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.     

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.     

Continuous hepatic arterial infusion of 5-fluorouracil with leucovorin for unresectable liver metastases from colorectal cancer

Twenty-three patients with liver metastases from colorectal cancer were treated by continuous hepatic arterial infusion chemotherapy with 5-FU and Leucovorin. The regimen was that 500 mg/body of 5-FU with 30 mg/body of Leucovorin was administered continuously for 5 days, followed by no medication for 16 days. The effect of this therapy was evaluated and the relationship between this therapy and the overexpression of vascular endothelial growth factor (VEGF) or microvessel density (MVD) was also studied. Complete response was obtained in 4 patients and partial response in 3 patients; the response rate was 32%. The response rate was 60% in patients who underwent more than 7 courses. The response rate was 44% in patients with positive VEGF and 33% in patients with negative VEGF. The response rate was 50% in patients with an MVD of more than 30 and 33% in patients with an MVD of less than 30. The 3-year survival rate for patients who underwent more than 7 courses was 37.5%. This therapy had to be abandoned in 6 patients due to occlusion of the catheter. Skillful maintenance of the catheter is necessary for a high response rate and satisfactory prognosis using this therapy.     

Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of concurrent systemic irinotecan and hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone in patients with unresectable hepatic metastases from colorectal cancer, to determine the safety of this combination in patients who have undergone cryosurgery, and to evaluate the pharmacokinetic effects of HAI FUDR on the metabolism of irinotecan. PATIENTS AND METHODS: Forty-six previously treated patients with unresectable liver metastases and no known extrahepatic disease were treated concurrently with intravenous irinotecan weekly for 3 weeks and with HAI of FUDR and dexamethasone for 14 days (both were recycled in 28 days). Parallel cohorts of patients treated with or without cryosurgery were entered at escalating dose levels. RESULTS: The MTD for patients who did not undergo cryosurgery was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAI FUDR (0.16 mg/kg/d x pump volume/flow rate) plus dexamethasone for 14 days of a 28-day cycle. The dose-limiting toxicities were diarrhea and neutropenia. The response rate (complete and partial) among all patients who did not undergo cryosurgery was 74%. All patients in the cryosurgery group responded, and seven of the eight cryosurgery patients developed normal positron emission tomography scans after chemotherapy. HAI FUDR had no effect on the metabolism of irinotecan. CONCLUSION: Combination therapy with HAI FUDR and dexamethasone plus systemic irinotecan may be safely administered to patients with unresectable hepatic metastases from colorectal cancer. The MTD has been reached for patients with unresectable disease, and we continue to investigate the MTD for patients who have undergone cryosurgery. Although the main objective of this study was to evaluate the toxicity of the combined regimen, a high response rate (74%) was observed.     

A clinical study of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for liver metastases

We followed patients who underwent hepatic arterial infusion chemotherapy (HAI) with 5-FU and Leucovorin for liver metastases. Since CR (complete response) and PR (partial response) were achieved, this therapy seems to be effective. 5-FU metabolized on its first pass through the liver, and the hepatic extraction with rapid HAI is lower than that with slow HAI. It is suggested that control of extrahepatic lesions thought rapid HAI is useful for life prolongation.     

Combination chemotherapy with hepatic arterial infusion of 5-fluorouracil (5-FU) and systemic irinotecan (CPT-11) in patients with unresectable liver metastases from colorectal cancer

PURPOSE: Hepatic arterial infusion (HAI) chemotherapy for hepatic metastasis from colorectal cancer has higher response rates compared with systemic chemotherapy, but can not control extrahepatic lesions. So the combination chemotherapy with HAI plus systemic chemotherapy is expected. This study ascertained the efficacy and toxicity of combined chemotherapy with HAI plus systemic CPT-11. METHODS: Seventeen patients were treated with concurrent HAI 5-FU 700-800 mg/m(2) on day 1, 8, 15, 22 and systemic CPT-11 70-80 mg/m(2) on day 1 and 15. Treatment was repeated every 28 days. RESULTS: The objective response rate for all patients was 76.5% (13 of 17 patients), and time to progression was about 10 months. Median survival time was about 20 months, and no difference was seen in the survival of patients without extrahepatic lesions and patients with extrahepatic lesions (21 months vs 18.5 months; p=0.5). The incidence of new extrahepatic metastasis in patients without extrahepatic lesions was 9% (1 of 11 patients). Grade 3 or 4 neutropenia was found in only 2 patients (11.8%). CONCLUSION: Combination therapy with HAI 5-FU plus systemic CPT-11 may be safely administered to patients with colorectal cancer. The incidence of new extrahepatic metastases was low in comparison with reports of HAI monotherapy.     

Efficacy of 5-FU hepatic arterial infusion with l-leucovorin for patients with unresectable colorectal liver metastasis

We investigated the efficacy of 5-FU hepatic artery infusion (HAI)for patients with unresectable colorectal liver metastasis. Fifteen patients who received HAI between June 2004 and December 2006 were studied. HAI was attempted as first-line chemotherapy in seven patients(Group A)and as second-line or more in eight(Group B). The response rate, time to progression, survival and toxicity were compared with those of 39 patients treated with systemic chemotherapy(18 as first-line: Group C, 21 as second-line or more: Group D). Response rate was 85.7%, 35.7%, 50.0%, and 4.8% in Groups A, B, C, and D, respectively. Time to progression was 12.5 months, 4.7 months, 5.8 months, and 2.3 months, in Groups A, B, C, and D, respectively, and significantly longer in Group A compared with Group C, as well as in Group B compared with Group D. Median survival was 15.4 months, 9.1 months, 11.3 months, and 8.0 months in Groups A, B, C, and D, respectively, and significantly longer in Group B compared with Group D. Grade 3 or 4 non-hematological toxicity was not observed in Group A and B. HAI was effective for the control of unresectable colorectal liver metastasis and improved survival as second-line chemotherapy or more.     

Evaluation of hepatic arterial infusion chemotherapy with low-dose leucovorin and 5-FU from reservoir for multiple liver metastases by colorectal cancer

5 patients with colorectal cancer with multiple liver metastases underwent resection of primary lesions. We then evaluated the effects of hepatic arterial infusion chemotherapy with low-dose leucovorin and 5-FU. Weekly, dl-leucovorin of 30 mg/body or l-leucovorin of 25 mg/body was administered as a bolus, then 5-FU of 500 mg/body was administered for 1 hour through the hepatic artery from the subcutaneous reservoir on an outpatient basis. 2 of 5 patients achieved a CR of liver metastases, but later 1 of these 2 cases had metastases of bone and lung. No adverse effects, such as nausea, vomiting, diarrhea or bone marrow suppression, were seen after this treatment in any of the patients.     

Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days. RESULTS: The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection. CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.     

Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.     

Phase I trial of hepatic arterial infusion (HAI) of floxuridine with modified oxaliplatin, 5-fluorouracil and leucovorin (m-FOLFOX6) in Chinese patients with unresectable liver metastases from colorectal cancer

Purpose

Chemoradiotherapy followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer. Although this approach decreases the risk of local recurrence, pelvic radiation is associated with long-term morbidity and delays systemic treatment. We conducted this study to evaluate the feasibility of neoadjuvant capecitabine and oxaliplatin (XELOX) plus bevacizumab as a treatment for high-risk localized rectal cancer.

Methods

Patients with T4 or lymph node-positive rectal cancer were treated with three cycles of XELOX plus bevacizumab and one additional cycle of XELOX. This was followed by TME performed 3–8 weeks after the last chemotherapy session.

Results

Twenty-five patients were recruited between December 2009 and November 2011. In seven of the patients (28.0 %), grade 3–4 adverse events occurred. After preoperative chemotherapy, the frequency of tumor (T) downstaging was 69.6 %, and that of lymph node (N) downstaging was 78.9 %. Seven patients discontinued the treatment after 2–3 cycles of XELOX plus bevacizumab. The frequency of subsequent surgery was 92 %, and all patients underwent R0 resections. Postoperative complications occurred in six patients (26.1 %). One patient achieved a pathological complete response (pCR) for the primary tumor and lymph nodes, whereas an additional four patients achieved near-pCR. After a median follow-up of 31 months, five patients displayed metastatic progression, including one who suffered local recurrence.

Conclusions

XELOX plus bevacizumab followed by TME is feasible for high-risk localized rectal cancer, as it achieves good tumor regression and causes manageable toxicity.     

UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer

A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.     

Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer

Purpose To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. Experimental Design Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m² as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m² bolus i.v. and leucovorin 20 mg/m² i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m² and 5-FU to 500 mg/m². Results Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3–4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. Conclusions Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.     

Validity of two-hour continuous hepatic arterial infusion chemotherapy with low-dose 5-FU for unresectable liver metastasis from colorectal cancer

The significance of hepatic arterial infusion chemotherapy for unresectable liver metastases from colorectal cancer was evaluated in 50 patients, who received either of the following regimens: 1 shot 5-FU + epirubicin + MMC (FAM group); hepatic arterial infusion of 5-FU for 2 hours + MMC (MF group); hepatic arterial infusion of 5-FU for 2 hours (5-FU group). There were no differences in the clinicopathological backgrounds of the patients among the groups. The mean survival time was 10.3 months, 16.0 months and 16.2 months in the FAM, MF and 5-FU groups. The effective percentages were 0%, 40% and 31% in the FAM, MF and 5-FU groups and the survival time of the effective cases was 18.1 months and 21.8 months in the MF and 5-FU groups. The MF group and 5-FU group showed significant improvement in prognosis. Concerning side effects, myelo-suppression and gastrointestinal toxicity appeared frequently in the MF group. In conclusion, 2-hour continuous hepatic arterial infusion with low-dose 5-FU for unresectable liver metastases from colorectal cancer may be helpful for improvement of prognosis.     

Five-hour hepatic arterial infusion of high-dose 5-FU on weekly schedule for liver metastases from colorectal cancer

The study of 5-hour hepatic arterial infusion of high-dose 5-FU on a weekly schedule (weekly high-dose 5-FU HAI: WHF) was conducted to reveal a new pump-free regimen to avoid the reduction of QOL due to continuous infusion pumps. By the phase I study, the recommended dose was determined to be 1.000 mg/m2/5 hrs qw. Thus far, 20 cases entered the phase II study of this regimen, and 1 CR and 10 PRs were observed in 15 evaluated cases without major toxicity. This regimen is highly effective for liver metastases from colorectal cancer without reduction of QOL in patients by pumps. A study of this regimen involving a large number of cases is required.     

Second-look hepatectomy after 5FU arterial infusion in patients with primary unresectable hepatic colorectal metastases

We treated primary unresectable hepatic colorectal metastases by hepatic arterial chemotherapy (HAC) combined with resection of the tumor. Patients underwent a resection of the primary colorectal tumor and a placement of HAC system, and received a 5-fluorouracil (5FU) administration once a week (320 mg/m(2)/day). Five patients underwent a 'second-look' hepatectomy in this series. Their shrinkage rate of the primary lesion ranged from 80-99%, as seen by computed tomography. The resected liver tumors were characterized as p53-positive and proliferating cell nuclear antigen-positive. The levels of fluorodeoxyuridylate (FdUMP) and thymidylate synthetase inhibition were low in the tumor tissue. These results might reflect a kind of resistance to 5FU therapy. Hepatectomy is one of the possible options to eradicate the residual SFU-resistant component of the malignancy. Our preliminary experience possibly indicates longer survival from combination approach than from HAC alone.     

Phase I dose-escalation trial of irinotecan with continuous infusion 5-FU first line, in metastatic colorectal cancer

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m(-2)) in combination with 250 mg m(-2) 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m(-2). However, three out of five patients at the 100 mg m(-2) irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m(-2). The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m(-2)) combined with a continuous infusion of 5-FU (250 mg m(-2)) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study.     

Hepatic arterial infusion (HAI) chemotherapy for liver metastases of colorectal cancer using 5-FU

Thirty-three patients with liver metastases of colorectal cancer were treated by intra-arterial 5-FU chemotherapy. The median survival time of all patients was 14 months. A partial remission could be observed in nine patients, and a further 15 patients had stable disease. Patients were treated on an outpatient basis and the toxicity of treatment was mild. We observed no case of sclerosing cholangitis or chemical hepatitis. Intra-arterial 5-FU chemotherapy provided treatment results similar to those reported for FUdR but with less hepatobiliary toxicity.