1 Department of Oncology, 3 Department of Surgery, 6 Department of Radiology and Department of Hepato-Gastroenterology, CHU Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil; 2 Department of Oncology and Department of Radiology, Centre Claudius Régaud, Toulouse; 4 Centre Jean Bernard, Le Mans; 5 Department of Surgery, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France; 7 International Drug Development Institute, Brussels, Belgium
Received 25 February 2003; revised 16 May 2003; accepted 4 June 2003
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Abstract |
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The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer.
Patients and methods:
Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m2 on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter.
Results:
The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months.
Conclusion:
The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.
Key words: colorectal cancer, hepatic artery infusion, irinotecan, liver resection, pirarubicin
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Introduction |
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Pirarubicin (THP-Adriamycin, Theprubicine®; Aventis Pharma, France) is an hemi-synthetic anthracycline with a pharmacokinetic profile favouring locoregional therapy and thus HAI [9]. From a phase I study, its recommended dose as a single agent for HAI is 60 mg/m2 over 40 min every 3 weeks with an excellent feasibility allowing further dose escalation according to tolerance [14]. Moreover, pirarubicin can be given on an outpatient basis or during a short hospital stay and is therefore more convenient and cost-effective than protracted FUDR. In a pilot study, pirarubicin administered through the hepatic artery yielded a 33% objective response rate in patients with liver metastases from colorectal cancer [15].
Because extra-hepatic recurrence is a major issue in patients treated by HAI chemotherapy [10], a combination of i.v. chemotherapy (IVC) and HAI chemotherapy is a logical treatment strategy for patients with metastases confined to the liver. If this strategy proves optimal, substantial improvements in survival might be expected, with a high degree of conversion from initially non-resectable to resectable patients after therapy. Based on this rationale, the European Association for Research in Oncology conducted a phase II trial with i.v. 5-FU/LV and irinotecan combined with HAI pirarubicin in patients with non-resectable liver metastases from colorectal cancer.
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Patients and methods |
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Procedures and treatment
Patients received IVC and HAI concurrently. Each 28-day cycle consisted of i.v. irinotecan given over 60 min at a dose of 150 mg/m2 on days 1 and 15; followed on days 1, 2, 15 and 16 by i.v. LV 200 mg/m2 over 2 h, i.v. bolus 5-FU 400 mg/m2 and i.v. infusional 5-FU 600 mg/m2 over 22 h. Appropriate antiemetic premedication, including a setron and a corticosteroid, was given. Irinotecan-related cholinergic syndrome was prevented by atropine 0.25 mg given subcutaneously before infusion in the absence of contraindications. HAI pirarubicin was given at day 16 of each cycle at a dose of 60 mg/m2 via a 60-min infusion. Hepatic artery catheters were inserted using standard interventional radiological techniques via a femoral route. The proper situation of the catheter was verified by abdominal radiography and its permeability was controlled before intra-arterial infusion. After removal of the catheter, the puncture site was compressed for 12 h and was monitored for signs of bleeding, haematoma or sepsis. Permanent intra-arterial devices with a subcutaneous infusion chamber were allowed as an alternative to hepatic artery catheterisation.
Toxicity and response assessment
In the case of an objective tumour response, treatment was to be continued for up to nine cycles. Therapy was to be stopped in the case of tumour progression, unacceptable toxicity or the patients refusal to continue. Tumour measurements were carried out every two cycles according to WHO criteria. In the case of an objective response, a confirmatory CT was required at 4 weeks. Blood counts were carried out weekly and liver chemistry, ionogram and serum creatinine were done before each cycle. Coagulation was controlled before each HAI. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria.
Dose adjustments
In the absence of toxicity during the first two cycles, the dose of irinotecan was subsequently increased to 180 mg/m2. Doses were to be reduced in the case of febrile neutropenia or grade 4 neutropenia, grade 4 thrombocytopenia, grade 3/4 diarrhoea, grade 3/4 mucositis, grade 3/4 bilirubinaemia, increase of transaminases or alkaline phosphatases >5x ULN, grade 3/4 nausea or vomiting and severe handfoot syndrome. The dose of irinotecan was reduced to 120 mg/m2 at days 1 and 15, and pirarubicin was reduced to 50 mg/m2 at day 16. In the case of toxicity occurring after a first dose reduction, subsequent doses were modified as follows: days 1 and 15, irinotecan 100 mg/m2; days 1, 2, 15 and 16, bolus 5-FU 300 mg/m2; days 1, 2, 15 and 16, infusional 5-FU 500 mg/m2; day 16, intra-arterial pirarubicin 40 mg/m2 (LV was not reduced). No further dose reductions were allowed and if severe toxicity occurred after the second dose adjustment, patients were removed from the study. In the case of any dose adjustments, further escalation was not allowed.
Chemotherapy was re-instituted after haematological recovery (neutrophils and platelet counts >1500 and >100 000/mm3, respectively) and recovery of all other toxicities to grade 0 or 1. Cycle delay >2 weeks was not permitted, and in this case patients were removed from the study.
Statistical considerations
The study was conducted using the two-stage design of Simon [17] with a planned accrual of 20 patients in step I and up to eight patients in step II. Six objective responses were to be observed in the step I accrual to proceed to the step II assuming the following hypotheses: null hypothesis: response rate <30%; alternative hypothesis: response rate >60%; type I error = 0.05; type II error = 0.05.
The primary end point was the objective tumour response rate and secondary end points were duration of response, time to progression, the proportion of patients benefiting from liver resection after tumour reduction, overall survival and treatment tolerance. Time to progression and survival were recorded from the day of inclusion. The KaplanMeier method was used to estimate survival [18].
Results of the study are strictly expressed following the intention-to-treat principle without excluding any patients.
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Results |
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Liver resection was made possible according to the criteria mentioned above [16] in 11 responding patients initially considered as inoperable (35%; 95% CI 21% to 53%). Patient characteristics and surgical procedures are given in Table 2. The margins of liver resections were free of any tumour deposit (R0 resection) in nine patients. After surgery most patients received consolidation chemotherapy with the same i.v. regimen without HAI for 23 months.
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Overall survival and time to progression
The median overall survival was 20.5 months for the entire population. In patients with R0 resection, median overall survival was not reached, whereas it was 13.9 months in the other patients. Two- and 3-year survivals were 100% and 65%, respectively in patients with R0 liver resection, and 22% and 15% in the other patients (Figure 1). Median progression-free survival was 9.1 months for the entire population. In patients with R0 resection, median progression-free survival was 20.2 months, whereas it was 4.2 months in the other patients. Two-year progression-free survival was 42% in patients with R0 liver resection, versus 0% in the other patients (Figure 2).
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A total of 141 arterial catheterisations were carried out, using interventional radiological techniques in 120 cycles and surgery in 21 cycles. Severe complications were uncommon and included non-functional catheter (n = 3), failure of hepatic artery catheterisation (n = 2), pain during HAI (n = 2), extravasation (n = 2), arterial thrombosis (n = 1), haematoma (n = 1) and non-complicated haemorrhage (n = 1).
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Discussion |
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Based on these considerations, the present study is an attempt to combine HAI and IVC in order to achieve an antiproliferative action on both hepatic and non-hepatic sites. A medico-economic study carried out on the meta-analysis dataset showed that most of the extra costs associated with HAI FUDR were related to the use of implantable pump devices [11]. A secondary objective of the present study was therefore to improve the feasibility of the HAI procedure and to decrease its cost.
The combination of irinotecan with 5-FU/LV regimens is now widely considered as one of the most active chemotherapy regimens in patients with advanced colorectal cancer. Such regimens have yielded tumour response rates ~50% in several phase III studies, and median survivals between 20 and 24 months with tolerable toxicity [6, 7].
In the present study, the choice of pirarubicin for the HAI chemotherapy was based on its pharmacological properties, and efficacy in early trials. Previous studies have demonstrated the hepatic metabolism of pirarubicin [9, 14, 15], and in a pilot study HAI pirarubicin yielded a 33% response rate in liver metastases from colorectal cancer [15]. Moreover, both feasibility with a temporary percutaneous catheter and tolerance of HAI pirarubicin are excellent.
The multimodal therapy used in the present study led to a 48% tumour response rate (15 of 31 patients), and to a 20.5 months median survival. When analyses are restricted to eligible and evaluable patients, the tumour response rate was 56% (15 of 27). The feasibility of the investigational regimen was generally good, with no toxic deaths, no severe complications related to repeated catheter placement, and manageable haematological toxicity.
Many of the goals of this study were achieved. The treatment used safely combined one of the most active i.v. regimens and an active HAI drug. The vast majority of the patients were treated using a repeated radiological insertion of an HAI catheter without significant complications. Finally, this approach resulted in a dramatic decrease in the risk of extra-hepatic failure as compared with HAI only approaches, and liver surgery was made possible in one-third of the patients, most of them having major liver involvement before chemotherapy. Interestingly, the survival of patients who remained inoperable after treatment was relatively poor compared with usually reported survival for patients receiving i.v. 5-FU/LV plus irinotecan [6, 7], whereas patients with R0 resection had a favourable outcome. Although this kind of comparison must be considered with caution, this result indicates that the patients included in the trial had pejorative prognostic factors.
The results presented here compare favourably with recently reported studies using HAI plus IVC [2022]. For example, in the trial reported by Copur et al. [21] using i.v. 5-FU, oral LV and HAI FUDR, the response rate was 45%, median progression-free survival 6 months, and median overall survival 13 months. In the trial recently reported by Kemeny et al. [22] using i.v. irinotecan and HAI FUDR, the response rate was 74% but median progression-free survival was 8.1 months and median overall survival was 17.2 months.
In conclusion, our study confirms that a relatively aggressive approach, combining i.v. and HAI chemotherapy, deserves further investigations. However, even though the combination used in this trial allowed metastasectomy in one-third of the patients, overall response rate and survival were not dramatically superior to best results reported with most recent IVC regimens. A synergistic or even additive effect between the i.v. and HAI regimens chosen must therefore be questioned, and further research should also address this issue.
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Acknowledgements |
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Footnotes |
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References |
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