Chemoembolisation of Hepatocellular Carcinomas Not Subject to Interventive Care by Idarubicin-loaded Beads - IDASPHERE II
Status:
Completed
Trial end date:
2018-05-01
Target enrollment:
Participant gender:
Summary
The most frequently used products in CHE are doxorubicin (36%), cisplatin (31%), and
epirubicin (12%). But until recently, there were no obvious reasons to use one product over
another. In fact, systemic chemotherapy is considered ineffective in HCC [hepatocellular
carcinoma], which does not allow any argument in favour of the product. Moreover, 2
randomised trials comparing the molecules (doxorubicin vs. epirubicin) proved to be negative
in terms of survival.
Cytotoxicity of different anticancer agents on HCC cell lines have been compared in order to
select the best candidate for CHE. Eleven chemotherapy molecules have been tested, including
those more frequently used in CHE. Among them, idarubicin (an anthracycline) proved to be the
most effective in vitro by far. The superiority of idarubicin (as opposed to doxorubicin) was
noted especially on the SNU-449 line, which is known for its resistance to several
chemotherapy agents. The best cytotoxicity of idarubicin can be explained by 2 mechanisms: 1)
idarubicin has a better intracellular penetration than the other anthracyclines. This is
probably due to its more considerable lipophily, facilitating thus its passage through the
membrane made up of a double lipid layer, 2) idarubicin is resistant to the multidrug
resistance system (MDR). The MDR mechanism, which is often noted in HCC, consists of membrane
pumps transporting the molecule outside the cell. These two particularities could explain a
more significant accumulation of idarubicin in the HCC cells, and thus better efficacy. It is
interesting to note that orally administered idarubicin (5 mg/day for 21 days) has proved to
be less toxic and is effective in HCC. Currently, idarubicin is used to treat leukaemia. Its
toxicity profile (especially, haematological and cardiac) is known.
On these grounds, A pilot study has been conducted in order to assess the tolerance and
efficacy of lipiodol-based CHE using a 10 mg dose of idarubicin in 21 patients with
unresectable HCC. These preliminary data reveal that CHE with idarubicin is effective and
less toxic.
Idarubicin can be loaded in microbeads. A phase I study (IDASPHERE) has been conducted on DC
Beads® microbeads (300-500µm) loaded with idarubicin (dose increased from 5 to 25 mg). The
DLT [dose-limiting toxicity] and MTD [maximum tolerated dose] have been determined in 21
patients using a CRM. The MTD of idarubicin was assessed at 10 mg. In our study, the
idarubicin-loaded beads did not give rise to any specific toxicity-related problem. The 10 mg
dose is compatible with the known toxicity profile of idarubicin: cumulative cardiotoxicity
of doxorubicin is noted from 550 mg/m², whereas that of idarubicin is noted from 93 mg/m².
There is thus a 5.9:1 ratio between their cumulative toxicities. The most frequently used
dose (and also the weakest one) for the doxorubicin-based CHE is 50 mg. The equivalent of the
idarubicin dose would thus be: 50 mg (doxorubicin) / 5.9 (doxorubicin/idarubicin ratio) =
approx. 10 mg of idarubicin.
It has been already demonstrated that hepatic extraction of idarubicin is better than those
of doxorubicin and daunorubicin in an animal sarcoma model. In this study, AUC 0-48h and AUC
0-72h were 1.35 times higher with idarubicin, proving that its intra-hepatic penetration was
35% higher.
The randomised phase II PRECISION V study compared conventional CHE (cCHE) with CHE by
doxorubicin beads (DC Bead®) in patients with HCC. It is currently the largest randomised
trial on CHE published. The PRECISION V data can be thus used to compare the other studies in
terms of efficacy and tolerance.
To continue our preliminary study and the phase I IDASPHERE study, investigators wish to
assess thus the efficacy and confirm the tolerance of idarubicin-loaded beads for the CHE of
HCC according to a protocol similar to PRECISION V, as part of a single-arm phase II study.