Kazutake Okada

Comparison between oral antibiotics and probiotics as bowel preparation for elective colon cancer surgery to prevent infection: Prospective randomized trial

BACKGROUND We have already reported that, for patients undergoing elective colon cancer operations, perioperative infection can be prevented by a single intravenous dose of an antibiotic given immediately beforehand if mechanical bowel preparation and the administration of oral antibiotics are implemented. Synbiotics has been reported to reduce the rate of infection in patients after pancreatic cancer operations. The effectiveness of oral antibiotics and probiotics in preventing postoperative infection in elective colon cancer procedures was examined in a randomized controlled trial. METHODS Three hundred ten patients with colon cancer randomly were assigned to one of three groups. All patients underwent mechanical bowel preparation and received a single intravenous dose of flomoxef immediately before operation. Probiotics were administered in Group A; oral antibiotics were administered in Group B; and neither probiotics nor oral antibiotics were administered in Group C. Stool samples were collected 9 and 2 days before and 7 and 14 days after the procedure. Clostridium difficile toxin and the number of bacteria in the intestine were determined. RESULTS The rates of incisional surgical-site infection were 18.0%, 6.1%, and 17.9% in Groups A, B, and C, and the rates of leakage were 12.0%, 1.0%, and 7.4% in Groups A, B, and C, respectively, indicating that both rates were lesser in Group B than in Groups A and C (P = .014 and P = .004, respectively). The detection rates of C. difficile toxin were not changed among the three groups. CONCLUSION We recommend oral antibiotics, rather than probiotics, as bowel preparation for elective colon cancer procedures to prevent surgical-site infections.

Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

Purpose: To assess the maximum tolerability of a combination of S-1 and preoperative radiotherapy and to evaluate the feasibility and activity in patients with locally advanced rectal cancer. Methods: Patients (n = 30) with adenocarcinoma of the middle or lower rectum were enrolled in a phase I (n = 9) and/or phase II (n = 21) trial. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, and S-1 was orally administered twice a day on days 1–14 and 22–35. Surgical resection was scheduled 4–8 weeks after the completion of chemoradiation. Results: In phase I, the recommended dose (RD) of S-1 was 80 mg/m2/day, and the maximum-tolerated dose was never reached. A total of 27 cases, including the 6 RD cases in phase I, were enrolled in phase II. In phase II, a pathological complete response (pCR) was observed in 6/27 patients (22%), pathological downstaging was observed in 21/27 patients (78%), and a tumor volume reduction of 69 ± 22% was obtained. These results were similar to the previously reported pCR rates of 16–18%, pathological downstaging rates of 49–59%, and tumor volume reduction of 68% after chemoradiotherapy with capecitabine. Grade 3 adverse events consisted of one case of leukopenia (4%), 2 cases of anemia (7%) and 3 cases of diarrhea (11%). Overall, the adverse events were very mild. Hand-foot syndrome was not observed. Conclusion: The efficacy of chemoradiotherapy with S-1 seems to be equivalent to the efficacy reported for chemoradiotherapy with capecitabine, but the adverse events were much milder, although further study is warranted.

Biopsy Specimens Obtained 7 Days After Starting Chemoradiotherapy (CRT) Provide Reliable Predictors of Response to CRT for Rectal Cancer

PURPOSE Preoperative chemoradiation therapy (CRT) significantly decreases local recurrence in locally advanced rectal cancer. Various biomarkers in biopsy specimens obtained before CRT have been proposed as predictors of response. However, reliable biomarkers remain to be established. METHODS AND MATERIALS The study group comprised 101 consecutive patients with locally advanced rectal cancer who received preoperative CRT with oral uracil/tegafur (UFT) or S-1. We evaluated histologic findings on hematoxylin and eosin (H&E) staining and immunohistochemical expressions of Ki67, p53, p21, and apoptosis in biopsy specimens obtained before CRT and 7 days after starting CRT. These findings were contrasted with the histologic response and the degree of tumor shrinkage. RESULTS In biopsy specimens obtained before CRT, histologic marked regression according to the Japanese Classification of Colorectal Carcinoma (JCCC) criteria and the degree of tumor shrinkage on barium enema examination (BE) were significantly greater in patients with p21-positive tumors than in those with p21-negative tumors (P=.04 and P<.01, respectively). In biopsy specimens obtained 7 days after starting CRT, pathologic complete response, histologic marked regression according to both the tumor regression criteria and JCCC criteria, and T downstaging were significantly greater in patients with apoptosis-positive and p21-positive tumors than in those with apoptosis-negative (P<.01, P=.02, P=.01, and P<.01, respectively) or p21-negative tumors (P=.03, P<.01, P<.01, and P=.02, respectively). The degree of tumor shrinkage on both BE as well as MRI was significantly greater in patients with apoptosis-positive and with p21-positive tumors than in those with apoptosis-negative or p21-negative tumors, respectively. Histologic changes in H&E-stained biopsy specimens 7 days after starting CRT significantly correlated with pathologic complete response and marked regression on both JCCC and tumor regression criteria, as well as with tumor shrinkage on BE and MRI (P<.01, P<.01, P<.01, P<.01, and P=.03, respectively). CONCLUSIONS Immunohistochemical expressions of p21 and apoptosis together with histologic changes on H&E-stained biopsy specimens obtained 7 days after starting CRT are strong predictors of the response to CRT.

Optimal duration of prophylactic antibiotic administration for elective colon cancer surgery: A randomized, clinical trial

BACKGROUND Procedures for perioperative infection prophylaxis in elective colon cancer surgery consist of preoperative mechanical preparation, chemical preparation with oral antibiotic administration, perioperative intravenous antibiotic administration, and others. However, the optimal combination of these procedures and drugs and their durations of administration have not yet been established. A randomized study was conducted to determine the optimal duration of perioperative antibiotic administration with use of mechanical and chemical preparation. METHODS A total of 370 patients who were to undergo elective colon cancer surgery were randomized into 2 groups. After mechanical and chemical preparations, a single, 1-g dose of flomoxef was administered immediately before surgery to patients in group A. Flomoxef 1 g was administered twice daily for a total of 4 days from the day of surgery to postoperative day 3 to patients in group B. RESULTS Comparison was performed between 179 patients in group A and 181 patients in group B with analyzable data. The incidences of incisional surgical site infections (SSIs), organ/space SSIs, and remote infections (RIs) were 15 patients (8.4%), 1 patient (0.6%), and 8 patients (4.5%), respectively, in group A, and 13 patients (7.2%), 2 patients (1.1%), and 6 patients (3.3%), respectively, in group B. There were no differences in the incidence of incisional SSIs, organ/space SSIs, or RIs between groups A and B. CONCLUSION It was shown that a single dose of intravenous antibiotic immediately before surgery is sufficient as perioperative infection prophylaxis in elective colon cancer surgery when mechanical and chemical preparation is performed.

Phase II Study of Preoperative Concurrent Chemoradiotherapy with S-1 plus Bevacizumab for Locally Advanced Resectable Rectal Adenocarcinoma

Objective: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of preoperative chemoradiotherapy (CRT) with concurrent S-1, bevacizumab, and radiation in patients with locally advanced rectal cancer (LARC). Methods: Fifty-two patients with LARC were enrolled. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, S-1 was administered orally twice a day on days 1-14 and 22-35, and bevacizumab was administered on days 1, 15, and 29. Surgical resection was scheduled 8 weeks (6-10 weeks) after completing the CRT. Results: All 52 patients underwent R0 radical surgery. Sphincter preservation was possible in 38 (73.1%) patients. A pathologic complete response was obtained in 10 (19.2%) patients, a pathologic downstaging was achieved in 37 (71.2%) patients, and the tumor shrinkage rate was 77.1%. The only grade 3 adverse events were leukopenia and rash in 1 (1.9%) patient. The rate of postoperative complications was 28.8%. Anastomotic leakage occurred in 9 (23.7%) of the 38 patients who underwent sphincter-preserving surgery. Perineal wound dehiscence developed in 2 (14.3%) of the 14 patients who received an abdominoperineal resection. Conclusions: Adding bevacizumab to S-1 clearly increased the incidence of wound-related complications, with no distinct enhancement of tumor response. i 2014 S. Karger AG, Basel

Randomized controlled trial comparing subcuticular absorbable suture with conventional interrupted suture for wound closure at elective operation of colon cancer.

BACKGROUND Subcuticular closure provides a superior cosmetic result in clean wounds. The aim of this work was to investigate the safety in terms of postoperative infection and cosmetic effectiveness of subcuticular wound closure after elective colon cancer surgery in clean-contaminated wounds. METHODS Patients who underwent elective resection of colon cancer were randomized to interrupted subcuticular and interrupted transdermal suture groups. The large bowel was prepared by mechanical washout with polyethylene glycol. All patients received metronidazole and kanamycin orally and flomoxef sodium once parenterally for antimicrobial prophylaxis. The primary end point was the incidence of incisional surgical-site infections within 30 days after operation. We assessed noninferiority of subcuticular suture within a margin of 10%. Analysis was by intent-to-treat. Secondary objectives include comparison of wound closure time, comfort, and cosmesis of the scar and satisfaction of patients. This study was registered with UMIN-CTR, UMIN000003005. RESULTS A total of 293 patients were randomized to the two groups. Incisional surgical-site infection rates were 11.0% (90% confidence interval 7.0-16.3%) for both groups. The relative risk of subcuticular suture was 1.00 (0.58-1.73, one-tail P = .57). Interrupted subcuticular suture was noninferior to interrupted transdermal suture (P = .0088). Throughout 6 months after operation, patients expressed a significant preference for the subcuticular suture technique, noting rapid relief from pain, decreased vascularity, and smaller width, although the procedure took twice as long. CONCLUSION Subcuticular suture did not increase the incidence of wound complications in elective colon cancer operation. Patients preferred a technique of interrupted subcuticular closure, citing better cosmetic results, and less pain.

Relationship between histologic response and the degree of tumor shrinkage after chemoradiotherapy in patients with locally advanced rectal cancer

Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in advanced rectal cancer. We studied whether the degree of tumor shrinkage can be used as a predictor of histologic response.

Monitoring of Serum Carcinoembryonic Antigen Levels after Curative Resection of Colon Cancer: Cutoff Values Determined according to Preoperative Levels Enhance the Diagnostic Accuracy for Recurrence

Objectives: Serum carcinoembryonic antigen (CEA) has been widely used for postoperative surveillance for colorectal cancer. However, serum CEA has a poor diagnostic accuracy for detecting recurrence. We tested the hypothesis that determining cutoff values according to the preoperative serum CEA levels would enhance the diagnostic accuracy. Methods: Serum CEA was measured before and 1-6 months after surgery in 783 patients with curatively resected colon cancer from 2005 through 2013. The cutoff values during surveillance were determined separately according to preoperative serum CEA levels. Results: In patients with negative preoperative serum CEA, the diagnostic accuracy for recurrence was 89.1% when a postoperative cutoff value was set at 5 ng/mL. However, in patients with positive preoperative serum CEA, the diagnostic accuracy was 58.4% when a postoperative cutoff value was set at 5 ng/mL, and was 75.6% when a cutoff value was set at 8 ng/mL. Among patients with positive preoperative serum CEA, the recurrence-free survival rate was significantly lower in patients with a serum CEA of ≥8 ng/mL than those with a serum CEA of <8 ng/mL (p = 0.0018). Conclusions: The diagnostic accuracy of serum CEA for recurrence is enhanced by separately setting cutoff values according to preoperative serum CEA.

A Phase II Trial of Combined Chemotherapy with Oral S-1 and 24-Hour Infusions of Irinotecan plus Bevacizumab in Patients with Metastatic Colorectal Cancer.

Objectives: Protracted low-dose infusion of irinotecan has been suggested to enhance antitumor activity. A phase II study was conducted to evaluate the safety and efficacy of oral S-1 combined with 24-hour infusion of irinotecan and intravenous bevacizumab for metastatic colorectal cancer (MCRC). Methods: The subjects were 79 patients with MCRC; 57 were chemotherapy naïve. Irinotecan (125 mg/m2) was administered as a 24-hour infusion on days 1 and 15, S-1 (80 mg/m2) was administered orally on days 1-14, and bevacizumab (5.0 mg/kg) was given on days 1 and 15. The treatment was repeated every 4 weeks. Results: Median follow-up was 20.0 months, and the mean number of cycles was 7. The overall response rate was 79.7% (95% CI, 69.2-88.0), 86.0% (95% CI, 74.2-93.7) for first-line and 63.6% (95% CI, 40.7-82.8) for second-line treatment. The median progression-free survival was 16.4 months (95% CI, 13.9-21.0) for first-line and 9.4 months (95% CI, 4.9-16.5) for second-line treatment. The median overall survival was not reached. Grade 3-4 toxicities were neutropenia (43%), leukopenia (20.3%), anorexia (19.0%), and diarrhea (10.1%). Toxicity was tolerable. Conclusions: Combination chemotherapy with oral S-1 and biweekly 24-hour infusions of irinotecan plus bevacizumab appears to be highly active and well tolerated both as first-line and second-line chemotherapy for MCRC.

Risk scores as useful predictors of perioperative complications in patients with rectal cancer who received radical surgery

BackgroundRectal cancer is associated with a higher rate of surgical complications. The ability to predict the risk of complications before treatment would facilitate the design of personalized treatment strategies optimally suited for each patient.MethodsWe retrospectively studied 260 patients with rectal cancer who underwent radical surgery to examine the relations between complications and 5 types of risk scores.ResultsComplications developed in 56 patients (21.5%). Nineteen patients had infectious complications, 16 had intestinal obstruction, and 12 had other complications. Twelve patients out of 187 patients who received low anterior resection had anastomotic leakage. Estimation of Physiologic Ability and Surgical Stress Comprehensive Risk Score (E-PASS CRS) and Neutrophil-to-lymphocyte Ratio (NLR) were significantly related to all complications, infectious complications, and anastomotic leakage. Surgical Apgar Score was significantly related to infectious complications. Prognostic Nutritional Index was significantly related to all complications and intestinal obstruction. Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity was significantly related to all complications, and infectious complications. A multivariate analysis showed that body-mass index, E-PASS CRS, and NLR were independent risk factors for anastomotic leakage. In particular, NLR was the only score that could be evaluated before surgery.ConclusionsFive types of risk scores were useful methods for evaluating the risks of complications in patients with rectal cancer. NLR is a score that can be evaluated before surgery and predicted the risk of anastomotic leakage, suggesting that it is useful for assessing the need for a diverting colostomy.