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Introduction Whether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear. Material and Methods Seventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test. Results The median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy. Conclusions In patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.

Background Cancer-related fatigue (CRF) is a common symptom and has a negative impact on prognosis in cancer patients. CRF could be improved by Korean red ginseng (KRG). Patients and methods For this randomised and double-blinded trial, colorectal cancer patients who received mFOLFOX-6 were randomly assigned to either KRG 2000 mg/day (n = 219) or placebo (n = 219) for 16 weeks. CRF was evaluated using the mean area under the curve (AUC) change from baseline of brief fatigue inventory (BFI) as the primary endpoint. Fatigue-related quality of life, stress, and adverse events were evaluated as secondary endpoints. Results In the full analysis group, KRG up to 16 weeks improved CRF by the mean AUC change from baseline of BFI compared to placebo, particularly in “Mood” and “Walking ability” (P = 0.038, P = 0.023, respectively). In the per-protocol group, KRG led to improved CRF in the global BFI score compared with the placebo (P = 0.019). Specifically, there were improvements in “Fatigue right now,” “Mood,” “Relations with others,” “Walking ability,” and “Enjoyment of life” at 16 weeks (P = 0.045, P = 0.006, P = 0.028, P = 0.003, P = 0.036, respectively). In subgroups of female patients, ≥60 years old, with high compliance (≥80%) or more baseline fatigue, the beneficial effects of KRG were more enhanced than that of placebo. Although neutropenia was more frequent in KRG than placebo, the incidence of all adverse events was similar. Conclusions KRG could be safely combined with mFOLFOX-6 chemotherapy in colorectal cancer patients, and reduced CRF compared with placebo.

Background: Although cancer patients are increasingly admitted to the intensive care unit (ICU) for cancer- or treatment-related complications, improved mortality prediction remains a big challenge. Current prognostic models for a general ICU population underestimate the mortality risk in cancer patients. Methods: We developed CanICU, a machine learning-based 28-day and 1-year mortality prediction program in adult cancer patients admitted to ICU from Medical Information Mart for Intensive Care (MIMIC) database in the USA (n=766), Yonsei Cancer Center (YCC, n=3,571), and Samsung Medical Center in Korea (SMC, n=2,563). We constructed the classifier and compared it with a general prognostic model. Findings: A total of 6,900 patients were included, with a 28-day mortality of 10.2%/12.7%/36.6% and 1-year mortality of 30.0%/31.4%/58.5% in the MIMIC, YCC, and SMC cohort, respectively. Nine clinical and laboratory factors were used to construct the classifier using a random forest machine-learning algorithm. CanICU had the area under the receiver operating characteristic (AUROC) of 0.95 (95% CI 0.93-0.97) for 28-day and 0.79 (95% CI 0.76-0.82) for 1-year mortality, showing better performance than a current prognostic model (Sequential Organ Failure Assessment [SOFA], 0.77 [95% CI 0.72-0.81] for 28-day and 0.67 [95% CI 0.64-0.70] for 1-year mortality). Application of CanICU in external data sets across the countries yielded better AUROC for 28-day mortality than SOFA (95% CI, 0.75-0.80 vs. 0.57-0.63 with SOFA in SMC; 95% CI, 0.72-0.79 vs. 0.64-0.72 with SOFA in MIMIC). Interpretation: CanICU offers improved performance for predicting short- and long-term mortality in critically ill cancer patients admitted to ICU. A user-friendly online implementation is available and should be valuable for better mortality risk stratification. This might help physicians to determine to allocate ICU care for patients with cancer. Funding Information: This study was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2019R1C1C1006709, 018R1A5A2025079, 2020M3F7A1094093), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, the Republic of Korea (No. KHIDIHI19C1015010020), and was also supported by the ational R&D Program for Cancer Control through the National Cancer Center (NCC) funded by the Ministry of Health & Welfare, Republic of Korea (HA21C0065). Declaration of Interests: The authors have no potential conflicts of interest to disclose. Ethics Approval Statement: The institutional review boards of all participating hospitals approved this study and waived the requirement for informed consent because of the observational nature of the research. All patient records and data were anonymized and de-identified before analysis.

Tumor rat sarcoma gene (RAS) status is a negative anti-epidermal growth factor receptor therapy biomarker in metastatic colorectal cancer (mCRC). Early tumor shrinkage (ETS) and depth of response (DpR) were evaluated for 270 patients with RAS wild type mCRC randomized to best supportive care with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of 14-day cycles). Panitumumab improved outcomes, and ETS and DpR might be useful efficacy markers. Introduction: Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS. Patients and Methods: Patients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of each 14-day cycle) in this open-label, multicenter, phase III study (20100007). RAS and BRAF mutation status were determined using Sanger sequencing. ETS was evaluated as maximum percentage change from baseline to week 8 ; DpR was calculated as the percentage change for tumor shrinkage at nadir versus baseline. Results: Overall, 270 patients had RAS wild type mCRC (panitumumab with BSC, n = 142 ; BSC, n = 128). For patients with wild type RAS tumors, median overall survival (OS ; hazard ratio [HR], 0.72 ; P =.015) and progression-free survival (PFS ; HR, 0.45 ; P

Summary Background Studies of a modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen suggest promising efficacy and tolerability profiles in the first-line and second-line settings. Therefore, we aimed to compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as a second-line therapy for metastatic colorectal cancer. Methods We did a multicentre, open-label, randomised, non-inferiority, phase 3 trial. We enrolled patients from 98 hospitals in Japan, China, and South Korea who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer. We randomly assigned patients (1:1) to receive either mXELIRI with or without bevacizumab (irinotecan 200 mg/m 2 intravenously on day 1 plus oral capecitabine 800 mg/m 2 twice daily on days 1–14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1) or FOLFIRI with or without bevacizumab (irinotecan 180 mg/m 2 intravenously on day 1, leucovorin 200 mg/m 2 intravenously on day 1, fluorouracil 400 mg/m 2 intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m 2 ], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1) via a centralised electronic system. We used the minimisation method to stratify randomisation by country, Eastern Cooperative Oncology Group performance status, number of metastatic sites, previous oxaliplatin treatment, and concomitant bevacizumab treatment. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was overall survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·30 for the hazard ratio (HR). This study is registered with ClinicalTrials.gov, number NCT01996306, and is ongoing but no longer recruiting participants. Findings Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive mXELIRI with or without bevacizumab (n=326) or FOLFIRI with or without bevacizumab (n=324). After a median follow-up of 15·8 months (IQR 8·7–24·9), a total of 490 patients had died (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab group) and the median overall survival was 16·8 months (95% CI 15·3–19·1) in the mXELIRI group and 15·4 months (13·0–17·7) in the FOLFIRI group (HR 0·85, 95% CI 0·71–1·02; p non-inferiority Interpretation mXELIRI with or without bevacizumab is well tolerated and non-inferior to FOLFIRI with or without bevacizumab in terms of overall survival. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for metastatic colorectal cancer, at least for Asian patient populations. Funding Chugai Pharmaceutical and F Hoffmann-La Roche.

Background: Cetuximab (chimeric monoclonal antibody to human epidermal growth factor receptor) is used to treat colorectal and head and neck cancers. Due to cross-reactivity with galactose-α-1,3-galactose (alpha-gal), it can induce hypersensitivity even at first administration. We aimed to determine the incidence and clinical manifestation of cetuximab-induced anaphylaxis, and to establish a means of predicting its incidence in patients ahead of treatment. Methods: Nationwide and single-center pharmacovigilance data from 2010 to 2017 were collected from the Korea Institute of Drug Safety-Korea Adverse Event Reporting System and Severance Regional Pharmacovigilance Center. Patients scheduled for cetuximab administration were enrolled prospectively. A skin prick test was carried out and serum IgE specific to cetuximab and cross-reactive allergens were measured. Reactions were monitored after cetuximab infusion. Results: Over 8 years, there were 23 reports of anaphylaxis nationwide. In a single-center study, incidence of cetuximab-induced anaphylaxis was 1.1%. Most anaphylaxis occurred at first injection (93.3%), even under pretreatment with anti-allergic drugs. Four of 64 patients (6.3%) experienced severe anaphylaxis. The median cetuximab-specific IgE titer was 6.9 kUA/L in patients experiencing anaphylaxis and 0 kUA/L in those who did not (P

Background and purpose To evaluate the efficacy and safety of upfront mFOLFOX6 followed by short-course radiotherapy (SCRT) and surgery in patients with locally advanced rectal cancer and liver-only metastases. Materials and methods This single-arm phase II study involved 32 patients. mFOLFOX6 was administered for four cycles followed by SCRT and another four cycles of mFOLFOX6. Surgery was performed 4–6weeks after the last chemotherapy cycle. The primary endpoint was complete (R0) resection rate. Secondary endpoints were response rate, progression-free survival (PFS), overall survival (OS), and complication rates. Results Surgical resection of the rectum and liver was performed in 25 patients (78%) and R0 resection was achieved in 20 patients (63%). Local tumor downstaging was observed in 54% of patients. Median OS and PFS were 38 and 9months, respectively. One patient discontinued treatment due to toxicity and no treatment-related deaths occurred. Patients who progressed after 4 cycles of mFOLFOX6 were less likely to receive resection. Conclusions This regimen was safe and effective in inducing local tumor response and achieving R0 resection in this patient population.

Background: Oxaliplatin-based adjuvant chemotherapy for rectal cancer patients after preoperative chemoradiotherapy (CRT) is currently based on extrapolated results from colon cancer patients. We evaluated the role of oxaliplatin as adjuvant chemotherapy in rectal cancer patients who received preoperative CRT with fluoropyrimidine monotherapy and total mesorectal excision (TME). Methods: The ADORE is a multicentre, randomised trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-fluorouracil 380 mg/m², leucovorin 20 mg/m²) or FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², 5-fluorouracil bolus 400 mg/m² on day 1, 5-fluorouracil infusion 2400 mg/m² for 46 hours). Stratification factors included ypStage and participating centre. Investigators were not blinded to the group assignment. Primary endpoint was disease-free survival (DFS), analysed according to the intention-to-treat principle (ClinicalTrials.gov registration number: NCT00807911). Findings: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. The 6-year DFS rates were 68·2% in the FOLFOX arm vs 56·8% in the FL arm, with a stratified hazard ratio (HR) of 0·63 (95% CI, 0·43-0·93, p=0·018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favourable to FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumour, and absence of lymphovascular or perineural invasion. The 6-year overall survival (OS) rate was 78·1% in the FOLFOX arm vs 76·4% in the FL arm (HR 0·73 [0·45-1·19], p=0·21). In the subgroup analysis for OS, FOLFOX was favourable to FL in patients with ypN2 and minimally regressed tumour. Interpretation: Adjuvant FOLFOX improved DFS in rectal cancer patients with ypStage II/III after preoperative CRT. Adjuvant FOLFOX should be chosen based on the postoperative pathologic stage in those received preoperative CRT and TME. Trial Registration Number: ClinicalTrials.gov registration number: NCT00807911 Funding: Sanofi-Aventis, Republic of Korea Declaration of Interest: TWK received research funding from Sanofi-Aventis, Taiho, and Roche. YSH received research funding from Bayer. All other authors have no conflicts of interest to declare. Ethical Approval: All patients provided written informed consent, and the study protocol was approved by the institutional review boards of all participating institutions.

Purpose The purpose of this study was to evaluate the rate of pathologic complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation therapy (CRT) with leucovorin (FL) versus irinotecan/S-1 (IS). Methods and Materials Patients with resectable LARC (clinical stage T3/4, lymph node positive, or both) were randomly assigned to receive preoperative radiation (45-50.4 Gy in 25 to 28 daily fractions) and concomitant chemotherapy either with a bolus injection of FL (400 mg/m 2 /day 5-fluorouracil and 20 mg/m 2 /day leucovorin) for 3 consecutive days every 4 weeks for 2 cycles (FL group) or with 40 mg/m 2 irinotecan on days 1, 8, 15, 22, and 29, and 35 mg/m 2 S-1 twice on the day of irradiation (IS group). Curative surgery was performed approximately 4 to 8 weeks after the completion of CRT. The postoperative chemotherapy regimen was FL with a primary endpoint of a pCR rate evaluation. Results One hundred forty-two eligible patients were randomly assigned, and the median follow-up duration was 43.8 months (95% confidence interval, 40.8-46.8 months). One hundred thirty-three patients (93.7%) of 142 underwent total mesorectal excision; pCR was achieved in 11 (16.7%) of 66 patients in the FL group and 17 (25.8%) of 67 patients in the IS group ( P =.246). When good responders were defined as patients with Mandard grades 1 and 2, the rate of good responders was significantly higher in the IS group than in the FL group (54.6% vs 36.4%, respectively, P =.036). The preoperative rates of grade 3 and 4 toxicities were higher in the IS group (7.0%) than in the FL group (1.4%, P =.095). The 3-year disease-free survival was not significantly different between the 2 groups (79.7% vs 76.6%, respectively, P =.896). Conclusions IS-based preoperative CRT did not increase pCR rate, but it did increase acute toxicities compared with standard 5-FU treatment. Therefore, further investigation is needed.

The outcomes of adjuvant chemoradiation for locally advanced rectal cancer are nonuniform among patients with matching prognostic factors. We explored the role of molecular markers for predicting the outcome of adjuvant chemoradiation for rectal cancer patients.The study included 68 patients with stages II to III rectal adenocarcinoma who were treated with total mesorectal excision and adjuvant chemoradiation. Chemotherapy based on 5-fluorouracil and leucovorin was intravenously administered each month for 6-12 cycles. Radiation therapy consisted of 54 Gy delivered in 30 fractions. Immunostaining of surgical specimens for COX-2, EGFR, VEGF, thymidine synthase (TS), and Raf kinase inhibitor protein (RKIP) was performed.The median follow-up was 65 months. Eight locoregional (11.8%) and 13 distant (19.1%) recurrences occurred. Five-year locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates for all patients were 83.9%, 78.7%, 66.7%, and 73.8%, respectively. LRFFS was not correlated with TNM stage, surgical margin, or any of the molecular markers. VEGF overexpression was significantly correlated with decreased DMFS (P=.045), while RKIP-positive results were correlated with increased DMFS (P=.025). In multivariate analyses, positive findings for COX-2 (COX-2+) and VEGF (VEGF+) and negative findings for RKIP (RKIP-) were independent prognostic factors for DMFS, DFS, and OS (P=.035, .014, and .007 for DMFS; .021, .010, and.0001 for DFS; and .004, .012, and .001 for OS). The combination of both COX-2+ and VEGF+ (COX-2+/VEGF+) showed a strong correlation with decreased DFS (P=.007), and the combinations of RKIP+/COX-2- and RKIP+/VEGF- showed strong correlations with improved DFS compared with the rest of the patients (P=.001 and.0001, respectively).Molecular markers can be valuable in predicting treatment outcome of adjuvant chemoradiation for rectal cancer patients.

We investigated the usefulness of a clinical risk scoring system (CRS) for guiding management and defining prognosis for patients with colorectal liver met"astases (CLM).We retrospectively analyzed data about the correlation between outcomes and Fong's CRS from 1989 to 2010 for patients treated for CLM at the Severance Hospital.Of 566 patients, 232 received adjuvant treatment after liver resection. Of these patients, 185 (81%) had a low CRS (0-2) and 47 (19%) had a high CRS (3-5). Stratification into high and low CRS allowed significant distinction between Kaplan-Meier curves for outcome. The 5-year survival rate was 88.5% and 11.5% among patients with a low and high CRS, respectively (P 0.001). Seventy patients with initially unresectable CLM underwent liver resection after tumor downsizing by induction chemotherapy. Shifting of the CRS from high to low (8 patients; 11.4%) improved disease-free survival and overall survival.High CRS is associated with worse survival after resection in resectable and unresectable disease. The CRS may be used for risk assessment when recommending oncological surgical timing in initially unresectable disease and treatment options for perioperative or adjuvant treatment in resectable disease.

Background and purpose The aim of this study is to evaluate the efficacy and safety of preoperative radiation therapy combined with S-1 and irinotecan (SI) in LARC. Materials and methods Patients were considered LARC if they had a T3/T4 lesion or node positive. Weekly doses of 40mg/m 2 irinotecan were intravenously administered once per week during weeks 1–5 of radiotherapy. S-1 (70mg/m 2 ) was given from Monday to Friday in all weeks of radiotherapy. 3-D conformal radiotherapy was given at daily fractions of 1.8Gy for 5days for a total dose of 50.4 (45+5.4)Gy. Surgery was performed 4–6weeks following the completion of chemoradiation. Results Between June 2006 and November 2007, 43 pts were enrolled. The stage was: cT3 24 patients, cT4 6 patients; 28 patients were cN+. Forty-one patients completed the chemoradiation and 42 patients underwent operation: a low anterior resection was performed in 36 patients, a total colectomy in 1 patient, and an abdominal perineal resection in 5 patients. T downstaging was observed in 50%; 23 N+ patients became N− (55%). The complete pathological response was observed in 9 patients (21%). The 3-year locoregional failure rate, distant failure rate, disease-free survival, and overall survival were 9.5%, 18.6%, 72.1%, and 94.3%, respectively. Only three patients experienced G3 diarrhea; one had G3 sepsis and two had septic shock. Hematological toxicity (G3–G4) was observed in five patients. Conclusions This study demonstrated the efficacy of preoperative CRT with S-1 and irinotecan with 21% of complete response. However, prompt recognition and management of infection is needed to use it in patients with locally advanced rectal cancer.

Background ABCB1 is responsible for multidrug resistance, the principal mechanism by which many cancers develop resistance to chemotherapeutic drugs. There is a controversy whether ABCB1 gene polymorphisms correlate with survival and response in cancer patients treated with chemotherapy. We evaluated the association between clinical outcome (safety and efficacy) of paclitaxel monotherapy in metastatic breast cancer patients with ABCB1 gene polymorphisms 2677G>T/A or 3435C>T. Patients and methods Patients with metastatic breast cancer were treated with 175 mg/m2 paclitaxel per 3-week cycle. Peripheral blood mononuclear cells from patients were used to genotype ABCB1 2677G>T/A and 3435C>T polymorphisms. Genotypes were investigated for their association with tumor response, survival, toxicity, and chemoresistance. Results ABCB1 3435 CT showed a significantly lower disease control rate than the CC genotype (P = 0.025). ABCB1 3435 CT was correlated with shorter overall survival (OS) in Cox regression analysis (P = 0.026). The 2677 GG genotype showed a significant association with chemoresistance to paclitaxel and anthracycline (P = 0.04 and 0.04, respectively). None of the ABCB1 genotypes correlated with toxicity. Conclusions ABCB1 genotypes may be a predictor of paclitaxel activity as well as a prognostic factor in metastatic breast cancer patients.

We investigated whether the level of bone marrow-derived progenitor cells and mature endothelial cells could be used as predictors of clinical outcome in patients receiving taxotere-based chemotherapy for advanced gastric cancer. Peripheral blood mononuclear cells were obtained from 49 gastric cancer patients who received taxotere combined with 5-FU and leucovorin and prophylactic G-CSF treatment. To categorize the cells, the cell markers CD34, vWF, P1H12, and CD31 were stained. Changes in these cells were examined before and after chemotherapy, and the clinical significance of these changes to response prediction and prognosis were investigated. Before the second cycle of chemotherapy, the number of CD34 + /vWF + and CD34 + cells was higher in non-responders as compared to the responders. Patients with ⩾6.2 CD34 + /vWF + cells/ml had a shorter progression free survival (3.7 months) as against patients with + /vWF + /ml (6.0 months, p = 0.076). Patients with ⩾5.8 CD34 + cells/ml had shorter progression free survival (4.0 months) than patients with + cells/ml (6.1 months, p = 0.046). In an ex vivo pharmacokinetic study, the maximum inhibition ( I max ) for HUVEC and YCC3 cells was 13.0 ± 6.6% and 74.0 ± 2.0%, respectively. The time to reach I max ( T max ) was 72 h in all HUVEC cells and 0.5 hours in YCC3 cells. We suggested that CD34 + /vWF + and CD34 + cells can be used as a biomarker for prediction and CD34 + cells for prognosis.

Background CpG island methylator phenotype (CIMP) is a subset of colorectal cancers characterized by promoter CpG island hypermethylation in multiple genes. CIMP-positive patients have a higher rate of KRAS mutation than CIMP-negative patients. While the KRAS mutation status has a predictive role in predicting response to anti-EGFR antibodies, the predictive role of CIMP has not been established. P16 (CDKN2A) is one of the CIMP markers and p16 hypermethylation also has been reported as a marker of fluorouracil and irinotecan resistance. Methods We retrospectively collected tumors from 49 patients with metastatic colorectal cancer (mCRC) who were treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) and cetuximab. Pyrosequencing was used to examine the methylation of six CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. To analyze the relation between CIMP markers and clinical outcome, logistic regression and Cox regression were carried out. KRAS mutation was available in 36 patients and is currently analyzing in 13 patients. Results There was a trend toward higher frequency of KRAS mutation in CIMP+ tumors (3/14, 21.4%) than CIMP tumors (2 of 35, 5.7%). The disease control rate (DCR, CR + PR + SD) was 64.3% (9/14 patients) in CIMP+ and 91.4% (32 of 35 patients) in CIMP- (Fisher's exact, P = 0.02). Although a trend toward shorter progression-free survival (PFS) and overall survival (OS) was seen in CIMP + , this was not statistically significant. Among our six CIMP genes, p16 methylation was strongly associated with lower DCR (Fisher's exact, P = 0.03), shorter PFS (log rank P = 0.002) and OS (log rank, P = 0.01). In multivariate analysis, KRAS mutation and p16 methylation were associated with shorter PFS and OS. Conclusions Promoter CpG island hypermethylation of p16 was predictive of clinical outcomes in mCRC patients treated with cetuximab and FOLFIRI.

Background: As the population of elderly cancer patients steadily increases, it is important to evaluate the feasibility of clinical trial in these patients to direct future care standard treatments and resource allocation. Elderly patients are very heterogeneous because the aging process is a highly individualized one and chronological age can't predict the changes involved in the aging process. The definition of elderly or fragile patients varies based on the different considerations such as disease-specific issue, risk of complications, estimation of life expectancy, and physician's view. With this heterogeneity, elderly patients have been underrepresented in both clinical trials and standard chemotherapy. Methods: Treatment of resectable colon cancer patients after age 70 of years were analyzed retrospectively focusing on clinical variables. The efficiency of adjuvant chemotherapy was evaluated in elderly colon cancer patients after a match by the propensity score method. Results: The elderly patients with resectable colon cancer received surgical treatment in more than 95% of cases regardless of their age or year of diagnosis. On the other hand, the proportion of patients who received adjuvant treatment increased among those who were diagnosed more recently, but it decreased abruptly with the increment of age. Recruitment of older patients into cancer clinical trial could be improved by (1) designing study grouped by age; (2) assessing patients to better distinguish the “well” older patients from the “frail” older patients. Conclusion: Currently, a comprehensive geriatric assessment (CGA) of elderly cancer patient has been recommended for the selection of proper treatment by predicting functional age and defining fragility including comorbidities. More personalized risk stratification of patients may be useful to elderly patients for optimal cancer treatment.

Background This study was designed to identify the significance of lymphovascular invasion as a prognosticator for tumor recurrence and survival in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME). Methods Between January 2003 and October 2010, the study included 328 patients with primary rectal cancer who had received preoperative CRT followed by TME. We analyzed the clinicopathologic factors that may be associated with survival, such as age, gender, carcinoembryonic antigen (CEA) value, pathologic T and N stage, tumor response, histologic grade, lymphovascular invasion (LVI), and perineural invasion. Results Higher pathologic T and N stage, poor tumorresponse, high-grade histology, and positive LVI were adverse prognostic factors for both disease-free survival (DFS) and overall survival (OS) on the multivariate analysis. Perineural invasion was a significant adverse prognostic factor affecting DFS (P = 0.046) but not OS (P = 0.08). Increased T and N stage and distant recurrence, but not local recurrence, were significant factors associated with LVI. The LVI-negative group had a higher DFS (71.4 versus 56.2%, P = 0.012) and OS rate (86.7 versus 63.4%, P = 0.020) at 5 years than the LVI-positive group did. Conclusions Positive LVI had a negative impact on survivalin patients with rectal cancer who received preoperative CRT and TME and is significantly associated with an increased chance of distant recurrence. Based on this finding, more tailored adjuvant chemotherapy is warranted for advanced rectal cancer patients with LVI to reduce the distant dissemination of tumor.

Background P16 (INK4a) inhibits cyclin dependent kinases (CDKs) and plays various roles in cancer and senescence. P16 aberrancy is frequently detected in various cancers and may contribute to multidrug resistance. Hypermethylation of CpG island of p16 occurs in a significant proportion in colorectal cancer (CRC) and also is one of the CpG island methylator phenotype (CIMP) markers. Patients and method We analyzed tumor samples from 49 patients with metastatic colorectal cancer (mCRC) who were treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) and cetuximab (1st line 22 pts, 2nd line 27 pts). Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. To analyze the relation between methylation status of CIMP markers including p16 and clinical outcome, logistic regression and Cox regression were performed. Result Hypermethylation of p16 gene was detected in 14 of 49 patients (28.6%) and was significantly associated with KRAS mutation (Fisher's exact, P = 0.01) and CIMP+ (Fisher's exact, P = 0.002). Patients with p16 unmethylated tumors had significant longer time to progression (TTP, median 9.0 vs 3.5 months; log-rank, P = 0.001) and overall survival (OS, median 44.9 vs 16.4 months; log-rank, P = 0.008) than those with p16 methylated tumors. KRAS mutation was also associated with shortened TTP (median 8.9 vs 4.4 months; HR = 3.1, P = 0.008) and OS (median 44.9 vs 16.1 months; HR = 5.2, P Conclusion Promoter CpG island hypermethylation of p16 was predictive of clinical outcome in mCRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation. Disclosure All authors have declared no conflicts of interest.