Atsuo Takashima

Randomized phase II study of gemcitabine plus S‐1 versus S‐1 in advanced biliary tract cancer: A Japan Clinical Oncology Group trial (JCOG 0805)

The oral fluoropyrimidine, S‐1, combined with or without gemcitabine is considered to be a promising agent for treating advanced biliary tract cancer; gemcitabine plus cisplatin is the current standard regimen. This randomized phase II trial was designed to evaluate the safety and efficacy of two regimens: gemcitabine plus S‐1 (GS) (gemcitabine: 1000 mg/m2, day 1 and day 8; S‐1: 60 mg/m2, twice daily on days 1–14, repeated every 3 weeks); and S‐1 (80 mg/m2, days 1–28, given orally twice daily for 4 weeks, followed by a 2‐week rest, repeated every 6 weeks). The regimen with a higher 1‐year survival would be selected for a subsequent phase III trial. Between February 2009 and April 2010, 101 patients were randomized. For the GS (n = 51) and S‐1 (n = 50) arms, the 1‐year survival was 52.9% (95% confidence interval, 38.5–65.5) and 40.0% (95% confidence interval, 26.5–53.1), and the median survival times were 12.5 and 9.0 months, respectively. Grade 3/4 hematological toxicities were more frequent in the GS arm (leucocytes 29.4%, neutrophils 60.8%, hemoglobin 11.8%, platelets 11.8%) than in the S‐1 arm (leucocytes 2.0%, neutrophils 4.0%, hemoglobin 4.0%, platelets 4.0%). Although two treatment‐related deaths occurred in the GS arm, all other grade 3/4 non‐hematological toxicities were reversible. In conclusion, GS was considered to be more promising and was selected as the test regimen for a subsequent phase III trial comparing GS with gemcitabine plus cisplatin combination therapy. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001685 (http://www.umin.ac.jp/ctr/index.htm).

Pharmacokinetic parameters from 3‐Tesla DCE‐MRI as surrogate biomarkers of antitumor effects of bevacizumab plus FOLFIRI in colorectal cancer with liver metastasis

Bevacizumab (BV) is an antivascular endothelial growth factor antibody. When administered with other chemotherapeutic drugs, BV‐combined regimens prolong survival of colorectal cancer patients. We conducted a phase II trial to confirm the pharmacokinetic parameters from 3‐Tesla dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as surrogate biomarkers of BV + FOLFIRI regimen efficacy in colorectal cancer with liver metastases. DCE‐MRI was performed before treatment, on the seventh day after first treatment and every 8 weeks thereafter using a 3‐Tesla MRI system. DCE‐MRI parameters‐area under the contrast concentration versus time curve at 90 and 180 s (AUC90 and AUC180, respectively) after contrast injection, and volume transfer constant of contrast agents (Ktrans and Kep) were calculated from liver metastases. Fifty‐eight liver metastases were analyzed. Univariate analysis revealed that a decrease in Ktrans ratios (ΔKtrans), Kep ratios (ΔKep), AUC90 ratios (ΔAUC90) and AUC180 ratios (ΔAUC180) correlated with higher response (all p < 0.0001) and longer time to progression (TTP) (ΔKtrans: p = 0.001; ΔKep: p = 0.004; ΔAUC90: p = 0.006; ΔAUC180: p < 0.0001). Multivariate analysis showed that ΔAUC180 was correlated with higher response (p = 0.009), and ΔKtrans and ΔAUC180 were correlated with longer TTP (ΔKtrans: p = 0.001; ΔAUC180: p = 0.024). ΔKtrans and ΔAUC180 are pharmacodynamic biomarkers of the blood perfusion of BV + FOLFIRI. Our data suggest that ΔKtrans and ΔKep can predict response to chemotherapy at 1 week. Changes in 3‐Tesla DCE‐MRI parameters confirmed the potential of these biomarkers of blood perfusion as surrogate predictors of response and TTP.

Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer

Background:Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies.Methods:Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing.Results:A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients.Conclusions:Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

Relationships of insulin-like growth factor-1 receptor and epidermal growth factor receptor expression to clinical outcomes in patients with colorectal cancer

Objectives: The present study evaluated the prognostic implications of insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2 in patients with colorectal cancer (CRC). Methods: Our subjects were 91 patients who underwent surgery and subsequently received fluoropyrimidines. Expressions of IGF-1R, EGFR and HER-2 in primary lesions were analyzed immunohistochemically to determine the prognostic significance of these biomarkers. Results: Overexpression was found for IGF-1R in 48 tumors (53%), EGFR in 57 (63%) and HER-2 in 2 (2%). Overexpression of IGF-1R was significantly correlated with shorter survival from the start of first-line chemotherapy (p = 0.033). Overexpression of EGFR was a significant predictor of clinical response to fluoropyrimidines (p = 0.032). Multivariate analysis of potential prognostic factors showed that IGF-1R expression and worsened performance status were independent predictors of poor outcomes. Conclusions: Our results suggest that anti-IGF-1R strategies may offer a useful approach in molecular therapy for CRC, which has the potential to improve outcomes.

Randomized Phase III Study of 5-Fluorouracil Continuous Infusion vs. Sequential Methotrexate and 5-Fluorouracil Therapy in Far Advanced Gastric Cancer with Peritoneal Metastasis (JCOG0106)

OBJECTIVE Owing to the risks of serious and sustained toxicity, anticancer drugs such as cisplatin and irinotecan cannot be readily administered to patients with gastric cancer and severe peritoneal metastasis. Therefore, a standard chemotherapy regimen has yet to be established for these types of patients. This randomized study investigated the utility of sequential methotrexate and 5-fluorouracil therapy vs. 5-fluorouracil continuous infusion for gastric cancer with peritoneal metastasis. METHODS Eligible patients had radiologically confirmed peritoneal metastasis with intestinal stenosis, peritoneal tumor or ascites. Treatment with 5-fluorouracil continuous infusion (800 mg/m(2)/day, ci, d1-5, q4w) or methotrexate and 5-fluorouracil therapy (methotrexate, 100 mg/m(2), bolus infusion, followed 3 h later by 5-fluorouracil, 600 mg/m(2), bolus infusion, with leucovorin rescue, q1w) was continued until disease progression or unacceptable toxicity. The projected sample size was 236, providing 80% power to detect a 40% increase in median overall survival in methotrexate and 5-fluorouracil therapy with a one-sided α of 0.05. RESULTS All 237 randomized patients were included in the primary analysis. The methotrexate and 5-fluorouracil therapy arm was not superior to the 5-fluorouracil continuous infusion arm (median survival time, 9.4 months in the 5-fluorouracil continuous infusion arm, 10.6 months in the methotrexate and 5-fluorouracil therapy arm; hazard ratio, 0.94; 95% confidence interval, 0.72-1.22; one-sided P = 0.31). Frequencies of Grade 3 or higher neutropenia, Grade 3 or higher anorexia and treatment-related deaths were 0.9, 27.4 and 1.7%, respectively, in the 5-fluorouracil continuous infusion arm, and 31.9, 33.6 and 0.9%, respectively, in the methotrexate and 5-fluorouracil therapy arm. CONCLUSIONS Methotrexate and 5-fluorouracil therapy is not suitable for use as standard therapy for advanced gastric cancer with peritoneal metastasis.

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912

BACKGROUND Since the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer. PATIENTS AND METHODS Endoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point. RESULTS Multivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status ≥ 1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites ≥ 2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1. CONCLUSION These correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer. CLINICAL TRIAL NUMBER C000000062, www.umin.ac.jp.

Impact of vascular endothelial growth factor receptor 1, 2, and 3 expression on the outcome of patients with gastric cancer

Tumor angiogenesis is a multistep interactive process in which vascular endothelial growth factor (VEGF) and its receptors have a major role. However, the clinical significance of these molecules in gastric cancer (GC) remains unclear. Our study group comprised 86 patients who underwent gastrectomy and subsequently received chemotherapy for recurrent or residual tumor. Using immunohistochemical techniques, we analyzed the expression of VEGF receptors (VEGF‐R) 1, 2, and 3. VEGF‐R1 expression (defined as >5% staining) was found in the tumor cells of 65 tumors (76%) and in the stromal vessels of 36 tumors (42%). VEGF‐R2 expression was found in tumor cells and stromal vessels of 0 and 46 tumors (0 and 53%), respectively, and VEGF‐R3 expression was found in tumor cells and stromal vessels of 0 and 75 tumors (0 and 87%), respectively. Univariate analysis revealed that VEGF‐R expression correlated with shorter survival (VEGF‐R1 in stromal vessels, P = 0.001; VEGF‐R2 in stromal vessels, P = 0.009; VEGF‐R3 in stromal vessels, P = 0.005) and lower response to S‐1 (VEGF‐R1 in stromal vessels, P = 0.039). Multivariate analysis of potential prognostic factors showed that VEGF‐R1 and VEGF‐R2 in stromal vessels were independent predictors of poor outcome. Our data suggest that VEGF‐R expression can be a predictor of unfavorable clinical outcome in GC. VEGF‐R are promising candidates as therapeutic targets. (Cancer Sci 2009; 100: 310–315)

A Phase II Clinical Trial of Endoscopic Submucosal Dissection for Early Gastric Cancer of Undifferentiated Type: Japan Clinical Oncology Group Study JCOG1009/1010

A Phase II clinical trial has been initiated to evaluate the efficacy and safety of endoscopic submucosal dissection for intramucosal (cT1a) gastric cancer of undifferentiated type. Patients with cT1a gastric cancer with undifferentiated-type adenocarcinoma are eligible for the study. The tumor size should be 2 cm or less without ulceration. The study will enroll a total of 325 patients from 51 institutions over a 4-year period. The primary endpoint is proportion of 5-year overall survival (% 5-year overall survival) in patients with undifferentiated dominant type. The secondary endpoints are overall survival, relapse-free survival, distant metastasis-free survival, % 5-year overall survival without either recurrence or gastrectomy, % en-bloc resection with endoscopic submucosal dissection, % pathological curative resection with endoscopic submucosal dissection, % 5-year overall survival in patients with differentiated dominant type, % 5-year overall survival in patients with pathologically curative resection with endoscopic submucosal dissection and adverse events.

Clinical tumor diameter and prognosis of patients with FIGO stage IB1 cervical cancer (JCOG0806-A)

OBJECTIVE In order to determine indications for less radical surgery such as modified radical hysterectomy, the risk of pathological parametrial involvement and prognosis of FIGO stage IB1 cervical cancer patients undergoing standard radical hysterectomy with pre-operatively assessed tumor diameter≤2 cm were investigated. METHODS We conducted a retrospective multi-institutional chart review of patients with FIGO stage IB1 cervical cancer who underwent primary surgical treatment between 1998 and 2002. The eligibility criteria for the analyses were (i) histologically-proven squamous cell carcinoma, adenocarcinoma or, adenosquamous cell carcinoma, (ii) radical hysterectomy performed, (iii) clinical tumor diameter data available by MR imaging or specimens by cone biopsy, and (iv) age between 20 and 70. Based on the clinical tumor diameter, patients were stratified into those with the following tumors: i) 2 cm or less (cT≤2 cm) and ii) greater than 2 cm (cT>2 cm). We expected 5-year OS of ≥95% and parametrial involvement<2-3% for patients with cT≤2 cm who underwent radical hysterectomy. RESULTS Of the 1269 patients enrolled, 604 were eligible for the planned analyses. Among these, 571 underwent radical hysterectomy (323 with cT≤2 cm and 248 with cT>2 cm). Parametrial involvement was present in 1.9% (6/323) with cT≤2 cm and 12.9% (32/248) with cT>2 cm. Five-year overall survivals were 95.8% (95% CI 92.9-97.6%) in cT≤2 cm and 91.9% (95% CI 87.6-94.8%) in cT>2 cm patients. CONCLUSION Patients with cT≤2 cm had lower risk of parametrial involvement and more favorable 5-year overall survival. They could therefore be good candidates for receiving less radical surgery.

Determination of Prognostic Factors in Japanese Patients With Advanced Gastric Cancer Using the Data From a Randomized Controlled Trial, Japan Clinical Oncology Group 9912

BACKGROUND In advanced gastric cancer (AGC), no globally accepted prognostic scoring system has been developed. Therefore, we explored baseline prognostic factors in Japanese AGC patients using the data from a randomized controlled trial, Japan Clinical Oncology Group (JCOG) 9912, which investigated the efficacy of systemic chemotherapy as a first-line treatment. PATIENTS AND METHODS Prognostic factors and prognostic indices for overall survival were screened and evaluated in patients enrolled in JCOG9912 using the Cox proportional hazard model. The Royal Marsden Hospital prognostic model was also applied to the JCOG9912 trial. RESULTS A total of 650 (92.3%) of the 704 patients randomized in the JCOG9912 trial, for whom complete data were available for multivariate analyses, was included in the present study (5-fluorouracil arm, n = 215; irinotecan plus cisplatin arm, n = 216; S-1 arm, n = 219). The median survival time (MST) for all patients was 11.8 months. To construct a prognostic index, we selected four risk factors by multivariate analysis: performance status ≥ 1, number of metastatic sites ≥ 2, no prior gastrectomy, and elevated alkaline phosphatase. MSTs were 17.0 months for patients categorized into the low-risk group, who had zero or one risk factor (n = 225); 10.4 months for patients in the moderate-risk group, who had two or three risk factors (n = 368); and 5.0 months for patients in the high-risk group, who had all four risk factors (n = 57). CONCLUSION In the present study, we propose a new prognostic index for patients with AGC. This can be used for more appropriate patient stratification in future clinical trials.