Irinotecan in liver metastases- the next indication for drug-eluting beads?

Irinotecan DEB
Irinotecan DEB

Recent symposium, sponsored by Biocompatibles, at the CIRSE meeting in Rome, Italy.

The chemotherapy-enhancing drug-eluting bead (DC Bead™) developed for the treatment of hepatocellular carcinoma (HCC) combining pharmaceutical and medical device technology to produce a chemotherapy-releasing product is showing promising results in liver metastases.

At a recent symposium, sponsored by Biocompatibles, at the CIRSE meeting in Rome, Italy, experts in their field were invited to discuss a new pharmaceutical compound utilised in the DC Bead, irinotecan. Irinotecan is a systemically active drug in the first- and second-line treatment of advanced colorectal cancer, and high-dose local treatment could be beneficial to patients refractory after systemic treatment.

Dr Andy Lewis began by outlining the concept of DC Bead with irinotecan. In the development of DC Bead, the backbone of the polymer has been substituted with some negatively charged sulphonic acid groups. Once irinotecan is added to the beads they will sequester the drug from the solution by ionic interaction, as the drug is positively charged.

Dr Lewis then outlined how the drug elutes from the beads in vitro over the first 24 hours. A "T-apparatus" was used, where the beads were placed in a well, simulating the diffusion and convection processes that occur in embolisation. The solution was then circulated through a spectrometer that detects the drug. The outcome demonstrated that there is an initial burst, especially with smaller beads (due to increase surface area), followed by a period of sustained release.

In order to examine whether DC Bead with irinotecan would be efficacious in an animal model, Dr Lewis sought the assistance of Professor Martin Berger from the German Cancer Research Institute. Prof Berger has previously published data on chemoembolisation of rat liver metastases and was using irinotecan and Spherex™. Dr Lewis commented that the model Prof Berger was using meant that the bead had to be reduced in size (average was 75µm). In the model, Prof Berger took rat colorectal cells, injected them into the liver, gave them a few days to grow and then performed a one shot embolisation procedure with the drug-eluting beads. He assessed how much the tumour burden in the liver was reduced.

He performed this analysis on doses in the range 20mg/kg to 30mg/kg and evaluated reduction in tumour load using a chemo-luminescent assay by the liver weight, which is also a measure of tumour burden. Dr Lewis highlighted one case (presented at this year's American Association for Cancer Research) that he believed was 'proof of concept' that DC Bead with irinotecan demonstrate efficacy in returning the liver to a normal size with much of the tumour eradicated. In contrast he stated that in the control group, (DC Bead without any drug), embolisation alone had no effect.

The group also carried out a safety and pharmacokinetic study with small (100-300µm) and large (700-900µm) beads. The two bead groups (loaded with the maximum dose of 50mg per ml of irinotecan) were compared to the intra-arterial administration of an equivalent dose of irinotecan, so that the pharmacokinetics of the groups could be compared. Particular attention was paid to irinotecan and its main metabolite, SN38, over a series of time points. The general health of the animals was monitored along with the effect on liver enzymes. Following sacrifice, gross and histopathological examinations were made of the liver and other organs.

In presenting the pharmacokinetic results, Dr Lewis explained that the group decided to begin collecting samples (particularly for the intra-arterial injection group) 12 minutes after the bolus of the drug was delivered (on average it took 12 minutes before embolisation was completed in the bead groups). The outcomes revealed that there did not appear to be much difference between the bead sizes in terms of systemic drug levels. However, Dr Lewis said when the group looked at the Cmax, "We see that it is much higher for the intra-arterial injection, and that is 12 minutes after injection, so it is likely that this peak is even higher." He commented, "We only selected 12 minutes to make it more comparable, but this even shows a significant decrease [in drug delivered from beads]." By correlating these data with the T-cell data, the group were able to establish a reasonable predictor of the amount of drug that is released from the beads which ends up in the systemic circulation in the first 24 hours.

Dr Lewis discussed the histopathology and commented on a recent article published in the Journal of Vascular and Interventional Radiology that examined doxorubicin beads and their affect in a similar model. He highlighted that although doxorubicin delivered from very small beads had quite a destructive effect on the tissue, this was not observed with irinotecan. He added that the two drugs had a different effect on normal liver enzymes: there was a transient increase in liver enzymes for doxorubicin, although they did return to normal levels. This transient increase was not observed with irinotecan, suggesting a milder cytotoxic action.

In discussing the loading procedure for irinotecan, Dr Lewis offered some useful tips and hints. It is recommended one should allow up to two hours when loading the compound. Importantly, Dr Lewis revealed data that showed that the size of the bead is linked to the time frame for loading; the smaller the size, the less time needed for loading. Regarding the mixture, he said the maximum dose that he has used was 50mg per ml of beads (hence, for a 2ml vial of DC Bead, 100mg of irinotecan can be loaded by addition of one vial of commercial Campto® formulation, which comes as 5ml of 20mg/ml irinotecan).

Camillo Aliberti
Camillo Aliberti

Italian clinical results

Following Dr Lewis, Dr Camillo Aliberti, Professor of Interventional Radiology at Delta Hospital in Ferrara, Italy, presented the preliminary results of a study to evaluate the feasibility of using irinotecan drug-eluting beads administered intratumourally to patients with liver metastases from colorectal cancer. The objective of this study was to determine the safety, feasibility, tolerance and tumour response of transarterial chemoembolisation (TACE) using irinotecan loaded DC Bead for the treatment of unresectable liver metastases in colorectal cancer patients.

A total of 20 patients were enrolled in the study with a total of 45 individual chemo-embolisations performed. Patients with liver metastases from colorectal cancer were treated with irinotecan-eluting beads at a dose of 100mg every three weeks. The dose was reduced by 50% after the first cycle if significant toxicity, grade 3 or 4 occurred. Chemoembolisation followed selective positioning of the catheter in the left or right hepatic artery.

Computed Tomography (CT) was performed 24 hours before and after TACE with irinotecan-loaded DC Bead. There was a 100% technical success rate with no technical failures or procedural complications. Symptoms displayed by patients included upper abdominal pain and fever. Vomiting and pain occurred at one hour after chemoembolisation. The maximum intensity of pain was reached six hours after chemoembolisation and decreased at 24 hours. Symptoms of fever appeared one day after chemoembolisation and disappeared in ten days.

After 30 days, Dr Aliberti reported a reduction of >50% of CEA levels (a marker used to diagnose or indicate recurrence of cancer). Reduction of lesional volume was observed in all patients under contrast enhancement. Within one month after treatment, CT scans showed significant reduction of metastatic tumours in all patients. In severe cases, Dr Aliberti demonstrated that before chemoembolisation the lesions were hypervascularised and after chemoembolisation with irinotecan-loaded DC Bead the lesions were hypovascular.

"In this study, chemoembolisation with irinotecan drug in loaded DC Bead is a safe and substantially well tolerated procedure," said Dr Aliberti, adding the study follow-up was too short to define detailed conclusions and further studies are necessary to confirm this 'promising' preliminary data.

In a question and answer session, Dr Aliberti was asked by Prof Alban Denys how response was defined in this study considering the difficulties in evaluating tumour response with a technique where the tumour is fully vascularised before but afterwards there is a large hypodense area.

He acknowledged that it is difficult to define the tumour response, as there is not a clear rule for the measurement of the lesions. However, by utilising echography and CT scans it is possible to evaluate the tumour rim and the other clinical aspects. Dr Aliberti said that the improvement seen in his patient could point to an improvement in the quality of life of patients with diseases that had previously failed treatment.

He added that one of the limitations of chemoembolisation in the past was in larger lesions. "Therefore, is it important to consider the entire situation of the patient, including the quality of life, the reduction in all kind of medication and best care of the patient. But this is another problem," said Dr Aliberti.

In response to a question from Dr Thierry DeBaere on prefered bead size, Dr Aliberti stated that in the first session 100-300µm and then 300-500µm were used. This is because, with the first shot it is better to use a smaller size as there is greater access to the tumour and you don't have the phenomenon of revascularisation. "So the first step is to use the smallest one. The second step is to adopt larger size microspheres. I think that is how we can explain the dramatic necrosis that we have witnessed," explained Dr Aliberti. The reasons for this are that the tumour is very distal and blocking the flow induces inflammatory reaction in the locality.

However, he stated that there is still much that is unknown regarding necrosis, interruption of the flow and high contact time. This, Dr Aliberti hypothesised, could be the explanation, "But we honestly don't know if this kind of result means more cure for the patient. Future follow-up will probably give us this kind of information. But this is open for discussion and further studies," he concluded.

German clinical results

The final presentation was given by Dr Renate Hammerstingl, a radiologist at the Institute of Diagnostic and Interventional Radiology, University of Frankfurt, Mainz, Germany. She presented the data on behalf of the Study Group in Frankfurt on the treatment of colorectal liver metastases using Precision TACE. Prof Thomas J Vogl is principal investigator and Dr Katrin Eichler leading coordinating investigator.

The basis of each chemoembolisation therapy is the dual blood supply of the liver parenchyma itself and in contrast the vascular supply of the liver tumour by arterial feeders from branches of the hepatic artery. High concentration of antiproliferative drugs can be achieved to the malignant infiltrations of the liver without interfering in the liver blood supply.

Hammerstingl said that in her hospital MRI is used to get a brief idea on the vascularity before commencing treatment. As an example she cited the case of a patient who, suffering from colorectal metastases, underwent unenhanced and contrast-enhanced MRI and the liver metastases were precisely depicted. The scan showed hypervascularity in the periphery with a rim enhancement, which was important to watch closely during the treatment periods as previously discussed by Drs Lewis and Dr Aliberti.

To obtain an understanding of oncological treatment using various modalities, the different approaches of Vogl's group at the University of Frankfurt, Mainz were highlighted. Laser therapy is the standard procedure for smaller metastases, where chemoembolisation is preferred in larger infiltrations. For large metastases however, the Frankfurt Study Group is searching for new concepts as the intravenous approach of chemotherapeutic treatment is not successful in all cases. One strategy is a superselective approach with several cycles of chemoembolisation to downsize these metastases, which can then be resected or treated by interventional modalities.

A current single-centre, prospective phase I study was outlined, which is under way in Prof Vogl's group. In this study ten patients will be included over a period of six months. Follow-up period for each patient is six months. The primary endpoint of the study is overall safety of chemoembolisation with irinotecan-loaded DC Bead. The secondary endpoints are tumour response measured by RECIST, extent of necrosis, and pharmacokinetic analysis of the plasma levels of irinotecan and its main metabolite SN38. The feasibility of chemoembolisation with irinotecan-loaded DC Bead will be evaluated.

Main inclusion criteria are: Confirmed diagnosis of stage IV colorectal cancer with unresectable metastases confined to the liver. The primary tumour must have been treated with complete surgical resection without evidence of residual tumour. At least one measurable lesion must be identified following the RECIST criteria. The overall tumour burden must be less than 30% of the overall liver.

Safety data is collected from physical examinations, vital signs and clinical laboatory profile. During treatment and follow-up, adverse events and severe adverse events are evaluated according to observed toxicities and side effects (graded by the SWOG toxicity criteria).

Efficacy data includes tumour response for the target lesions only, and overall tumour response, measured by MRI. The response criteria are complete response, partial response, stable disease and progressive disease according to RECIST definition. Objective response will be the main criterion and is defined as complete or partial response. Newly detected lesions in previously untreated areas are not classified as progression, but will be documented in the case report form. Necrosis is calculated as total necrotic tumour volume divided by total treated tumour volume multiplied by 100.

For chemoembolisation, DC Bead loaded with irinotecan is used at a concentration of 50mg/ml. Product is available in 100-300, 300-500, 500-700, 700-900µm, although in general the smallest size is used. A dose of up to 8ml beads (400mg irinotecan) per patient was used. The schedule for the overall treatment is four chemoembolisations in three-week-intervals and the chemoembolisation is conducted superselectively via the supplying artery until a complete stasis of the blood flow is achieved. No traditional embolisation is used in the study to achieve the endpoint.

So far three patients have been included in the study, with no severe adverse events. To date one patient has shown stable disease, one patient partial response and one patient progressive disease.

Regarding the overall plasma concentration of irinotecan a relative increase was noted in two of these patients, but not in the third. The same pattern was observed for the plasma concentration of the main metabolite SN-38: a high peak for two patients and a smaller peak for the third patient. Measurements were obtained in all patients using a standard procedure. The study group pointed out that the patient with the very small increase of plasma concentration of irinotecan and its metabolite documented a progressive disease in comparison to the other two patients who documented stable disease or partial response.

In summary, the data from the Frankfurt Study Group have demonstrated so far that safety and tolerability of the therapy with irinotecan loaded DC Bead is acceptable. A relative increase in the plasma concentration of irinotecan and its main metabolite appears to correlate with local tumour response. Moreover, the study has demonstrated so far that chemoembolisation with irinotecan-eluting beads is technically feasable. The overall data is promising and the investigation will continue in an interdisciplinary set-up to achieve best results in this field of new treatment procedures.

TACE with Irinotecan
TACE with Irinotecan DC Bead

 

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