Patients were enrolled at 19 centers in five countries (France, Germany, Switzerland, Austria, and Greece) between 25 November 2005 and 27 June 2007. A total of 212 patients were randomized to TACE with DC Bead (n
= 102) or cTACE (n
= 110). Due to dropouts prior to first treatment, the MITT population included 93 and 108 patients. The last-observation-carried-forward (LOCF) principle was used so that the primary endpoint could be assessed using the full MITT population (Fig. ). At baseline there were no major differences between the treatment groups with regard to patient demographics, tumor burden, or health status (Table ). The majority of patients (66.7%) in both groups were considered more advanced, as they met the higher risk criteria for one or more of the four prognostic factors, i.e., Child Pugh B, ECOG 1, bilobar or recurrent disease (63 of 93 DC Bead and 72 of 108 cTACE patients). The mean total dose of doxorubicin administered was higher in the DC Bead group compared with the cTACE group (295 vs.
223 mg) and in all subgroups. The mean volume of lipiodol administered was 10 ml per treatment in the cTACE group [32
]. The numbers of chemoembolizations in each treatment group were similar: 93 and 108 patients, respectively, received a first; 82% of patients in each group received a second; and 61% and 57%, respectively, received a third chemoembolization.
Patient characteristics, health status, and tumor burden at baseline
Efficacy (Tumor Response—EASL)
At 6 months, a complete response was achieved in 25 (26.9%) vs. 24 (22.2%) patients, a partial response in 23 (24.7%) vs. 23 (21.3%) patients, and stable disease in 11 (11.8%) vs. 9 (8.3%) patients in the DC Bead vs. cTACE arm, respectively. Progressive disease was observed in 30 (32.3%) vs. 44 (40.7%) patients, respectively; 4 DC Bead patients and 8 cTACE patients withdrew prior to the first MRI scan. Reasons for these withdrawals were AEs (four DC Bead and four cTACE), withdrawn consent (two cTACE), and post consent ineligibility (two cTACE). Therefore, the OR rate was 51.6% vs. 43.5% in the DC Bead vs. cTACE arm, respectively; the hypothesis of superiority was not met (one-sided P = 0.11) (Fig. ). The difference between groups in favor of DC Bead was 8.1% (two-sided 95% repeated confidence interval (RCI), −4.8 to 22.6%). The disease control rates were 63.4% vs. 51.9%, respectively (two-sided P = 0.11). Boundary P-values were not exceeded in the interim analyses.
Fig. 2 Tumor response at 6 months (LOCF) (MITT population and advanced patient group*, **). * More advanced disease was at least one of Child-Pugh B, ECOG 1, undergone prior curative treatment (i.e., recurrent disease), and presence of bilobar (more ...)
Supplementary analyses showed that in the 67% of patients with more advanced disease (Child Pugh B, ECOG 1, bilobar or recurrent disease), the incidence of OR and disease control rates were statistically higher (P = 0.038 and P = 0.026, respectively) in the DC Bead compared with the cTACE group (Fig. ). The greatest difference in disease control rates between DC Bead and cTACE occurred in the ECOG 1 and Child-Pugh B subgroups (both, 63% and 32%, respectively; Fig. ).
Fig. 3 a Complete response, objective response, and disease control rate (cumulative number [%] of patients) of all patients at 6 months. b Complete response, objective response, and disease control rate (cumulative number [%] of patients) of patients by stratification (more ...)
There was no statistically significant (P = 0.86) difference between treatments for the primary safety endpoint (treatment-related SAEs within 30 days of a procedure): 19 (20.4%) DC Bead patients experienced 28 events and 21 (19.4%) cTACE patients experienced 24 events. Supplementary post hoc analysis indicated that the incidence of SAEs within 30 days of a procedure was consistently lower in the DC Bead group both for the less advanced and for the more advanced patients based on the four stratification factors (Table ).
Incidence of serious adverse events within 30 days of a procedure, by stratification (safety population)
The overall frequency of treatment-emergent AEs (TEAEs) per 100 treatments was lower in the DC Bead compared with the cTACE group, as were treatment-related TEAEs, Southwestern Oncology Group (SWOG) toxicity Grade 3 or 4 TEAEs, Grade 3 or 4 treatment-related TEAEs, and treatment-related SAEs. The majority of TEAEs were mild or moderate in intensity, with a lower frequency of severe events (20.4% vs. 30.6%) reported in DC Bead vs. cTACE patients. The only event with a difference in incidence of ≥10% was alopecia, reported in 2.2% of DC Bead and 19.4% of cTACE patients. Serious liver toxicity postchemoembolization was also lower in the DC Bead group. Observed postprocedural increases in the liver enzymes AST and ALT were significantly less in the DC Bead group than in the cTACE group. The mean maximum ALT increase in the DC Bead group was 50% less than in the cTACE group (95% CI, 39–65%; P < 0.001) and 41% less with respect to AST (95% CI, 46–76%; P < 0.001) (Fig. ). Cardiac function (measured by echocardiography, isotopic ventriculography, or MRI) was maintained in the DC Bead group, whereas there was a deterioration in left ventricular ejection fraction in the cTACE group (DC Bead, +2.7 ± 10.1 percentage points; cTACE, −1.5 ± 7.6 percentage points; P = 0.018). Sixteen deaths were reported during the study (eight in each arm). Of these, two DC Bead and six cTACE patients died within 30 days of a procedure. Four patients died due to disease progression (one DC Bead, three TACE). Other causes of death were liver failure (two in each arm), cardiac events (two DC Bead, one cTACE), infection (one DC Bead, two cTACE), and, in one DC Bead patient, each of GI bleed and unknown cause.
Fig. 4 Comparison of treatment groups for-fold changes in liver enzymes by chemoembolization procedure and maximum-fold change across all procedures (mean, 95% confidence interval [CI]). Analysis using t-test for log-transformed data; results back-transformed (more ...)
With regard to the systemic side effects of doxorubicin (alopecia, skin discoloration, mucositis, and marrow suppression), post hoc analyses established a significant benefit (estimate of true incidence, −14.1%; 95% CI, −24.7% to –3.5%; P = 0.012) in favor of DC Bead over cTACE: 12 events in 11 (11.8%) patients vs. 40 events in 28 (25.9%) patients, respectively. Alopecia, the most commonly occurring event, was almost completely absent in DC Bead patients (1 vs. 23 events). The only DC Bead alopecia event was mild (Grade 1), while in the cTACE arm almost half of the alopecia events (11 events) were of pronounced/total hair loss (Grade 2). Marrow suppression and mucositis were more common and of greater severity in cTACE compared with DC Bead patients, and skin discoloration occurred in equal numbers (Table ).Using the assumption of independence of events, the difference in frequencies of doxorubicin-related events was also significant (P = 0.0001). The incidence and frequency of post embolization syndrome events were comparable in the treatment groups: 35 events in 23 (24.7%) DC Bead and 43 events in 28 (25.9%) cTACE patients.
Effects of systemic doxorubicin (safety population)