At the CIRSE meeting 2008, held in Copenhagen, Denmark, Professors Johannes Lammer, Anthony Watkinson, and Riccardo Lencioni presented new data supporting the use of Biocompatibles’ PRECISION TACE with DC Bead (DC Bead loaded with doxorubicin) for the treatment of hepatocellular carcinoma (HCC). The multi-centre study compared drug-eluting beads (DEB) with conventional transarterial chemoembolization (cTACE).
Professor Johannes Lammer, Medical University of Vienna, Austria, presented an overview of the PRECISION V trial, first discussing the epidemiology of HCC. He stated that the disease is globally the fifth most common cancer, and over 600,000 new cases are diagnosed worldwide each year. HCC particularly affects the Eastern Asian population (370,000 cases each year), followed by Japan, Europe and the US populations, with 40,000, 32,000 and 19,000 new cases identified each year, respectively. Lammer added that HCC is the third leading cause of cancer-related mortality, and is the leading cause of death in cirrhotic patients.
The BCLC (Barcelona-Clinic Liver Cancer) Staging and Treatment Schedule for HCC categorises three main stages for treating the disease, explained Lammer. Stage 0 (early stage) normally results in resection, although, liver transplantation or PEI/RF (Percutaneous ethanol injection/radiofrequency) may be indicated. Stage A-C (intermediate stage) typically results in chemoembolization, PEI/RF or the administration of new agents, such as sorafenib. For terminal stage cancer, Stage D, symptomatic treatment only is administered (Figure 1).
The aim of the PRECISION V randomised phase II study was to investigate the safety and efficacy of chemoembolisation with DC Bead loaded with doxorubicin (PRECISION TACE with DC Bead) in an international, multi-centre trial. Roughly 200 patients were recruited in 23 European centres, with 100 patients randomised to each arm. Patients assigned to the control arm of the study were administered cTACE using doxorubicin mixed with lipiodol followed by a bland embolic. Patients received up to three treatments occurring at baseline, two and four months, and follow-up was for six months.
The primary endpoint was six-month tumour response rate measured by magnetic resonance imaging (MRI) and response criteria according to the EASL (European Association for the Study of the Liver). Secondary endpoints were safety (toxicity according to the South West Oncology Group and focussing on doxorubicin related events), time to progression, tumour response according to RECIST (Response Evaluation Criteria In Solid Tumors), local tumour response (EASL), time to discharge, cardiotoxicity, quality of life (QoL) and healthcare resource use.
Inclusion and exclusion criteria
According to Lammer, patients included in the study had HCC not suitable for curative treatments, multinodular HCC without vascular invasion or extrahepatic spread, recurrence following resection or percutaneous ablation, preserved liver function (Child Pugh A and B), or were on the transplant list but may not receive a transplant within six months.
Excluded patients were those with another primary tumour, previously treated with chemo- or radiotherapy, advanced liver disease, advanced tumoural disease, any contraindication for doxorubicin administration, and any contraindication for hepatic embolization procedures.
Lammer reported that after three treatments, technical success for the DC Bead group was 97% compared with 99% in the cTACE group (Figure 2). In terms of dose, the mean dose of doxorubicin for treatment 1 was 142.1mg vs. 102.9mg for the DC Bead and cTACE groups, respectively. For the second treatment, the dose was 115.3mg vs. 91.6mg, respectively, and for the third treatment it was 95.8mg vs. 85.4mg, respectively.
Efficacy outcomes – the primary endpoint
Professor Lammer, who was the principal investigator for the study, also presented tumour response data, which demonstrated greater tumour response in patients treated with PRECISION TACE with DC Bead.
DC Bead demonstrated an advantage in complete response (27 vs. 22%), objective response (52 vs. 44%) and disease control (63 vs. 52%). Furthermore, Professor Lammer showed that in patients with more advanced disease (those with Child Pugh B, ECOG 1, Bilobar or Recurrent Disease) DC Bead was significantly more effective (p<.05).
Professor Anthony Watkinson, the Royal Devon and Exeter Hospital, Peninsular Medical School, Exeter, UK, presented the safety outcomes of the PRECISION V trial, which was measured by the rate of adverse events and serious adverse events (SAEs), treatment-related events, and doxorubicin-related events.
He reported that the total number of adverse events was higher in the cTACE group (497) compared with the DC Bead group (423). SAE rates were equal for both groups (22) and related SAEs were slightly more common in the cTACE group (7) compared with the DC Bead group (6). In the majority of cases, it was observed that the number of SAEs by organ system was higher in the cTACE group than DC Bead (Figure 3).
In patients with more advanced disease, such as Child Pugh B, ECOG 1, bilobar disease, and recurrent disease, SAEs were more common in the cTACE group within 30 days of treatment, explained Watkinson. Death due to disease progression was also higher in the cTACE group than the DC Bead group (3 vs. 1, respectively), however, the total number of deaths due to all causes were equal (8).
In terms of doxorubicin-related side effects, such as alopecia, mucositis, marrow suppression and skin discolouration, the occurrence of each was very significantly higher in the cTACE group (Figure 4).
In discussing the safety outcomes and patient impact, Watkinson said the trial showed that patients treated with PRECISION TACE with DC Bead experienced fewer treatment-related SAEs, Grade 3 and 4 adverse events, and adverse events overall. Compared with the DC Bead group, 100 patients treated with cTACE experienced an additional two more related SAEs, eight more related Grade 3 and 4 adverse events, 24 more doxorubicin-related events, and 46 more adverse events related to the treatment.
He concluded by stating that PRECISION TACE with DC Bead is safe, shows equivalent overall numbers of events when compared to cTACE, but there is a significant (p=.0001) benefit from the DC Bead in reducing the effects of systemic doxorubicin. He also added that there is a near complete absence of alopecia and a marked reduction in serious liver toxicity in DC Bead patients, and the safety of the DC Bead therapy is maintained in advanced patients.
PRECISION V – Summary of results
To summarise the data and interpret the results, Professor Riccardo Lencioni, Pisa University Hospital of Medicine, Pisa, Italy, reported that overall, DC Bead has a greater rate of objective response (p=.11) and lower treatment-related adverse events and SAEs. Furthermore, DC Bead has a significant (p<.05) advantage in objective response in more advanced patients (p=.038) and disease control in more advanced patients (p=.026). Lencioni added that DC Bead demonstrates a highly significant (p<.01) advantage in the reduction of doxorubicin-related side effects (p=.0001) in all patients.
PRECISION TACE with DC Bead is “safe, efficacious and reproducible”, he said. Adding, “There is a significant advantage of using DC Bead in patients with more advanced disease – those with more compromised liver function, poorer performance status, bilobar tumour and recurrent tumour – greater response, greater disease control and improved safety.”. He observed that DC Bead offered a rare example of a new cancer treatment with greater efficacy and also reduced toxicity.
Currently, the AASLD (American Association for the Study of Liver Diseases) guidelines do not recommend chemoembolization for Child B and ECOG 1 patients, but given the results from the PRECISION V trial, the data shows that these patients can now be safely treated with PRECISION TACE with DC Bead, Lencioni concluded.