Randomized phase II study of 5-fluorouracil hepatic arterial infusion with or without antineoplastons as an adjuvant therapy after hepatectomy for liver metastases from colorectal cancer.

BACKGROUND: Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. METHODS: Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. FINDINGS: Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm. INTERPRETATION: Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov UMIN000012099.

Demethylation effect of the antineoplaston AS2-1 on genes in colon cancer cells.

Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. antineoplastons have been shown to control neoplastic growth. In the present study, we investigated demethylation effect of the antineoplaston AS2-1 (a mixture of phenylacetylglutamine and phenylacetate in the ratio of 1:4) on various genes in colon cancer cells. An HpaII-MspI methylation microarray was used to investigate the methylation status of 51 genes at the promoter region in HCT116 and KM12SM human colon cancer cells before and after treatment of AS2-1. The expression of protein and mRNA of the demethylated genes by AS2-1 in HCT116 cells was evaluated. In 19 of the 34 methylated genes in HCT116 and in 7 of the 8 methylated genes in KM12SM, the methylation status was downregulated after treatment with 2 mg/ml of AS2-1 for 24 h. AS2-1 dramatically downregulated the methylation status of p15 and ESR1 in HCT116 cells and of MTHFR and MUC2 in KM12SM cells. Both mRNA and protein expression of p15 increased in a dose- and time-dependent manner after treatment with AS2-1. The antineoplaston AS2-1 may normalize the hypermethylation status at the promoter region in various genes including tumor suppressor genes, resulting in activation of the transcription and translation in colon cancer.

Multicenter Phase II Study of a New Effective S-1 and Irinotecan Combination Schedule in Patients with Unresectable Metastatic or Recurrent Colorectal Cancer.

INTRODUCTION: This multicenter phase II study determined the efficacy and safety of new daily oral S-1 and weekly irinotecan (CPT-11) combination schedule in patients with previously untreated advanced or recurrent colorectal cancer. PATIENTS AND METHODS: Patients received first-line chemotherapy comprising S-1 80 mg/m(2)/day given on days 3 to 7, 10 to 14, and 17 to 21 and 60 mg/m(2) CPT-11 administered intravenously on days 1, 8, and 15 of a 28-day cycle. RESULTS: A total of 45 eligible patients were enrolled in this study. The overall response rate was 48.9%. Median progression-free survival and median overall survival was 8.1 months and 20.9 months, respectively. The rates of grade 3 or 4 toxicity were as follows: neutropenia, 8.9%; anemia, 4.4%; anorexia, 6.7%; and diarrhea, 6.7%. CONCLUSIONS: This new S-1 and irinotecan combination schedule appeared to be an effective, well-tolerated, and convenient regimen in patients with advanced colorectal cancer as compared with conventional regimens such as FOLFIRI and IRIS.

Molecular mechanisms of sequence-dependent antitumor effects of SN-38 and 5-fluorouracil combination therapy against colon cancer cells.

BACKGROUND: The aim of this study was to clarify the molecular mechanisms of the sequence-dependent antitumor activity of SN-38 and 5-fluorouracil (5-FU) against colon cancer cells. MATERIALS AND METHODS: KM12SM and HCT116 colon cancer cells were exposed to 5-FU and/or SN-38 in various conditions. The nature of interactions was determined by median-effect analysis. Cell cycle, apoptosis, and expression of thymidylate synthase (TS) were analyzed. RESULTS: A strong synergism was observed after initial sequential exposure of SN-38, and the activity was enhanced by a 24 h-interval to the drug-exposure. Antagonism was observed after low-dosage initial sequential exposure of 5-FU. Low-dosage 5-FU caused G(2) arrest and high-dosage 5-FU caused G(1) arrest. TS protein level significantly decreased after exposure to SN-38. CONCLUSION: The sequence dependency between SN-38 and 5-FU against colon cancer cells may be related to the dual action on cell cycle regulation by 5-FU and to the down-regulation of TS level by SN-38.

Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma.

BACKGROUND: A phase II study was designed to evaluate the efficacy, safety and predictors for response of metronomic chemotherapy using weekly low-dosage CPT-11 and doxifluridine (5'-DFUR) in 45 patients with metastatic colorectal cancer. PATIENTS AND METHODS: Forty mg/m2 of CPT-11 was administered for 3 consecutive weeks in a 4-week treatment cycle, with 5'-DFUR (800 mg/day) given orally. RESULTS: One or more adverse effects were seen in 42 patients. However, most of these were mild at grade 1 or 2, including only leucopenia in 2, neutropenia in 1, diarrhea in 1 and nausea in 1 as grade 3. The objective response rate was 36% with a median overall survival of 452 days. The response rate in patients with a high expression of thymidine phosphorylase (dThdPase) in tumor cells (47%) was higher (p=0.092) than that (19%) in patients with a low expression. CONCLUSION: The efficacy of metronomic chemotherapy using low-dosage weekly CPT-1 and 5'-DFUR is worthy of further clinical study, especially in patients with a high expression of dThdPase in primary tumor cells.

[A resected case of advanced gastric cancer after treatment with low-dosage TS-1].

We report a case of advanced gastric cancer that responded well to low-dosage TS-1. A 72-year-old woman was diagnosed as having unresectable advanced gastric cancer with ascites and hydronephrosis in the right kidney. She was treated with chemotherapy using a low-dosage of TS-1 (80 mg/body/day) administered perorally for 4 weeks followed by a drug-free 2 weeks, in six-week cycles. However, she developed weight loss, appetite loss, and stomatitis. We therefore reduced the dosage of TS-1 from 80 mg/body/day to 60 mg/body/day. The ascites and hydronephrosis gradually improved during the following 3 months, whereupon she could undergo total gastrectomy. The postoperative findings showed no ascites and no peritoneal dissemination. The postoperative pathological findings showed that the cancer cells were localized to within the mucosa, and there were no cancer cells in the greater and lesser omentum. Three weeks after the operation, TS-1 was resumed at 60 mg/body/day. However, 3 months later,ascites and metastasis to the abdominal skin developed, and she died 9 months after the operation.

Oral fluoropyrimidines may not reduce the risk of postoperative recurrence in colorectal cancer associated with mesenteric lymph node metastasis.

To clarify the efficacy and problems of postoperative adjuvant chemotherapy using oral fluoropyrimidines, the clinicopathological data of 307 colorectal cancer patients treated with or without postoperative chemotherapy were analyzed retrospectively. Patients in the chemotherapy group (n=188) who underwent curative resection were followed by administration of oral fluoropyrimidine. The other 119 patients underwent surgery alone. The disease-free survival rates were compared between the two groups. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery alone. However, no significant difference in disease-free survival rate was found for those with tumors that were associated with mesenteric lymph node involvement and tumors with a high grade of lymphatic invasion or high grade of venous invasion. Postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT (litegafur +4:uracil) and 5'-DFUR (doxifluridine) might not reduce the risk of recurrence in colorectal cancer with mesenteric lymph nodes involvement.

The expression of vascular endothelial growth factor determines the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

The aim of this study was to determine any correlation between the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. The data were reviewed retrospectively on 342 patients with colorectal cancer at stage II or III, who underwent potentially curative resection between 1988 and 1998. Of these, 225 received post-operative administration of oral fluoropyrimidines such as UFT and 5'-DFUR, while the other 117 patients underwent surgery alone. Immunostaining for VEGF was performed using colorectal tumours. Overall, VEGF was positively expressed in primary tumour cells in 48% of patients. The disease-free survival rate and the overall survival rate in the chemotherapy group were higher than those in the surgery-alone group, although not significantly. However, the disease-free survival rate and the overall survival rate were similar between the two groups in patients with a tumour positive for VEGF. Multivariate analysis revealed that the VEGF expression was an independent factor for post-operative recurrence, and the VEGF expression and post-operative adjuvant chemotherapy were an independent factor for overall survival, in addition to the lymph node metastasis and the venous invasion. In conclusion, the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines may not be as great for patients with a tumour positive for VEGF having a greater risk of post-operative recurrence. The results support further investigation on efficacy of molecular targeting therapy for VEGF in combination with oral fluoropyrimidines as post-operative adjuvant therapy in colorectal cancer positive for VEGF.

The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

BACKGROUND: The aim of this study was to determine any correlation between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the matrix metalloproteinase 9 (MMP-9) expression in primary colorectal cancer tissues. PATIENTS AND METHODS: The data on 307 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy, were reviewed. Of these, 188 received postoperative administration of oral fluoropyrimidines such as UFT and 5'-DFUR (chemotherapy group), while the other 119 patients underwent surgery alone (surgery-alone group). Immunostaining for MMP-9 was performed using surgical specimens of all 307 primary tumors and 18 recurrent tumors. RESULTS: Overall, MMP-9 was positively expressed in the primary tumor in 44% of patients. Multivariate analysis revealed that the MMP-9 expression was a worse prognostic factor with a second highest hazard ratio for recurrence. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery-alone group. However, no significant difference in disease-free survival rate between the two groups was found in patients with a tumor positive for MMP-9. There was a strong positive correlation of MMP-9 expression between the primary tumors and the recurrent liver or lung tumors. CONCLUSIONS: The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat.

We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat.

Upregulation of thymidine phosphorylase in rectal cancer tissues by mitomycin C.

BACKGROUND AND OBJECTIVES: We have investigated the regulation by mitomycin C (MMC) of thymidine phosphorylase (dThdPase) and dihydropyrimidine dehydrogenase (DPD), which enhances or reduces the efficacy of capecitabine and its metabolite 5'-deoxy-5-fluorouridine (5'-DFUR), in rectal cancer tissues. MATERIALS AND METHODS: In 31 patients with a rectal cancer, tumor biopsies were performed before and after pre-operative venous administration of 4 mg/m2, 6 mg/m2, or 10 mg/m2 of MMC. The dThdPase and DPD levels in the biopsy and surgical specimens were measured using ELISA, and immunostaining for dThdPase was performed. RESULTS: The fitting multiple linear regression models indicated that the dThdPase levels increased after MMC administration, in particular in the patients with a pre-treatment dThdPase level less than 56.2 U/mg protein (median value). The time course analysis indicated that the increase in the dThdPase level by 4 mg/m2 of MMC administration continued for 3 weeks. The dThdPase/DPD ratio was increased after MMC administration in patients with a pre-treatment dThdPase/DPD ratio less than 1.79 (median value). MMC enhanced the expression of dThdPase protein both in the tumor cells and in the stromal cells. The disease free-survival rate in the Dukes B or C patients with a high dThdPase/DPD ratio in surgical specimen who received 5'-DFUR based adjuvant chemotherapy tended to be higher than that in those with a low dThdPase/DPD ratio. CONCLUSION: MMC may upregulate the dThdPase level and the dThdPase/DPD ratio in rectal cancer tissues. Combined use of MMC with capecitabine or 5'-DFUR may offer a more effective colorectal cancer therapy.

The benefit of post-operative adjuvant chemotherapy using oral fluoropyrimidines in rectal cancer.

Recent meta-analysis has shown that oral fluoropyrimidenes is effective as post-operative adjuvant therapy in stage II or III colorectal cancer. However, because the efficacy of oral fluoropyrimidines was expected to be mild, it is important to know patients who respond to this mild chemotherapy for reasonable adjuvant therapy for rectal cancer. To clarify the benefit and problems of the post-operative adjuvant chemotherapy using oral fluoropyrimidines, the clinicopathological data of 169 rectal cancer patients treated with or without the post-operative chemotherapy were analyzed retrospectively. Patients in chemotherapy group (n = 100) underwent curative resection with lymphadenectomy were followed by administration of oral fluoropyrimidine. Other 69 patients underwent surgery alone. The disease-free survival rates were compared between the two groups. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery alone. However, no significant difference in disease-free survival rate was found for those with tumor which was associated with metastasis of mesenteric lymph node or node belonging to the internal iliac artery, and tumor with lymphatic invasion or venous invasion. Post-operative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR might not reduce the risk of recurrence in rectal cancer with metastasis of mesenteric lymph node or node belonging to the internal iliac artery, and with lymphatic permeation and venous invasion.

Effects of antineoplaston AS2-1 against post-operative lung metastasis in orthotopically implanted colon cancer in nude rat.

We have investigated the efficacy and mechanisms of antineoplaston AS2-1 against post-operative lung metastasis following removal of implanted human colon cancer in nude rat. The influence of AS2-1 on in vitro KM12SM human colon carcinoma cell activities (growth, cell cycle, and apoptosis) was evaluated. AS2-1 was administered perorally after removal of the implanted KM12SM cecal cancer in nude rat. AS2-1 inhibited KM12SM cell proliferation through G1 cell arrest and, at a higher concentration, induction of apoptosis. AS2-1 showed significant reduction in lung metastasis at 5 weeks after cecal removal. The survival rate in the AS2-1 group was significantly higher than that in the control. TUNEL staining on the lung metastatic tumors revealed that the apoptosis index (AI) in the AS2-1 group was significantly higher. Antineoplaston AS2-1 showed an antimetastatic effect against post-operative lung metastases from colon cancer through G1 cell arrest and the subsequent induction of apoptosis.

Repeat pulmonary resection for isolated recurrent lung metastases yields results comparable to those after first pulmonary resection in colorectal cancer.

Pulmonary resection for colorectal metastases is well accepted. However, the main cause of death after pulmonary resection is recurrence in the lung. The aim of this study was to clarify whether a repeat pulmonary resection was warranted in patients with recurrent lung metastases. The records of 76 patients undergoing initial pulmonary resection, including 14 patients undergoing a repeat operation for lung metastases, were reviewed for survival, operative morbidity, and mortality. Overall, pulmonary resection was performed 96 times in this group of patients. The operative mortality was 0%, morbidity involved only one case of major postoperative hemorrhage associated with the first operation. The cumulative 5-year survival rate for the 76 patients was 32%. After the second pulmonary operation, recurrence was identified in 79% (11 of 14) of the patients. In 10 patients with isolated lung recurrence after a first pulmonary resection, who showed no extrapulmonary disease before or at the time of first thoracotomy, the 3-year, and 5-year-survival rate after the second pulmonary resection was 67%, and 33%, respectively, comparing favorably with the survival rate in those who underwent primary pulmonary resection. In contrast, all 4 patients with extrapulmonary disease before or at the time of thoracotomy had poor prognosis. Repeat pulmonary operation for isolated recurrent colorectal metastases to the lung yielded results comparable to those after the first pulmonary resection in terms of operative mortality and survival in the absence of hilar/mediastinal lymph node or extrathoracic involvement.

Prognostic factors after potentially curative resection in stage II or III colon cancer.

It is important to identify factors that are predictive of outcome after a curative resection in colon cancer in order to optimize adjuvant therapy. To investigate these prognostic factors we conducted a retrospective analysis of our clinicopathological data. A total of 190 patients with a pathological stage II or III colon cancer underwent potentially curative resection with lymphadenectomy at our hospital between 1990 and 1998. These patients received no preoperative chemotherapy, immunotherapy or radiotherapy. Postoperative adjuvant chemotherapy using oral fluoropyrimidines was performed in 127 patients, and the other 63 patients underwent surgery alone. Univariate and multivariate analyses for prognostic factors were carried out. The univariate analysis revealed that invasion to adjacent organs, N1-2, positive mesenteric lymph node metastasis (MLN+), lymphatic permeation (ly)1-3, venous invasion (v)1-3, and v2-3 were each significant factors indicating worse disease-free survival, and that N1-2, MLN+, ly1-3, v1-3 and v2-3 were each significant factors for worse overall survival. In the multivariate analysis, MLN+ and vl-3 were significant factors for worse disease-free survival, and for worse overall survival. In conclusion, stage II or III colon cancer patients positive for mesenteric lymph node metastasis or for venous invasion have a greater risk of recurrence and death after potentially curative resection. Postoperative adjuvant chemotherapy using oral fluoropyrimidines did not significantly reduce the risk of recurrence and death in these patients. More effective adjuvant chemotherapy than oral fluoropyrimidine should be considered, especially in such high-risk patients.

Long-term survival following treatment with antineoplastons for colon cancer with unresectable multiple liver metastases: report of a case.

We report a case of survival for nearly 8 years after treatment of unresectable multiple liver metastases from colon cancer, using microwave ablation and the nontoxic antitumor agent, the antineoplastons. A 72-year-old man diagnosed with adenocarcinoma of the ascending colon and 14 bilateral liver metastases underwent a right hemicolectomy combined with microwave ablation of six metastatic liver tumors. We also decided to give antineoplastons to inhibit metastatic tumor growth and recurrence. Antineoplaston A10 was given intravenously, followed by oral antineoplaston AS2-1. Computed tomography scans done 1 and 4 years after the initial diagnosis showed recurrent tumors in S(4) and S(7), respectively. The patient underwent a second and a third microwave ablation of the recurrent tumors, and has survived for nearly 8 years without suffering any serious adverse effects. He is currently free from cancer. This case report demonstrates the potential effectiveness of the nontoxic antitumor agent, the antineoplastons, for controlling liver metastases from colon cancer.

The UPAO test in preoperative evaluation for major pulmonary resection: an operative case with markedly improved ventilatory function after radical pulmonary resection for lung cancer associated with pulmonary emphysema.

A 65-year-old man was admitted to our hospital for treatment of a squamous cell carcinoma in his right lung. Respiratory function testing showed an extremely reduced forced expiratory volume in 1 second (FEV1) of 1.0 l (29.9% of predicted), and a reduced FEV1/FVC ratio of 24.1%. Arterial blood gases on room air showed a pH of 7.41, a PaCO(2) of 36.7 mmHg, and a PaO(2) of 79.3 mmHg. To assess the predictive postoperative cardiopulmonary function, unilateral pulmonary artery occlusion (UPAO) testing was performed. In the condition of right main PA occlusion, the mean pulmonary artery pressure (mPAP), cardiac index (CI) and total pulmonary vessel resistance index (TPVRI) was 18 mmHg, 3.2 l/min/m(2) and 443.37 dyne.sec.cm(-5)/m(2), respectively. He underwent a middle lobectomy with combined partial resection of both the upper and lower lobes. He also underwent simultaneous resection of a giant bulla arising from the right upper lobe as lung volume reduction surgery. At 80 days after the operation, his FEV1 rose to 1.88 l, and the PaO(2) on room air was improved to 88.9 mmHg. UPAO testing was suggested to be more useful than routine pulmonary function test to determine the accurate predictive postoperative cardiopulmonary function and to decide indication for a radical operation.

Endoluminal ultraflex stent for palliative treatment of malignant rectosigmoidal obstruction.

Rectosigmoidal obstruction due to a malignant tumor usually requires emergency surgical treatment, and colostomy is usually inevitable. This report describes our experience with the use of endoluminal self-expanding metallic stents in the treatment for rectosigmoidal obstruction in patients with unresectable recurrent colorectal cancer or intra-abdominal dissemination. A total of 5 cases were included (4 male and 1 female) with a mean age of 70.8 (range, 63-80) years. A self-expanding noncovered Ultraflex, 10 cm in length and 22 mm in diameter, was emplaced at the site of the obstruction under both endoscopic and fluoroscopic guidance. Each patient had a recurrent malignancy (colorectal cancer, 3; ovarian cancer, 1; gastric cancer, 1). No subsequent surgery was planned due to ascites or extensive intra-abdominal dissemination. There was no mortality related to the procedure. Immediate decompression with symptomatic relief was achieved. One stent later became obstructed due to tumor ingrowth, and in two cases there was intermittent bleeding from the tumor and these were treated by argon plasma coagulation (APC) endoscopically. The use of self-expanding Ultraflex stent provides good palliation for unresectable advanced tumors that cause left colonic obstruction.

Transanal dilation using circular stapling for benign rectal stenosis: report of a case.

When a simple procedure such as bougie, balloon dilation and transanal incision are not effective for severe stenosis after colorectal anastomotic leakage, a surgical operation is required. We report a case of transanal dilation using circular stapling for severe stricture in the colorectal anastomosis following low anterior resection.