Mutsumi Fukunaga

Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): a multicentre, randomised, controlled phase 3 trial.

INTRODUCTION The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin. METHODS In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis. RESULTS A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups. CONCLUSION The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Usefulness of staging laparoscopy for advanced gastric cancer.

PurposeThe aim of this study was to clarify the usefulness of staging laparoscopy for planning the treatment strategy in patients with advanced gastric cancer.MethodsThis was a retrospective study of patients with gastric cancer who underwent staging laparoscopy. The patients were divided into three groups according to the presence/absence of peritoneal metastasis (P) and positive peritoneal cytology (CY): P negative (0) CY0, P0CY positive (1), and P1CY1. The treatment strategy after staging laparoscopy was as follows: (1) surgery for the P0CY0 group, (2) surgery with neoadjuvant chemotherapy (NAC) for the P0CY1 group, and (3) chemotherapy for the P1CY1 group. Survival was estimated by the Kaplan-Meier method and statistical differences were analyzed by the log-rank test.ResultsThirty-four patients were included in this study: 11 in the P0CY0 group, 13 in the P0CY1 group, and 10 in the P1CY1 group. A gastrectomy was done in 11, 10, and no patients, respectively. The survival rate of the P0CY0 patients was significantly better than that of the P0CY1 or P1CY1 patients (P = 0.0106 and 0.0031, respectively).ConclusionStaging laparoscopy is useful for planning the treatment strategy and estimating the prognosis of patients with advanced gastric cancer.

Ephrin-A1 mRNA is associated with poor prognosis of colorectal cancer

We previously studied hypoxic tumor cells from hepatic metastases of colorectal cancer (CRC) and determined several potential prognostic factors, including expression of ephrin-A1 (EFNA1), which was highly induced by hypoxia. Here, we further evaluated the prognostic impact of EFNA1 expression. Samples from a total of 366 CRC patients from 11 institutes were analyzed by either microarray (n=220) or quantitative reverse-transcriptase polymerase chain reaction (n=146). EFNA1 was an independent prognostic factor for CRC (p<0.05). In vitro assays revealed that loss of EFNA1 following siRNA treatment was associated with reduced proliferative activity and decreased invasion and migration of CRC cell lines. EFNA1 expression is a useful marker for predicting high risk of relapse and cancer-related death in patients who have undergone curative resection for CRC.

Micrometastasis Volume in Lymph Nodes Determines Disease Recurrence Rate of Stage II Colorectal Cancer: A Prospective Multicenter Trial

Purpose: We reported in a retrospective study that the presence of micrometastasis in lymph nodes, when assessed by carcinoembryonic antigen (CEA)-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer. The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial. Experimental Design: From November 2001 to December 2005, a total of 419 colorectal cancer cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II colorectal cancer cases were enrolled. After RNA quality check, 304 colorectal cancer cases were analyzed for CEA mRNA in lymph nodes by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method. Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Postoperative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-fluorouracil derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for 1 year, whereas chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (high MMV, n = 95) was an independent poor prognostic factor for 5-year disease-free survival (DFS; P = 0.001) and 5-year overall survival (OS; P = 0.016). Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II colorectal cancer. Clin Cancer Res; 22(13); 3201–8. ©2016 AACR.

Multicenter prospective randomized phase II study of antimicrobial prophylaxis in low-risk patients undergoing colon surgery

PurposePostoperative antimicrobial therapy is generally administered as standard prophylaxis against postoperative infection, despite a lack of sufficient evidence for its usefulness. This study was a phase II study to evaluate the necessity of postoperative antibiotic prophylaxis in patients undergoing a colectomy.MethodsPatients received 1 g cefmetazole or flomoxef immediately after anesthetic induction, every 3 h during surgery, and then later once again on the next day. They were randomly assigned to receive either cefmetazole or flomoxef.ResultsNinety-one patients were enrolled in the study. A surgical site infection (SSI) occurred in 7.7% (7/91) of patients. All cases were superficial incisional infections. When comparing the two drugs, SSI occurred in 8.3% (4/48) of patients treated with cefmetazole and in 7.0% (3/43) treated with flomoxef, showing no significant difference (P > 0.99).ConclusionAntimicrobial prophylaxis was well tolerated when used on the day of a colectomy and once again on the next day.

Middle-Preserving Pancreatectomy for Multifocal Metastatic Renal Cell Carcinoma Located in the Head, Body and Tail of the Pancreas. A Case Report

CONTEXT Postoperative endocrine and exocrine insufficiencies following traditional pancreatectomies might cause a deterioration of the quality of life and surgical outcome. Parenchyma-sparing pancreatectomies have been utilized in benign lesions and low-grade malignancies. CASE REPORT A 67-year-old female with a past history of right nephrectomy for renal cell carcinoma 20 years earlier was referred to our institute with obstructive jaundice and multiple nodules in the pancreas. Computed tomography demonstrated five well-demarcated, strongly enhanced nodules with diameters of 5.5 cm in the head, 2.0 and 1.8 cm in the body, and 1.2 and 1.0 cm in the tail. Fluorine-18 fluorodeoxyglucose positron emission tomography did not demonstrate any extrapancreatic uptake. A middle-preserving pancreatectomy was performed after ultrasonography had confirmed arterial perfusion in the middle segment. A histological study demonstrated metastatic clear cell renal carcinoma. To date, the patient has remained without recurrence for two and a half years since surgery. A minimal administration of insulin has been necessary; however, C-peptide is detectable and nutritional status is comparatively good. CONCLUSION A middle-preserving pancreatectomy is a useful procedure in a parenchyma-sparing pancreatectomy for resecting multifocal lesions in the head, body and tail of the pancreas.

SCGB2A1 is a novel prognostic marker for colorectal cancer associated with chemoresistance and radioresistance

We recently showed that liver metastatic tissue from patients with colorectal cancer (CRC) was a useful model for identifying novel, hypoxia-inducible genes and prognostic markers. We showed that the expression of secretoglobin, family 2A, member 1 (SCGB2A1) was a potential prognostic factor for CRC. Here, we further evaluated the prognostic impact and function of SCGB2A1 in 222 patients with CRC. The impact of SCGB2A1 expression on disease-free survival (DFS) and overall survival (OS) was assessed with mRNA expression profiling. The function of SCGB2A1 was analyzed by evaluating mRNA expression profiles in cells derived from patients with CRC and by testing the effects of transfecting SCGB2A1 into different CRC-derived cell lines. We evaluated the effects of SCGB2A1 on proliferation, chemosensitivity, radiation sensitivity and sphere formation. Univariate and multivariate analyses indicated that the expression of SCGB2A1 was an independent prognostic factor for CRC (p<0.05), together with lymph node metastasis (p<0.05). Enforced expression of SCGB2A1 in CRC-derived cell lines promoted proliferation (DLD1, SW480 and LoVo cells; p<0.05), decreased chemosensitivity to 5-fluorouracil and oxaliplatin (DLD1 and SW480 cell lines; p<0.05), and significantly increased the viability of irradiated cells (DLD1, SW480 and LoVo cell lines; p<0.05). SCGB2A1 expression was also correlated to cancer stemness-related genes (Wnt, Zeb1 and Twist). Consistent with this correlation, SCGB2A1 expressing cells (SW480) showed increased sphere formation (p<0.05). These results indicated that SCGB2A1 represented a novel, prognostic factor for CRC, and that expression of SCGB2A1 correlated with chemoresistance, radioresistance and cancer cell stemness.

A Phase II Study of Combined Chemotherapy with 5-Week Cycles of S-1 and CPT-11 plus Bevacizumab in Patients with Metastatic Colon Cancer

Objective: Combined chemotherapy with S-1 and irinotecan (IRIS) for metastatic colorectal cancer has been reported to be effective and safe. However, there are only a few studies on the effects of adding bevacizumab to IRIS. We conducted a clinical study to evaluate the efficacy and safety of IRIS plus bevacizumab as first-line therapy for metastatic colorectal cancer. Methods: Forty metastatic colorectal cancer patients were enrolled in this phase II study. All patients received irinotecan (80 mg/m2) and bevacizumab (7 mg/kg) on days 1 and 15 and S-1 (40-60 mg twice daily) on days 1-21 of a 5-week repeated cycle. Results: The response rate was 47.4% [95% confidence interval (CI) 31.5-63.2], progression-free survival was 11.9 months (95% CI 9.4-16.8), and overall survival was 23.4 months (95% CI 19.0-inf). The only grade 3 hematological toxicity was neutropenia (16%) and the incidences of grade 3 nonhematological toxicity were low at <10%, other than diarrhea (10.9%). Conclusion: In this clinical study, we revealed IRIS plus bevacizumab to be a promising first-line regimen for metastatic colorectal cancer with a low incidence of serious toxicities, in which favorable response rates and extension of survival time can be expected.

A Feasibility Study of UFT/LV and Irinotecan (TEGAFIRI) in Advanced or Metastatic Colorectal Cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG) PROG 0304

OBJECTIVE This is a feasibility trial of oral uracil/tegafur (UFT)/oral leucovorin (LV) and irinotecan (TEGAFIRI) with maximum dose confirmed in Japan. To document the toxicity and define the objective response rate (RR); and determine progression-free and overall survival. METHODS Patients with advanced or metastatic colorectal cancer (CRC) received: UFT 300 mg/m(2), LV 75 mg/body and CPT-11 150 mg/m(2) (UFT and LV given on days 1-14, and CPT-11 on day 1, every 3 weeks). Eligibility: ECOG performance status (PS) 0-1, adequate bone marrow/liver function and serum creatinine level less than institutional normal value. RESULTS Eighteen patients enrolled, 17 evaluable for toxicity and response and 1 patients recalled chemotherapy upon registration. Characteristics: 61% male, median age 63.5 years (51-71). Seventy-two per cent PS 0, 50% first line. One hundred and eighty-six cycles have been delivered. The common Grade 3-4 toxicities were neutropenia (35.3%), leukopenia (29.4%), diarrhea (5.9%), anorexia (5.9%), vomiting (5.9%) and dizziness (5.9%). There was no episode of febrile neutropenia. No death occurred on treatment: Overall RR was 41.2% [7/17: 1 complete response (CR) + 6 partial response (PR)]. Progression-free survival (PFS) is 6.9 months, median survival time (MST) is 25.1 months and 1-year survival rate is 70.6%, whereas PFS 15.0 months, MST 43.6+ months and 1-year survival rate 100% in cases with CR or PR. CONCLUSIONS Approved dose of CPT-11 is 150 mg/m(2) in Japan. As is lower dose with CPT-11, TEGAFIRI for patients with advanced or metastatic CRC in Japan seems to have the similar effect with that reported abroad and indicates prolonged PFS and MST in cases with CR or PR.

Preliminary results of phase I trial of oral uracil/tegafur (UFT), leucovorin plus irinotecan and radiation therapy for patients with locally recurrent rectal cancer

BackgroundSurgical attempts for locally recurrent rectal cancer often fail due to local re-recurrence and distant metastasis. Preoperative chemoradiation may enhance better local control and survival. The aim of this study was to assess the safety of oral uracil and tegafur (UFT) plus leucovorin (LV), and irinotecan combined with radiation and determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of the triple drug regimen.Patients and methodsPatients with locally recurrent rectal cancer received escalating doses of irinotecan on days 1, 8, 15, and 22 (starting at 30 mg/m2, with 10 mg increments between consecutive cohorts) and fixed doses of UFT (300 mg/m2) plus LV (75 mg/day) on days 3 to 7, 10 to 14, 17 to 21, and 24 to 28. Radiation was given 5 days per week totaling 40 to 50 Gy (2Gy/day).ResultsSix patients were treated at the starting dose, and 2 received the full scheduled chemoradiotherapy. The other 4 patients had grade 3 diarrhea and diarrhea was the DLT. One patient had partial response and he had subsequently radical surgical resection. Median progression free survival for local recurrence was 320 days.ConclusionIrinotecan plus UFT/LV with concomitant radiotherapy in patients with locally recurrent rectal cancer was not feasible due to diarrhea in this setting. Modification of the treatment is needed.