1 Institut Gustave Roussy, Villejuif; 2 Institut Val dAurelle, Montpellier; 3 Centre François Baclesse, Caen; 4 Clinique Courlancy, Reims; 5 Centre Paoli Calmette, Marseilles; 6 Hopital Croix Rousse, Lyon; 7 Centre Oscar Lambret, Lille; 8 Centre René Gauducheau, Saint Herblain; 9 CHR Bordeaux, Pessac; 10 Laboratoire Aventis France, Paris; 11 Hopital Ambroise Paré, Boulogne, France
Received 5 November 2002; revised 16 December 2002; accepted 27 January 2003
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Abstract |
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A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy.
Patients and methods:
From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis.
Results:
Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively.
Conclusions:
In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.
Key words: colorectal cancer, hepatic arterial chemotherapy, liver metastases, pirarubicin
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Introduction |
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When metastases are unresectable but confined to the liver, arterial hepatic infusion (HAI) can be a valid therapeutic option. Used in these conditions, several studies have shown that HAI chemotherapy was able to increase response rates [4, 5]. The rationale for HAI has been extensively reported, and results from the livers dual blood supply and the clearance by the liver of many drugs. Briefly, it was demonstrated that liver metastases larger than 1mm are irrigated by the hepatic artery, whereas normal tissue liver is supplied by the portal vein, and that the hepatic clearance of many drugs before extra-hepatic passage allows one to increase, by a factor of 10100, the drugs exposure in the tumoral site and to reduce greatly the systemic side-effects [46].
Arterial hepatic infusion efficacy has been demonstrated in randomized trials using arterial infusion of 5'-deoxy-5-fluorouridine (FUDR), using an implanted pump (Infusaid 400; Infusaid Inc., Norwood, MA) and results in a significant increase of both the tumoral response rates in all studies [712] and the overall survival compared with symptomatic treatment or intravenous 5-fluorouracil (5-FU) bolus chemotherapy in two studies [12, 14]. The benefits of hepatic intra-arterial chemotherapy (HAIC) have been well illustrated in meta-analysis [13], and suggest an increase in median survival of 16 versus 12 months in favor of HAI, so encouraging the continued use of HAIC and the use new drugs, despite hepatic toxicity and systemic recurrences [13]. In contrast, a significant difference in terms of quality of life was not shown between HAIC and i.v. treatment [14, 15]. Finally, a medical economic study showed that the balance of cost/efficiency seemed to be acceptable for HAIC treatment [16].
Pirarubicin (THP)doxorubicin is an anthracycline obtained by hemisynthesis of daunorubicin or doxorubicin. It is rapidly incorporated into tumor cells and shows antitumor activity by inhibiting nucleic acids synthesis, followed by cell death due to cessation of the cell cycle at the G2 phase. Like other anthracyclines, i.v. administration of pirarubicin demonstrates good clinical responses in breast cancer, cervical cancers and Hodgkins lymphoma, but not in colorectal cancer. Furthermore, HAIC with doxorubicin has not increased its therapeutic index and has shown limited advantages over systemic administration, with no reduction in systemic toxicities and a modest decrease in peripheral plasma levels. Nevertheless, THPdoxorubicin is active in HAIC on CRC liver metastases usually unresponsive to doxorubicin. In rabbits with Vx2 tumor implanted in the liver, the anti-tumor effect of THP upon HAI administration was better than that upon i.v. injection [17]. So the activity of THP was stronger than other anthracyclines because of its high clearance and high extraction during the first hepatic passage (80%). Toxicities caused by IA administration of pirarubicin, such cardiotoxicity, loss of hair and gastrointestinal adverse reactions, are low, which has been confirmed by experimental and clinical studies [18]. The risk of observing cardiac insufficiency is only 1% with a cumulative dose of 700 mg/m2 (against 20% with doxorubicin). The limiting toxicity is neutropenia and the dose advised using the systematic route is 50 mg/m2. Clinical studies in humans show that the tolerated dose during hepatic intra-arterial administration is greater than the tolerated dose when administered i.v. In this phase II study, in colorectal cancer patients with metastasis confined to the liver, THP (IA) was initiated at 60 mg/m2 with a 10 mg/m2 increment until grade 2 hematotoxicity. The maximum tolerated dose was 85 mg/m2 (range 60120); 19 patients receiving a dose of HAI pirarubicin 60 mg/m2 of every 3 weeks showed good results, with a partial response (PR) observed in 33% of cases, with no hepatic or cardiac toxicity, but with severe neutropenia as the limiting toxicity [19].
These results demonstrate that HAI pirarubicin produced high locoregional concentrations with faster cellular uptake and reduced systemic exposure. It can also achieve responses in metastatic liver disease of colorectal origin, which led our group to set-up a multicentric phase II study testing the efficacy and tolerance of the combination of HAI pirarubicin with systemic 5-FU and folinic acid.
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Patients and methods |
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Treatment plan
Chemotherapy cycles were planned every 4 weeks. At day 1 of each cycle, HAI pirarubicin was administered at the dose of 70 mg/m2 during a 1 h perfusion through a subcutaneous access connected to a surgically placed arterial catheter. A decrease of 10 mg/m2 was indicated at the following cycle in case of WHO grade 4 neutropenia (neutrophils <0.5 x 109/l) and/or thrombocytopenia (platelets count <25 x 109/l) at day 15 of the previous cycle, and then eventually a second decrease of 10 mg/m2 if a grade 4 toxicity was observed again.
Intravenous chemotherapy was administered from days 1 to 5 of every cycle, using 5-FU at a dose of 400 mg/m2/day for 1-h infusion; this dose was decreased by 50 mg/m2 in the following cycle in cases of WHO grade 4 neutropenia and/or thrombocytopenia (platelets count <25 x 109/l), and/or grade 4 stomatitis or diarrhea at day 15 of the precedent cycle, a subsequent decrease of 50 mg/m2 was allowed. In case of persistence of grade 4 toxicity after two reductions, the treatment was stopped.
Folinic acid was administered by i.v. bolus at a dose of 20 mg/m2/day just before i.v. perfusion of 5-FU from day 1 to day 5, without dose adaptation. No other antitumoral treatment was authorized during the study (chemotherapy, radiotherapy). Symptomatic medications were authorized but avoided during the first cycle. Corticoids and non-steroidal anti-inflammatory drug (NSAID) were not allowed because of gastro-intestinal toxicity.
Follow-up
At inclusion and every 4 weeks physical examination, performance status and vital signs evaluations were collected. A biological work-up including ionogram, lactate dehydrogenase (LDH), -glutamyl-transpeptidase, serum bilirubin, alkaline phosphatase, aspartate and alanine aminotransferase, serum creatinine, glycemia, prothrombine time and carcinoembryogenic antigen were performed. A complete blood count was made every week. An electrocardiogram was taken before each cycle.
Treatment evaluation
Efficacy evaluation was done using an abdominal CT scan at inclusion and then every three cycles. Chest X-ray and/or thoracic CT scan were carried out if there was any suspicion of lung metastases.
Tumor response was evaluated according to WHO criteria: a complete response (CR) was defined as the total resolution of all measurable sites of disease for a minimum of 4 weeks. A PR was defined as a ≥50% decrease in the sum of the products of the perpendicular dimensions of all measurable lesions for a minimum of 4 weeks without the appearance of new lesions; minor response corresponded to a decrease between 25% and 50%; stable disease (NC) was defined as no change or no increase or decrease >25% and no new lesions over 12 weeks, and progression (PD) was defined as an increase ≥25% or the development of new lesions.
Assessment criteria, sample size and statistical methods
The primary end point was response rate according to WHO criteria. The secondary end points were survival, time to hepatic progression, time to extra-hepatic progression and toxicity, which were analyzed according to WHO criteria.
Since the primary end point was response rate according to WHO criteria, 14 eligible and evaluable patients had to be included in succession. Indeed, if no response had been observed then the probability that treatment had an antitumoral activity >20% would have been <5%. It has been estimated that if at least one response was observed, 50 evaluable patients should be included to get a precise evaluation of the response rate.
Two analyses were planned: an intention-to-treat analysis including all eligible patients enrolled onto the protocol, and a per-protocol analysis, which considered only patients who received at least one complete HAI cycle. In the per-protocol analyses, all the responses were reviewed by an independent external panel of expert radiologists.
Survival was calculate from the date of randomization to the date of death. Survival and time to progression curves were estimated using the KaplanMeier method [20]. Coxs proportional hazard modeling was used for the determination of prognosis factors for survival [21].
For each patient, the maximum grade for each type of toxicity was recorded. Frequency tables were analyzed to determine toxicity patterns.
Ethical considerations
The protocol was approved by the French Groupe de Reflexion sur lEthique Biomedicale de Bicêtre (GREBB).
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Results |
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Response rate
In the intention-to-treat analysis, one CR was observed (1.5%) and a 21 PRs (30.4%), the overall response rate was 31.9%. Twenty-six patients (37.7%) had NC and 21 patients (30.4%) only experienced PD.
Of the 64 patients considered for per-protocol analysis, a PR was observed in 24 patients (39.3%), 17 patients (27.9%) had stable disease and 20 patients (32.8%) had PD.
Time to hepatic progression
Median time to hepatic progression was 8.3 months [95% confidence interval (CI) 5.614.3] in intention-to-treat analysis and 11 months (95% CI 7.016.3) in per-protocol analysis (Figure 1).
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The results of the uni- and multivariate analysis showed no significant interaction between serum LDH and overall survival.
Toxicity
A functioning problem of the catheter appeared in 29 patients; intra-arterial hepatic catheter was unusable in 21 patients: five just after implantation and 16 after three cycles of chemotherapy. These complications included hepatic artery thrombosis, misperfusion and/or thrombosis of the catheter and catheter leakage. The average number of cycles without functioning problem was five. One patient discontinued therapy because of major infectious complications (cholangitis) and another patient because of abdominal pain. One patient died of respiratory insufficiency after one complete cycle.
Clinical toxicity was minimal; non-hematological toxicity was mainly nausea and vomiting grade 3 reported during 15 cycles in eight patients; alopecia grade 3 in 19% of the patients; and grade 3 diarrhea in 10% of patients. Table 2 shows complete results concerning clinical toxicity. No cardiac toxicity was reported during the study.
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Discussion |
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The objective of our study was to determine the feasibility, efficacy and safety of HAI using pirarubicin in combination with systemic chemotherapy using a 5-FUfolinic acid protocol in a palliative situation. The response rate in the present study (34.4%) does not appear to be different from those previously observed using intrahepatic FUDR. Most of the phase II studies have reported a response rate of about 40%, whichever agent is used [5]; however, it is interesting to underline the fact that this response rate may be obtained with a simplified HAI method using a subcutaneous access and a 1 h monthly intra-arterial administration in ambulatory patients. The median survival was 19 months in the present study which is equivalent to those reported by many studies [713]. The prognosis factors found in this study were performance status, hepatic replacement by metastases >50% and CEA elevation have already been reported [23].
The role of HAI has been widely discussed because of its limitations. Extra-hepatic progression is one of the principal factors of failure. In an early experience using intrahepatic FUDR, 5070% extra-hepatic metastases were observed after 1 year of treatment [13]. However, this progression was not typical because it was often delayed and occurred in unusual sites, such as skin, brain, bones and suprarenal glands. In our study there was a relatively low rate of extra-hepatic evolution (23%), which suggests the possibility that the association of HAI with systemic chemotherapy may have provided some additional short-term therapeutic benefit and could be recommended to prevent occurrence of extra-hepatic metastases. A few prospective studies have demonstrated the benefit of HAI combined with intravenous chemotherapy. Lorenz et al. [24] revealed the superiority of HAIC with FUDR combined with 5-FU i.v. and folinic acid i.v. versus HAIC with FUDR alone, in terms of median time to progression (9.2 versus 5.9 months) and median survival (18.7 versus 12.7 months). In a randomized study by Safi et al. [25], 21 patients received treatment by FUDR (HAI i.v.) and 23 by FUDR (HAI); extra-hepatic progression was less frequent with the combined treatment (33% versus 61%) without significant difference in terms of hepatic response or overall survival. In a phase II study, combination of intravenous chemotherapy with 5-FUfolinic acid and HAIC with FUDR, a 62% objective response rate, a time to progression of 9 months and a median survival of 18 months were reported [26]. In a study conducted in the UK, the association of systemic folinic acid to an intra-arterial continuous infusion of 5-FU gave interesting results [2729], which has not been confirmed in a randomized trial.
Intra-arterial monotherapy with mitomycin C (MMC) gave only a 20% overall response rate (ORR) [30]; however, Cantore et al. [3133] reported the efficiency of the combination of 5-FU plus MMC plus epirubicin (HAI) associated with systemic 5-FU and folinic acid with an ORR of 50% and a median survival of 18 months.
Although the efficiency seems similar with intra-arterial pirarubicin, treatment with FUDR is regarded at present more critically due to its severe side effects. In our study, pirarubicin gave rise to no biliary toxicity, no cardiac toxicity and very low digestive toxicity. Biliary toxicity depends on the used protocol and has been observed mainly with the use of continuous HAI using FUDR; its frequency increases with the dose and duration of drip. In the French randomized trial, the risk of hepatitis was 35% and the risk of biliary sclerosis 25% after 1 year of HAIC [12]. No such risks were reported with the use of monthly HAI pirarubicin, apart from one patient who suffered from septic cholangitis.
Because the usefulness of HAIC therapy in controlling liver metastases in unresectable disease has previously been demonstrated, the search for the optimal intra-hepatic or systemic agent to use in combination with HAIC is the focus of current studies.
The Medical Research Council has conducted a prospective study comparing LV5FU2 (HAIC) with doses amounted to LV5FU2 (i.v.) with negative results, but with a very high rate of technical failure (ECCO 11).
The high rate of technical failure and catheter thrombosis in multicenter HAI studies is a major problem, and in this study five patients never received their local treatment for this reason. In 16 other patients, HAI has been interrupted for catheter dysfunction and an overall proportion of 39% of patients had functioning problems with their catheter. This underlines the necessity of using HAI in specialized centers.
The development of the combined treatment, using the most active products, could be a promising treatment allowing progression and widening indications to patients with extra-hepatic metastases of small volume. Finally, new modes of 5-FU administration, such as systemic chronomodulated chemotherapy [34].
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Conclusions |
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Acknowledgements |
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Footnotes |
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References |
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