling pathways in advanced GCs that can significantly improve their clinical management through accurate patient selection for targeted therapeutics. [ABSTRACT FROM AUTHOR]

Purpose: Although anemia is considered to be a contributor to intra-tumoral hypoxia and tumor resistance to ionizing radiation in cancer patients, the impact of pretreatment anemia on local control after neoadjuvant concurrent chemoradiotherapy (NACRT) and surgery for rectal cancer remains unclear. Materials and Methods: We reviewed the records of 247 patients with locally advanced rectal cancer who were treated with NACRT followed by curative-intent surgery. Results: The patients with anemia before NACRT (36.0%, 89/247) achieved less pathologic complete response (pCR) than those without anemia (p = 0.012). The patients with pretreatment anemia had worse 3-year local control than those without pretreatment anemia (86.0% vs. 95.7%, p = 0.005). Multivariate analysis showed that pretreatment anemia (p = 0.035), pathologic tumor and nodal stage (p = 0.020 and 0.032, respectively) were independently significant factors for local control. Conclusion: Pretreatment anemia had negative impacts on pCR and local control among patients who underwent NACRT and surgery for rectal cancer. Strategies maintaining hemoglobin level within normal range could potentially be used to improve local control in rectal cancer patients. [ABSTRACT FROM AUTHOR]

Background: In the past few years, the number of clinical trials has increased rapidly in East Asia, especially for gastric and hepatobiliary cancer that are prevalent in Asian populations. However, the actual degree of understanding or perceptions of clinical trials by cancer patients in East Asian countries have seldom been studied. Methods: Between July 1st and November 30th of 2011, we conducted a prospective study to survey cancer patients regarding their awareness of, and willingness to participate in, a clinical trial. Patients with gastrointestinal/ hepatobiliary cancer who visited the Hematology-Oncology outpatient clinic at Samsung Medical Center (SMC) were enrolled. A total of 21 questions were asked including four questions which used the Visual analogue scale (VAS) score. Results: In this survey study, 1,000 patients were asked to participate and 675 patients consented to participate (67.5%). The awareness of clinical trials was substantially higher in patients who had a higher level of education (p<0.001), were married (p=0.004), and had a higher economic status (p=0.001). However, the willingness to participate in a clinical trial was not affected by the level of education or economic status of patients. The most influential factors for patient willingness to participate were a physician recommendation (n=181, 26.8%), limited treatment options (n=178, 26.4%), and expectations of effectiveness of new anti-cancer drugs (n=142, 21.0%). Patients with previous experience in clinical trials had a greater willingness to participate in clinical trials compared to patients without previous experience (p<0.001). Conclusions: This large patient cohort survey study showed that Korean cancer patients are more aware of clinical trials, but awareness did not translate into willingness to participate. [ABSTRACT FROM AUTHOR]

Background Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to treatment with cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor. Statins have reported antitumor activity, but it is unknown whether simvastatin can reverse cetuximab resistance in KRAS mutant CRC. Methods Human CRC cell lines with KRAS mutations (LS153, LS174T, DLD1, LoVo, SW403, SW480, SNU175, and LS1034) or with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations (DiFi, SW48, HT29, and RKO) were used to test the effect of cetuximab, simvastatin, and cetuximab plus simvastatin on cell proliferation and apoptosis in vitro. Because BRAFV600E mutant may be responsible for cetuximab resistance in KRAS wild-type cells, we measured the growth of xenograft tumors originating from KRAS mutant and BRAF mutant cells in mice treated with cetuximab alone or plus simvastatin (n = 5 mice per treatment group). We used immunoblot assays to study RAS-regulated activation of BRAF protein after simvastatin treatment. All statistical tests were two-sided. Results Addition of simvastatin (0.2 μM) to cetuximab (0.03–1.0 μM) reduced cell proliferation of KRAS mutant (P < .001) but not of BRAF mutant CRC cells in vitro. Treatment of KRAS mutant cells with simvastatin reduced BRAF activity and induced apoptosis. Treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (eg, for tumors originating from DLD1 cells, cetuximab vs cetuximab + simvastatin, mean tumor volume = 49.4 vs 20.2 cm3, mean difference = 29.2 cm3, 95% confidence interval = 19.7 to 38.5, P < .001); treatment with cetuximab alone or in combination with simvastatin had no effect on the growth of BRAF mutant tumors. Conclusion Simvastatin may overcome cetuximab resistance in colon cancer cells with KRAS mutations by modulating BRAF activity and inducing apoptosis. [ABSTRACT FROM PUBLISHER]

Background: To evaluate the palliative role of radiotherapy (RT) and define the effectiveness of chemotherapy combined with palliative RT (CCRT) in patients with a symptomatic pelvic mass of metastatic colorectal cancer. Methods: From August 1995 to December 2007, 80 patients with a symptomatic pelvic mass of metastatic colorectal cancer were treated with palliative RT at Samsung Medical Center. Initial presenting symptoms were pain (68 cases), bleeding (18 cases), and obstruction (nine cases). The pelvic mass originated from rectal cancer in 58 patients (73%) and from colon cancer in 22 patients (27%). Initially 72 patients (90%) were treated with surgery, including 64 complete local excisions; 77% in colon cancer and 81% in rectal cancer. The total RT dose ranged 8- 60 Gy (median: 36 Gy) with 1.8-8 Gy per fraction. When the α/β for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the median RT dose was 46.8 Gy10 (14.4-78). Twenty one patients (26%) were treated with CCRT. Symptom palliation was assessed one month after the completion of RT. Results: Symptom palliation was achieved in 80% of the cases. During the median follow-up period of five months (1-44 months), 45% of the cases experienced reappearance of symptoms; the median symptom control duration was five months. Median survival after RT was six months. On univariate analysis, the only significant prognostic factor for symptom control duration was BED≥40 Gy10 (p < 0.05), and CCRT was a marginally significant factor (p = 0.0644). On multivariate analysis, BED and CCRT were significant prognostic factors for symptom control duration (p < 0.05). Conclusions: RT was an effective palliation method in patients with a symptomatic pelvic mass of metastatic colorectal cancer. For improvement of symptom control rate and duration, a BED ≥ 40 Gy10 is recommended when possible. Considering the low morbidity and improved symptom palliation, CCRT might be considered in patients with good performance status. [ABSTRACT FROM AUTHOR]

Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy. We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy. There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS ( P = 0.56) or OS ( P = 0.61) in patients with colon cancer ( n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS ( P = 0.11) and OS ( P = 0.94). For patients with genotyping/IHC agreement ( n = 108), there was no difference in DFS ( P = 0.57) and OS ( P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors. The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D. [ABSTRACT FROM AUTHOR]

Background: Encephalopathy is a rare drug toxicity of fluorouracil therapy. Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes, thymidylate synthase and dihydropyrimidine dehydrogenase. Methods: Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5-fluorouracil-based chemotherapy presented with acute mental change and hyperammonemia. To evaluate the genetic background of the fluorouracil-associated hyperammonemic encephalopathy, analysis of the polymorphisms of the TYMS, DPYD and MTHFR genes was performed. Results: The patients revealed to be TYMS suppressors showing homogenous deletion of 6 bp in the 3′-UTR and 3RC/3RC genotype in the promoter enhancer region (TSER), respectively. Conclusion: Genetic polymorphisms of the TYMS gene would contribute to the 5-fluorouracil-associated hyperammonemic encephalopathy. The prospective validation of the clinical implication of TYMS gene polymorphisms is warranted. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: Extraosseous osteosarcoma (EOO) is a rare soft tissue form of osteosarcoma without involvement of the skeletal system. Due to the rarity of disease, its clinical features and optimal treatment are yet to be defined. Methods: Between 1 January 1999 and 30 June 2008 ten patients were pathologically confirmed with extra-skeletal osteosarcoma. A retrospective analysis of the ten patients was performed. Results: The anatomical distribution of the osteosarcomas was as follows: lower extremities ( n = 3), upper extremities ( n = 2), breast ( n = 2), lung ( n = 1), cheek ( n = 1) and retroperitoneum ( n = 1). Nine patients initially underwent resection of the primary mass. One patient, who received six cycles of adjuvant doxorubicin and cisplatin chemotherapy was alive in remission at 42.6 months. One patient with postoperative radiotherapy after curative surgery was alive in remission at 6.2 months. However, all three patients who received curative resection but no postoperative radiotherapy or chemotherapy died of the disease at 10.7, 11.1 and 15.6 months after surgery. The median time to failure was only 4.4 months (95% CI, 0.6, 8.2 months) and the median survival time of all patients was only 11.1 months (95% CI, 5.6, 16.6 months). At the time of analysis, seven patients were dead and all died of the disease recurrence. Conclusion: EOO should be treated as a soft tissue sarcoma with aggressive behavior and multimodality treatment should be actively sought to improve treatment outcome. The impact of adjuvant chemotherapy on survival of EOO needs further investigation. [ABSTRACT FROM AUTHOR]

Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, anti-angiogenesis, and apoptosis. This phase II trial evaluated the efficacy and toxicity profile of conventional FOLFIRI chemotherapy plus simvastatin in metastatic colorectal cancer patients. Patients received irinotecan 180 mg/m2 as a 90-min infusion followed by leucovorin 200 mg/m2 in a 2-h infusion, and then 5-FU 400 mg/m2 bolus injection followed by 2,400 mg/m2 as a 46-h continuous infusion. Treatment cycles were repeated every 2 weeks until documented disease progression, unacceptable toxicity, or patient’s refusal. Simvastatin 40 mg tablet was given once daily per oral everyday during the period of chemotherapy without a rest. From October 2005 to June 2006, 49 patients were enrolled. The overall response rate (ORR) was 46.9% (95% CI, 31.0–58.8) by intent-to-treat analysis and 45.8% (95% CI, 33.3–62.8) by per-protocol analysis. There were one complete response (CR) and 22 partial responses (PRs). Both CR and PRs were confirmed at least 4 weeks later. The disease-control rate was 83.7% (95% CI, 73.4–94.0). The median follow-up duration was 25.6 months (range, 20.9–28.8 months). The median survival of all patients was 21.8 months (95% CI, 14.4, 29.2). The median TTP was 9.9 months (95% CI, 6.4, 13.3). No patients experienced additional adverse effect that was definitely caused by simvastatin drug therapy in this trial. The combination of simvastatin plus FOLFIRI was a feasible regimen with promising antitumor activity. [ABSTRACT FROM AUTHOR]

There are no known reliable biomarkers which can predict poor clinical outcome following curative resection of gastric adenocarcinoma. Given the importance of signal transducer and activator of transcription 3 (STAT3) activation in carcinogenesis, we attempted to determine whether STAT3 activation is prognostic of survival in curatively resected gastric cancer patients. We analyzed 311 surgically resected gastric cancer specimens for STAT3 activation and its downstream molecules such as matrix metalloproteinase (MMP)-9, MMP-10, cyclin D1, survivin, vascular endothelial growth factor (VEGF)-C, and VEGFR-3 using immunohistochemical studies and assessed their correlation with clinical outcome. Using immunohistochemistry, 303 specimens were interpretable for pSTAT3tyr705 expression. The pSTAT3 was detected in 79 (26.1%) of 303 gastric cancers. Of the downstream molecules tested, STAT3 activation was significantly associated with MMP-9 and MMP-10 expressions. On univariate analyses, 5-year disease-free survival (DFS) and overall survival (OS) for the tumors with STAT3 activation were considerably poorer than for those without STAT3 activation with statistical significance (5-year DFS 58.2% vs 68.3%; pSTAT3(−) vs pSTAT3(+); p = 0.0223; 5-year OS 59.5% vs 70.5%; pSTAT3(−) vs pSTAT3(+); p = 0.0128). On multivariate analyses, STAT3 activation was independently associated with inferior DFS (p = 0.049, hazard ratio [HR] = 1.445, 95% CI, 1.025, 2.120) along with AJCC stage IIIA or IIIB (p = 0.004, HR = 1.708, 95% CI, 1.178, 2.475). The STAT3 activation was also strongly correlated with inferior OS (p = 0.042, HR = 1.506, 95% CI, 1.025, 2.213). Based on our data, pSTAT3tyr705 may be a novel prognostic marker for poorer clinical outcome following curative resection and adjuvant therapy in gastric cancer. The clinical impact of a STAT3-targeted agent should be investigated in gastric cancer patients. [ABSTRACT FROM AUTHOR]

Objectives: This prospective, multicenter, phase 2 study evaluated the efficacy and safety of imatinib mesylate and assessed KIT and PDGFRA gene mutation status in Korean patients with gastrointestinal stromal tumors (GISTs). Methods: Forty-seven patients with pathologically proven KIT-positive metastatic or unresectable GISTs were accrued from eight institutions in Korea. Imatinib was administered orally at 400 mg once daily. In case of disease progression, the dose was escalated to 600 mg once daily, then 400 mg twice daily. KIT and PDGFRA mutations were analyzed in 29 of the 47 patients. Results: Imatinib produced partial responses in 30 patients (63.8%; 95% confidence interval, 50.1–77.6%) and stable disease in 13 patients (27.7%). The median time to response was 2.6 months (range, 1.0–6.2 months). With a median follow-up of 62 months (range, 32–67 months), 4-year progression-free survival and overall survival rates were 50 and 65%, respectively. The most common adverse events were anemia, neutropenia, edema, and skin rash (predominantly of grade 1–2). There were no treatment-related deaths. In the subset evaluated for mutational status, 24 patients (82.8%) had KIT exon 11 mutations and 1 (3.4%) had a KIT exon 9 mutation. Conclusions: Imatinib is effective and safe in Korean patients with metastatic or unresectable GIST. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We designed a phase II trial of the combination with oxaliplatin and doxorubicin for patients with unresectable HCC to evaluate the overall response rate (ORR) and the toxicity. Forty patients with inoperable, systemic chemotherapy naive HCC were enrolled. Finally, 32 patients received oxaliplatin (130 mg/m2) and doxorubicin (60 mg/m2) every 3 weeks. Eighty-two treatment cycles were administered (median 2 cycles, range 1–6). There was no treatment-related mortality. The ORR was 15.6% (95% CI, 3.3–28.7) with five partial responses. The median overall survival and median overall progression free survival were 31 weeks (95% CI, 22–40 weeks) and 12 weeks (95% CI, 5-19 weeks). Nausea and peripheral neuropathy were most frequent non-hematologic toxicities (nausea, n = 15; peripheral neuropathy, n = 10). The most frequent grade 3–4 hematologic adverse event was neutropenia (14 of 82 cycles) including three cases of febrile neutropenia. The combination of oxaliplatin and doxorubicin showed modest activity and a tolerable toxicity profile in advanced HCC patients. [ABSTRACT FROM AUTHOR]

Background: Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy. Methods: The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival. Results: At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61-0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52-0.83) were independent negative prognostic factors for overall survival. Conclusion: Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer with bone marrow metastases is known to pursue a rapidly deteriorating clinical course. We conducted a retrospective analysis to evaluate clinical manifestations and prognosis of gastric cancer patients with bone marrow metastases. Methods: Between September 1994 and February 2006, 39 gastric cancer patients with pathologically confirmed bone marrow dissemination were selected. Results: The majority of the patients showed younger age, poorly differentiated adenocarcinoma or signet ring cell carcinoma, thrombocytopenia, anemia, elevated lactate dehydrogenase and alkaline phosphatase. Poor prognostic factors for survival were serum sodium ≤133 mmol/l [relative risk (RR) 4.57; 95% CI 1.99–10.52; p < 0.001], the presence of lung metastasis (RR 3.47; 95% CI 1.48–8.15; p = 0.007) and the presence of peritoneal seeding (RR 2.17; 95% CI 1.06–4.43; p = 0.036). Median survival durations after bone marrow metastases for patients without any adverse factors (n = 19, 48.7%) and those with 1–3 adverse factors (n = 20, 51.3%) were 67 and 23 days, respectively (p = 0.013). Patients without any adverse factors did benefit from palliative chemotherapy (p = 0.048). Conclusion: We suggest that gastric cancer patients with bone marrow metastases should receive more tailored therapies according to different risk factors in order to enhance survival. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Biliary tract cancer is one of the most aggressive and chemotherapy-refractory tumors. Although only curative treatment modality is surgery, most patients are not suitable for surgery due to advanced stage of the disease at diagnosis. Thus most patients with biliary tract cancer are possible candidates for palliative chemotherapy. The standard chemotherapeutic regimen is still to be defined, however. We performed a phase II study of combination chemotherapy with capecitabine and cisplatin in these patients to evaluate efficacy and toxicity of the regimen. Patients with previously untreated metastatic, recurrent, or inoperable biliary tract cancer were enrolled. Eligible patients were screened as following: (1) histologically confirmed, (2) age between 18 and 75 years, (3) at least one measurable lesion according to RECIST criteria, (4) ECOG performance status ≤2, (5) a life expectancy of at least 3 months, and (6) adequate laboratory values. Patients received capecitabine (2,500 mg/m2/day, days 1 to 14) and cisplatin (60 mg/m2, day 1) every 3 weeks. Response was assessed for every two cycles of chemotherapy and treatment was stopped when tumor had progressed or stable with no further response. Thirty-two patients were enrolled, 20 (62.5%) were male and 12 (37.5%) were female and the median age was 54 years (33–71 years). Fifteen patients (46.9%) had gallbladder cancer, 13 (40.6%) had intrahepatic cholangiocarcinoma, and 4 (12.5%) had extrahepatic biliary cancer. The most frequent metastatic sites were lymph nodes (20/32, 62.5%) and liver (28/32, 56.3%). No complete response was observed and partial response was observed in 13/32 patients. By the intent-to-treat analysis, the overall response rate was 40.6% (95% CI, 23.7–59.4) with 0 CR and 13 PRs. Stable disease was observed in 3 patients (9.4%), and 11 patients (34.4%) had progressive disease. The median time to progression was 3.5 months (95% CI, 1.3–5.8), and the median overall survival was 12.4 months (95% CI, 6.3–18.5) after the median follow-up duration of 9.5 months (4.8–26.1 months). A total of 108 cycles of chemotherapy was delivered. Grade 3 hematologic toxicities included neutropenia (5, 15.6%), anemia (1, 3.1%), and thrombocytopenia (1, 3.1%) per patient, and no grade 4 hematologic toxicities were observed. Grade 3 non-hematologic toxicities included hyperbilirubinemia (2, 6.3%), increase of alkaline phosphatase (2, 6.3%), hand–foot syndrome (2, 6.3%), anorexia, and diarrhea (1, 3.1%) per patient, respectively. There was no treatment-related death. The combination chemotherapy of capecitabine and cisplatin demonstrated a promising antitumor activity with mild toxicity profile in patients with advanced biliary tract cancer. [ABSTRACT FROM AUTHOR]