The future of interventional oncology

Treatment with drug-eluting beads

Simple Loading Procedure

Presentation of preliminary data on treatments using Biocompatibles' drug-eluting beads (DC Bead™).

At the recent CIRSE meeting held in Rome, Biocompatibles and Terumo Interventional Systems Europe hosted an interventional oncology satellite symposium focusing on treatment with drug-eluting beads. Two renowned interventional oncology pioneers presented preliminary data on treatments using Biocompatibles' drug-eluting beads (DC Bead™) for hepatocellular carcinoma (HCC), lung cancer and liver metastases of the colon.

Treatment of lung cancer and colon liver metastases

Professor Thomas Vogl, from the Institute of Diagnostics and Interventional Radiology at JW Goethe University, Frankfurt, Germany, is a specialist in interventional oncology and an expert in percutaneous laser treatment and embolisation therapy. Presenting a short report on the treatment of lung cancer and colon liver metastases with drug-eluting beads, Prof Vogl explained that second to breast cancer, lung cancer, even in level 1 evidence studies, is becoming one of the major topics of interest. He and his colleagues have been working together with the University of Charleston, South Carolina, US, trying to expand ideas on experimental and new therapy forms.

Prof Vogl began his discussion by referring to a patient who presented to his department in 2003 with multiple liver metastases. After local intra-arterial chemotherapy, they were able to significantly reduce all metastases in size and were able to finalise treatment with thermal ablation.

"Even with advanced liver cancer in this form of liver metastases it is possible with just interventional therapy to direct the therapy and obtain these results, which is something we are emulating with the drug-eluting beads," he explained.

"The concept behind this is that for smaller lesions we might now have techniques available for thermal ablation, but for larger metastases we're still not satisfied with systemic-chemotherapies to obtain the desired results. This could be a new concept for reducing the size of tumours and resulting in possible candidates for ablation."

Data from two preliminary clinical studies was presented by Prof Vogl.

Clinical study CA1011

The first study entitled 'Transarterial chemoembolisation (TACE) using DC Bead loaded with irinotecan for the treatment of unresectable metastases of the liver in patients with colorectal cancer', is a single-centre, prospective (phase I) study, involving ten patients. Expected enrolment duration is six months and individual patient participation is also expected to be six months.

Patient criteria

Patients with a confirmed diagnosis of stage IV colorectal cancer, with unresectable metastases confined to the liver, are included in the study. It was required that the primary tumour had also been treated with complete surgical resection without evidence of residual tumour. Patients must have at least one measurable lesion (Response Evaluation Criteria in Solid Tumours [RECIST] criteria) and no more than eight lesions in total. Prior treatment is permitted, but the last treatment must be completed at least four weeks before the DC Bead trials. Other criteria include: Haematologic function: WBC = 3.0 x 109/L, platelets = 50 x 109/l, prothrombin time > 50% of normal.

Adequate organ function as measured by:

a. serum creatinine < 1.5 x upper limit of normal (ULN)
b. serum transaminases (AST & ALT) < 4 x ULN
c. bilirubin < 3 x ULN

Treatment

Drug-eluting beads, as Prof Vogl discussed, are spherical, compressible sulphonate modified N-Fil hydrogel microspheres. Irinotecan is a topoisomerase inhibitor which causes DNA strands to break. Active uptake of irinotecan into the beads from irinotecan solution occurs by an ion-exchange mechanism. Complete drug loading is achieved in 120 minutes. (Figures 1 and 2).

The simple loading procedure can be performed in the pharmacy department of the hospital immediately prior to use. The protocol allows for up to 400mg irinotecan per procedure. This can be delivered in 8ml DC Bead with a loaded concentration of 50mg/ml beads.

According to Prof Vogl, in this study, the patient treatment schedule is for four chemoembolisations at three-week intervals. Superselective chemoembolisation of the supplying artery is performed until complete stasis of blood flow is achieved.

The data to be recorded includes:

• the amount of contrast agent delivered to the patient
• dose of radiation during imaging
• time exposed to fluoroscopic imaging
• the vessels embolised
• volume of embolising agent used
• all medications used during the procedure, including pain management.

Results

Prof Vogl reported that three patients have been treated and have shown a stable, partial and progressive response to treatment. After three treatments, the first patient with multiple liver metastases, achieved a stable disease situation, the second patient with regression, showed a reduction in the tumour load in the upper part of the liver and the third patient with solitary liver metastases demonstrated progression. A significant improvement in the tumour size resulted (Figures 3, 4, 5 on page 2). In terms of adverse effects, local pain was the most commonly reported effect.

Clinical study CA1010

The second clinical experimental study which Prof Vogl addressed, was Biocompatibles' 'Transpulmonary chemoembolisation (TPCE) with doxorubicin-loaded DC Bead for the treatment of primary and secondary lung cancer' study.

"Why is this concept of interest?" asked Prof Vogl. "We have seen from liver studies that it is possible to have a low systemic doxorubicin exposure and this could be of advantage to the lung," he responded.

The trial is a single centre, prospective study enrolling 20 patients with individual patient participation planned for six months.

Inclusion criteria

Patients who, in the opinion of the oncologist have no further therapeutic option, were recruited. Those with unresectable stage I or IIA/B (due to the medical condition) non-small cell lung cancer (NSCLC) or patients with up to ten unresectable lung metastases (maximum of five lesions per lung lobe) are treated. In metastatic patients, the primary cancer has been treated with complete surgical resection without residual tumour.

Treatment

DC Bead loaded with 150mg doxorubicin was administered at three weekly intervals. Data to be recorded included:

• vessels embolised and volume of embolic agent used
• the amount of contrast agent delivered to the patient
• dose of radiation during imaging
• time exposed to fluoroscopic imaging
• all medications used during procedure, including pain management regime.

Results

Currently, four patients have been included with a total of seven tumours treated. Primary tumours were located in breast (n=2), colon carcinoma (n=1), and NSCLC (n=1).

Adverse events were found to be no more problematic than with other treatments. Such adverse events included:

• pleural effusion (n=2)
• infection (n=1)
• pneumonia (n=1)
• ausea, vomiting (n=2)

Pancreatitis was also reported but was not related to treatment. One patient died of pancreatitis 169 days after treatment.

The summary of results for the four patients in this preliminary study of the lung as reported by Prof Vogl resulted in one patient showing stable disease, two patients with progressive disease and one drop out patient. Tumour analysis to date shows:

• tumour volume pre-treatment mean: 245.9ml (range 40ml - 485ml)
• tumour volume post-treatment mean: 543.4ml(range 458.9ml-662.9ml)

Summary

Given the data presented thus far, it can be deduced that Vogl's preliminary results demonstrate that the drug-eluting bead concepts in the treatment of lung cancer and colon liver metastases are safe.

Combined PRECISION TACE and RFA in HCC treatment

Well respected and highly regarded interventional oncologist Professor Riccardo Lencioni, Medical Director of the Department of Diagnostic and Interventional Radiology, University of Pisa, Italy, presented findings of a pilot study entitled 'Combined RF ablation and doxorubicin-eluting beads (DC Bead, Biocompatibles) arterial embolisation (PRECISION TACE) in HCC: a pilot clinical trial', to address the issue of using a combined technique to combat large HCC tumours.

As Prof Lencioni explained, RF ablation is now accepted as a curative, radical treatment option for early-stage HCC, and has been successfully used for more than six years. Using this technique on small tumours of 3cm or less achieves reproducible ablations with a single needle insertion. This approach has shown impressive complete response rates and long-term survival rates that are comparable to those of hepatic resection.

However, Prof Lencioni said, "RF ablation may be less effective on large tumour masses. We are now learning a lot of lessons from centres that use RF ablation as a bridge treatment before transplantation. So at the time of the transplant, they have the ability to realise what was the outcome of the treatment at the histological level. If you look at some recent data, you can see when tumours are above the 3cm threshold, only 50% of them are actually completely killed by RF ablation (David Lu from the UCLA in Radiology 2005). In addition, in as many as 44% of the cases, viable satellite nodules are found around the treated tumour (Brillet from the Hopital Beaujon in Paris in the AJR 2006). Clearly the two factors are related because it is well established that in HCC tumours, the larger the size, the higher the chance of microvascular invasion and therefore of microsatellites close by to the tumour."

In March this year Prof Lencioni chaired a Research Consensus Panel (RCP) set up by the CAIRR (The Cooperative Alliance for Interventional Radiology Research) which was held in Toronto during the SIR meeting. The RCP was aimed at identifying a pivotal trial believed by the panellists to be the most important in the field of Liver Interventional Oncology. Not surprisingly, the study that was prioritised as number one, was the investigation of combination of RF ablation and intra-arterial treatments versus RF ablation alone in the treatment of HCC patients beyond the early stage.

The majority of the work to date involving combination of thermal ablation and intra-arterial therapies, has been performed by using chemoembolisation in the first instance, followed by RF ablation. The intention of this was to explore the bio-heat equation which determines the success of coagulation necrosis induced by RF, and particularly to minimise the heat loss through vessels (heat loss by convection), which is typically a limiting factor for RF, particularly in a highly vascularised tumour such as HCC.

Prof Lencioni mentioned the results of the study by Veltri A et al in Turin, who recently published in European Radiology 2006. The researchers selected 46 patients with large lesions ranging from 3-8cm (mean 4.9cm) and used TACE with a conventional protocol of epirubicin-lipiodol plus embolisation, then performing RF ablation on the same day or within 24 hours of the TACE procedure. A 2% mortality, and 6.5% complication rate was observed, and the ability to obtain a sustained complete response in solitary tumours was 48% after a median follow-up of 15 months.

New approaches: drug-eluting beads

New approaches are now available for chemoembolisation, with particular focus on drug-eluting beads. There are a number of experimental studies - performed by the group of Nahum Goldberg and published during the past few years - that address the issue of how doxorubicin exposure and RF ablation can interact in animal models. Prof Lencioni believes that it has been convincingly shown that if RF ablation is performed and followed by administration of doxorubicin intravenously, an increased accumulation of the drug is seen along the periphery of the treated tumour, which results in increased tumour destruction. "Tumour cells not killed by RF ablation but nevertheless exposed to sub-lethal temperatures are damaged, and unable to resist the effects of a high concentration of the drug" said Prof Lencioni.

Combined RF ablation and doxorubicin pilot study

To verify if what was seen in animal studies could be confirmed in humans, Lencioni and colleagues initiated a pilot study combining RF ablation and transarterial chemoembolisation of HCC.

Prof Lencioni's hypothesis is that performing PRECISION TACE intra-arterially following RF ablation allows for better treatment of large HCC tumours, based on the following points:

• If most of the tumour mass is destroyed, DC Bead can be delivered selectively to the viable source of the tumour (including micro satellites)
• If PRECISION TACE is performed shortly after RF ablation, the RF-induced hyperemia will allow an increased peritumoural blood flow that will result in much higher concentrations of the drug. Local drug concentration may be 10-20 times higher than can be accomplished by using PRECISION TACE as a stand alone treatment
• DC Bead allow a sustained drug release and activity which will be able to kill tumour cells, as the prior damage by sublethal heating makes them less resistant to the doxorubicin.

In the pilot phase, 20 patients with large HCC above 3cm showing clear cut evidence of residual viable tumour following RF ablation were selected for the study. PRECISION TACE with doxorubicin was administered 24 hours after RF ablation.

Results

Prof Lencioni presented the results from 14 patients for the first time at the CIRSE meeting. He explained that these 14 patients with a mean tumour size of 5.1cm were selected out of 58 - showing unequivocal evidence of incomplete response to RF ablation. RF ablation was performed by using expandable multi-tined electrodes (RITA Medical Systems). Arterial embolisation was performed 24 hours after RFA by using 50-125mg doxorubicin loaded in either 100-300 or 300-500µm bead (DC Bead; Biocompatibles). Treatment efficacy was evaluated by CT and MRI at one month and at three-month intervals during the follow-up.

The treatment protocol was successfully completed in all patients. The range of volumes of unenhancing tissue representing coagulation necrosis increased from 15.4-128.9cm (mean, 47.7 ± 37.2) after RFA alone to 16.8-171.7cm (mean 76.6 ± 53.9) after doxorubicin-eluting beads arterial embolisation, with an increase of 5-134% (mean, 58.8% ± 42.4). The increase in unenhancing volume resulted in complete ablation of 9 (64.3%) of 14 tumours. Five tumours had minimal amounts of viable tissue, less than 10% by volume, that persisted after the procedure.

Conclusion

"I think we have proven that exposure of HCC in humans to high concentrations of doxorubicin following RF ablation does result in a substantial increase in ablation volume," said Prof Lencioni. "We have experienced no deaths and no major complications or adverse events in these patients and this is probably because treatment with PRECISION TACE (DC Bead) is much easier on the patient than conventional TACE.

"We also have early data concerning the effectiveness, taking into account that we only selected patients for this study who were resistant to RF ablation i.e. patients with much more aggressive biological behaviour. Of course, we cannot make a claim that this is the best approach for large HCC tumours. I think when the study is complete we will probably have a clear picture of the clinical benefits of this approach, however investigation should continue through a large multi-centre randomised study that will eventually show us if this is truly the way to go."

Outcomes with various treatments

 

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