Continuous infusion of hepatic arterial irinotecan in pretreated patients with colorectal cancer metastatic to the liver

J. M. G. H. van Riel1, C. J. van Groeningen2, J. de Greve3, G. Gruia4, H. M. Pinedo2 and G. Giaccone2,*

1 Department of Internal Medicine, St Elisabeth Hospital, Hilvarenbeekseweg 60, 5000 LC Tilburg, The Netherlands; 2 Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; 3 Vrije Universiteit Brussels, Belgium; 4 Aventis Pharma, Antony, France

Received 14 May 2003; revised 13 August 2003; accepted 11 September 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Irinotecan is an active drug in colorectal cancer. In patients with liver metastases, hepatic arterial infusion of irinotecan could theoretically result in higher exposure to the drug. In order to determine the efficacy of hepatic arterial irinotecan we conducted a phase II study in pretreated patients with liver metastases of colorectal cancer.

Patients and methods:

Patients with measurable liver metastases of colorectal cancer with World Health Organization performance status (WHO PS) <2 were treated with a 5-day continuous infusion of hepatic arterial irinotecan every 3 weeks at a dose of 20 mg/m2/day.

Results:

Of the 25 patients included, 22 were evaluable for response. Three of 22 patients (13.6%) had a partial response, nine (40.9%) had stable disease and 10 (45.4%) had progressive disease. No complete responses were observed. Median time to progression was 2.8 (range 1.2–23.8) months. Major toxicities were vomiting and diarrhea. There was no major hematological toxicity.

Conclusions:

Five-day continuous hepatic arterial infusion of irinotecan 20 mg/m2/day has low activity in patients with liver metastases of colorectal cancer previously treated by chemotherapy.

Key words: clinical trial, colorectal cancer, intra-arterial chemotherapy, irinotecan, liver metastases, phase II study


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The liver is involved in 35–60% of patients with metastatic colorectal cancer and in ~40% of patients the liver is the only metastatic site. Patients with liver metastases have a poor prognosis with reported 1- and 3-year survival rates of 31% and 2.6%, respectively [14]. In selected patients, surgical resection of liver metastases of colorectal cancer results in a 5-year overall survival of 39% [5]. However, surgery is feasible in only a minority of patients and most patients are treated with systemic chemotherapy.

Hepatic arterial chemotherapy is a liver-directed approach that has been studied for many years. The main advantage of hepatic arterial chemotherapy over systemic chemotherapy is the achievement of higher drug concentrations at the site of the tumor at the cost of less systemic toxicity [68]. Despite the significantly higher response rates observed with hepatic arterial treatment, most phase III studies comparing intravenous (i.v.) 5-fluorouracil (5-FU) with hepatic arterial fluorodeoxyuridine (FUDR) or 5-FU do not report a significant prolongation of survival with hepatic arterial treatment compared to i.v. treatment, even when meta-analyses were performed [916].

Irinotecan is an active drug in first- and second-line treatment of advanced colorectal cancer [1719]. Theoretically, it might be of value in the liver-directed treatment of disease confined to the liver. In a phase I and pharmacokinetic study performed at our institute with 5-day continuous hepatic arterial infusion of irinotecan, the recommended dose advised for further phase II studies was 20 mg/m2/day [20]. Diarrhea and neutropenia were the dose-limiting toxicities at a dose level of 25 mg/m2/day. The pharmacokinetic evaluation of this phase I study showed an increased metabolism of irinotecan with increased systemic levels of the active metabolite SN38 during hepatic arterial infusion compared to i.v. infusion. However, the latter did not result in increased systemic toxicity. Because pharmacokinetics do not reflect the intratumoral concentrations during hepatic arterial infusion and, since the drug is delivered directly into the liver, it is likely that the liver metastases are exposed to higher concentrations of the drug than during i.v. administration. We conducted a phase II study in order to deter-mine the efficacy of 5-day continuous infusion of hepatic arterial irinotecan in patients with liver metastases of colorectal cancer.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient selection
Patients were eligible if they had a histologically or cytologically documented colorectal cancer metastatic to the liver and not amenable to surgery. The liver metastases should be measurable, with a size ≥2 cm. The presence of extrahepatic sites of disease was only allowed if the bulk of the disease was in the liver. Performance status had to be ≤2 (WHO criteria), life expectancy ≥3 months and age ≤70 years. The anatomy of the liver arteries defined by angiography had to allow placement of a catheter into the hepatic artery for adequate liver perfusion. Other criteria for eligibility were white blood cell count ≥4 x 109/l, platelet count ≥100 x 109/l, serum transaminases ≤2 x the upper limit of normal, prothrombin time ≤1.25 the upper limit of normal, serum bilirubin ≤20 µmol/l and serum creatinine ≤110 µmol/l or creatinine clearance ≥60 ml/min. No more than two prior chemotherapy regimens were allowed and the last chemotherapy or prior radiotherapy had to be discontinued at least 4 weeks prior to study entry, or 6 weeks for nitrosureas and mitomycin C. Exclusion criteria were prior treatment with topoisomerase I inhibitors, a history of inflammatory bowel disease or extensive intestinal resection, central nervous system involvement, uncontrolled infection, and a history of other cancer except adequately treated in situ carcinoma of the cervix or basal or squamous carcinoma of the skin. The study protocol was approved by the Medical Ethical Committee of the participating hospitals, and all patients gave written informed consent before study entry.

Treatment
Irinotecan was administered as a 5-day continuous infusion every 3 weeks at a dose of 20 mg/m2/day. In case of grade 3 or 4 non-hematological toxicity (other than nausea, vomiting or alopecia), grade 4 neutropenia, or febrile neutropenia, the dose was reduced by 25% in subsequent cycles. If a patient developed grade 3 or 4 non-hematologic toxicity or grade 4 neutropenia, despite two successive dose reductions, the patient went off study. Other reasons for treatment termination were progressive disease, hematological or non-hematological toxicity persisting for more than 5 weeks (2-week delay), or patient refusal. Prophylactic anti-emetic treatment was allowed.

Drug administration
Hepatic arterial infusion was performed either by percutaneous catheterization of the femoral artery or by placement of an arterial port-a-cath (Deltec, SIMS Deltec, Inc., St Paul, MN, USA). The arterial port-a-cath was inserted by laparotomy, and the tip of the catheter was placed in the ligated gastroduodenal artery. A cholecystectomy was performed to prevent chemical cholecystitis. Irinotecan (Campto; Rhone-Poulenc Rorer, Anthony, France) was supplied in 5-ml vials with sterile solution, containing irinotecan 100 mg. The appropriate volume of irinotecan was added to an infusion bag containing 1000 ml of 0.9% sodium chloride or 5% dextrose for patients treated with catheter and bedside pump or diluted to 250 ml for patients treated with port-a-cath and portable pump. For bedside pumps the infusion rate was 1000 ml/day and for the portable pump 41 ml/day. Patients with a bedside pump received prophylactic subcutaneous heparin to prevent deep venous thrombosis. Patients with an arterial port-a-cath received no anticoagulant therapy.

Study end points
The primary objective of this study was to determine the response rate and the duration of response to a 3-weekly 5-day continuous hepatic arterial infusion of irinotecan. The secondary objective was to characterize the toxic effects of this regimen.

Evaluation of response and toxicity
Response was evaluated every 6 weeks by a computed tomography (CT) scan of the liver and measurement of other evaluable lesions. Ideally all measurable lesions were measured at each assessment; however with multiple liver metastases at least three representative lesions were selected. Lesions were measured by the sum of the products of the largest perpendicular diameters of all measurable lesions. Complete response was defined by disappearance of all known disease determined by two observations not <4 weeks apart. Partial response was a decrease of at least 50% as determined by two observations not <4 weeks apart. It was not necessary for all lesions to have regressed to qualify for partial response, but no lesion should have progressed and no new lesions have appeared. Stabilization was defined as tumor decrease <50% and increase <25%. Progressive disease was defined as ≥25% increase or the appearance of new lesions. Time to progression and survival were calculated from the start of therapy until progression of disease or death.

Pretreatment evaluation included a complete history and physical examination, a complete blood cell count, blood chemistry tests including creatinine, alkaline phosphatase, {gamma}-glutamyl-transferase, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), bilirubin and prothrombin time. These tests were repeated before each course. Before the first course and every other course thereafter an ECG, a chest X-ray and an abdominal CT scan were performed. On day 3 of the irinotecan infusion, serum bilirubin, ALAT and ASAT were also repeated. Hematology, bilirubin, ASAT and ALAT were evaluated weekly during treatment. All toxicities were scored according to National Cancer Institute Common Toxicity Criteria.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
Twenty-five patients were entered on the study. Table 1 lists the patient characteristics. All patients had prior chemotherapy for metastatic colorectal cancer, most being 5-FU containing regimens. The median time between the last chemotherapy and study entry was 5 (range 2–41) weeks. The median number of prior regimens was one [13].


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Table 1. Patient characteristics
 
Treatment received
In the 25 patients included, a total of 123 treatment courses were delivered. The median number of treatment courses delivered was four (range 1–13). The relative dose intensity was 0.96 (range 0.76–1.10). Three patients required dose reduction, two because of non-hematological toxicity and one because of both hematological and non-hematological toxicities. Only two of 123 treatment courses were delayed for drug-related non-hematological toxicity. The reasons for treatment discontinuation were progressive disease in 17 patients, withdrawal of consent in two patients after 11 and 13 courses, respectively, dislocation of the port-a-cath catheter into the biliary tract after the fifth course in one patient, neutropenic fever after the sixth course in one patient, cumulative gastrointestinal toxicity (vomiting, diarrhea and anorexia) after the fifth course in one patient, fatal gastrointestinal bleeding in one patient after the fifth course, hepatic artery thrombosis after the first course in one patient, and death due to acute myocardial infarction after the first course in one patient.

Response evaluation
One patient included in the study was not eligible because of a history of breast cancer and because she had more than two prior treatment regimens for metastatic colorectal cancer. Two patients were not evaluable for response because they went off study after the first cycle, one patient because of hepatic artery thrombosis and one patient due to fatal acute myocardial infarction. As a result, 22 patients were eligible and evaluable for response. Of these 22 patients, three (13.6%) had a partial response, nine (40.9%) had stable disease (including four patients with minor response) and 10 (45.4%) had progressive disease. No complete responses were observed. The median time to progression was 2.8 (range 1.2–23.8) months. With a median follow-up of 2.9 years, median survival was 8.1 (range 0.3–31.4) months. The first site of progression was located in the liver in 18 patients, outside the liver only in three patients and not known in four patients.

Toxicity
Adverse events observed in >5% of patients are listed in Table 2. Vomiting (seven of 25, 28%), diarrhea (seven of 25, 28%) and alopecia (three of 25, 12%) were the most frequently observed grade 3 or 4 toxicities. Furthermore, most patients (17 of 25, 68%) developed mild (grade 1–2) asthenia. There was no serious hematological toxicity. Only one of 25 (4%) patients developed a grade 4 leukopenia. Grade 3–4 neutropenia and grade 3–4 thrombocytopenia were not observed. Two patients died within 30 days after the end of treatment. One patient experienced a lethal acute myocardial infarction 9 days after the start of the first cycle. The other patient died as a result of massive upper intestinal bleeding after the fifth cycle.


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Table 2. Number of patients with adverse events observed in >5% of patients during treatment that were possibly or probably related to treatment
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
At present, systemic chemotherapy is the only established treatment in patients with liver metastases of colorectal cancer, who are not eligible for surgery. Irinotecan is an active drug in colorectal cancer, with response rates of 13–27% observed in phase II studies of both chemo-naïve and 5-FU-pretreated patients using a weekly or 3-weekly i.v. schedule [17, 21]. A phase III study comparing irinotecan to best supportive care in 5-FU refractory patients showed a survival benefit of 2.7 months [22]. In patients with mainly liver metastases of colorectal cancer, studies have been performed using regional chemotherapy. Although high response rates are observed, the results of hepatic arterial 5-FU or FUDR infusion are inconclusive with respect to survival [916]. In a phase I and pharmacokinetic study of a 5-day continuous hepatic arterial infusion, we observed an increased metabolism of irinotecan to its active metabolite SN38. There was, however, no hepatic extraction of the drug [20]. Because the drug levels in the hepatic metastases could be significantly higher after hepatic arterial infusion than after i.v. infusion, a phase II study of a homogeneous patient population was necessary to evaluate the efficacy of hepatic arterial treatment with irinotecan.

The present study examined 5-day continuous hepatic arterial infusion of irinotecan 20 mg/m2/day in patients with liver metastases of a colorectal cancer. An overall response rate of 13.6% was observed. The median time to progression was 2.8 months, and the median overall survival 8.1 months. There was no serious hematological toxicity observed in our study and the non-hematological toxicities observed were well manageable.

Comparing our study to studies employing irinotecan i.v. in pretreated patients with colorectal cancer is difficult, due to the different mode of administration (i.v. versus hepatic arterial) and the liver being the major site of disease in our study. However, the response rate observed is comparable to the response rates observed in phase II studies of i.v. irinotecan in 5-FU-pretreated and 5-FU refractory patients [17, 21]. Earlier findings in a phase I and pharmacokinetic study on 5 days continuous hepatic arterial infusion showed higher conversion of irinotecan to its active metabolite SN38 with hepatic arterial infusion compared to i.v. infusion of the same regimen [20]. This is most probably due to the high carboxyl esterase content of the liver. Furthermore, direct hepatic arterial infusion theoretically would result in higher drug levels at the metastatic site. Despite these potential advantages, the response rate observed in our study does not suggest superiority of hepatic arterial infusion over i.v. infusion. However, for a direct comparison a randomized trial of hepatic arterial versus i.v. irinotecan is needed. Systemic distribution of the metabolite SN38 and failure of entrapment into the liver metastases might be an important cause. Furthermore, the schedule used in our study might be less effective than shorter infusions of higher dosages. There are, however, indications that prolonged infusion of irinotecan is more active than short bolus administration of irinotecan. Irinotecan is a cell cycle specific drug and as a consequence its activity is thought to be dependent on the exposure time rather than on the peak concentration reached. Although in preclinical models the activity of CPT-11 is highly schedule-dependent with enhanced activity during protracted dosing [2325], the activity of prolonged infusion schedules has not been tested in patients with colorectal cancer. There are no studies comparing continuous to bolus i.v. infusion. Another possibility is to lower the dose level considering the minor toxicities observed in our study. However, in the phase I study 5 days continuous infusion of 20 mg/m2/day was the maximal tolerated dose [20].

Recently, phase III studies in colorectal cancer comparing combination chemotherapy consisting of 5-FU, leucovorin and irinotecan or oxaliplatin with 5-FU and leucovorin showed promising results. 5-FU, leucovorin and irinotecan given in a weekly or 2-weekly schedule showed response rates up to 49%, and a significant prolongation of the median overall survival of about 2 months compared to 5-FU/leucovorin or irinotecan monotherapy with response rates of 18–26% for the single-agent regimens [26, 27]. Combination treatment with 5-FU, leucovorin and oxaliplatin resulted in an overall response rate of 50.7% whereas 5-FU/leucovorin showed a response rate of 22.3%. However, no significant prolongation of survival was found [28]. These studies show that in patients with colorectal cancer, combination therapy is active. As with hepatic arterial 5-FU or FUDR, the high response rates obtained with combination treatments result in small improvement of survival and more effective regimens are warranted. However, the results obtained with combination systemic treatment with the newer agents challenge the use of hepatic arterial therapy in first-line colorectal cancer with its technical difficulties and complications related to hepatic arterial delivery [29]. In conclusion, based on the results of our study, single-agent 5-day continuous hepatic arterial infusion of irinotecan 20 mg/m2/day does not appear to offer advantages over i.v. administration. However, because of the lack of hematological toxicity it might be suitable for combination with other drugs in order to improve efficacy.


    FOOTNOTES
 
* Correspondence to: G. Giaccone, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel: +31-20-4444321; Fax: +31-20-4444079; E-mail: G.Giaccone{at}vumc.nl Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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