Patterns of Relapse after Definitive Chemoradiotherapy in Stage II/III (Non-T4) Esophageal Squamous Cell Carcinoma.

PURPOSE: The purpose of this study was to investigate the utility of surveillance after definitive chemoradiotherapy (dCRT) in patients with squamous cell carcinoma. METHODS: Patients who underwent dCRT for stage II/III (excluding T4) esophageal squamous cell carcinoma were analyzed. First failures following complete response were classified into luminal relapse (LR), regional relapse (RR), distant metastasis (DM), new cancer diagnosed by esophagogastroduodenoscopy (NC-E), and new cancer other than NC-E (NC-O). We focused on LR, RR, and NC-E, and analyzed their frequency, timings and survival outcomes after local treatments. RESULTS: Among 302 patients treated with dCRT, 204 achieved complete response. The number of patients who recurred with LR, RR, DM, NC-E, and NC-O were 28 (14% of 204), 13 (6%), 39 (19%), 34 (17%), and 16 (8%). Ninety-three percent of LRs were diagnosed within 3 years after dCRT, and all RRs were diagnosed within 2 years. Annual odds of NC-E did not decrease over time. Twenty-three patients with LR, 6 with RR, and 32 with NC-E underwent local treatment, and their median overall survivals were 49.2, 19.5, and 108.9 months. CONCLUSION: Surveillance with esophagogastroduodenoscopy may be important in the first 3 years after dCRT to detect LR and to detect NC-E beyond 3 years.

A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer.

Currently, no prospective data exists to support a "stop-and-go" modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n = 1; partial response, n = 23; stable disease, n = 21; progression, n = 1; and not evaluated, n = 4. Median time to treatment failure was 7.7 months (80% CI: 6.2-8.0), and median progression-free survival was 12.8 months (80% CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients.

Sequential chemotherapy with methotrexate and 5-fluorouracil for chemotherapy-naive advanced gastric cancer with disseminated intravascular coagulation at initial diagnosis.

PURPOSE: Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis before treatment with no current standard chemotherapy (CTx) regimen. However the prognosis is extremely poor without CTx. We investigated the effectiveness of sequential CTx with methotrexate and 5-fluorouracil (MF) in chemotherapy-naive AGC patients with DIC. METHODS: We retrospectively examined AGC patients who received first-line CTx and selected those who were diagnosed with DIC before starting CTx to investigate clinical characteristics and responses. RESULTS: From July 1999 to January 2007, 1,365 patients with unresectable or recurrent AGC received first-line CTx at the National Cancer Center Hospital in Tokyo, Japan. DIC was diagnosed in 22 (1.6%) patients (16 men and 6 women; median age, 56 years) and the performance status of all the patients was 1/2/3 = 9/10/3. Nineteen patients (86%) had histologically diffuse-type adenocarcinoma and 18 (82%) had bone metastasis. Patients received sequential MF every week until progressive disease was confirmed, with DIC improving in 17 (77%) patients. The median time-to-treatment failure for AGC and overall survival were 98 days [95% confidence interval (CI), range 50-146 days] and 154 days (95% CI, range 126-180 days), respectively. Grade 3 or greater toxicities consisted of neutropenia (4 patients, 18%), anemia (9 patients, 40%), thrombocytopenia (4 patients, 18%), and bilirubinemia (1 patient, 5%). CONCLUSIONS: MF was an effective and well-tolerated regimen for improving DIC in chemotherapy-naive AGC patients with DIC; however, the prognosis of the patients remained poor even with improved DIC parameters.

A phase i study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel (FLTAX) as first-line therapy for advanced gastric cancer.

OBJECTIVE: To determine the dose-limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of combination chemotherapy with leucovorin-modulated weekly bolus 5-fluorouracil (5-FU) and weekly paclitaxel in patients with advanced gastric cancer (GC). METHODS: Chemotherapy-naive patients with histologically proven metastatic or recurrent GC were enrolled. Paclitaxel was administered as a 1-h intravenous (i.v.) infusion followed by 5-FU as a bolus i.v. infusion on Days 1, 8 and 15. A 2-h i.v. infusion of l-leucovorin was started at the same time as the paclitaxel infusion on Days 1, 8 and 15. Treatment cycles were repeated every 28 days until disease progression or unacceptable toxicity occurred. Patients were scheduled to receive 5-FU, l-leucovorin and paclitaxel at four dose levels (mg/m(2)/week): 500/250/60 (level 1), 500/250/80 (level 2), 600/250/80 (level 3) and 600/250/100 (level 4), respectively. RESULTS: Eighteen patients were enrolled. During the first cycle of the highest dose level (level 4), two of the six patients had DLT involving Grade 3 diarrhea and Grade 3 skin rash. Furthermore, three of the four patients who received the second consecutive cycle of treatment at dose level 4 had Grade 4 neutropenia. Dose level 3 was thus determined to be the MTD. Eleven (61%) of the 18 patients had partial responses, and the median progression-free survival time was 6.8 months. CONCLUSIONS: The MTD and the recommended dose for phase II studies of this regimen were determined to be 5-FU 600 mg/m(2)/week, l-leucovorin 250 mg/m(2)/week and paclitaxel 80 mg/m(2)/week.

Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer.

PURPOSE: Expression levels of insulin-like growth factor type 1 receptor (IGF-IR), epidermal growth factor receptor (EGFR), and HER2 expressions have been linked to clinical outcomes in several solid tumors. However, the clinical significance of these biomarkers in gastric cancer (GC) remains unclear. This study was designed to delineate the clinical implications of these three biomarkers in GC. EXPERIMENTAL DESIGN: The study group comprised 87 patients who underwent gastrectomy at National Cancer Center Hospital and subsequently received chemotherapy for recurrent or residual tumors. Using immunohistochemical techniques, we analyzed the expressions of IGF-IR, EGFR, and HER2 on formalin-fixed paraffin-embedded specimens of surgically removed primary tumors. RESULTS: IGF-IR expression (defined as >10% membranous staining) was found in 67 tumors (77%), EGFR expression in 55 (63%), and HER2 expression in 16 (18%). Positive coexpression of IGF-IR and EGFR was found in 48 tumors (55%), that of IGF-IR and HER2 in 16 (18%), and that of EGFR and HER2 in 13 (15%). Multivariate survival analysis showed that IGF-IR-positive expression [hazard ratio (HR) 2.14, 95% confidence interval (95% CI) 1.20-3.82; P = 0.01], performance status 1 or 2 (HR 1.83, 95% CI 1.15-2.91; P = 0.01), and diffuse type tumors (HR 1.71; 95% CI 1.08-2.70; P = 0.02) were significant predictors of poor survival. CONCLUSIONS: IGF-IR expression in surgical GC specimens, poor performance status, and diffuse type tumors are significant predictors of poor outcomes in patients with GC. Our data suggest that anti-IGF-IR strategies may prove valuable in such patients.