Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Comparison of controlled and Glisson's pedicle transections of hepatic hilum occlusion for hepatic resection.

BACKGROUND: For hepatic resection, intraoperative bleeding is reduced by clamping the afferent blood flow. Selective clamping at the hepatic hilum can be accomplished using the standard controlled method or Glisson's pedicle transection method. The safety and efficacy of these two methods have not previously been compared. STUDY DESIGN: The intraoperative findings and complications were retrospectively reviewed in 90 patients who underwent major hepatectomy with selective inflow clamping between 1988 and 1997. RESULTS: Blood loss and operative time did not differ between the two groups. Bile leakage was observed in 3 of 43 patients (7.0%) in the standard controlled method group and 11 of 47 patients (23.4%) in the Glisson's pedicle transection method group (p = 0.031). In the Glisson's pedicle transection method group, bile leakage occurred more frequently in patients who underwent left lobectomy than in those who underwent right lobectomy (p = 0.023). CONCLUSIONS: There were no differences in intraoperative findings and postoperative complications analyzed between the standard controlled method and Glisson's pedicle transection method for major hepatectomy except for the rate of bile leakage. In particular, attention must be paid to the bile duct injuries when the Glisson's pedicle is dissected.

Longterm effects of hepatic arterial interleukin-2-based immunochemotherapy after potentially curative resection of colorectal liver metastases.

BACKGROUND: Our previous study of hepatic arterial infusion of interleukin-2 (IL-2)-based immunochemotherapy demonstrated a high response rate of patients with unresectable liver metastases. In this study, we applied this therapy to the prevention of liver recurrence in patients who underwent potentially curative resection of liver metastases. STUDY DESIGN: A pilot study was conducted of 18 patients with liver metastases from primary colorectal cancer who underwent potentially curative liver resection followed by adjuvant immunochemotherapy. The regimen consisted of a weekly hepatic arterial infusion of IL-2 (1.4-2.1 X 10(6) U) and 5-fluorouracil (250 mg) and a bolus of mitomycin C (2-4 mg) for 6 months. RESULTS: Among 18 patients, 14 are still alive with a median postoperative survival of 52 months (as of April 1998). The 5-year overall survival rate was 75%. Although recurrent cancer developed in 6 of the 18 patients, no patients had recurrence in the residual liver. This complete prevention of liver recurrence is believed to have contributed to the high 5-year survival rate (75%) as compared with the survival rate of patients treated with surgery alone (average, 30%-40%) or with several other forms of adjuvant therapy. CONCLUSIONS: Interleukin-2-based immunochemotherapy is useful in combination with liver resection for the prevention of liver recurrence in colorectal cancer patients with liver metastases. A multicenter randomized trial is recommended.

[MultiCycle software for cell cycle analyses].

MultiCycle software (M-cycle), a computer cell cycle analysis program that has a background debris and aggregation compensating function, was utilized in this study to prove the usefulness of the M-cycle. The S phase fraction (SPF) calculated by the M-cycle was compared to that of bromodeoxyuridine labelling index (BLI) using colorectal carcinoma cell lines. The SPF value was slightly lower using the M-cycle than that of the BLI in Colo 201 and Colo 320 and lower significantly in Widr. This may indicate that the M-cycle effectively compensated for the background existing in the DNA histogram. The SPF value was computed both by the M-cycle and the sum of broadened rectangles model (SOBR). The SPF value of these cell lines showed a lower figure in the M-cycle than in the SOBR. The SPF value of paraffin-embedded material through the M-cycle and the SOBR was compared according to DNA ploidy patterns. The SPF value computed by the M-cycle was significantly lower in both ploidy patterns than that of the SOBR. In conclusion, the M-cycle is a useful tool for cell cycle analyses of simple DNA flow cytometric histograms obtained by paraffin-embedded material.

[Analysis of malignant potential on colorectal carcinoma utilizing expression of epidermal growth factor and DNA ploidy patterns].

Human epidermal growth factor (EGF) and DNA ploidy patterns were investigated in order to elucidate malignant potential of 216 surgically resected colorectal carcinomas. EGF positive was detected in 140 out of 216 (64.8%) cases and DNA aneuploidy was found in 137 out of 216 (63.4%). No significant correlations were recognized between EGF expressions and DNA ploidy patterns. We subclassified the cases into four groups according to their histological EGF expressions and DNA ploidy patterns. In these groups, the relationship among EGF expressions, DNA ploidy patterns and clinicopathological findings was studied. Subgroups had a significant relation to depth of invasion, lymph node metastasis, lymphatic invasion and clinical stage. In patients with curative operation, the prognosis was significantly lower in EGF-positive-DNA aneuploidy group than in EGF-negative-DNA diploidy group. In DNA diploidy, the prognosis of EGF-positive group was poorer than in the EGF-negative group. In conclusion, the EGF expression as well as DNA ploidy patterns may be useful to assess malignant potential in colorectal carcinoma.

[Flow cytometric DNA analysis of malignant potential in colorectal carcinoma--DNA ploidy pattern and liver metastasis].

On the purpose of elucidating the malignant potential, flow cytometric DNA analyses were carried out using paraffin-embedded materials of 82 subserosal, serosal and adventitial invasive colorectal carcinoma. The ratio of DNA diploidy against DNA aneuploidy was one to two. DNA ploidy pattern was not correlated with histological grade but with histopathological factors such as lymphatic permeation, lymph node metastasis and venous invasion. At the primary operation, the rate of the liver metastasis in DNA aneuploid cancer was 16.4% but in DNA diploid cancer the liver metastasis was not observed at all. On the liver metastasis, the 5-year disease free survival rates were lower in patients with DNA aneuploidy (72.8%) than those with DNA diploidy (95.2%). These results indicate that DNA ploidy pattern is related to liver metastasis. Furthermore, the 5-year survival rates in patients with absolute curative resection were lower significantly in DNA aneuploidy (62.5%) than DNA diploidy (92.9%). In conclusion flow cytometric DNA analysis is useful for evaluating the biological malignant potential and predicting the liver metastasis in colorectal carcinoma.

Clinical study on the antiseptic effect of povidone-iodine solution for the surgical field of digestive tract operations.

Our previous study showed 10% povidone-iodine solution (Isodine) to be safe and effective for skin antisepsis in healthy young adults. The present study was carried out in 45 adult and old-age patients undergoing surgery (average age 62 years). 10% povidone-iodine solution was effective for skin antisepsis; however, after completion of the intra-abdominal procedures, contaminations were found due to the type II and IV operations with unprotected incision sites and wound walls. Diabetes was found to be one of the most important factors in surgical site infection. In conclusion, the antiseptic efficacy immediately after application of 10% povidone-iodine solution was evidenced in surgical patients with class II wounds. The solution was also effective for the prevention of postoperative skin wound infection.

The significance of bivariate cytokeratin and DNA flow cytometry in paraffin-embedded specimens of non-small cell lung cancer.

BACKGROUND: The presence of non-tumor cells inside cancer tissue is one of the causes of errors in cell cycle analysis by DNA flow cytometry. The recent establishment of bivariate cytokeratin and DNA flow cytometry has made feasible the accurate assessment of tumor proliferative activity. METHODS: Bivariate flow cytometry and immunohistochemistry examinations of paraffin-embedded specimens were performed in 92 patients with non-small cell lung cancer (NSCLC). Determination of the S-phase fraction by flow cytometry, with cytokeratin gating (CK-gated SPF) and without gating (ungated SPF), and the expression of proliferating cell nuclear antigen by immunohistochemistry (PCNA labeling index), were used to assess cancer cell proliferation. RESULTS: Two tumors had DNA histograms with a coefficient of variation of more than 8.0% and were excluded from the flow cytometric analysis. In DNA diploid tumors (n = 25), the ungated SPFs (8.7 +/- 3.6%) showed a lower distribution than the CK-gated SPFs (14.3 +/- 4.7%) (P < 0.0001). In DNA aneuploid tumors (n = 65), there was no difference in distribution between the ungated SPFs (15.0 +/- 8.3%) and the CK-gated SPFs (15.1 +/- 7.1%) (P = 0.94). The CK-gated SPF and the PCNA labeling index of an individual tumor had a good correlation (P < 0.0001), and this agreed with the result showing that DNA diploid and aneuploid tumors had equal proliferative activity (P = 0.64 and P = 0.63, respectively). CONCLUSION: The technique using CK-gating markedly improved the SPF measurement in DNA diploid tumors. This assessment showed no difference in proliferative activity between DNA diploid and aneuploid tumors in NSCLC. Bivariate cytokeratin and DNA flow cytometry is an accurate and objective method for cancer-specific analysis, and will surely be informative in clinical oncology.