K-W Lee

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer.

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m−2 at week 1 and 250 mg m−2 weekly thereafter until disease progression. Oxaliplatin (100 mg m−2) and leucovorin (100 mg m−2) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m−2) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1–65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5–6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-α levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.

Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis

BACKGROUND Many patients with refractory or relapsed gastric cancer after first-line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care. PATIENTS AND METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980-2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013. RESULTS The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52-0.79, P < 0.0001] was observed with salvage chemotherapy. When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40-0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56-0.90, P = 0.004) for docetaxel. CONCLUSION This meta-analysis demonstrated evidence to support second-line chemotherapy in advanced gastric cancer.

The incidence, risk factors and prognostic implications of venous thromboembolism in patients with gastric cancer

Summary.  Background: Data on venous thromboembolism (VTE) in gastric cancer (GC) are very scarce. Objective: To investigate the incidence, risk factors and prognostic implications of VTE in Asian GC patients. Methods: Prospective databases containing clinical information on GC patients (n = 2,085) were used. Results: The 2‐year cumulative incidences of all VTE events were 0.5%, 3.5% and 24.4% in stages I, II–IV(M0) and IV(M1), respectively. Advanced stage, older age and no major surgery were independent risk factors for developing VTE. When the VTE cases were classified into extremity venous thrombosis (EVT), pulmonary thromboembolism (PTE) or intra‐abdominal venous thrombosis (IVT), IVTs (62%) were more common than EVTs (21%) or PTEs (17%). Although peri‐operative pharmacologic thromboprophylaxis was not routinely administered, the VTE incidence after major surgery was only 0.2%. During chemotherapy, EVT/PTE developed more frequently than IVT (54% vs. 19%); however, during untreated or treatment‐refractory periods, IVT developed more frequently than EVT/PTE (69% vs. 36%). In multivariate models, the development of EVT/PTE was a significant predictor of early death when compared with no occurrence of VTE (P < 0.05). However, IVT did not affect survival. Conclusion: This is the largest study that specially focused on VTE in GC and the VTE incidence in Asian GC patients was first demonstrated. Considering the low incidence of post‐operative VTE development, the necessity of peri‐operative pharmacologic thromboprophylaxis should be evaluated separately in Asian patients. The clinical situation of the development of EVT/PTE and IVT differed. Only EVT/PTE had an adverse effect on survival and IVT had no prognostic significance.

Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma

BACKGROUND We evaluated the efficacy and toxicity of combination chemotherapy with capecitabine and cisplatin (XP) in patients with metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS From September 2003 to July 2007, we enrolled patients with HCC who had more than one measurable extrahepatic metastatic lesion. Patients received oral capecitabine (2000 mg/m(2)/day) with a schedule of 2 weeks on and 1 week off and cisplatin (60 mg/m(2)) on the first day of the 3-week cycle. RESULTS The study cohort consisted of 32 patients with a median age of 53 years. Overall response rate was 6.3% and disease control rate was 34.4%. The median time to progression (TTP) was 2.0 months [95% confidence interval (CI) 1.5-2.4] and the median overall survival (OS) time was 12.2 months (95% CI 6.5-17.8). The grade 3/4 hematologic toxic effects included thrombocytopenia (7.6%), neutropenia (4.3%) and anemia (2.1%). The grade 3/4 non-hematologic toxic effects included elevated hepatic aminotransferase (12.9%), jaundice (3.2%), mucositis (3.2%) and nausea (3.2%). There was no treatment-related mortality. CONCLUSIONS Based on the observed response rate and TTP, XP combination chemotherapy showed modest antitumor efficacy in patients with metastatic HCC as systemic first-line treatment. However, XP combination chemotherapy showed tolerable toxicity and demonstrated favorable OS time.

Lacrimal drainage obstruction in gastric cancer patients receiving S-1 chemotherapy

BACKGROUND This study was conducted to determine the incidence and clinical characteristics of lacrimal drainage obstruction (LDO) in patients receiving S-1 chemotherapy. PATIENTS AND METHODS Consecutive 170 patients with gastric cancer who underwent curative surgery and received adjuvant S-1 chemotherapy were enrolled. S-1 was administered orally (40 mg/m2 b.i.d. on days 1-28 every 6 weeks) for 1 year. Ophthalmologic examinations were carried out on patients complaining of epiphora. RESULTS Thirty-one patients (18%) developed epiphora. Among 31 patients, 25 underwent ophthalmologic examinations and 22 (88%) were diagnosed with LDO. The median time to the onset of LDO was 2.9 months. The most common site of obstruction was the nasolacrimal duct [86% (19/22)]; punctal [23% (5/22)] and canalicular obstruction [14% (3/22)] were also noted. In multivariate analysis, total gastrectomy [versus partial gastrectomy: hazard ratio (HR), 2.9; P=0.014] and creatinine clearance<50 ml/min (versus ≥50 ml/min: HR, 2.9; P=0.038) were independent risk factors for the development of LDO. CONCLUSION Considering the high incidence of LDO in patients receiving S-1 chemotherapy, oncologists should be alert to epiphora and cooperate with ophthalmologists in the early stages to improve the quality of life of patients and avoid more complicated ophthalmologic procedures.

Adjuvant capecitabine chemotherapy using a tailored-dose strategy in elderly patients with colon cancer

BACKGROUND This study was conducted to analyze the feasibility of adjuvant capecitabine therapy using a tailored-dose escalation strategy in elderly patients with colon cancer (CC). METHODS CC patients (≥ 70 years of age) who received adjuvant capecitabine were enrolled. The starting dosage of capecitabine was 2000 mg/m(2)/day (days 1-14, every 3 weeks). On the second cycle, the dosage was escalated to 2500 mg/m(2)/day if the patient tolerated the first cycle. Dose intensity (DI), toxicity, and the change in quality of life (QoL) were evaluated. RESULTS Of 82 patients enrolled, 67 completed eight cycles. Dose escalation to 2500 mg/m(2)/day was possible in 56 patients, and this dosage was maintained in 24 patients until the completion of chemotherapy (eight cycles). Forty-one patients completed therapy with a DI ≥ 1333 mg/m(2)/day [relative dose intensity (RDI) ≥ 80%]. Toxic effects were tolerable and the QoL was not compromised during treatment. Creatinine clearance < 50 ml/min and Charlson-Age comorbidity index ≥ 8 were related to a reduced capecitabine dosage (RDI < 80%). CONCLUSIONS A tailored-dose escalation strategy was feasible in elderly CC patients receiving adjuvant capecitabine chemotherapy. Decreased renal function and an increased number of comorbidities were independently predictive of reduced administration of the capecitabine dose.

Phase III, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

Abstract Background There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients and methods Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician’s choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9–1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4–2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Conclusions Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. Trial registration ClinicalTrials.gov: NCT02625623.

P3-16-06: Phase II Trial of TS-1 in Combination with Oxaliplatin (SOX) in Patients with Metastatic Breast Cancer (MBC) Previously Treated with Anthracycline and Taxane Chemotherapy [TORCH] [Korean Cancer Study Group (KCSG) BR07-03].

Background Oxaliplatin, a platinum analogue, is an active drug in advanced anthracycline and taxane-pretreated breast cancer patients as a single agent and with 5-fluorouracil (5-FU) combination. TS-1 was developed by the scientific theory of both potentiating antitumor activity of 5-FU and reducing gastrointestinal toxicity. This trial was performed to evaluate the efficacy and safety of TS-1 in combination with oxaliplatin in metastatic breast cancer (MBC) patients previously treated with anthracycline and taxane chemotherapy. Methods: Between October 2007 and October 2009, MBC patients were enrolled in this prospective multicenter trial. Eligible criteria included age ≥18 years, at least one measurable lesion, prior treatment with anthracycline and taxane chemotherapy, and ECOG Performance Status 0–2. TS-1 40 mg/m2 b.i.d. on days 1–14 with oxaliplatin 130 mg/m2 on day 1 were administered every 3 weeks till disease progression. Primary end-point was response rate, and secondary end-points were time-to-progression (TTP), overall survival (OS), duration of response (DOR) and toxicities. Response was evaluated every 6 weeks according to the RECIST criteria v. 1.0 and toxicity was assessed with NCICTCAE v.3.0.(ClinicalTrials.gov identifier NCT00527930). Results: A total of 87 patients were enrolled. Median age was 48 years (range 30–71 years). Nineteen patients (21.8%) had de novo stage IV and 68 patients (78.2%) had recurrent disease. Thirty-five patients (40.2%) received two-lines of prior chemotherapy in palliative setting. Forty-eight patients (55.2%) had ≥ 3 disease sites. Fifty-four patients (62.1%) were hormone receptor positive, and 25 patients (28.7%) were triple negative. Five patients received prior anti-HER2 therapy. A total of 525 cycles were administered (median 6 cycles, range: 1 ∼ 22+ cycle). In per-protocol analysis, overall response rate was 38.5% (95% CI: 27.7−49.3) (CR 0%, PR 38.5%) and disease control rate (CR, PR, and SD) was 67.9% (95% CI: 57.5−78.3). Median TTP, OS, and DOR were 6.0 months (95% CI: 5.1−6.9 months), 19.4 months (95% CI: not estimated), 6.6 months (95% CI: 3.7−9.6 months), respectively. RR was not different by triple negativity (39.1% in TNBC vs. 38.2% in non-TNBC, P=0.361). TTP was not different according to the number of prior chemotherapy regimens. Reported grade 3 or 4 toxicities (per cycle) were neutropenia (10.3%), thrombocytopenia (5.5%), diarrhea (1.9%), vomiting (1.9%), and stomatitis (0.2%). There was no treatment-related death. Conclusions: SOX is an effective regimen in anthracycline and taxane pretreated MBC patients with manageable toxicities. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-06.

P4-11-20: Observational Study of Body Weight Changes and Metabolic Syndrome in Breast Cancer Patients Receiving Adjuvant Therapy: Characteristics of Dietary Pattern in Korean Breast Cancer Patients.

Backgroud : Obesity, postdiagnosis weight gain, and presence of metabolic syndrome in breast cancer are reported to adversely affect survival among breast cancer survivors. Most of the studies on weight gain and metabolic syndrome in breast cancer are from Western countries and few information is available on Asian population. We designed this prospective observational study to characterize weight and metabolic changes during adjuvant treatment in women with early breast cancer and to identify factors associated with occurrence of metabolic syndrome, focusing on dietary pattern. Methods : Patients aged 18–75 who underwent curative surgery with stage I-III invasive breast cancer were enrolled from 2008 to 2010. We measured glucose (FBS), hemoglobin A1c (HbA1c), total cholesterol (TC), HDL cholesterol, and triglyceride (TG) level in fasting serum samples before starting adjuvant therapy, at 6 months and 12 months after enrollment. Body weight, body mass index (BMI), body fat mass, and percent body fat at baseline, 6 months, and 12 months were also measured. Dietary intake was assessed using valid semi-quantitative Food frequency questionnaire (FFQ). Results : Total of 63 patients were enrolled. Median age of the enrolled patients were 48 (range, 25–68), with premenopausal/postmenopausal 40 (63.5%)/ 23 (36.5%). Fifty (82.0%) and 10 (16.4%) received adjuvant chemotherapy followed by hormone therapy and hormone therapy alone. Hormone receptor positive (ER+/PR+) and HER2 positive cancer accounted for 52 (83.9%) and 7 (12.1%). Mean FBS, HbA1c, TC, HDL, and TG level was 99.9 mg/dL (range, 83–159), 5.59 mg/dL (range, 4.8−7.5), 197.4 mg/dL (125-298), 51.9 mg/dL (range, 30–90), and 119.7 mg/dL (42-371). Mean height, weight, and BMI was 158 cm (range, 149–169), 61.7kg (range, 46.2−96.0), and 24.7 kg/m 2 (range, 18.7−35.7), respectively. According to the WHO and NTH guidelines for Asian, normal (BMI 18.5−22.9), overweight (BMI 23–24.9), and obesity (BMI≥25) was 18 (28.6%), 13 (20.6%), and 32 (50.8%), respectively. Number of patients with metabolic syndrome was 18 (34%). Mean BMI (26.1 vs 24.0, p=0.021) and TG (180.6 vs 92.0, p 6.0) (p=0.071). The TG level of patients who indigested high carbohydrate was significantly higher (143.8 vs 102.9, p=0.023). The HDL level of patients who took high fat diet (>20% of total calorie) was lower (45.3 vs 53.5, p=0.045). Conclusion : In our cohort of Korean breast cancer patients, 34% had metabolic syndrome at baseline. Those patients with metabolic syndrome consumed higher proportion of carbohydrate, which resulted in significantly higher level of TG. Our data suggest that composition of calorie intake is different in Asian population compared to Western countries, warranting for reappraisal on the recommendation on life style modification and diet. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-20.