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.

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.

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. ' 2005 Wiley-Liss, Inc.Key words: preclinical lung metastases model; angiogenesis; apoptosis; postoperative adjuvant therapy Colorectal cancer remains one of the major causes of cancer death worldwide. The mainstay of treatment for colorectal cancer with curative intent is surgical resection. However, recurrences to the liver or lung may occur in some patients even after a potentially curative operation. 1 For instance, the overall 5-year-survival rate for stage III cancer is approximately 60 % 2 due to postoperative recurrences even if the patients receive adjuvant chemotherapy. It is thought that the development of distant metastases depends on the spread of cancer cells from the primary tumor and that micrometastases already established prior to primary tumor resection appear as recurrent tumors after the operation. Therefore, to improve the postoperative prognosis of patients with colorectal cancer, effective adjuvant therapies against the micrometastases such as chemotherapy and immunotherapy should be considered. Since the 1990s, chemotherapy using 5-fluorouracil and leucovorin (5-FU/LV) has become standard treatment for stage III colon cancer after successful surgery. 3,4 However, this chemotherapy is still insufficient for patients at a high risk to recurrence who have biologically aggressive tumors, and the need to improve the outcome in such patients has increased the interest in developing more intensive or more targeted therapeutic strategies.It has been shown that solid tumor growth beyond a certain size requires neovascularization to supply the tumor with oxygen and nutrients. 5 In other words, without neovascularization, micrometastasis cannot grow. Therefore, it has been suggested that antiangiogenic therapy is effective against various solid tumors by inhibiting neovascularizat...

Abstract. 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.

Summary: We clarify the significance of total mesorectal excision (TME), lateral lymphadenectomy (LLA), and of autonomic nerve preservation (ANP) compared to conventional surgery (CVS), for lower rectal cancer. All 458 patients curatively resected between 1962 and 1997 were retrospectively investigated. In Period I from 1962-1974, when CVS only was performed, in Period II from 1975-1984, THE or THE+LLA was performed, and in Period III from 1985-1997, THE+ANP, THE+ANP+LLA, or THE+LLA was performed. In Dukes A+B disease, there was no significant difference among the three periods, regardless of operation methods. In Dukes C disease, in Period I, CVS (42 patients: pts) had a local recurrence (LR) rate of 45.2% and 5-year disease-free survival (5YDFS) rate of 33.3%. In Period II, THE+LLA (82 pts) had a lower LR rate of 26.8% (p=0.0628) and higher 5YDFS 51.0% (p<0.05) vs CVS. In Period III, THE+ANP (12 pts) had LR 25.0% and 5YDFS 55.6%, TME+ANP+LLA (45 pts) had LR 13.3% (p<0.005, vs CVS) and 5YDFS 56.1 % (p<0.01, vs CVS), and THE+LLA (18 pts) had LR 16.7% (p<0.05, vs CVS) and 5YDFS 20.8%. Also, CVS had the lowest curability rate 64.8% and the highest mortality rate 7.2%. THE and/or LLA was significant for reducing LR and improving survival in patients with Dukes C lower rectal cancer, compared to CVS. ANP was beneficial with LLA. THE+ANP was suitable for Dukes A or B disease.

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.

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.

BackgroundAntineoplastons 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.MethodsSixty-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.FindingsOverall 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.InterpretationAntineoplastons (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 informationClinicalTrials.gov UMIN000012099