We hypothesized that intra-arterial gemcitabine/oxaliplatin administered as second-line treatment could strongly improve objective response rate at 4 months after inclusion in patient with non-metastatic unresectable intra-hepatic cholangiocarcinoma.
Cholangiocarcinomas are rare tumors with an extremely poor prognosis. The best therapeutic option (i.e. resection) can only be done in 20% of cases. Combinations of gemcitabine/platinum compounds were identified as the new standard first-line therapy For patients with hepatic-only disease, therapy intensification using Intra-Arterial (IA) chemotherapy could be an attractive option since: * Vascularisation of hepatic tumors is almost exclusively provided by the hepatic artery. * Gemcitabine and oxaliplatin have a high rate of hepatic extraction during the first passage, thus allowing the drugs to reach high intra-tumoral concentrations with low systemic toxicity. * The plasma concentration of gemcitabine after IA injection is 1/7th of that observed following Intra-Venous (IV) injection. No grade 3-4 toxicity has been observed in doses \<1400mg/m². * Phase I and I/II studies have shown dose-limiting toxicity between 150-175mg/m² for IA oxaliplatin every 3 weeks. * We reported (Ghiringhelli, Chemotherapy 2013) in 12 patients with progressive intra-hepatic cholangiocarcinoma after IV gemcitabine/oxaliplatin, a partial response in 8 cases (stability in 3 cases) after IA gemcitabine/oxaliplatin. Among them, two were resected (R0) and three were treated by stereotactic radiation therapy). Hepatic IA chemotherapy has rarely been used for the treatment of intra-hepatic cholangiocarcinoma (IHC), essentially in case-reports from Asia and in a few case-series that have mainly used IA monotherapy. The implantation of a hepatic arterial catheter has now been mastered by interventional radiologists and makes it possible to increase the intra-tumoral concentration of the drugs and probably to limit their systemic toxicity. Very recently, we have reported that this combination in progressive IHC following systemic gemcitabine/oxaliplatin has led to partial responses and allowed certain patients to benefit from curative treatment. This suggests that the intra-arterial approach increases the efficacy of these 2 drugs. For locally-advanced IHC, such a loco-regional approach is worth exploring in this poor-prognosis tumor, especially since so far 1) there is insufficient evidence to recommend a second-line chemotherapy schedule in this tumor and 2) targeted therapies have demonstrated no survival benefit over systemic chemotherapy alone. It is a multicenter single-arm phase II trial aiming to determine the objective response rate 4 months after inclusion following IA gemcitabine / oxaliplatin administered as second-line treatment in patients with non-metastatic unresectable intra-hepatic cholangiocarcinoma. It will be the first French phase II trial for 2nd line treatment in intrahepatic cholangiocarcinoma.
Vascularisation of hepatic tumors is almost exclusively provided by the hepatic artery. Gemcitabine and oxaliplatin have a high rate of hepatic extraction during the first passage, thus allowing the drugs to reach high intra-tumoral concentrations with low systemic toxicity.
The implantation of a hepatic arterial catheter has now been mastered by interventional radiologists and makes it possible to increase the intra-tumoral concentration of the drugs and probably to limit their systemic toxicity. Very recently, we have reported that this combination in progressive IHC following systemic gemcitabine/oxaliplatin has led to partial responses and allowed certain patients to benefit from curative treatment. This suggests that the intra-arterial approach increases the efficacy of these 2 drugs. For locally-advanced IHC, such a loco-regional approach is worth exploring in this poor-prognosis tumor.
Amiens University Hospital
Amiens, France
RECRUITINGAngers University Hospital
Angers, France
RECRUITINGBordeaux University Hospital
Bordeaux, France
objective response rate
The primary outcome is to evaluate the objective response rate (complete or partial response) 4 months after inclusion using RECIST 1.1 evaluation.
Time frame: 4 months after inclusion
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Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Centre Georges François Leclerc
Dijon, France
RECRUITINGUhmontpellier
Montpellier, France
RECRUITINGHôpital Européen Georges Pompidou
Paris, France
RECRUITINGInstitut Gustave Roussy
Villejuif, France
RECRUITING