Yoshinori Hirashima

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.

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.

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.

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)

Combination chemotherapy with cisplatin and irinotecan in patients with adenocarcinoma of the small intestine

BackgroundSmall-bowel adenocarcinoma (SBA) is a rare tumor that has a poor response to chemotherapy and a poor prognosis. Treatment strategies for SBA have not been clearly established.MethodsAll patients with SBA treated using a combination of cisplatin and irinotecan (IP) as first-line chemotherapy at the National Cancer Center Hospital in Japan between January 1999 and February 2007 were studied retrospectively.ResultsEight patients received IP as first-line chemotherapy. The median follow-up was 9.5 months (range, 4.2–37.5 months). The median number of cycles of IP was three (range, 1–5). The overall response rate (complete or partial response) was 12.5% (complete response, n = 0; partial response, n = 1). The disease control rate (complete or partial response or stable disease) was 75%. The median time to treatment failure was 4.5 months (95% confidence interval, 0.9–5.8 months), and overall survival was 17.3 months (range, 1.9–21.3 months). The most common adverse events were neutropenia and anorexia.ConclusionIP combination chemotherapy may be an acceptable option for patients with SBA. Further studies are warranted to determine the optimal chemotherapeutic regimen for SBA.

Second-line chemotherapy with irinotecan plus cisplatin after the failure of S-1 monotherapy for advanced gastric cancer

BackgroundFor advanced gastric cancer (AGC), second-line chemotherapy after the failure of S-1 has not yet been established. The present study aimed to retrospectively evaluate the efficacy and safety of irinotecan plus cisplatin (IP) therapy after the failure of S-1 in patients with AGC.MethodsThe subjects included 87 patients with AGC who received IP therapy as second-line chemotherapy. Irinotecan (70 mg/m2) was administered by intravenous infusion followed by an intravenous infusion of cisplatin (80 mg/m2) on day 1. On day 15, irinotecan (70 mg/m2) alone was administered. The treatment was repeated every 4 weeks until disease progression, patient refusal, or severe adverse events.ResultsThe median patient age was 62 years (range, 39–75 years), and the median number of treatment cycles was 3 (range, 1–9). Out of the 87 patients, 70 were assessable for clinical response. There were 2 complete responses and 18 partial responses. The overall response rate was 28.6% (95% confidence interval [CI], 18.4%–40.6%) and the disease control ratio was 70.0%. The median time to progression and median survival time from the first day of IP therapy were 4.3 months and 9.4 months, respectively. The 1-year survival rate was 34.6%. Severe (grade 3/4) leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 34%, 40%, 28%, and 8% of patients, respectively. Grade 3/4 nonhematologic toxicities included anorexia (17%), febrile neutropenia (10%), diarrhea (6%), fatigue (5%), nausea (2%), and elevated creatinine (1%).ConclusionsThe combination of irinotecan plus cisplatin as second-line chemotherapy for AGC appears to be an effective and feasible treatment option after S-1 failure.

Chemosensitivity of patients with recurrent esophageal cancer receiving perioperative chemotherapy

Perioperative chemotherapy (CT) and chemoradiotherapy are widely used for advanced esophageal cancer. We evaluated the chemosensitivity of patients displaying recurrent esophageal cancer after esophagectomy with perioperative CT. From the database at National Cancer Center Hospital in Tokyo, we extracted recurrent esophageal cancer cases after perioperative CT and evaluated the effectiveness of the first CT against the recurrent disease according to the duration between termination of the original perioperative CT and recurrence with treatment-free intervals (TFIs) <or=6 and >6 months. Systemic CT for their recurrent disease was performed for 30 esophageal cancer patients after perioperative CT. All patients received 5-fluorouracil and cisplatin as perioperative CT, with relapses occurring at TFIs <or=6 months in 11 patients (eight received platinum-containing regimens and three received docetaxel for their recurrent disease) and >6 months in 19 patients (all received platinum-containing regimens). The response rate of patients experiencing a recurrence at TFIs <or=6 and >6 months was 0 and 37% (P = 0.029), the median progression-free survival was 2.8 and 4.8 months (log-rank P = 0.001) and the median overall survival was 6.1 and 10.2 months (log-rank P = 0.012), respectively. Recurrence at the TFI <or=6 months could represent resistance to CT, so regimens may need to be altered depending on a patients specific TFI.

Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report

BackgroundThe oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.Case presentationWe describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.ConclusionThis is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.

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.

Abstract A167: A phase I study of single-agent BEZ235 (SDS sachet), once- or twice-daily, in Japanese patients with advanced solid tumors.

Background: BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. In previous phase I studies in mainly Western patients, the maximum tolerated dose (MTD) of single-agent BEZ235 solid dispersion system (SDS) sachet once daily (QD) was declared as 1200 mg and the recommended dose (RD) as 1000 mg; the MTD of the same formulation of BEZ235 twice daily (BID) was declared as 400 mg (Rodon EORTC-NCI-AACR 2012, Arkenau ASCO 2012). Here we present the results of a phase I, multicenter, open-label, dose escalation study of single-agent BEZ235 SDS sachet, administered QD or BID, in adult Japanese patients with advanced solid tumors (NCT01195376). Methods: Patients with histologically confirmed, unresectable advanced solid tumors not amenable to standard therapy, received continuous oral BEZ235, QD or BID in 28-day cycles. The primary objective was to determine the MTD/RD of single-agent BEZ235 in adult Japanese patients, based on dose-limiting toxicity (DLT) using a standard 3+3 method for dose escalation. MTD was defined as the highest dose causing DLT in no more than 1/6 patients in Cycle 1. Secondary objectives included preliminary antitumor activity (RECIST v1), safety profiles (CTCAE v3), and pharmacokinetics (PK). Results: As of Feb 10, 2013, 32 patients (mean age 58 yrs) were treated with BEZ235 at 2 dosing schedules; 27 patients received BEZ235 QD at 5 dose levels: 400, 800, 1000, 1200, or 1400 mg; and 5 patients received BEZ235 BID at 400 mg. 2 DLTs were reported with QD dosing: Grade 2 allergic reaction (1200 mg) and Grade 4 thrombocytopenia (1400 mg). Although equivalent DLT ratios were recorded at 1200 mg and 1400 mg (1/6 evaluable patients each), clinical observation led to 1200 mg being declared as the maximum, clinically tolerable dose and 1000 mg being declared as the RD of single-agent BEZ235 QD. The primary reason for discontinuation was disease progression (63%). Common suspected BEZ235-related AEs (≥40%) were diarrhea, decreased appetite, nausea, stomatitis, fatigue, vomiting, and rash; no difference in AE profile was observed between QD and BID schedules. Three patients experienced serious suspected BEZ235-related AEs: infectious enterocolitis, pneumonia, and diarrhea. No death related to treatment was reported. Best overall response was stable disease in 15/27 evaluable patients (56% disease control rate). After Feb 10, 2013, 3 additional patients were enrolled at 400 mg BID (8 in total) and 1 DLT (Grade 2 liver dysfunction) out of 6 evaluable patients was observed. PK data revealed a slow rate of absorption, less than dose-proportional exposure, and large interpatient variability for single-agent BEZ235 SDS sachet. Conclusions: The maximum, clinically tolerable dose of BEZ235 QD was declared as 1200 mg and the RD was declared as 1000 mg, in agreement with previous studies in Western populations. In addition, the tolerability of 400 mg BEZ235 BID was confirmed. The findings of this first-in-Japanese study suggest no major difference in BEZ235 tolerability and PK profile between Japanese and Western populations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A167. Citation Format: Koichiro Watanabe, Hironobu Minami, Satoshi Otsu, Yoshinori Hirashima, Ryotaro Morinaga, Kazuo Nishikawa, Yasushi Hisamatsu, Toru Mukohara, Naomi Kiyota, Naoko Chayahara, Masanori Toyoda, Yoshinori Imamura, Yutaka Fujiwara, Cornelia Quadt, Matthew Robson, Kazuto Natsume, Takuji Aoki, Kuniaki Shirao. A phase I study of single-agent BEZ235 (SDS sachet), once- or twice-daily, in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A167.