Combined therapy combats HCC tumours

At the World Conference on Interventional Oncology (WCIO) in Italy earlier this year, the latest results from Biocompatibles International's PRECISION clinical trial programme were presented by Professor Josep M Llovet, associate professor of medicine, HCC Research Director, Division of Liver Diseases, Mount Sinai School of Medicine, New York.

The PRECISION (Pharmacokinetic study of doxoRubicin in the trEatment of hepatocellular CarcInoma by drug eluting bead emboliSatION) trials were designed to evaluate the safety and efficacy of Biocompatibles' drug eluting bead (DC Bead) technique in the treatment of HCC and recruited patients at centres in Asia and Europe.

The chemotherapy-enhancing drug eluting bead (DC Bead) technology distributed by Terumo Interventional Systems Europe, for the treatment of HCC combines pharmaceutical and medical device technology to produce a chemotherapy-releasing product that potentially is more effective than either technology on its own. The pharmaceutical compound used in the DC Bead is doxorubicin. The medical device used in the DC Bead is an embolic microsphere based on N-fil Technology (biomedical polymers that include a calibrated microsphere made from a compressible polyvinyl alcohol hydrogel).

PRECISION trials
The PRECISION I trial (Barcelona), characterised by the absence of drug-related toxicities, including myelosuppression and alopecia in any of the patients, was directed by Dr Jordi Bruix, Head of the Barcelona Clinic Liver Cancer Group within the Liver Unit at the Hospital Clinic in Barcelona. The trial also included a 'dose escalation phase' with a maximum dose of 150mg of doxorubicin. Twenty eight patients with intermediate stage HCC were recruited and the first cohort progressed through dose esculation with no dose-related toxicities observed. Twenty three patients were evaluted for tumour response at six months and complete response was reported in 30%. Patients in the second cohort were treated at the maximum dose available (150mg) where tumour response was 87%.

Bruix commented "The results of the PRECISION I clinical trial confirm that the drug eluting beads represent a very promising new treatment for patients with this disease profile."

The results of the PRECISION II clinical trial (Hong Kong) were reviewd at WCIO and demonstrated consistentcy with those results of PRECISION I. Improved tumour response and a lower rate of serious adverse events were shown in both studies in comparison with reference trials for Conventional TACE, the current standard of care. The Conventional TACE procedure involves a chemotherapeutic agent being mixed into a slurry and injected via a catheter, locally at a tumour site.

It was reported that in the 27 patients in PRECISION I, the six-month tumour response rate was 66% in comparison with tumour response in the reference TACE trial of 40%. The rate of serious adverse events in this trial was 7%.

In comparison with the data from PRECISION II, the patients had a greater mean tumour burden (49mm; +45%) and a greater mean number of tumours (three; +50%). By the time of the six-month measurement, the tumour response in PRECISION II patients was 39%.

Professor Ronnie Poon, based at the University of Hong Kong and principal investigator for PRECISION II, said the results from the trial show "good response and excellent tolerability in a demanding set of patients".

PRECISION VI (Frankfurt) has recently been announced and will evaluate the drug eluting bead in lung cancer.

Combination therapy clinical study
This year's American Society for Clinical Oncology (ASCO) held in Georgia, US in June 2nd, featured pilot clinical trial data on the treatment of primary liver cancer using the RITA Medical Systems' radiofrequency ablation (RFA) technology in combination with arterial embolisation using Biocompatibles' DC Bead with doxorubicin.

In his presentation titled 'Approach and management of lesions detected in HCC surveillance programs', Professor Riccardo Lencioni, medical director of the Department of Diagnostic and Interventional Radiology, University of Pisa, Italy, presented preliminary data from a study of patients with hepatocellular carcinoma (HCC) who had incomplete ablation with RFA.

In the study, 'Combined radiofrequency ablation and doxorubicin eluting beads arterial embolisation in hepatocellular carcinoma: a pilot clinical trial', the aim was to investigate whether Biocompatibles' PRECISION TACE (Trans Arterial Chemo Embolisation by drug eluting beads loaded with doxorubicin) combined with RFA allows more effective treatment of large HCC tumours. Lencioni commented that current treatment options that can provide radical cure of early-stage HCC - such as RFA - are not fully satisfactory when used in larger tumours. The researchers therefore selected for this pilot phase patients with compensated cirrhosis and a large HCC, in whom RFA treatment - performed in the first place - resulted in incomplete tumour ablation.

In the study, ten patients with primary liver cancer tumours greater than 7cm in size were first treated with RFA, followed by immediate arterial embolisation performed 24 hours after RFA using PRECISION TACE. On CT and MRI-scans, using this sequential treatment approach, the mean increase in the volume of coagulation necrosis was 64.2% (range: 5-134%), compared to tumours treated with RFA alone.

Lencioni explained that the volume of coagulation necrosis increased from a mean 61cm3 after RFA alone to a mean 95cm3 after the PRECISION TACE . Complete ablation was seen in six out of ten tumours treated. In the remaining four tumours, minimal tumour persistence (less than 10% of total tumour volume) was observed.

"These preliminary data show that arterial embolisation with doxorubicin eluting beads substantially increases the effect of RFA in the treatment of large HCC tumours," said Lencioni. "The ability to treat larger tumours through a combined therapeutic approach could open new prospects in the treatment of liver cancer by expanding the indication for RFA far beyond its current limits.

"Patients diagnosed with HCC at an early stage currently have a wide spectrum of radical treatment options, including liver transplantation, resection, and percutaneous ablation. These patients achieve an impressive 50-70% survival at five years if properly managed. Unfortunately, in most cases the diagnosis of HCC is done at a more advanced stage, and the patients can only be considered for palliative treatments. I think this combined treatment strategy could substanially increase the percentage of patients who can be radically cured."

Adverse effects
Because the doxorubicin is uploaded into the DC beads, the event of any adverse effects is minimal since the systemic distribution of the drug is very low. In the study, there were no cases of drug-related adverse effects even when up to 125mg of doxorubicin was administrated. Furthermore, even the largest tumours are partially destroyed and de-vascularised by RFA, thus the DC Beads are selectively delivered into the vital part of the tumour, resulting in a much higher local concentraion of the drug.

Combination therapies to treat other cancers
According to Lencioni, the potential for combination therapies in cancer treatment is huge. He explained "With this trial, we have shown in a clinical setting that there is a substantial synergy between RFA and doxorubicin, confirming what had emerged from animal studies. I can easily anticipate that this is only the first step in a new area of cancer treatment, where image-guided thermal ablation is used in combination with novel methods for targeted drug release."

Following the data which emerged from the interim analysis, Lencioni and colleagues have decided to extend the study to 20 patients, in which he will present updated data at the forthcoming Cardiovascular and Interventional Radiology Society of Europe (CIRSE) on September 13, 2006.