The preventive effect of weekly high-dose 5-FU infusion (WHF) after resection of hepatic metastasis from colorectal cancer

Hepatic metastasis is often found even after resection of hepatic metastases from colorectal cancer. This implies that the micrometastasis already existed in residual liver when the resection was performed, and so complete recovery with resection alone is rare. We have been using a weekly high-dose 5-FU HAI (WHF = 5-FU 1,000 mg/m2/5 hrs/qw) since 1991, which has preventive effects for metastasis in residual liver as compared to a group treated without infusion chemotherapy. Hepatectomy was performed in 30 of 113 cases of hepatic metastasis from colorectal cancer during the past 16 years. For comparison, we divided the 30 cases into group A1 (16 cases H1:12, H2:4), which received hepatectomy only, and group A2 (14 cases H1:8, H2:4, H3:2), which additionally received infusion chemotherapy. The 1- and 3-year (cumulative) survival rates were 64.6% and 32.3% in group A1, and 100% and 75.3% in group A2 respectively in which the treatment outcome was significantly higher. The 1- and 3-year recurrence rates were 41.7 and 66.3 in group A1, and 8.3% each in group A2, respectively, which reveals that metastasis in residual liver was controlled in group A2. Other metastases were seen in lung (6 cases), bone (2 cases), hepatic hilar lymph node (3 cases), brain (1 case) and local (3 cases) in group A1, while only one metastasis in each brain and locally was seen in group A2 so far. WHF after resection of hepatic metastasis from colorectal cancer has a preventive effect not only for the recurrence in residual liver but also for other metastases. Therefore, as improvement in the survival rate is expected.     

Intra-arterial preventive chemotherapy for residual liver after resection of hepatic metastasis from colorectal cancer

We treated 18 cases with intra-hepatic arterial infusion chemotherapy after resection of hepatic metastasis from colorectal cancer (June 1991-September 1997). Eight cases were H1, 7 were H2, and 3 were H3. Hepatic lobectomy was done in 3 cases, lobectomy + partial resection in 2 cases, and partial resection in 13 cases. All cases received high-dose intermittent 5-FU infusion (WHF = 5-FU 1,000 mg/m2/5 hrs/w) on an outpatient basis. The total frequency of WHF was 4-54 times (average 29), and total 5-FU doses ranged from 6.0 to 81.0 g (average 40 g). The 1- and 5-year cumulative survival rates were 100% and 77.5% in all patients 100% and 87.5% in H1 group and 100% and 64.3% in H2 + H3 group, respectively. There was no significant difference of survival between the H1 and H1 + H3 groups. The 1- and 5-year recurrence rates in residual liver were 5.9% and 14.4%, respectively. One of 2 cases with residual liver recurrence was resected for metastasis again, and the patient is now in a disease-free state. WHF after resection of hepatic metastasis from colorectal cancer has a preventive effect for their survival, not only in H1 group but also in H2 + H3 group.     

Comparison in survival between hepatic metastases of gastric and colorectal cancers

BACKGROUND/AIM: The outcome after hepatectomy and non-surgical treatment of liver metastases from gastric and colorectal malignancies are reported. METHODOLOGY: Between April 1988 and March 1994, 176 patients with metastatic liver cancer were treated at the First Department of Surgery, Kyoto Prefectural University of Medicine Hospital. RESULTS: All patients received multi-disciplinary treatment, and 51 underwent hepatectomy. The survival after hepatectomy for metastatic liver cancer from a colorectal primary was better than that for gastric cancer. The survival after hepatic arterial infusion (HAI) therapy for metastases from gastric cancer was better than that for colorectal cancer. CONCLUSION: Surgical resection may be the best treatment for liver metastases from colorectal cancer. HAI may be a better option for liver metastases from gastric cancer.     

Hepatic arterial chemotherapy for liver cancer over a period of 8 years

Hepatic arterial chemotherapy was performed for 27 patients with primary (3), metastatic liver cancer (21), and 3 other cases, over a period of 8 years. Chemotherapy was performed by intermittent hepatic arterial infusion of 5-FU or FAM (in case of metastatic tumor from colorectal cancer), FAM (from gastric cancer), and CDDP or Farmorubicin (HCC). Hepatic resection was performed in 10 cases of metastatic tumor from colorectal cancer, and 8 cases of 10 were curative operation. The 5-year survival rates of curative liver resection group, and non-curative liver resection or non-resection group were 57.1% and 12.5%, respectively. As is the case with metastatic cancer from gastric cancer, pancreatic cancer, and hepatocellular carcinoma (HCC), the prognosis was poor except for one CR case of HCC. We concluded that hepatic arterial chemotherapy may be recommended for a curative resected case of liver metastasis from colorectal cancer.     

Resection of hepatic metastases from colorectal cancer

BACKGROUND/AIMS: Long term results of hepatic resection for metastases from colorectal cancer depend upon several factors which are related to both features of primary cancer and of metastases. The aim of this study was to evaluate prognostic factors that best correlate with long-term results. MATERIALS AND METHODS: Fifty-eight hepatic resections were performed for colorectal cancer metastases. Long-term results were evaluated in relation to age of patients, features of primary tumor, features of metastases, section margin, number of intra-operative blood transfusions and execution of adjuvant chemotherapy. RESULTS: Overall 5-year survival rate was 17%. 5-year survival rate in patients with stage B primary tumor was 63%, in patients with late metachronous metastases it was 28%, in patients with section margin > 1 cm it was 33% and in patients who did not receive intra-operative transfusions it was 45%. Patients with a solitary metastasis or with metastases sized less than 4 cm and those who received adjuvant chemotherapy also showed a better survival than the others. CONCLUSIONS: Better results were observed in patients without nodal involvement of the primary tumor. Patients with a small solitary metachronous metastasis that appeared more than one year after the colorectal resection and resected with a section margin of more than 1 cm, also showed good results.     

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.     

Long-term survival in a case of multiple liver metastasis from postoperative gastric cancer effectively treated by hepatic intraarterial infusion chemotherapy using MMC and pirarubicin

We experienced a case of multiple liver metastasis from postoperative gastric cancer who showed long-term survival with hepatic arterial infusion chemotherapy (HAI) of MMC and pirarubicin. A catheter was inserted into the hepatic artery, and 4 mg of MMC and 20 mg of pirarubicin were administered through an implantable port catheter every two to four weeks. The total dose of MMC and pirarubicin by the time of this report was 164 mg and 820 mg, respectively. The follow-up CT scan 2 months after the beginning of HAI showed a decrement of the liver tumors. The decrease rate at 12 and 17 months was 50% and 70%, respectively, which was diagnosed as partial response (PR). The therapeutic effect at 49 months is still PR without any sign of tumor enlargement of extra hepatic lesion.     

Pharmacokinetic evaluation of percutaneous hepatic venous isolation for administration of regional chemotherapy

Hepatic artery infusion (HAI) chemotherapy has been used to treat patients with unresectable liver tumours. We report a preclinical study of the pharmacokinetics of HAI combined with hepatic venous drug extraction (HVDE) for regional administration of doxorubicin. HVDE was aided by a double balloon catheter inserted via femoral vein cutdown into the inferior vena cava to collect all hepatic vein blood. Pigs received doxorubicin 0.5-9.0 mg kg-1 over 90 min via HAI or systemic infusion (SYSI). HVDE was performed for 240 min. SYSI pigs underwent hepatic venous isolation without drug filtration. Doxorubicin levels were assayed using high-pressure liquid chromatography (HPLC). HAI/HVDE reduced systemic exposure to doxorubicin with equivalent hepatic exposure at all doses. Pharmacokinetic enhancement ranged from 7.0 to 22.3 for peak concentration, 8.8-23.2 for the area under the curve and 2.9-4.2 for tissue concentration. HAI/HVDE also prevented the mortality which was observed with SYSI administration of high-dose (5.0 and 9.0 mg kg-1) doxorubicin. We conclude that HAI/HVDE reduces systemic exposure to doxorubicin as compared with SYSI of equivalent doses. Pharmacokinetic enhancement indices suggest that HAI/HVDE may allow equivalent hepatic drug exposure with reduced systemic exposure. This method may be applicable to other drugs and to other anatomic settings in which enhanced regional drug delivery is desirable.     

Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases

BACKGROUND: Although the survival benefit of hepatic resection for colorectal metastasis has been established, some controversy remains regarding the significance of adjuvant chemotherapy after hepatic resection. METHODS: One hundred thirty-two consecutive patients who had liver resection for colorectal metastasis at our hospital between 1980 and 1997 were studied. After curative hepatic resection, 37 patients underwent systemic chemotherapy, administered orally or intravenously, and 38 patients underwent regional chemotherapy, given intra-arterially or intraportally. Forty patients had no adjuvant chemotherapy. The chemotherapeutic agents used for oral administration were uracil and Tegafur or Tegafur alone. Mitomycin C (MMC) or 5-FU was used for IV chemotherapy. Combinations of 5-FU/leucovorin or MMC/5-FU (doxorubicin) were used for regional chemotherapy. Univariate and multivariate analyses were applied to test the significance of adjuvant chemotherapy for patient survival or disease-free survival. RESULTS: Overall 5-year survival was 42.2% (95% CL: 31.2%, 53.2%). Among the possible prognostic factors studied, univariate analysis showed a significant difference in survival based on the number of tumors and lymph node metastases in the hepatic hilum. There was a significant difference in disease-free survival based on adjuvant chemotherapy and lymph node metastasis. The multivariate analysis for patient survival selected four prognostic factors (P < .05), including adjuvant chemotherapy, lymph node metastasis, disease-free interval, and tumor size. The multivariate analysis for disease-free survival selected adjuvant chemotherapy, lymph node metastasis, and disease-free interval as significant factors. The most common recurrence site was remnant liver, regardless of adjuvant chemotherapy. CONCLUSIONS: Adjuvant chemotherapy significantly improved survival and disease-free survival after hepatic resection for colorectal metastases. It did not decrease recurrence rate in the remnant liver.     

Evaluation of intra-arterial infusion chemotherapy for advanced gastric cancer

We evaluated the therapeutic efficacy of intraarterial infusion chemotherapy in advanced gastric cancer, its side effect and patient prognosis, in comparison with systemic infusion. Of 125 cases of advanced gastric cancer, 41 cases received intraarterial chemotherapy (A group) and the rest were given systemic infusion (S group). Protocols of chemotherapy were 5-FU + MTX in 49 cases, 5-FU + cisplatin in 62, and 5-FU + MMC in 14. Location of the disease was the peritoneum in 69 cases, nodes in 59, liver in 38, and other sites, 33. The response rate of A group was significantly higher than that of S group, at 31% and 13% respectively. Although 41% of cases showed side effects (> or = grade 2), there was no significant difference between the 2 groups. The median survival period and 1-year survival rate were 8.4 months and 35%, respectively, and there was no significant difference between the 2 groups. In cases with liver metastasis, the prognosis of A group was better than that of S group. The results suggest that intra-arterial infusion chemotherapy is an effective treatment for liver metastasis from gastric cancer.     

Evaluation of hepatic resection and hepatic arterial infusion chemotherapy for multiple liver metastases from colon cancer

We examined the significance of hepatic resection and hepatic infusion chemotherapy for multiple liver metastases from colon cancer. Twelve patients underwent curative hepatic resection for multiple liver metastases (more than five), and 10 of them received arterial infusion chemotherapy. The number of metastases ranged 5 to 30 (mean 9.4). Recurrence rates in the remnant liver were 50%, and five-year survival rates were 31%.     

A study of treatment modalities for nonresectable primary liver cancer

This paper reports the results of multimodality treatment in 200 patients with nonresectable primary liver carcinoma (PLC) from April 1964 to July 1993. PLC was verified histologically in all cases. They were divided into two groups according to the methods of treatment. In group 1, 115 cases received anticancer agents by hepatic artery infusion (HAI). The 1- and 2-year survival rate was 10.4% and 1.7%, respectively and only one patient survived 65 months. In group 2, 85 cases received multimodality treatments by various combinations of hepatic artery chemoembolization (HACE), hepatic artery ligation (HAL), microwave coagulation (MIC) of tumor and ethanol injection into tumor (EIT). The 1-, 2-, 3- and 5-year survival rate was 34.1%, 21.2%, 12.0% and 6.7%, respectively. Five patients had been alive for 41 to 63 months and second-stage hepatic resection performed in another 6 patients. The results suggest that multimodality treatment is an effective approach to improve the long-term survival of patients with nonresectable PLC.     

Cryosurgical ablation of hepatic tumors

BACKGROUND: Cryosurgical ablation of hepatic tumors relies on nonspecific tissue necrosis due to freezing as well as microvascular thrombosis. Patients with selected primary and metastatic hepatic malignancies who are not candidates for surgical resection are afforded potentially curative benefit using this technique. METHODS: Forty patients underwent cryosurgery for hepatic malignancy related to colorectal metastasis (n = 27), hepatocellular carcinoma (n = 8), metastatic breast (n = 2), metastatic neuroendocrine (n = 2), and metastatic ovarian carcinoma (n = 1). Intraoperative ultrasound (IOUS) was used in all patients to help locate the tumor and guide the cryosurgical trocar to the lesions. RESULTS: Indications for cryosurgical ablation included bilobar and centrally located disease, poor medical risk, insufficient hepatic reserve, and involved margin after wedge resection. Major complications included hepatic parenchyma cracking requiring transfusion in 5 patients, 1 postoperative biliary stenosis, and 1 inferior vena cava injury. There were 3 postoperative deaths from non-hepatic-related events. Based on Kaplan-Meier analysis the estimated overall survival for patients with hepatocellular carcinoma (60% at 18 months) was compared with patients with colorectal metastases (30% at 18 months). Nine patients (23%) are currently free of disease with an average follow-up of 17.7 months. The pattern of failure was identified at the site of cryosurgical ablation in 2 of 88 lesions. CONCLUSIONS: Cryosurgical ablation of selected hepatic malignancies is a safe and viable treatment for patients not amenable to surgical resection.     

Transcatheter arterial chemoembolization to hepatic metastases from colorectal cancer

Response of transcatheter arterial chemoembolization (TAE) and transcatheter arterial infusion chemotherapy to hepatic metastases was reported in 25 cases of colorectal cancer. The severity of liver metastases was H1 in 12 cases, H2 in 9 cases, and H3 in 4 cases. Liver metastases were found during surgery in 12 of these patients, and 13 showed metastases or recurrence in the liver after resections of primary lesions. Catheters were inserted selectively to the proper hepatic artery by Seldinger's method, followed by injection of embolizing agents (gelfoam particles of Lipiodol) with adriamycin or 5-FU + leucovorin in most cases. Response was assessed by blood CEA levels, diagnostic imaging, and period of survival. In 5 cases in whom liver resections were performed following TAE, response was assessed by histopathological findings of the resected specimens. Two patients showed partial response (PR), 12 no change (NC) and 11 progressive disease (PD) by diagnostic imaging. Blood CEA levels fell to less than 50% of pre-treatment levels in 26% of cases. Histological changes by TAE were confirmed in 4 of 5 cases after liver resections, but viable cancer cells were observed in all cases. A case of mucinous cancer showed no change histologically. As the other case of mucinous cancer showed PD by diagnostic imaging, TAE was not suggested to be suitable to treat cases of mucinous cancer. More improvements in the dosage, drugs and times of treatment were suggested to yield a better response rate in TAE therapy for liver metastases from colorectal cancer.     

G proteins in carotid body chemoreception

This study explored the efficacy of hepatic arterial therapy, comparing both injection and infusion of 5-fluorouracil (5-FU) in prolonging the survival of 92 patients with recurrent unresectable hepatic metastasis from colorectal cancer. With respect to pretreatment carcinoembryonic antigen doubling time (CEA-DT), 56 patients were treated with intra-arterial injection, and 36 with intra-arterial infusion. In 21 patients with a CEA-DT of less than 40 days, the cumulative survival of patients treated with arterial injection was significantly longer than that of patients treated with arterial infusion. In 45 patients with a CEA-DT of 40-80 days, the survival curves of patients did not differ from each other. Of the remaining 26 patients with a CEA-DT of more than 80 days, those treated using arterial infusion had an excellent prognosis, in contrast to those treated using arterial injection, with statistical significance. CEA-DT may be useful when choosing a chemotherapy regimen, and may help to accurately establish the prognosis of patients with unresectable hepatic metastasis from colorectal cancer.     

Value of oncologic follow-up of patients operated for colorectal cancer. A prospective study of 1000 patients

OBJECTIVE: The purpose of our prospective study was to evaluate the contribution of follow-up in resected colorectal cancer. METHODS: One-thousand patients with colorectal adenocarcinoma who underwent radial resection from January 1975 to January 1990 were prospectively divided into two groups: the first group (n = 442, 42%) entered a 5-year follow-up protocol and the second group (n = 558, 56%) was free to make unscheduled visits in case of symptoms. RESULTS: Recurrence was found in 31.5% of the patients in the first group compared with 33% in the second group. Chorioembryonic antigen was the most accurate test detecting recurrence: 77% of the cases (97% for hepatic metastasis). Surgical resection of recurrent tumors was performed in 37% of the group 1 patients (curative resection in 15%) and in 9% (curative resection in 1.5%) of the group 2 patients (p < 0.001). 5-year survival after recurrence in group 1 was 11.5% versus 1% in group 2 (p < 0.01). CONCLUSION: These results emphasize the rational for a follow-up program in patients undergoing surgery for colorectal cancer.     

Is resection of pulmonary and hepatic metastases warranted in patients with colorectal cancer?

BACKGROUND: Conventional management of stage IV colorectal carcinoma is palliative. The value of resecting both liver and lung colorectal metastases that occur in isolation of other sites of metastasis is undetermined. OBJECTIVES: Our objectives were to (1) assess the efficacy of resecting both hepatic and pulmonary metastases, (2) investigate the influence of the sequence and timing of metastases, and (3) identify the profile of patients likely to benefit from both hepatic and pulmonary metastasectomy. Patients and methods: Of 48 patients identified with resection of colorectal cancer and, at some point in time, both liver and lung metastases, 25 patients underwent metastasectomy (resection group). The remaining 23 patients comprised the nonresection group. Risk factors for death were identified by multivariable analyses. RESULTS: Median survival was longer after the last metastatic appearance in the resection group (16 months) than in the nonresection group (6 months; P <.001). The pattern of risk also differed; it peaked at 2 years and then declined in the resection group but was constant in the nonresection group. In the resection group, patients with metachronous resections survived longer after colorectal resection (median, 70 months) than patients with synchronous (median, 22 months) or mixed resections (median, 31 months; P <.001). Risk factors for death included older age, multiple liver metastases, and a short disease-free interval. CONCLUSIONS: Younger patients with solitary metachronous metastases to the liver, then the lung, and long disease-free intervals are more likely to benefit from resection of both liver and lung metastases. Patients with risk factors also had better survival with resection than without resection.     

Prospective assessment of the hepatic perfusion index in patients with colorectal cancer

BACKGROUND: This prospective study was designed to test the hypothesis that abnormal liver blood flow is related to poor prognosis in patients with colorectal cancer. METHODS: The hepatic perfusion index (HPI), measured by dynamic hepatic scintigraphy, was assessed in 202 patients with colorectal cancer. Assessment for overt hepatic metastasis included liver palpation at laparotomy and perioperative computed tomography (CT). Follow-up at a dedicated clinic included regular abdominal ultrasonography and CT. RESULTS: The HPI was abnormal (greater than 0.37) in 92 (88 per cent) of 105 patients with overt liver metastases. Of 89 patients with no evidence of overt metastases or residual tumour after primary resection, 52 had an abnormal and 37 a normal HPI. At a median follow-up of 39 (range 13-76) months, 25 of 38 patients with recurrence had an abnormal HPI. Some 31 of 45 patients who died had an abnormal HPI. The HPI predicted overall recurrence (P=0.04, log rank test). Multivariate analysis showed the HPI was independent of Dukes stage for predicting disease-free survival (P=0.04, relative risk 1.94 (95 per cent confidence interval (c.i.) 1.03-3.67)) but this just failed to attain significance for overall survival (P=0.055, relative hazard 1.88 (95 per cent c.i. 1.00-3.58)). CONCLUSION: The HPI predicts a poor outcome in patients with colorectal cancer and may be useful in patient selection for adjuvant chemotherapy.     

Combination hepatic intra-arterial 5-fluorouracil and CDDP administration with oral regimen in patients with colorectal cancer metastasis to the liver

We investigated therapeutic effectiveness and side effects of a combination weekly high-dose 5-FU plus one shot CDDP HAI (WHF + CDDP method) with oral regimen in patients with colorectal cancer metastasis to the liver. All 24 patients enrolled in this study showed 54% efficacy whereas patients combined HAI with oral regimen over one week obtained 83% efficacy for multiple liver metastasis. They showed good quality of the life during combination chemotherapy without any symptoms of metastatic lesions. The WHF + CDDP method combined with oral regimen is a promising treatment for colorectal cancer metastasis to the liver as well as extrahepatic distant organs, and this protocol may be satisfactorily accepted by most colorectal cancer laden patients because of negligible side effects.     

5''-nucleotidase activity in lymphocytes from patients affected by B-cell chronic lymphocytic leukemia

Port site metastasis often occurs after laparoscopic colorectal resection of Dukes B and Dukes C tumors. To evaluate the feasible indication for laparoscopic surgery for the cure of colorectal cancer, we performed a clinicopathologic study with special reference to tumor size. A total of 233 patients who underwent curative resection of colorectal cancer at our department during 15 years were examined. There were 59 Dukes A tumors, and their mean size was 2.86 cm. Tumors < 2 cm, compared with tumors > 2 cm, were characterized by grossly superficial type (68% vs. 9%, p < 0.01), negative serosal invasion (95% vs. 24%, p < 0.01), and absence of lymph node metastasis (91% vs. 60%, p < 0.01). Among tumors < 3 cm, node-negative cases were distinguished by location in the colon (73% vs. 22%, p < 0.05) and by histologically well-differentiated type (75% vs. 11%, p < 0.01) in comparison with node-positive cases. All 14 patients with Dukes A tumor undergoing laparoscopic colectomy were free of recurrence during a mean follow-up period of 34 months. The results indicate that all cancers < 2 cm and well-differentiated colon cancers < 3 cm are good candidates for laparoscopic colorectal surgery for cure.