The 5-fluorouracil hepato-arterial infusion with oral UFT therapy for the hepatic and extra hepatic metastases of colorectal cancer

BACKGROUND: The 5 fluorouracil hepato-arterial infusion (5-FU HAI) therapy has a good effect on the liver metastases of colorectal cancer. To gain the antitumor effect of the extra-hepatic lesion, an oral UFT was combined with 5-FU HAI (pharmacokinetic modulating chemotherapy, PMC) to enhance the plasma 5-FU concentration. METHODS: UFT (200-400 mg/day) was orally administered daily and a continuous infusion of 5-FU (1,000-1,500 mg/5 h) was given once a week. Eight patients were treated with this regimen. Five of the eight have extra-hepatic lesions with liver metastases when this treatment was started. The response, time to progression, survival, and toxicity were detected. RESULTS: Four of the five patients with extra-hepatic lesion were evaluated. The response rate was 50% (1 CR, 1 PR, and 2 SD). For the liver metastases, the response rate was 62.5% (1 CR, 4 PR, 2 SD, and 1 PD). Grade 2 leukopenia was found in 1 patient. CONCLUSIONS: The 5-FU HAI with an oral UFT therapy had a good effect on the extra-hepatic lesions as well as hepatic metastases of colorectal cancer.     

Long survival in a case of unresectable hepatic metastasis from rectal carcinoma treated with second-look hepatectomy plus pharmacokinetic modulating chemotherapy (PMC)

A 67-year-old female with rectal cancer and multiple liver metastases underwent low anterior resection by total mesorectal excision (TME), cholecystectomy and hepatic arterial cannulation in June 1995. She was treated with hepatic arterial infusion chemotherapy (HAI) (5-FU 600 mg/m2/day x 2 days/w) and oral UFT (400 mg/body, 5 days/w) once a week for 6 months on an outpatient basis. As the metastatic foci of the liver significantly decreased (83.3%) and extrahepatic disease were not observed, partial resection of the liver (second-look hepatectomy) was performed in March 1996. She continued arterial infusion PMC and venous infusion PMC as an outpatient. During the follow-up period a lung metastasis appeared in November 1997. Her regimen was changed to modified PMC with MMC (mitomycin C) and CPT-11. She has been managed at our outpatient clinic while the lung metastasis remained but with no liver metastasis for 57 months after the first operation, until the present. Second-look hepatectomy and PMC with a two-way port system was a useful option for unresectable hepatic metastases from colorectal carcinoma.     

A case of unresectable liver metastases from rectosigmoid colon cancer with survival for over 3 years after multidisciplinary treatment

A 61-year-old man underwent curative low anterior resection for rectosigmoid colon cancer. Follow-up ultrasonography revealed unresectable multiple liver metastases at 10 months after surgery. Arterial infusion therapy with 5-fluorouracil (5-FU) was given at 1,500 mg every 2 weeks up to a total dose of 37.5 g, resulting in complete remission (CR) of the liver metastases. However, recurrence was seen 4 months after CR. Following partial hepatectomy and local ablation therapy, he received multidisciplinary treatment including local ablation therapy, arterial infusion of 5-FU and mitomycin C, and systemic chemotherapy with 5-FU/Leucovorin/CPT-11. The patient died of liver failure at 3 years and 7 months after the detection of hepatic metastases. If arterial infusion therapy achieves CR of unresectable hepatic metastases from colorectal cancer, the patient may survive for several years with multidisciplinary treatment including surgery, local ablation therapy, and systemic chemotherapy.     

Hepatic arterial infusion of low-dose leucovorin/5-FU chemotherapy for unresectable hepatic metastases from colorectal cancer

Hepatic arterial infusion (HAI) chemotherapy for unresectable liver metastases from colorectal cancer (CRC) is generally indicated to patients without extrahepatic lesions. This study was performed to examine whether or not it was possible to obtain a comparable survival time, response rate (RR) and modest toxicity combining low-dose LV and 5-FU (LV/5-FU) with HAI for the patients with unresectable liver metastases from CRC. Twenty two patients with unresectable multiple liver metastases were enrolled in the study. These were patients who had been admitted from 1994 to 2003 in our hospital. Patients were given LV at 25 mg/body immediately followed by 5-FU at 500 mg/body as a 2-hour HAI daily for 5 consecutive days every 5 weeks. The median survival time (MST) of HAI patients was 24.5 months. According to the treatment in the HAI patients, one patient was CR, 6 were PR, 9 were NC, 6 were PD, and the response rate (RR) was 31.8% (7 of 22 patients). The toxicities to this regimen on HAI were observed in 12 patients, and grades 3 or 4 were in 3 patients only. These results suggested that HAI with LV/5-FU can be useful for unresectable liver metastases from CRC.     

5-FU pharmacokinetic study of 5-FU hepato-arterial infusion with oral UFT

5-FU hepato-arterial infusion (HAI) is powerful chemotherapy for liver metastases of colorectal cancers. Event though hepatic lesions are controlled by 5-FU HAI, we have found that extra-hepatic lesions are the limiting factor for colorectal cancer patients. General chemotherapy is necessary in addition to 5-FU HAI. The chemotherapy of 5-FU venous infusion plus oral UFT is called "pharmacokinetic modulating chemotherapy (PMC)." This protocol is very effective for colorectal cancers, because UFT reduces the rate of metabolism of infused 5-FU. We studied the plasma 5-FU concentration at the time of weekly high dose 5-FU HAI plus oral UFT. The plasma concentration of 5-FU in 5-FU HAI plus UFT is 1.5-6 times as high as with 5-FU HAI only. 5-FU concentration in the liver tissue is likely to be much higher at the time of 5-FU HAI. 5-FU HAI plus oral UFT can be more effective for not only liver metastases but also for extra-hepatic lesions than 5-FU HAI alone.     

A case of liver and lung metastases of rectal cancer responding well to 5-FU hepato-arterial infusion (HAI) with combined use of oral UFT

We have studied the pharmacokinetics of 5-FU hepato-arterial infusion (HAI) with combined use of oral UFT for colorectal cancer cases previously. The plasma 5-FU concentration in cases of 5-FU HAI plus UFT is 1.5-6 times as high as with 5-FU HAI only. We report a rectal cancer case with liver and lung metastases treated successfully with this protocol. A 75-year-male underwent low anterior resection for rectal cancer as Rab, 3.5 x 3 cm, well, ai, n2, P0, H3, M1 on March 26, 2002. For synchronous hepatic and lung metastases, he received weekly 5-FU 1,000 mg HAI, UFT 4T 2 x postoperatively. As a result, liver and lung metastases disappeared over 6 months. We recommend weekly 5-FU HAI with combined use of UFT, which can be more effective not only for liver metastases but also for extra-hepatic lesion of colorectal cancer.     

Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases

BACKGROUND: Pharmacokinetic modulating chemotherapy (PMC) is a new therapeutic concept in combination with continuous 5-fluorouracil (5-FU) infusion and UFT. UFT enhanced plasma 5-FU concentration and antitumor effects during 5-FU infusion. The authors report on their experiences with arterial 5-FU infusion and UFT after resection of hepatic colorectal secondaries. METHODS: Fifty-eight patients were divided into two groups after hepatectomy. Group A, 30 patients, underwent hepatic arterial infusion (HAI) via implantable port system with perfusion 5-FU for 2 consecutive days per week at 600 mg/m(2)/day, and oral administration of UFT at 400 mg/day for 5-7 days per week, repeated 10 times, and Group B, 28 patients, underwent oral administration of UFT at 400 mg/day for 6 months. All the patients were managed at the outpatient clinic at Hyogo College of Medicine, and recurrence, survival, and toxicity were documented. Plasma 5-FU concentrations during chemotherapy were detected using high performance liquid chromatography. RESULTS: Maximum plasma concentrations of 5-FU in Group A reached 144.0 ng/mL and in Group B 58.7 ng/mL. Cumulative 5-year survival rate after hepatectomy in Group A was 59% and in Group B was 27%. (P = 0.00001) HAI-PMC drastically decreased hepatic recurrence (median hepatic recurrence free times were 34.2 months in Group A vs. 18.4 months in Group B; P = 0.00002). Grade 3 toxicity in Group A was found in 3 patients CONCLUSIONS: Pharmacokinetic modulating chemotherapy was designed as a uracil-related biochemical modulation. HAI-PMC significantly decreased hepatic recurrence after curative resection. This new chemotherapy concept significantly improved prognosis in patients with hepatic colorectal metastases.     

A long survival case of sigmoid colon cancer patient with initially unresectable hepatic metastases

The prognosis of a colorectal cancer patient with unresectable hepatic metastases is extremely poor. To improve the prognosis, when the hepatic metastases were initially unresectable, we performed second-look hepatectomy (s-l hepatectomy) after neoadjuvant hepatic arterial 5-FU infusion plus UFT (HAI-PMC). Here, we report the case of a sigmoid colon cancer patient with initially unresectable hepatic metastases showing a prolonged survival (6.5 years) by second-look operation after HAI-PMC. A 57-year-old woman was diagnosed with sigmoid colon cancer with unresectable liver metastases. Sigmoidectomy and hepatic arterial catheterization were performed in the initial operation, and HAI-PMC was performed 6 months after. Metastatic foci of the liver had shrunk (90.9%), but solitary metastatic lung cancer was detected during HAI. As no other metastatic lesion was observed, partial resection of the liver and lung was performed as a second-look operation, 6 months after the initial operation. The woman continued venous infusion chemotherapy as an outpatient, and she survived for 6.5 years after the initial operation. This result suggests that strategic multidisciplinary treatment utilizing s-l hepatectomy after neoadjuvant chemotherapy can lead to better prognosis for colorectal cancer patients with hepatic metastases.     

Present and future of home anti-cancer chemotherapy for unresectable recurrence of colorectal cancer

Continuous hepatic arterial infusion chemotherapy (HAI) was performed for 100 colorectal cancer patients with unresectable liver metastases in our outpatient clinic. The administration schedule was 5-FU 250 mg/day for 7 days every other week. In this study, 93 cases were evaluable. The average dose of 5-FU was 24 g (3.0-66.5 g). The response rate was 59.1% (CR: 4 cases, PR: 51 cases, NC: 12 cases and PD: 26 cases). The prognostic outcome was significantly prolonged in the effective cases (50% survival duration was as follows: CR: 764 days, PR: 620 days, NC: 255 days and PD: 152 days). The complication rate with HAI was 15.1%, but nobody died from these complications. Hepatectomy after HAI was performed in 19 cases (20.4%) because of the effect of HAI. The three-year survival rate was 35.3% for HAI with hepatectomy and 3.8% for only HAI. There was statistically significant difference (p < 0.0001) between these two groups. Hepatectomy after HAI is a new strategy for unresectable liver metastasis of colorectal cancer. Recently, we performed home systemic chemotherapy using 5-FU for 3 recurrent patients of colorectal cancer and were able to continue this therapy safely for more than 2 months.     

Hepatic arterial infusion (HAI) chemotherapy achieved a complete response (CR) for multiple liver metastases of colorectal cancer--two case reports

We encountered two cases of concurrent multiple liver metastases of colorectal cancer in two patients who achieved a complete response (CR) to hepatic arterial infusion (HAI) chemotherapy. The first case is a 64-year old man who was found to have anemia, and a diagnosis of ascending colon cancer was made. There were 6 metastatic lesions in both lobes of the liver. A right hemicolectomy was performed. Postoperative chemotherapy consisted of 2 g of oral UFT-E as well as 3 mg of CDDP and 500 mg of 5-FU administered by HAI. The metastatic lesions disappeared after 9 courses of chemotherapy were carried out. A partial hepatectomy was performed in the scarred area. Histopathological examination revealed no cancer cells. No recurrence has been observed for 4 years and 10 months since achieving CR. The second case is a 69-year-old man who had thin stool and bloody stool. Rectal cancer was diagnosed. Five metastatic lesions were noted in both lobes of the liver. A low anterior resection was performed. l-LV 25 mg and 5-FU 500 mg were given postoperatively by HAI. After three courses of chemotherapy postoperatively, metastatic lesions disappeared. No recurrence has been noted for 2 years and 1 month since achieving CR. HAI chemotherapy is considered one of the useful treatment options for patients with multiple liver metastases of colorectal cancer.     

Two cases of multiple liver metastases from colorectal cancer which responded well to hepatic arterial infusion (HAI) using 5-fluorouracil and l-leucovorin

We present two cases of multiple liver metastases from colorectal cancer, which did not respond to hepatic arterial infusion (HAI) using 5-fluorouracil (5-FU 1250 mg/body weekly) alone, but responded to HAI using 5-fluorouracil (5-FU 750 mg/body weekly) and l-leucovorin (l-LV 50 mg/body weekly) achieving a complete response (CR). The first case: A 71-year-old man with Stage II rectal cancer who underwent lower anterior resection developed multiple liver metastases 5 months after the surgery. As the weekly HAl using 5-FU for nine courses showed no response, l-LV was combined, and the liver metastases disappeared after 10 courses to achieve CR. The second case: A 65-year-old man with rectal cancer, sigmoid colon cancer and multiple liver metastases underwent lower anterior resection. The weekly HAl using 5-FU for seven courses showed no response. By combining 5-FU to l-LV, the liver metastases disappeared after fifteen courses. No toxic event was observed. In these two cases, it was suspected that a reduced foliate may be responsible for the failure by the 5-FU treatment alone.     

The usefulness of pharmacokinetic modulating chemotherapy (UFT plus 5FU) in the treatment of unresectable colorectal carcinomas

This study was performed to improve the prognosis of unresectable (primary non-curative and recurrent) colorectal carcinoma by using pharmacokinetic modulating chemotherapy (PMC), a combination of oral UFT and continuous venous 5FU infusion. The subjects were 120 patients who were prospectively selected for this study. The patients selected PMC or alternative treatment. Fifty-six patients received PMC. The PMC group received 200-400 mg/body/ day UFT orally 5-7 days per week and 600 mg/m2/24 h 5FU infusion once a week. PMC markedly improved the median survival period (26.6 months vs. 9.2 months P<0.000001). This significant improvement as observed in unresectable primary colorectal carcinoma (P=0.0003), recurrent tumors (P<0.00001), local extension (P=0.01), lung metastases (P=0. 03), liver metastases (P=0.0001), and peritoneal seedings (P=0.02). One of 56 patients who received PMC developed grade 4 toxicity. PMC significantly improved the prognosis of unresectable colorectal carcinoma which has a low survival rate. PMC also indicated tolerable compliance and cost effectiveness.     

A case report of unresectable colon cancer that disappeared following pharmacokinetic modulation chemotherapy (PMC)

We encountered a case of unresectable colon cancer that disappeared following pharmacokinetic modulating chemotherapy (PMC). A 41-year-old male underwent ileotransverse anastomosis following a diagnosis of ileus due to unresectable colon cancer with peritoneal dissemination and multiple liver metastases. He was treated weekly with an intravenous infusion of 5-FU, 1,000 mg/body/24 hours and an oral administration of UFT 400 mg/day (PMC). After 6 months of weekly treatment of PMC, colon tumor disappeared and metastatic liver tumors decreased in size. PMC can be administered to outpatients without serious side effects; thus, this therapy improves the prognosis and the patient's quality of life.     

Chemotherapy for liver metastasis of colorectal cancer

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. Although surgical resection is the first choice of treatment for liver metastasis of colorectal cancer, there are many cases we cannot choose the surgical treatment. The chemotherapy is very important in such cases. We examined 18 cases of unresectable liver metastases from colorectal cancer which were adapted a hepatic arterial infusion of 5-FU (HAI) with a weekly high-dose infusion method (WHF) as the first-line treatment, and then systemic chemotherapy of CPT-11 in combination with 5-FU as the second-line treatment. The response rate of this treatment is 72% (13/18) and the 1-, 2-, 3-year survival rates were 100% (16/16), 83% (10/12), and 50% (5/10), respectively. The combination chemotherapy of HAI with systemic chemotherapy using CPT-11 seemed to be an effective treatment method.     

A case of colon carcinoma with unresectable multiple liver metastases responding to various combined chemotherapies centering on hepatic arterial infusion therapy

We have experienced a case of colon carcinoma with unresectable multiple liver metastases responding to various combined chemotherapies centering on hepatic arterial infusion therapy. A 42-year-old female with descending colon carcinoma and synchronous unresectable multiple liver metastases underwent left hemicolectomy in September 2001. She was treated with chemotherapy centering on hepatic arterial infusion (HAI) following implantation of a reservoir in the outpatient setting. Pharmacokinetic modulating therapy (PMC), and HAI with Leucovorin/CDDP/5-FU and Levoforinate/CDDP/5-FU were conducted sequentially. Alternative HAI of 5-FU with intravenous infusion of Levoforinate and systemic irinotecan/CDDP were continued biweekly after release of the hepatic artery occlusion. Liver metastases shrunk after 6 months of treatment and were remarkably decreased in size in May 2003. Although 3 metastatic lesions existed in both lungs, good quality of life has been maintained in the 2 years following surgery.     

A case of gastric cancer with multiple liver metastases that were completely responsive to hepatic arterial infusion chemotherapy]

A 70-year-old male was hospitalized with a diagnosis of gastric cancer. Multiple liver metastases were detected by CT scan and ultrasonography, but no other metastases were found. After distal gastrectomy with lymphadenectomy, an intra-arterial catheter was inserted and hepatic arterial infusion (HAI) chemotherapy was started with the following regimen: epirubicin, 40 mg (once in 4 weeks); MMC, 4 mg (once in 2 weeks); and 5-FU, 500 mg (once a week). Oral administration of 300 mg/day of tegafur-uracil (UFT) was given concurrently. The metastatic liver tumors were gradually reduced, and then disappeared. The patient has been free from recurrence after HAI. As gastric cancer tends to spread (e.g. peritoneal dissemination) more than colorectal cancer, the indication for HAI in cases of gastric cancer is limited. However, the present case suggests that it may be useful in achieving long-term survival for patients with metastases localized in the liver.     

Results of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for unresectable liver metastases from colorectal cancer

PURPOSE: Hepaticarterial infusional(HAI)5-FU chemotherapy, which involves the use of interventional radiology technique, has matured technically in Japan in the 1990's. The antitumor effect of 5-FU is enhanced by combination with leucovorin. This study was performed to evaluate the efficacy and toxicity of HAI 5-FU and leucovorin chemotherapy for patients with unresectable liver metastases from colorectal cancer. METHODS: Treatment was given to 20 patients with unresectable liver metastases from colorectal cancer. The chemotherapy regimen consisted of weekly HAI of 5-FU(1,000 mg/body)and leucovorin(250 mg/body)over five hours. The survival and response rates to the therapy were assessed according to RECIST. Hematologic and non-hematologic toxicity was assessed according to CTCAE v3.0. RESULTS: Combined HAI 5-FU and leucovorin therapy was carried out an average of 27 times. The response rate for liver tumors was 75%, and the median survival time was 22 months. The applied regimen caused only mild adverse events. There was no evidence of myelosuppression except for platelet decrease(grade 3)in a patient with chronic renal failure. CONCLUSION: This HAI approach using 5-FU and leucovorin was effective and the therapy for unresectable liver metastases from colorectal cancer was tolerated well. Therefore the HAI approach should be reconsidered as an effective therapy against this disease in Japan.     

A case report--combination chemotherapy with oral UFT and CPT-11, 5-FU, l-LV by hepatic arterial infusion for multiple hepatic metastasis from sigmoid colon cancer

A 64-year-old woman was diagnosed with multiple hepatic metastases from sigmoid colon cancer. She underwent resection of the colon and catheter insertion into the hepatic artery for arterial infusion in August 2006. She was then treated with postoperative combination chemotherapy consisting of UFT and CPT-11, 5-FU, l-LV. UFT was administered orally at 400 mg/body/day every day and CPT-11 was injected at 100 mg/body/week, 5-FU at 750 mg/body/week, and l-LV at 300 mg/body/week for 8 continuous weeks. After 2 months of the chemotherapy, the metastatic liver tumors disappeared. So hepatic arterial infusion with the same regimens was injected once every month 4 more times. Oral UFT was administered every day. After 6 months of the combined chemotherapy above, we judged the effects of the chemotherapy to be a complete response. Then the chemotherapy was followed by oral UFT only. As severe nausea and vomiting were seen in this patient with an initial dose of 150 mg/body/week of CPT-11 at first, we reduced the dose of CPT-11 to 100 mg/body/week. From then, outpatient care was possible because no severe events were observed. Combined chemotherapy consisting of oral UFT and CPT-11, 5-FU and l-LV by hepatic arterial infusion is suggested to be a new and effective treatment for multiple liver metastases from colorectal cancer.     

A case of unresectable rectal cancer with liver and pulmonary metastases that responded remarkably to pharmacokinetic modulating chemotherapy

We treated a patient with unresectable rectal cancer with multiple liver, pulmonary and lymph node metastases that responded remarkably to pharmacokinetic modulating chemotherapy (PMC). The patient was a 63-year-old male. Colonoscopy showed a type 3 advanced lower rectal cancer. Examinations by computed tomography and chest X-ray revealed unresectable rectal cancer invading the sacrum and bladder with multiple liver and pulmonary metastases and swollen para-aortic lymph nodes. The patient was treated by colostomy and postoperative PMC. UFT (400 mg/day) was orally administered daily and a continuous infusion of 5-FU (1,000 mg/24 h) was given once a week. After 10 courses of treatment with PMC, the primary lesion was remarkably reduced. This chemotherapy also produced partial responses in the pulmonary metastases and para-aortic lymph node swelling. The patient experienced few side effects and had good QOL in the terminal stage. This chemotherapy regimen appears to be an effective and promising therapy with few side effects, even for patients with unresectable advanced colorectal cancer.     

Combined chemotherapy with oral leucovorin (LV) + tegafur/uracil (UFT) and hepatic arterial infusion (HAI) therapy for liver metastasis of colorectal cancer

The liver is the most frequent metastatic site from colorectal cancer, and the control of liver metastasis is an important issue in the treatment of progressive colorectal cancer. Hepatic arterial infusion (HAI) therapy can achieve a high drug concentration in the liver and relatively low level in the systemic circulation because of the first pass effect of the drug metabolism. With the high response rate, several reports have failed to show a significant survival benefit of HAI monotherapy, partially due to its inability to control extrahepatic metastasis. In this report, we used oral tegafur/uracil (UFT) and Leucovorin (LV) combined with HAI of 5-FU for four patients with liver metastasis of colorectal carcinoma. One of two patients with unresectable multiple hepatic metastases could undergo resectional surgery after 5 courses of this therapy. Two other cases in an adjuvant setting have been surviving free of tumors. In this series, adverse effects of this therapy were acceptable, including one case of grade 3 thrombocytopenia. The benefit of this combined therapy for survival in a case of liver metastasis from CRC remains to be evaluated. We are planning phase I and II clinical studies to evaluate the efficiency and feasibility of this combination therapy.