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PURPOSE Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748 ) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC). Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates. The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group. The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.

SummaryTAS-117 is a potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm single-center phase 2 study of TAS-117 in heavily treated patients with tumors refractory to systemic chemotherapy and harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations. Patients with gastrointestinal (GI) cancers were orally administered 16 mg TAS-117 daily, and those with non-GI tumors were administered 24 mg on a 4 days on/3 days off schedule. The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, safety, and tolerability. Thirteen patients were enrolled: eight with non-GI (breast, ovarian, endometrial, and non-small cell lung) and five with GI (colon, rectal, gastric, and gallbladder) cancers. Ten patients were treated with TAS-117 after ≥ 4 lines of therapy. Twelve patients showed PIK3 catalytic subunit alpha (PIK3CA) mutations; one harbored an Akt1E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8 %, and DCR was 23 %. The median PFS and OS were 1.4 and 4.8 months, respectively. Grade 3–4 treatment-related adverse events were anorexia (grade 3, 8 %) and hyperglycemia (grade 3, 8 %; grade 4, 8 %).Grade 3–4 treatment-related adverse events occurred in 27 % of grade 3 anorexia (9 %) and hyperglycemia (grade 3, 8 %; grade 4, 9\%). TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

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.

Purpose Although sorafenib as a standard of care for advanced hepatocellular carcinoma (HCC) prolongs overall survival (OS), its efficacy is limited owing to its unsatisfactory objective response and marginal survival benefit. To counter these limitations, we designed a single-arm, phase II trial with liver-directed concurrent chemoradiotherapy (LD-CCRT) and sequential sorafenib treatment in patients with advanced HCC. Methods and Materials We enrolled advanced HCC patients diagnosed between 2014 and 2017 who were ineligible for curative treatment. During the first and last 5 days of 5-week radiation therapy, concurrent hepatic arterial infusion with 5-fluorouracil (500 mg/d) and leucovorin (50 mg/d) through an implanted port was administered 4 weeks after initiation of LD-CCRT and sequential sorafenib treatment (400 mg, twice daily). The primary endpoint was OS. This trial has been registered at clinicaltrials.gov . Results Among the enrolled patients (n = 47), objective response rates 4 weeks after LD-CCRT and during/up to sorafenib maintenance were 44.7% and 53.2%, respectively. Overall, 9 patients (19.1%) underwent curative resection or transplantation after down staging. The median radiation dose was 60 Gy. The median OS was 24.6 months for the entire cohort and 13.0 months for the subgroup with tumor invasion into the main portal trunk or its first branch, whereas the median progression-free survival for the cohort and subgroup was 6.8 and 5.6 months, respectively. The most frequent treatment-related adverse events were diarrhea (36.2%) and hand-foot skin reaction (34%), which were manageable with conservative treatment. Conclusions LD-CCRT and sequential sorafenib treatment provided favorable OS and progression-free survival with good tolerability. Tumor reduction using an initial LD-CCRT enabled down staging, subsequent curative treatment, and long-term survival in about 20% of the patients with advanced HCC. However, further randomized trials are required to confirm these results.

Serum carcinoembryonic antigen (CEA) is a widely used tumor marker in colorectal cancer (CRC), but within normal range of preoperative CEA levels the clinical significance of CEA is unknown. The aim of this study was to evaluate the usefulness of CEA within the normal range as a prognosticator of non-metastatic CRC. This retrospective cohort study included 2021 CRC patients with normal preoperative CEA who underwent elective curative surgery (discovery group). We determined the optimal cut-off value for disease-free survival (DFS) discrimination using the Contal and O’Quigley method. We also assessed the prognostic significance of the cut-off value in a prospective cohort of 171 stage III colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (validation group). The optimal cut-off CEA value was 2.1 ng/mL in the discovery group. The DFS rates were significantly poorer in patients with high-normal preoperative CEA levels (2.1–5.0 ng/mL) than in those with low-normal CEA levels (

Introduction Some patients with cancer may present with progressive or persistent disease at a limited number of sites following a period of treatment response. We evaluated the safety and effectiveness of metastasis-directed radiotherapy (MRT) for oligoprogressive or oligopersistent disease in patients receiving systemic treatment for metastatic colorectal cancer (mCRC). Patients and methods Patients with mCRC who received 5-fluorouracil, leucovorin, and oxaliplatin; 5-fluorouracil, leucovorin, and irinotecan; and/or capecitabine chemotherapy between 2011 and 2020 at a single institution were identified. Then, those who underwent MRT for five or fewer lesion sites while receiving systemic treatment for other metastases were categorized. The primary endpoint was time to change to systemic therapy. Secondary endpoints included MRT-related toxicity, overall survival, and local control. Results Among 4157 patients included, 91 (2%) received MRT to limited lesion sites (55 oligoprogressive and 36 oligopersistent) during systemic treatment following a period of treatment response. The median time to change to next-line systemic therapy was 5 months in the overall cohort (measured from the current chemotherapy session) and 9.5 (range, 6.0–40.6) months in the MRT group (measured from the MRT session). No severe toxicity or systemic treatment interruption was observed following MRT. The 1-year local control and overall survival rates were 69% and 99%, respectively. Conclusion In patients with oligoprogressive or oligopersistent mCRC, MRT may be performed safely in conjunction with systemic treatment to maximize the benefit of systemic therapy and to prolong the time to change to systemic therapy. Further prospective studies should confirm these findings. MicroAbstract Our study explored the role of metastasis-directed radiotherapy (MRT) for oligoprogressive or oligopersistent tumor from metastatic colorectal cancer (mCRC). We observed that MRT was performed safely while continuing systemic treatment and showed postponement of the time to change to next-line systemic therapy. Prospective evaluation of this approach is warranted in patients with mCRC.

Background and purpose To evaluate the safety and efficacy of preoperative chemotherapy (CTx) followed by chemoradiotherapy (CCRT) for high-risk gastric cancer (GC). Methods and materials The inclusion criteria were as follows: (1) Borrmann type 4; (2) large Borrmann type 3 (≥8 cm); (3) single bulky (≥3 cm × 1) or multiple lymph nodes (≥1.5 cm × 3). Patients received two 21-day courses of induction CTx of TS-1 (35 mg/m2, p.o, twice daily on days 1–14), docetaxel (30 mg/m2, i.v., days 1 and 8), and cisplatin (30 mg/m2, i.v., days 1 and 8) followed by CCRT (two courses of TS-1 and cisplatin in combination with 45 Gy radiation). Results Forty-two patients were enrolled between March 2014 and February 2016, and 39 of these completed sequential CTx and CCRT. Among the 33 patients who underwent R0 resection, the pathologic response rate was 39.4% [no residual carcinoma (n = 5, 15.2%), with 1–10% residual carcinoma (n = 8, 24.2%)]. Overall, 4 patients (12.1%) were pathologic stage 0, 7 (21.2%) were stage I, 10 (30.3%) were stage II, and 12 (36.4%) were stage III. The overall survival rate at 3 years was 77.9% for stages 0 and I, 66.8% for stages II–III, and 33.3% for unresectable cases (P = 0.001). Toxicity was mild to moderate with grade 4 neutropenia (n = 1) and neutropenic fever (n = 1) as the most prominent side-effects. Conclusions Sequential CTx and CCRT prior to surgery are feasible and effective for high-risk GC. Trial registration number: NCT02495493.

Although adjuvant chemotherapy can have an impact on physical activity (PA), PA level has not been studied in patients with stage II–III colon cancer. This study investigated PA levels during and between chemotherapy cycles. We objectively measured PA levels for 2 weeks during the 2nd and 11th chemotherapy cycles. In addition, self-reported PA levels were assessed before chemotherapy initiation, during 2nd, 6th, and 12th chemotherapy cycles. This study included 22 men and 33 women with stage II–III colon cancer patients (57 ± 9 years). Before the initiation of chemotherapy, most cancer patients were minimally active. Compared with the 1st week of chemotherapy, moderate- and light-intensity PA levels significantly increased during the 2nd week of chemotherapy. Patients increased moderate- and light-intensity PA from 217.4 to 290.3 min per week and from 585.7 to 657.8 min per week, respectively (p

Background The National Lung Screening Trial (NLST) and NELSON trial showed that low-dose chest computed tomography (LDCT) screening significantly reduced the mortality form lung cancer. Although cancer survivors are known to have high risk for second malignant neoplasm (SMN), the usefulness of LDCT screening for lung cancer in cancer survivors is not clear. Methods Between August 2016 and August 2017, 633 long-term colorectal cancer (CRC) survivors visited the survivorship clinic in Cancer Prevention Center, Yonsei Cancer Center, Seoul, Republic of Korea. We surveyed the smoking status and recommended LDCT screening to ever-smoking CRC survivors aged 55–80 years. The participants were classified into three risk groups: risk group 1 (RG1) who met the NLST criteria (Age 55–74 years, ≥ 30 pack-years of smoking, smoking cessation < 15 years); risk group 2 (RG2) who would not meet the NLST criteria but were at increased 6-year risk of lung cancer (PLCOM2012 ≥ 0.0151); risk group 3 (RG3) who did not meet any of the criteria above. Results Among 176 ever-smoking CRC survivors, 173 (98.3%) were male, 32 (18.2%) were current-smoker, and median age was 66 years (range, 55–79 years). We found 38 positive findings (non-calcified nodule ≥ 4 mm), 8 clinically significant findings, 66 minor abnormalities, and 64 negative findings on LDCT. Positive findings were identified in 15 of 79 (19.0%) of RG1, in 9 of 36 (25%) of RG2, and in 14 of 61 (23.0%) of RG3. Second primary lung cancers were found in 2 patients of RG2, and in 1 patient of RG3. SMN was most frequently found in RG2 (11 of 36 patients, 30.6%), compared with RG1 (12.7%) or RG3 (9.8%) (P = 0.016). Conclusions LDCT screening for lung cancer in Korean CRC survivors is feasible. Well-designed clinical trial for defining high risk patients for lung cancer among CRC survivors is needed.

Bone metastasis is known as a poor prognostic factor in colorectal cancer (CRC), but its clinical manifestations and outcomes are uncertain. CRC with bone metastasis was searched from January 2006 to April 2016. Of 11,551 CRC patients, 321 (2.7%) patients had bone metastasis. Bone-only metastasis was found in only 8.7% of patients. Synchronous bone metastasis was present in 147 (45.8%) patients. In patients with metachronous bone metastasis, the median time from CRC diagnosis to bone metastasis (TTB) was 27.2 months. KRAS mutation status was a marginally significant factor affecting TTB (median TTB, KRAS wild-type or mutation: 29 or 25.8 months, respectively, P = 0.068). Skeletal-related events (SREs) were noted in 200 (62.3%) patients. Median overall survival (OS) from diagnosis of bone metastasis was 8.0 months. On multivariate analysis, multi-organ metastasis, peritoneal metastasis, neutrophil-to-lymphocyte ratio (NLR) ≥ 2.7, and alkaline phosphatase (ALP) ≥ 123 were independent factors for OS. Palliative chemotherapy prolonged survival in CRC patients with bone metastasis (HR 0.25, 95% CI 0.2–0.33). In conclusion, bone metastasis of CRC is rare, but it is related to SREs. Most patients have other organ metastasis and survival is 8.0 months. Attention should be paid to bone metastasis in CRC patients.

Purpose/Objective(s) There is a paucity of data studying the significance of neutrophil-to-lymphocyte ratio (NLR) in peripheral blood of patients with locally advanced rectal cancer (LARC) planning to undergo preoperative RT. We aimed to investigate the prognostic impact of NLR in patients with LARC and whether there are modifiable factors in RT which influencing the level of NLR. Materials/Methods We studied 1366 patients treated with neoadjuvant RT with concurrent or sequential chemotherapy for LARC from 2006 to 2019. Most (97.8%) were treated with long-course RT (50-50.4 Gy in 25-28 fractions) with 3DCRT (n = 851) or helical tomotherapy (n = 504). Short-course RT (25 Gy in 5 fractions, followed by 6-week XELOX) was used in 30 cases (NCT03676517). The absolute neutrophil and lymphocyte counts were obtained from the sample collected at the time of initial diagnosis, before and during the course of preoperative RT and before surgery. The primary endpoint was distant metastasis-free survival (DMFS). Results With the median follow-up time of 61.3 months (4.1-173.7 months), the 5-year DMFS was 80.1%. 5-year DMFS was significantly associated with the level of NLR after RT, but not with the level of NLR before RT. In Cox multivariate model, post-RT NLR greater than 4 was independently correlated with worse DMFS (HR 1.37, 95% CI, 1.08-1.73), along with higher icT stage, ypT stage and ypN stage. The 5-year OS of patients with post-RT NLR > 4.0 was 83.2%, compared to 94.4% in post-RT NLR ≤ 4 patients (P 4.0) was more frequently developed after long-course RT (OR, 2.77, P = 0.032) or helical tomotherapy (OR, 1.29, P .05). Conclusion Elevation of NLR after neoadjuvant RT is associated with increased risk of DM development and poor OS in LARC. Development of high NLR following RT is directly related to RT fractionation and delivery modality, and tumor characteristics. Incorporation of SCRT with 3D-CRT or active bone marrow sparing-IMRT may be a modifiable factor that can indirectly affect DMFS by means of attenuating NLR in LARC patients, which needs further investigations.

Background We aimed to explore the clinical benefit of adjuvant chemotherapy (AC) with fluoropyrimidine in patients with ypT0-3N0 rectal cancer after preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME). Methods Patients with ypT0-3N0 rectal cancer after preoperative CRT and TME were included using prospectively collected tumor registry cohort between January 2001 and December 2013. Patients were categorized into two groups according to the receipt of AC. Disease-free survival (DFS) and overall survival (OS) were compared between the adjuvant and observation groups. To control for potential confounding factors, we also calculated propensity scores and performed propensity score-matched analysis for DFS and OS. Results Of the 339 evaluated patients, 87 patients (25.7%) did not receive AC. There were no differences in DFS (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.562–1.507; P = 0.742) and OS (HR, 0.835; 95% CI, 0.423–1.648; P = 0.603) between the adjuvant and observation groups. After propensity score matching, DFS (HR, 1.129; 95% CI, 0.626–2.035; P = 0.688) and OS (HR, 1.200; 95% CI, 0.539–2.669; P = 0.655) did not differ between the adjuvant and observation groups. Advanced T stage and positive resection margin were independently associated with inferior DFS and OS on multivariate analysis. Conclusions AC did not improve DFS and OS for patients with ypT0-3N0 rectal cancer after preoperative CRT followed by TME in this cohort study. The confirmative role of AC in locally advanced rectal cancer should be evaluated in prospective randomized trials with a larger sample size. Electronic supplementary material The online version of this article (10.1186/s12885-017-3624-7) contains supplementary material, which is available to authorized users.

// Ji Soo Park 1 , Jong-Chan Youn 2, 3, * , Chi Young Shim 3 , Geu-Ru Hong 3 , Choong-Kun Lee 4 , Jee Hyung Kim 4 , Hyung Soon Park 4 , Su Jin Heo 4 , Seung Hoon Beom 4 , Hyo Song Kim 4 , Sun Young Rha 4 , Hyun Cheol Chung 4 , Seok-Min Kang 3 and Minkyu Jung 4, * 1 Cancer Prevention Center, Yonsei Cancer Center, Seoul, Republic of Korea 2 Division of Cardiology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Republic of Korea 3 Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 4 Divison of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Minkyu Jung, email: minkjung@yuhs.ac Jong-Chan Youn, email: jong.chan.youn@gmail.com Keywords: trastuzumab, cardiotoxicity, incidence, HER2, gastric cancer Received: December 29, 2016 Accepted: May 15, 2017 Published: June 27, 2017 ABSTRACT Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a prospectively-collected database that included prospective clinical trials at Yonsei Cancer Center, Republic of Korea. TIC was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10 percentage points from the baseline to a value less than 55%, as identified by a multiple-gated acquisition scan or an echocardiogram. Among the 115 patients, 70 patients (60.9%) received trastuzumab combined with chemotherapy, and 45 patients (39.1%) received chemotherapy alone as a first-line therapy. Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in LVEF was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40–29.8; P =0.257]. TIC was observed more frequently in elderly patients than in younger patients (HR, per age in year, 1.16; 95% CI, 1.02–1.31; P =0.019). Similar to prior observations in breast cancer, TIC in gastric cancer patients is not frequent or reversible. However, the asymptomatic drop in LVEF should be monitored continually in HER2-positive gastric cancer patients treated with trastuzumab, especially in elderly patients.

We aimed to find the clinical value of metastatic tumor burden evaluated with F18-FDG PET/CT in gastric cancer patients, considering the human epidermal growth factor receptor 2 (HER2) status. We retrospectively reviewed 124 patients with locally advanced or metastatic gastric cancer at Yonsei Cancer Center between January 2006 and December 2014 who had undergone baseline FDG PET/CT before first-line chemotherapy. We measured the maximum standardized uptake value from the primary tumor (SUVmax) and whole-body (WB) PET/CT parameters, including WB SUVmax, WB SUVmean, WB metabolic tumor volume (WB MTV), and WB total lesion glycolysis (WB TLG), in all metabolically active metastatic lesions (SUV threshold ≥2.5 or 40% isocontour for ≤2.5), and we determined their association with patient survival outcomes. SUVmax was higher in HER2-positive gastric cancers (median 12.1, range 3.4–34.6) compared to HER-2 negative (7.4, 1.6–39.1, P 600, which is indicative of a high metastatic tumor burden, showed worse progression-free survival (PFS) [hazard ratio (HR), 2.003; 95% CI, 1.300–3.086; P = 0.002] and overall survival (OS) (HR, 3.001; 95% CI, 1.950–4.618; P

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

Carcinoembryonic antigen (CEA) is the most widely used tumor marker in colon cancer; however, there has been controversy regarding the significance of preoperative serum CEA level as a prognostic factor for recurrence. In this study, we evaluated the optimal cutoff value and prognostic significance of preoperative serum CEA level in stage III colon cancer. Based on a retrospective cohort of 965 patients with stage III colon cancer who underwent elective curative surgery and adjuvant chemotherapy with fluoropyrimidine and oxaliplatin (training set), we determined the optimal cutoff value of CEA for recurrence using the Contal and O’Quigley method. We assessed the prognostic value of this cutoff value in terms of disease-free survival (DFS) and overall survival (OS) in a prospective cohort of 268 patients with stage III colon cancer (validation set). A Cox proportional hazards model was used to explore the association of prognostic variables with DFS and OS. The statistically determined best cutoff value for CEA was 3 ng/mL in the training set. A high CEA level (≥3 ng/mL) was associated with inferior DFS (hazard ratio [HR] 4.609, 95 % confidence interval [CI] 2.028–10.474) and OS (HR 3.956, 95 % CI 1.127–13.882) in the validation set, while multivariate analysis showed that a high CEA level was an independent risk factor for DFS and OS in both study subsets. Preoperative serum CEA level is an independent prognostic factor for DFS and OS in patients with stage III colon cancer after curative resection and adjuvant chemotherapy.

// Hyo Song Kim 1 , Su-Jin Shin 2 , Seung-Hoon Beom 1 , Minkyu Jung 1 , Yoon Young Choi 3 , Taeil Son 3 , Hyoung-Il Kim 3 , Jae-Ho Cheong 3 , Woo Jin Hyung 3 , Sung Hoon Noh 3 , Hyunsoo Chung 4 , Jun Chul Park 4 , Sung Kwan Shin 4 , Sang Kil Lee 4 , Yong Chan Lee 4 , Woong Sub Koom 5 , Joon Seok Lim 6 , Hyun Cheol Chung 1 , Sun Young Rha 1 , Hyunki Kim 2 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea 3 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea 4 Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 5 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea 6 Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea Correspondence to: Hyunki Kim, email: kimhyunki@yuhs.ac Sun Young Rha, email: rha7655@yuhs.ac Keywords: gastric cancer, molecular subtypes, immunohistochemistry, in-situ hybridization Received: April 04, 2016 Accepted: May 29, 2016 Published: June 16, 2016 ABSTRACT Gastric cancer (GC) is a leading cause of death. We aim to establish a clinically relevant assay that encompasses recent molecular classifications and provides useful clinical information in a large cohort of GC patients. A consecutive series of 438 GC patients that underwent palliative chemotherapy between 2014 and 2015 were assessed using 10 GC panels: EBER in-situ hybridization, immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (RTKs; HER2, EGFR, and MET), PTEN, and p53 protein. With a median of one aberration, 3.3 % of samples analyzed were Epstein-Barr virus (EBV)-positive; 4.8%, MMR-deficient. RTKs were overexpressed in 218 patients; EGFR was most commonly overexpressed (39.9%), followed by HER2 (13.5%) and MET (12.1%). Furthermore, 2.5 % and 10.7 % of cases had simultaneous overexpression of three and two RTKs, respectively. p53 overexpression/null tumors were identified in 259 patients (59.1%), and PTEN loss was identified in 89 patients (20.3%). EBV-positivity was mutually exclusive with MMR-deficiency, predominantly identified in male patients, and these tumors were undifferentiated with proximal location. p53 mutant type was significantly found predominantly in the EBV-negative (60.6% vs 14.3%, P=0.001) and HER2-positive (78.0% vs 56.2%, P=0.002) groups. We described a molecular spectrum of distinct GC subtypes using clinically applicable assay. This assay will provide a convenient screening tool and facilitate the development of targeted agents in clinical trials.

Background: Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). However, it is unclear whether MSI affects the prognosis of recurrent CRCs. Methods: This study included 2940 patients with stage I–III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed. Results: A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P

Purpose Identification of biomarkers to predict recurrence risk is essential to improve adjuvant treatment strategies in stage II/III gastric cancer patients. This study evaluated biomarkers for predicting survival after surgical resection. Materials and methods This post-hoc analysis evaluated patients from the CLASSIC trial who underwent D2 gastrectomy with or without adjuvant chemotherapy (capecitabine plus oxaliplatin) at the Yonsei Cancer Center. Tumor expressions of thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and programmed death-ligand 1 (PD-L1) were evaluated by immunohistochemical (IHC) staining to determine their predictive values. Results Among 139 patients, IHC analysis revealed high tumor expression of TS (n=22, 15.8%), ERCC1 (n=23, 16.5%), and PD-L1 (n=42, 30.2%) in the subset of patients. Among all patients, high TS expression tended to predict poor disease-free survival (DFS; hazard ratio [HR], 1.80; p=0.053), whereas PD-L1 positivity was associated with favorable DFS (HR, 0.33; p=0.001) and overall survival (OS; HR, 0.38; p=0.009) in multivariate Cox analysis. In the subgroup analysis, poor DFS was independently predicted by high TS expression (HR, 2.51; p=0.022) in the adjuvant chemotherapy subgroup (n=66). High PD-L1 expression was associated with favorable DFS (HR, 0.25; p=0.011) and OS (HR, 0.22; p=0.015) only in the surgery-alone subgroup (n=73). The prognostic impact of high ERCC1 expression was not significant in the multivariate Cox analysis. Conclusion This study shows that high TS expression is a predictive factor for worse outcomes on capecitabine plus oxaliplatin adjuvant chemotherapy, whereas PD-L1 expression is a favorable prognostic factor in locally advanced gastric cancer patients.

Purpose Interstitial lung disease (ILD) is a serious adverse effect of gefitinib. We examined the incidence and clinical characteristics of drug-induced ILD in Korean non-small cell lung carcinoma patients treated with gefitinib. Materials and Methods A retrospective cohort study was performed in non-small cell lung cancer (NSCLC) patients who started gefitinib treatment at Seoul National University Hospital from January 2002 through December 2011. Patients who developed new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as having possible adverse pulmonary reactions. The patients’ medical records were reviewed independently by investigators to identify the causes of pulmonary toxicities. Results Among the 1,114 patients evaluated, 128 patients (11.5%) developed pulmonary adverse reactions after taking gefitinib. An infectious complication occurred in 98 patients (8.8%) and 15 patients (1.3%) developed ILD. Nine of the 15 patients (60.0%) with gefitinib-induced ILD experienced a fatal clinical course that met either the Common Terminology Criteria for Adverse Events grade 4 (n=3) or grade 5 (n=6). In the multivariate analysis, a lower serum albumin level (≤ 3.0 g/dL) at baseline was significantly associated with the development of gefitinib-induced ILD (odds ratio, 3.91; 95% confidence interval, 1.20 to 12.71). Conclusion The incidence of gefitinib-induced ILD in Korean NSCLC patients was similar to that reported worldwide, but lower than values reported for Japanese population. ILD was usually a life-threatening adverse effect of gefitinib, and the development of ILD was significantly associated with a lower baseline serum albumin level.

Background The neutrophil-lymphocyte ratio (NLR) is a marker of poor prognosis in lung cancer patients. However, previous data have been based on an heterogeneous population of lung cancer patients and various treatments. In this study, we evaluate the prognostic value of NLR in an homogeneous population of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients. Methods We restrospectively evaluated the data of 250 NSCLC patients with EGFR mutations. All data are based on first-line treatment. Results All tumors harbored in-frame deletions in exon 19 or an L858R point mutation. Eighty-five patients were treated with tyrosine kinase inhibitors (TKIs), while 165 received cytotoxic chemotherapy as first-line treatment. Multivariate survival analysis revealed that the NLR was a significant prognostic factor for first-line progression-free survival (PFS) in the chemotherapy group (hazard ratio [HR] 1.882, 95% confidence interval [CI] 1.319–2.686, P = 0.001), but was not significant in the TKI group (HR 1.239, 95% CI 0.693–2.215, P = 0.469). The response rate (RR) to first-line treatment was 76.5% in the TKI group and 29.5% in the chemotherapy group; however, the RR, according to the NLR (≤3 vs. > 3), was the same for both groups. Conclusions The NLR was a significant prognostic factor in the chemotherapy group, but it did not affect either RR or PFS in EGFR-mutant NSCLC patients treated with TKIs.

Background Patients with stage I colorectal cancer (CRC) have excellent prognosis after curative surgery. However, approximately 5% to 10% of patients experience recurrence and have a poor prognosis. Because the incidence of stage I CRC is increasing with active screening programs worldwide, a more accurate and easy-to-use predictive tool for recurrence is becoming more important. This study aimed to develop a predictive nomogram for recurrence in stage I CRC. Patients and Methods A total of 1538 patients who underwent curative surgery for stage I CRC were enrolled. Predictive factors for recurrence were determined by multivariate Cox regression model and were used to develop a predictive nomogram. This model was internally validated, and performance was evaluated through calibration plots. Results The cumulative recurrence rate at 5 years after surgery for stage I CRC was 5.3%. In multivariate Cox analysis, independent predictors of recurrence were tumor location at rectum, pT2 stage, and presence of lymphovascular invasion. The 5-year recurrence rate was significantly different depending on the number of risk factors (0.7% for 0, 5.8% for 1, and 9.7% for ≥ 2 risk factors). On this basis, a nomogram for recurrence-free survival was developed and internally validated. The concordance index of the nomogram was 0.71, and the performance was acceptable. Conclusion We developed and internally validated a nomogram that can predict postoperative recurrence in stage I CRC patients. This nomogram may be used to more accurately stratify the risk of recurrence and to perform personalized postoperative surveillance in stage I CRC patients.

Background: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinical significance in patients with metastatic clear cell RCCs (ccRCCs). Methods: We analyzed 206 metastatic ccRCC patients who received the first-line vascular endothelial growth factor (VEGF) targeted therapy including sunitinib (n = 33), pazopanib (n = 120), and sorafenib (n = 53) between 2006 and 2016. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to membranous staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). Results: TG2 staining intensity was negative in 20.9% of ccRCC (n = 43), 1+ in 46.6% (n = 96), 2+ in 9.71% (n = 20), and 3+ in 22.8% (n = 47). The survival analysis showed a significant association between stronger TG2 expression (≥ 2+) and worse progression-free survival (PFS) (P = 0.032) in the 1st line VEGF-targeted therapy. On multivariate analysis including previous nephrectomy, number of metastatic organs, and International Metastatic RCC Database Consortium Risk Score, stronger TG2 expression was a significant independent predictive indicator for poor PFS (P = 0.004). Conclusions: Our study is the first to demonstrate the significance of TG2 expression on clinical outcome in metastatic ccRCCs. TG2 expression was a significant negative predictive marker for PFS in 1st line VEGF-targeted therapy and targeting TG2 may be a new therapeutic approach to metastatic ccRCC. Citation Format: Seung-Hoon Beom, Sejung Park, Woo Sun Kwon, Sang Joon Shin, Soo-Youl Kim, Nam Hoon Cho, Sun Young Rha. Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A053. doi:10.1158/1535-7163.TARG-19-A053

Background Pneumococcal vaccination (PCV13) is recommended to cancer patients undergoing systemic chemotherapy. However, the optimal time interval between vaccine administration and initiation of chemotherapy has been little studied in adult patients with solid malignancies. Methods We conducted a prospective randomized controlled trial to evaluate whether administering PCV13 on the first day of chemotherapy is non-inferior to vaccinating two weeks prior to chemotherapy initiation. Patients were randomly assigned to two study arms, and serum samples were collected at baseline and 4 weeks after vaccination to analyze the serologic response against Streptococcus pneumonia using a multiplexed opsonophagocytic killing assay. Results Of the 92 patients who underwent randomization, 43 patients in Arm A (vaccination 2 weeks before chemotherapy) and 44 patients in Arm B (vaccination on the first day of chemotherapy) were analyzed. Immunogenicity was assessed by geometric mean and fold-increase of post-vaccination titers, seroprotection rates (percentage of patients with post-vaccination titers > 1:64), and seroconversion rates (percentage of patients with > four-fold increase in post-vaccination titers). Serologic responses to PCV13 did not differ significantly between the two study arms according to all three types of assessments. Conclusions The overall antibody response to PCV13 is adequate in patients with gastric and colorectal cancer during adjuvant chemotherapy, and no significant difference was found when patients were vaccinated two weeks before or on the day of chemotherapy initiation. Clinical trial identification KCT0003379. Legal entity responsible for the study The authors. Funding National Research Foundation of Korea (NRF), Ministry of Health and Welfare of Korea. Disclosure All authors have declared no conflicts of interest.

Background: IM156 is a novel oral potent biguanide, which has anticancer activity through AMPK activation and reduction of oxidative phosphorylation. Inhibition of oxidative phosphorylation (OXPHOS) is detrimental to OXPHOS dependent cancer cells, which are prone to energy stress. Preclinical experiments demonstrated that IM156 can be effective in glioblastoma, gastric cancer and other solid tumors. Methods: This is an open label, first-in-human, single center, dose-escalation study (NCT03272256) using the 3+3 design to determine the maximum tolerated dose and/or recommended Phase II dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of IM156 in patients with advanced solid tumors. Eligible patients are adults with advanced solid tumors refractory to standard therapies with adequate performance status (ECOG Results: To date, 12 patients (gastric cancer, 5; endometrial cancer, 2; ovarian cancer, 2; other, 3) were enrolled to 4 dose levels (100mg to 800 mg orally every other day). There have been no DLTs or >other grade 3 treatment-related adverse events (AEs). Most frequent AEs included nausea (67% of patients), vomiting (17%), diarrhea (23%), insomnia (17%), epigastric and abdominal pain (17%), weakness (8%), neuropathy (8%) and fatigue (8%); however, there were all grade 1 except for four grade 2 episodes (nausea, 2; insomnia, 1; diarrhea, 1; epigastric pain, 1). Mild elevations ( Conclusion: IM156 has been well tolerated with manageable AE profile. The dose escalation continues with a planned change from every other day administration to daily dosing. Citation Format: Sun Young Rha, Seung Hoon Beom Seung Hoon Beom, Gun Min Kim, Young Geun Shin, Dong-Seok Yim, Hyo Song Kim, Jong Hee Chang, Jae-Ho Cheong, Young Woo Lee, Yun Seon Chong, Vincent O’Neill, Sang Hee Yoo, Filip Janku. Phase I study of an oxidative phosphorylation inhibitor IM156 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT021.

We tested the clinical utility of combined profiling of Ion Torrent PGM based next-generation sequencing (NGS) and immunohistochemistry (IHC) for assignment to molecularly targeted therapies. A consecutive cohort of 93 patients with advanced/metastatic GC who underwent palliative chemotherapy between March and December 2015 were prospectively enrolled. Formalin fixed paraffin embedded tumor biopsy specimens were subjected to a 10 GC panels [Epstein Barr virus encoding RNA in-situ hybridization, IHC for mismatch repair proteins (MMR; MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (HER2, EGFR, and MET), PTEN, and p53 protein], and a commercial targeted NGS panel of 52 genes (Oncomine Focus Assay). Treatment was based on availability of targeted agents at the time of molecular diagnosis. Among the 81 cases with available tumor samples, complete NGS and IHC profiles were successfully achieved in 66 cases (81.5%); only IHC results were available for 15 cases. Eight cases received matched therapy based on sequencing results; ERBB2 amplification, trastuzumab (n = 4); PIK3CA mutation, Akt inhibitor (n = 2); and FGFR2 amplification, FGFR2b inhibitor (n = 2). Eleven cases received matched therapy based on IHC; ERBB2 positivity, trastuzumab (n = 5); PTEN loss (n = 2), PI3Kβ inhibitor; MMR deficiency (n = 2), PD-1 inhibitor; and EGFR positivity (n = 2), pan-ERBB inhibitor. A total of 19 (23.5%) and 62 (76.5%) cases were treated with matched and non-matched therapy, respectively. Matched therapy had significantly higher overall response rate than non-matched therapy (55.6% vs 13.1%, P = 0.001). NGS and IHC markers provide complementary utility in identifying patients who may benefit from targeted therapies.

We report the first case of adrenocortical carcinoma secreting cortisol (Cushing's syndrome) and aldosterone (Conn's syndrome) with extensive distant metastasis at the time of diagnosis. A 72-year-old male with exertional dyspnea sought evaluation at our institution. The pattern of tumor spread (lung, pleura, bone and adrenal gland) and respiratory symptoms secondary to the tumor led clinicians to diagnose the primary tumor site as lung cancer and the adrenal mass as a metastatic site. However, endocrinologic studies and a biopsy revealed the primary site to be adrenocortical carcinoma. After histopathologic confirmation, the patient was treated with palliative chemotherapy, including mitotane, cisplatin, etoposide and doxorubicin. The patient died on the 14th day after chemotherapy of rapidly progressive and unexpected pneumonia, which was thought to be an opportunistic infection secondary to Cushing's syndrome. Our case suggests that a thorough endocrinologic investigation is important in patients with an adrenal mass and clinicians should be aware that patients with adrenocortical carcinoma and Cushing's syndrome are susceptible to infections and need to be observed carefully for the possible development of unrecognized opportunistic infections.

BACKGROUND/AIMS We investigated the clinical characteristics and prognosis of elderly patients with acute lymphoblastic leukemia (ALL). METHODS We reviewed the clinical data, laboratory findings, bone marrow findings, and cytogenetic analysis of elderly patients (≥ 60 years) with ALL, and data of an additional 101 younger adult patients (< 60 years) with ALL were reviewed for comparison. RESULTS Twenty-six elderly patients (≥ 60 years) and 101 younger adult patients (< 60 years) with ALL were retrospectively enrolled. The median follow-up duration was 6.0 months (range, 0.4 to 113.2) in the elderly patients and 21.7 months (range, 1.0 to 122.7) in the adult patients. In total, 34.6% (9 patients) of the elderly patients and 24.8% (25 patients) of the adult patients had Philadelphia chromosome positive ALL. The overall complete remission (CR) rate was much higher in the younger than in the elderly patients (94.1% vs. 57.7%, p < 0.001). The median overall survival (OS) of the younger patients (< 60 years) was 26.3 months, whereas that of the elderly patients (≥ 60 years) was 10.3 months (p = 0.003). In the elderly patients with ALL, T cell lineage and the presence of lymphadenopathy were significant prognostic factors for OS in a univariate analysis (p = 0.033 and 0.041, respectively). CONCLUSIONS The outcomes of Korean elderly patients with ALL were poor, and the shorter OS was mainly due to the low CR rate. T-cell lineage and the presence of lymphadenopathy were significant prognostic factors in Korean elderly patients with ALL.

Background: There is increasing interest in the influence of body composition on oncologic outcomes. Using computed tomography (CT) scan, we evaluated the role of skeletal muscle and fat among patients with gastric cancer (GC) who underwent gastrectomy with or without adjuvant chemotherapy, as well as those changes' associations with survival outcomes. Methods: The present study evaluated 136 patients with GC who were enrolled in the CLASSIC trial at Yonsei Cancer Center. Baseline body compositions including skeletal muscle area, Hounsfield units (HU), visceral fat area, and subcutaneous fat area were measured by preoperative CT scan. The L3 region contains the psoas, paraspinal muscles, and abdominal muscles, which were quantified using the pre-established HU thresholds for skeletal muscle tissue (HU: -30~150). Visceral fat and subcutaneous fat areas (HU:-150~-30) were measured using axial slices at the level of the lumbar vertebra (L3). CT before and after the gastrectomy was used to determine the 6-month relative changes in body composition parameters. Continuous variables were dichotomized according to the best cut-off values by Contal and O'Quigley method. Results: Seventy-three patients (53.7%) underwent surgery alone, and 63 patients (46.3%) underwent surgery followed by adjuvant chemotherapy. The median baseline values were 46.8 cm2/m2 for SMI, 47.5 HU, 33.9 cm2/m2 for VFI, and 34.6 cm2/m2 for SFI. The baseline body composition parameters were not associated with disease-free survival (DFS) or overall survival (OS). However, patients with marked loss of skeletal muscle mass ( Conclusion: Marked loss in body composition parameters significantly predicted shorter DFS and OS among patients with GC who underwent gastrectomy. Postoperative nutrition and active health care interventions could improve the prognosis of these GC patients. CT data are readily obtainable during routine clinical practice, which makes this approach useful for identifying prognostic biomarkers. Citation Format: Si Won Lee, Hyung Soon Park, Seung Hoon Beom, Sun Young Rha, Woo Jin Hyung, Song-Ee Baek, Minkyu Jung. CT scan reveals that marked loss of muscle, visceral fat or subcutaneous fat after gastrectomy was a poor prognostic marker in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 661.

3528Background: Whether patients with resectable colorectal cancer liver metastases (CRLM) gain a survival benefit or not from neoadjuvant chemotherapy remains controversial. The addition of bevaci...

The survival benefit of adjuvant chemotherapy after colorectal cancer (CRC) lung metastasectomy is uncertain. We enrolled 221 CRC patients who underwent pulmonary metastasectomy between October 2002 and July 2013, including those with previous liver metastasis that had been curatively resected. Disease-free survival (DFS) and overall survival (OS) were calculated from the day of lung metastasectomy. Among all patients, 176 (79.6 %) received adjuvant chemotherapy after lung metastasectomy. Median follow-up was 34.7 months from the time of lung metastasectomy [95 % confidence interval (95 % CI), 7.4–90.9 months]. Patients treated with adjuvant chemotherapy had longer DFS compared with surgery alone (median 32.7 vs 11.2 months respectively, P = 0.076). Multivariate analysis revealed previous liver metastasis, preoperative carcinoembryonic antigen ≥5 ng/mL, disease-free interval

Introduction: For recurrent and metastatic gastric cancer, systemic chemotherapy is used for palliative purposes, and a paclitaxel- or irinotecan-based regimen is typically used in the second-line setting. Recent advances in research including the TCGA project now enable gastric cancer to be divided into four molecular subgroups, yet whether there are differences in chemotherapy response for each molecular subgroup remain largely unknown. Our aim in this study is to retrospectively compare the efficacy of paclitaxel as second-line chemotherapy according to molecular subtype and to evaluate prognostic value for these markers. Method: A total of 235 metastatic gastric cancer (mGC) patients who have been treated with second-line paclitaxel-containing regimen (paclitaxel monotherapy, FL/paclitaxel) between 2005-2017 were assessed. Archived formalin-fixed, paraffin-embedded tissue blocks obtained before the start of paclitaxel treatment were examined for EGFR, HER2, and PTEN status using immunohistochemistry (IHC). HER2 positivity was defined as either IHC 3+ or 2+ with amplification confirmed by FISH/SISH, and EGFR positivity was defined as IHC 3+. PTEN loss was defined as having complete loss of PTEN expression. MSI-H and EBV-positive group was excluded in this study. Treatment response was based on CT images taken every 2 to 3 cycles of chemotherapy and evaluated according to the RECIST criteria. Overall survival (OS) and progression-free survival (PFS) were calculated based on the starting point of second-line chemotherapy until death or disease progression, respectively. Those negative for all three markers (HER2, EGFR, PTEN loss) were categorized as genome stable (GS)-like molecular group. Result: Patients were classified into subgroups based on HER2, EGFR, and PTEN expression; 19.6% (46/235) were HER2 positive, 15.0% (26/173) were EGFR positive, and PTEN loss was observed in 11.6% (20/173). Expression status for the three markers showed tendency towards mutual exclusivity. When coexpression rates were taken into account, 35.3% (61/173) showed positivity in at least one of the markers, and 64.7% (112/173) were negative for all three. This latter group, categorized as GS-like molecular group, showed a tendency towards poor overall survival compared with patients positive for at least one molecular marker, with median survival of 5.7 vs 8.8 months (P=0.012). There were no significant differences in OS or PFS in terms of HER2 and EGFR status. However, patients with PTEN loss had significantly longer overall survival than those with intact PTEN expression, with median survival time of 12.0 months (95% confidence interval [CI], 7.0 - 21.2) and 6.2 months (95% CI, 4.7-7.2), respectively (P=0.003). Conclusion: In mGC patients treated with second-line paclitaxel chemotherapy, HER2 and EGFR status had no predictive or prognostic value. Contrary to the general association of PTEN loss with poor prognosis in many solid cancers including gastric cancer, PTEN loss group showed better survival outcome for second-line paclitaxel treatment in our study. Indirect association of PTEN with other pathways of multidrug resistance or cell cycle-related molecules that ultimately affect the PI3K/Akt pathway may play a role. Further investigation is needed for specific mechanisms and factors that lead to increased paclitaxel sensitivity in the PTEN loss group. Citation Format: Kyoo Hyun Kim, Jeong Hyun Jo, Sejung Park, Minkyu Jung, Woo Sun Kwon, Jee Hung Kim, Hyo Song Kim, Seung-Hoon Beom, Hyun Cheol Chung, Sun Young Rha. Prognostic value of PTEN loss for second-line paclitaxel treatment efficacy in metastatic gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B138.

e15678 Background: Patients with advanced hepatocellular carcinoma (HCC) have a particularly poor prognosis of the median overall survival of less than 12 months. Even though sorafenib has been approved for treating advanced stage HCC, the unsatisfactory objective response rate still remain unresolved. In the current study, we aimed to evaluate the efficacy and safety of localized concurrent chemoradiotherapy (CCRT) followed by sequential sorafenib treatment for advanced hepatocellular carcinoma. Methods: This study is an ongoing, phase II trial. Patients with advanced HCC not amenable for curative treatments were eligible. In the course of radiotherapy for 5 weeks, hepatic arterial infusion of 5-fluorouracil (500mg/day) via implanted port was applied during the first 5 days and the last 5 days of radiotherapy. Four weeks after localized CCRT, sorafenib (400mg bid) was maintained. The primary endpoint was overall survival. Results: A total of 47 patients were enrolled. After the completion of localized CCRT, the objective response rate was 31.9%. During the overall treatment course, the objective response rate was 46.8% respectively. Overall, 7 patients (14.9%) underwent curative resection or transplantation after down-staging. The median overall survival was 18.4 months and the progression-free survival was 6.8 months. Adverse events were predictable and manageable with conservative care. Conclusions: Localized CCRT followed by sequential sorafenib treatment in patients with advanced HCC showed significant activity and good tolerability. Furthermore, such a treatment modality, when compared to the use of sorafenib alone, might provide the additional therapeutic benefit through initial tumor reduction, allowing curative treatment after down-staging in 14.9% of patients, Further randomized trial should be required to make the more robust evidence. Clinical trial information: NCT02425605.

755 Background: Oxaliplatin-based chemotherapy is commonly used chemotherapy in the adjuvant setting for colorectal cancer patients. In clinical practice, those patients may be retreated with oxaliplatin after relapse. The efficacy and predictive factor of oxaliplatin re-treatment are little known. Methods: We carried out a retrospective study of 53 consecutive patients who underwent surgery and adjuvant FOLFOX chemotherapy and who were re-treated oxaliplatin-based chemotherapy after relapse at Yonsei Cancer Center from April 2009 through October 2015. The main end-point was progression-free survival (PFS). Results: Among enrolled patients, 33 (62.2%) received curative resection in initially non-metastatic setting and the other 20 (37.7%) did R0 resection including metastasectomy in stage 4 at the time of previous oxaliplatin treatment. Median time from last cycle of adjuvant FOLFOX to the first cycle of palliative oxaliplatin based chemotherapy was 31.5 months. Palliative oxaliplatin was given as second and third or later in 37 (69.8%) and 16 (30.2%) patients respectively. Median PFS and overall survival (OS) were 5.1 and 17.5 months. Response rate and disease control rate to palliative oxaliplatin based treatment were 17.0 % and 66.0%. Patients with both shorter interval from first oxaliplatin exposure to recurrence (

e15536Background: We conducted an exploratory study to identify potential biomarkers to predict therapeutic effect of ramucirumab in combination with paclitaxel as a second line treatment for recur...

4063Background: Despite a large number of randomized trials, there is no global consensus as to the standard regimen for front-line chemotherapy of recurrent/metastatic gastric cancer. We conducted...

501 Background: Although colorectal cancer (CRC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CRC, patterns of recurrence has not been precisely investigated. We aim to explore patterns of recurrence and prognosis of CRC with MSI-H (high-frequency MSI) in comparison to MSI-L (low-frequency of MSI)/MSS. Methods: Patients with stage I-III colorectal cancer who received complete surgical resection were included using retrospective cohort of Yonsei Cancer Center. Patients were categorized to MSI status (MSI-H vs. MSS-L/MSS). Patterns of recurrence, disease free survival (DFS) and overall survival (time from diagnosis to death as OS1 and time from recurrence to death as OS2) between two groups were compared. Results: A total of 2944 patients were evaluated. Of all, 263 patients (8.9%) has MSI-H tumor. Patients with MSI-L/MSS tumor experienced more systemic recurrence events than patients with MSI-H tumor (13.1% vs. 4.6%). In patients who experienced recurrence, MSI-H tumor has tendency toward young age, proximal location and poorly differentiated histology. MSI-H tumor is more likely to recur as peritoneal metastasis (33.3% vs. 8.0%, p-value 0.002) and lymph node metastasis (25.0% vs. 7.7%, p-value 0.033). In contrast, MSI-L/MSS tumor is more likely to recur as lung metastasis (37.1% vs. 0.0%, p-value 0,008). There was no difference in DFS [hazard ratio (HR) = 0.753, p-value 0.241] and OS1 [HR = 1.486, p-value 0.203]. However, OS2 was marginally inferior in MSI-H tumor [HR = 1.779, p-value 0.064]. Conclusions: Patterns of recurrence in MSI-H CRC is different from that of MSI-L/MSS and modification of surveillance strategy in MSI-H CRC should be considered. In addition, prognosis of recurred MSI-H CRC is not superior than MSI-L/MSS and prognostic value of MSI in this circumstance should be evaluated using larger sample size.

760 Background: Clinical benefit of adjuvant chemotherapy (AC) is still controversial in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation therapy (CRT) followed by total mesorectal excision (TME). We aim to explore the role of adjuvant chemotherapy with fluoropyrimidine for ypT0-3N0 patients. Methods: Patients with ypT0-3N0 rectal cancer after neoadjuvant CRT and TME were included using retrospective cohort of Yonsei Cancer Center. Patients were categorized according to receipt of adjuvant chemotherapy (AC vs. no AC). Disease free survival (DFS) and overall survival (OS) between treatment groups were compared using all patients’ cohort (APC) and propensity score-matched patients’ cohort (PSMPC). Results: total of 339 patients were evaluated. Of all, 87 patients (25.7%) did not receive AC. There was no difference in DFS between two groups [hazard ratio (HR) = 1.079, p-value = 0.782 in APC; HR = 1.22, p-value in PSMPC]. Also there was no difference in OS between two groups (HR = 1.140, p-value 0.717 in APC; HR = 1.366, p-value 0.472 in PSMPC). Advanced T stage and positive resection margin were associated with inferior DFS and OS by multivariate analysis. In subgroup analysis by baseline characteristics, we could not find any group with benefit of adjuvant chemotherapy. Conclusions: AC did not improve DFS and OS of patients with ypT0-3N0 rectal cancer after neoadjuvant CRT followed by TME. The role of AC in LARC with ypT0-3N0 after preoperative CRT should be evaluated in prospective randomized trials with larger sample size.

Background Growth modulation index (GMI) and tumor growth rate (TGR) have been proposed as signs of activity in early phase clinical trials. We explored utility of the efficacy end points in metastatic gastric cancer. Patients and Methods We carried out a retrospective study in metastatic gastric cancer patients receiving weekly paclitaxel regimen as second or more line treatment between 2005 and 2013 in Yonsei Cancer Center, and evaluate the association of GMI and TGR with efficacy outcomes respectively. The growth modulation index (GMI) was defined the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn−1 with the n-1th line. TGR was computed during the pretreatment period (reference) and the experimental period. Comparisons used chi-squared and log-rank tests. Results A total of 133 patients were enrolled in this study. The median TTPn was 2.7 months, whereas the median TTPn−1 was 5.3 months. Thirty-one patients experienced GMI > 1.2 (23.3%). Median OS was highly correlated with GMI: 6.3 and 7.5 months with GMI ≤ 1.2 and GMI > 1.2 (P = 0.0009). TGR could be evaluated in 52 patients. Among them, 37 patients (71.1%) exhibited a decrease in TGR. The decrease of TGFR was associated with PFS (P = 0.043) and OS (P = 0.045). Conclusions GMI and TGR seem to be interesting end points that provides additional information compared with classical criteria. GMI >1.2 and decrease of TGR are associated with significant OS improvement. Citation Format: Seung-Hoon Beom, Minkyu Jung, Hyo Song Kim, Joong Bae Ahn, Sun Young Rha, Hyun Cheol Chung. Utility of growth modulation index and tumor growth rate to evaluate efficacy in metastatic gastric cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C143.

e14593 Background: The role of metastasectomy for treatment of lung metastasis from colorectal cancer (CRC) is widely accepted. However, the clinical use of adjuvant chemotherapy after lung metasta...