Chemoembolization (TACE) of Unresectable Intrahepatic Cholangiocarcinoma with Slow-Release Doxorubicin-Eluting Beads: Preliminary Results
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- Aliberti, C., Benea, G., Tilli, M. et al. Cardiovasc Intervent Radiol (2008) 31: 883. doi:10.1007/s00270-008-9336-2
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The purpose of this study was to evaluate the safety and efficacy of TACE with microspheres preloaded with doxorubicin in unresectable intrahepatic cholangiocarcinoma (UCH). Twenty patients with UCH were observed; 9 refused, preferring other palliative care or chemotherapy, and 11 agreed to be treated with one or more cycles of DC beads loaded with doxorubicin (100–150 mg) in a TACE procedure between February 2006 and September 2007. A total of 29 individual TACE procedures were performed. Follow-up imaging was performed on all patients before, immediately after, and 4 weeks after each TACE procedure to evaluate the response and need for further treatment. Each patient received i.v hydration, antibiotics, and medications against nausea and pain before TACE. Survival rate was calculated using Kaplan-Meier survival curve. A response rate of 100% followed RECIST criteria was observed. Eight of eleven patients are alive, with a median survival of 13 months. TACE was well tolerated by all patients. One patient developed hepatic abscess requiring antibiotic therapy. No evidence of marrow toxicity has been reported. Only one of nine patients treated with chemotherapy or palliative care is alive (with a median survival of 7 months in this group of patients). In conclusion, we suggest that doxorubicin-eluting beads TACE is a feasible and effective treatment in patients with UCH. Survival seems to be clearly prolonged in the treated group with respect to the palliative group. We consider that doxorubicin-eluting beads TACE of 100–150 mg may be an appropriate palliative therapy for these patients. Further studies are warranted to confirm these interesting preliminary data.
KeywordsChemoembolizationDrug-eluting beadsDoxorubicinCholangiocarcinomaDC Beads
Cholangiocarcinoma represents 10% of primary liver tumors, with an incidence of 1–2 per 100,000 people in the United States and 2–6 per 100,000 people in Western countries. This tumor is slightly more frequent among the male population (M:F, 1.5:1), with a median age of 60 .
The risk factors are correlated with pathological conditions characterized by chronic inflammation with injury to the bile duct epithelium, such as primary sclerosing cholangitis, choledochocele, Caroli’s disease, intrahepatic biliary lithiasis, and hepatic fibrosis. In 95% of cases, it is defined as adenocarcinoma and is commonly classified according to its anatomical location. About 5–15% of cases are intrahepatic; 60–70% are perihilar (Klatskin’s tumor), and 20–30% are distal extrahepatic cases .
Surgery is the only curative treatment; however, due to the growth characteristics and the vague and late clinical signs, surgery is only possible in 27–30% of cases and is more frequently aimed at extrahepatic forms . Prognosis is poor for unresectable intrahepatic forms, with a median survival of 3–6 months without treatment .
The palliative therapies available, like systemic chemotherapy (ChT), have not shown a significant improvement in terms of survival (range, 5–12 months for ChT) compared to observation.
To ameliorate the clinical results new drugs such as capecitabine combined with intra-arterial ChT have not shown a significant improvement in terms of survival (range 5–12 months for ChT). Encouraging results have been obtained with the combination of systemic chemotherapy with capacitabine and with intra-arterial ChT  On the basis of the survival results obtained with intra-arterial TACE of hepatocarcinomas  and of the evidence of better outcomes shown by TACE in unresectable cholangiocarcinomas [7–9], we planned a study to assess the possibility of performing TACE using microspheres (DC Beads; Biocompatibles UK, Surrey, UK) loaded with doxorubicin in the treatment of intrahepatic cholangiocarcinomas that cannot be surgically removed The rationale is to administer high doses of selective chemotherapy (doxorubicin) intra-arterially into the liver, in combination with embolization of the arteries afferent to the tumor, with consequent strengthening of the therapeutic efficacy through prolonged contact of the drug with the neoplastic cells, due to the reduced washout and the hypoxic stress that occurs after embolization.
The embolizing agent is represented by polyvinyl alcohol beads capable of binding the doxorubicin molecules via reversible ionic exchange to then guarantee slow release into the intralesional area , optimizing the action of TACE as it seem to be demonstrated for hepatocellular carcinoma treatment using DC Beads . No other studies have been reported to date using this therapeutical approach in unresectable intrahepatic cholangiocarcinomas (UCH).
For these reasons the aim of this paper is to assess the feasibility and efficacy of arterial chemoembolization using microspheres loaded with doxorubicin in the treatment of unresectable cholangiocarcinomas.
Materials and Methods
Between February 2006 and May 2007, 20 patients suffering from UCHs, with a mean age of 68.5 years (range: 60–82 years), were enrolled in our study. All patients had previously been treated with surgery and/or systemic chemotherapy, normal liver function levels or up to 2 × ULN (upper limit of normal) at the time of recruitment, performance status (Karnofsky) ≥60%, and a parenchymal invasion percentage of <60%. The mean tumor size was 6.5 cm (range, 3.5–9 cm).
Nine of the 20 patients preferred to continue chemotherapy mainly based on fluorouracil-, cisplatin-, and doxorubicin-containing regimens or other palliative care such as steroids, analgesics, and complementary alternative medicine. Eleven patients agreed, after informed consent, to undergo TACE with DC Beads loaded with doxorubicin. None of them required biliary drainage due to bilirubin levels lower than 2 × ULN.
The clinical and MDCT evaluation was performed before the procedure (median time, 7.5 days, with a range of 1–12 days before TACE), 1 month after TACE (median time interval, 32.5 days, with a range of 28–36 days), and every 3 months thereafter (median time interval, 94.6 days, with a range of 87–98 days). Follow-up assessments included verification of the clinical-laboratory status (liver and kidney function, hematocrit) and multidetector computed tomography (MDTC; Brilliance 64 slice, Philips Medical Systems, Netherlands).
CT scans included triphasic study of the liver, with evaluation of the enhancement pattern of target lesions and tumor response rate according to RECIST criteria. Clinical complications were classified according to WHO scale. Each patient was asked to fill in an ESAS questionnaire (Edmonton Symptom Assessment System) to assess quality of life.
We adopted the same program of supportive treatment and intra-arterial lidocaine used in a previous study [12, 13]. The prophylactic treatment to prevent renal failure was i.v. hydration, which started on the day before TACE and continued on days 0, +1, and +2 with 2000 ml (1000 ml of saline solution, 1000 ml of 5% glucose) with the addition of ranitidine, 900 mg, infused for 24 h. Ranitidine was used to reduce the risk of gastric and pancreatic toxicity. The prophylactic treatment against nausea and vomiting was based on tropisetron, 5 mg, 1 vial before TACE and 1 vial after 6 h on day 0, and dexamethasone, 8 mg at 0800 and 2000 h, on days 0, +1, +2, +3, +4, and +5. The prophylactic treatment against pain was based on morphine, 10 mg, 1 vial 30 min before and 6 h after TACE. Intra-arterial lidocaine, 5 ml, was infused selectively to the vascular bed to be treated, immediately before TACE. Prophylactic treatment against infections was based on cefazolin, 2000 mg at 0800 and 2000 h, on days 0, +1, and +2. The supportive treatment was maintained whenever required on days +3, +4, and +5.
The suspension saline in the microspheres was removed and they were mixed with a doxorubicin solution at a dose of 75 mg/2 ml at least 1 h before the procedure. Digital subtraction angiography (DSA) was performed transfemorally. The study performed was extended to the abdominal aorta to assess hepatic circulation and blood supply to the tumor, with subsequent therapeutic planning. Following insertion of a 5-Fr Cobra or Simmons catheter, a 3-Fr microcatheter (Renegade Hi-Flo; Boston Scentific, Medi-Tech, USA) was then placed and selective hepatic catheterization of lobar or segmental branches afferent to the neoformed tissue was performed in all patients.
DC Beads (DEB; Biocompatibles UK) infusion was preceded by selective intra-arterial infusion of 5 ml lidocaine to reduce the local pain, and verapamil for arterial vasodilation and to prevent vasospam induced by contact of the drug with the endothelium of the vessel. Subsequently, for every TACE, 75–150 mg doxorubicin preloaded in 2- to 4-ml beads of 100–300/300–500 μm was administered. TACE was performed with 75 mg-pre-loaded DC beads in the first five patients and with 150 mg in the following six patients. We increased the dose due to the lack of significant side effects observed and in the hope of obtaining a better clinical outcome.
A total of 29 TACE procedures were performed. In one case, only one cycle of TACE was administered; in two cases, two cycles, and in eight cases, three cycles of treatment were administered. We obtained 100% technical success in 29 of the TACEs performed, and no complications due to the procedure occurred. In seven cases we performed TACE of both lobar arteries and in four cases embolization of only one lobe was required (segmental TACE was performed in two of these cases).
In one case only there was an hepatic abscess, treated with wide-spectrum antibiotic therapy, which resolved after 30 days. In 27 cases (95%) there were episodes of nausea and vomiting (WHO Grade 2) in the 12 h following treatment, which regressed after 24 h; in 29 cases (100%) there was right hypochondrial pain (Grade 2), which regressed after an average of 10 h (range, 3–24 h); and in 29 cases (100%) neoplastic fever starting 72 h after treatment and lasting an average of 2 days (range, 1–7 days).
Only one of nine patients treated with chemotherapy or palliative care is alive (with a median survival of 7 months in this group of patients).
In the DC Bead arm, 10 patients declared an improvement in quality of life according to the ESAS questionnaire. The mean duration of hospitalization was 3.2 days (range, 2–5 days).
Feasibility of surgical treatment for cholangiocarcinoma is limited to a minority of cases (27–30%), because of local extension and invasion of major liver vascular structures . Available nonsurgical approaches have shown poor benefits for survival or controversial results, often not supported by randomized trials . Cholangiocarcinomas are relatively sensitive to ChT (traditionally based on 5-FU, doxorubicin, cisplatin, and mitomycin C), with response rates that vary between 10% and 30% . Better results have been obtained with newer combined regimens involving Gemcitabine  or with combination with radiotherapy (RT), with mean survival of 5–12 months .
External radiotherapy does not show a significant impact on survival or on quality of life. Promising results have been obtained with local RT (intraoperative or intraluminal brachytherapy) , but these therapeutic options, as well as photodynamic therapy, are not currently supported by a large population or randomized trials. Intra-arterial ChT represents another therapeutic option that seems to obtain promising results [5, 7, 15].
The possibility of response is strictly related to the initial performance status of patients. In this context, it is advisable to use new palliative treatments that are suitable for improving quality of life and survival when other “traditional” therapies have often failed. The most promising results are linked to the use of “target” therapies with the aim of optimizing the selective therapeutic effect directly into the lesion.
Target therapies include intra-arterial hepatic chemoembolization (TACE), as a combination of selective drug infusion and embolization of feeding arteries of the tumor. TACE has been shown to prolong survival in hepatocellular carcinoma patients [6, 11] but experience with cholangiocarcinoma is limited. Encouraging preliminary results can be found in the literature on the use of TACE in unresectable cholangiocarcinomas, using several chemotherapy agents, such as gemcitabine, mitomycin C, and doxorubicin, in a lipiodol vehicle, with subsequent embolization through traditionally used agents (Spongostan, gelfoam) [8, 9].
New products that have the characteristic of binding drug molecules via reversible electrochemical binding and simultaneously determining selective arterial embolization, such as DC Beads, have recently been developed [7–20]. DC Beads combine the characteristic of chemically binding doxorubicin or Irinotecan molecules and slowly releasing them inside the lesion; these products seem to guarantee minor blood dispersion of the drug compared with the agents traditionally used in TACE and a high drug concentration for a long time in the target lesion [10, 17]. In vitro and in vivo evaluation of DC Beads showed a decrease in size (by a maximum of 25–30%) when loaded with drug [18, 19].
Preliminary experience with TACE with preloaded drug microspheres in the treatment of HCC indicates a higher index of necrosis and a reduction of side effects, even with high doses of chemotherapy . Promising results have also been obtained with our experience in treating liver metastases from colorectal carcinomas using TACE with DC Beads preloaded with Irinotecan [12, 13].
The present results suggest that the use of this method is also feasible for intrahepatic cholangiocarcinomas, which have a different vascularization from hepatocarcinomas, often presenting large dimensions and having a different sensitivity to chemotherapy agents, thereby requiring high drug (doxorubicin) doses. The use of TACE in patients with cholangiocarcinoma requires some considerations. The size and frequent perihilar localization of the tumor impose a careful preliminary angiographic study to assess the arteries that supply the tumor, often adjacent to both liver lobes, with the subsequent need to treat a large part of the liver parenchyma. Superselectivity in these patients is often not possible and therefore not worthwhile, with an insufficient necrotic effect. It is often necessary to infuse the drug into the lobar or proximal segmental branches and treatment frequently extends to both lobes. For extended lesions with diffuse substitution of the liver volume, for which it is necessary to treat both sides, on the basis of our experience, treatment should be divided into two sessions, with a 15- to 20-day interval in order to avoid liver failure.
The doxorubicin dose and the quantity of microspheres to use should be decided on the basis of the tumor size and bilirubin levels. In our population we explored higher doxorubicin doses (150 mg) after the fifth patient had been treated at a dose of 75 mg due to the mild toxicity observed. The only significant complication was the onset in one case of a liver abscess, which required wide-spectrum antibiotic treatment and resolved within a month. This complication is foreseeable in all TACE procedures, especially in weakened patients with an unstable clinical condition. These patients, especially if they carry biliodigestive anastomoses, can be slightly more susceptible to postnecrotic infectious complications, but suitable antibiotic cover, in our opinion, can minimize these events. The good tolerability of the method has lead us to propose extra TACE cycles for most patients after 2 months, except in cases of clinical worsening or liver failure.
The results obtained have shown a high percentage of intratumoral necrosis, as also confirmed by the perfusion CT study performed before and after TACE. The size reduction (RECIST), evident in all cases at the 3-month CT scan, confirms the therapeutic effect of drug-eluting beads loaded with doxorubicin.
Together with these results, an improved quality of life in 90% of cases (ESAS questionaire) should also be pointed out, in patients who often suffer a reduced performance status. The survival data are rather encouraging as shown by the Kaplan-Maier curve analysis of the patient group that underwent TACE versus the one that received traditional palliative care. A marked survival advantage is noted in the first group (Fig. 4), with a mean survival of 13 months, compared with 7 in the second group.
On the basis of the above, TACE with doxorubicin microspheres can be proposed as a valid palliative therapy for UHCs, with promising preliminary results that must be confirmed in studies on larger populations and with mid- to long-term results, especially in terms of survival and quality of life.