Catheter Occlusion by Calcium Carbonate: A Well-Known Problem Persists in Spite of Better Knowledge

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 E-mail Information@Karger.de www.karger.com developed a catheter blockade due to formation of calcium carbonate (calcite) [3]. The time from initiation of therapy to catheter obstruction ranged from 8 to 24 weeks. After the encouraging clinical results of the ‘Ardalan’ schedule, the original regimen was modified by other groups to avoid the inconvencience of two i.v. infusions which led to the development of the ‘AIO’ variant, i.e. the prior administration of a 2-h infusion of calcium folinate followed by the 24-h infusion of 5-FU via a portable infusion pump. This mode of application represented a compromise between the need for one i.v. device only and the pharmacological rationale of parallel toxification of 5-FU by folinic acid. However, keeping in mind the half lives of folinic acid with approximately 7 hours and 5FU with a few minutes, this compromise a priori renounces optimal toxification of 5-FU, especially towards the end of the 24-h infusion. In the first quarter of 2002, the initially restricted approval for calcium folinate was extended and then permitted the mixture of calcium folinate with 5-FU. The basis for this extension was the in vitro compatibility without any loss of drug by complex formation for 48 h in a mixture of calcium folinate (4 mg/ml) and 5-FU (20 mg/ml) as demonstrated by high performance liquid chromatography (HPLC). These data were integrated into the summary of producer characteristics (SPC) of several suppliers without any further in vivo confirmation at that time. Based on this presumably valid recommendation, Bruch and Esser started biomodulated, high-dose 5-FU therapy in a patient with stage IV rectal cancer and administered a mixture of calcium folinate and 5-FU over a period of 24 h once a week via a port-a-cath as described in a case report in this volume [4]. During the course of this therapy, the patient developed port occlusion and needed port explantation. The thorough work-up of the occluding firm material from inside the lumen of the removed catheter revealed calcium carbonate as reason for the obstruction. The time to development of The so-called ‘AIO’ regimen with high-dose 5-FU (5-fluorouracil) and calcium folinate is a standard regimen in the treatment of advanced colorectal cancer. In this well-known combination therapy, the 2-h infusion of calcium folinate (500 mg/m2) precedes the 24-h continuous infusion with high-dose 5-FU (2,600 mg/m2). The basis for this schedule was given by the clinical study done by Ardalan and co-workers in the year 1991 [1]. In the original regimen, 5-FU and calcium folinate were administered simultaneously via a central venous device, generally a Hickman catheter or a port-a-cath® system. Why are calcium folinate and 5-FU applied sequentially in the AIO-regimen although the original data were produced with a mixed infusion? To answer this question we have to look back to the early times of treatment of metastatic colorectal cancer with calcium folinate and high-dose 5-FU. First pre-clinical studies had been done on human colon cancer xenografts comparing different infusion schedules of calcium folinate. By comparing i.v. bolus, 4-h infusion and 24-h infusion schedules of fixed doses of calcium folinate and 5-FU, variations of reduced folate levels in human colon cancer xenografts depending on the duration of infusion could be demonstrated [2]. Interestingly, the most pronounced increases of intratumoral folate levels were seen after the 24-h infusion. Based on these data, Ardalan and co-workers started their clinical study with 5-FU and calcium folinate mixed together in a continuous infusion over 24 h [1]. By using this new schedule they reached a remarkable response rate accompanied by a survival time of more than 22 months and moderate toxicity. Unfortunately, it became evident that many catheters were obstructed by crystal formation after a certain number of cycles. As a consequence, Ardalan et al. changed the mode of administration and furthermore used two separate venous accesses to avoid catheter occlusion. Four years later, Ardalan reported in full length that 11 of the 22 treated patients had Catheter Occlusion By Calcium Carbonate: A Well-Known Problem Persists in Spite of Better Knowledge