Communication Cite This: Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Comment on “In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma” Walter González,*,† Jean-Marc Idée,† and Sebastien Ballet‡ †
Research Department, Guerbet, 95943 Roissy CDG, France Medical Affairs Department, Guerbet, 95943 Roissy CDG, France
‡
Mol. Pharmaceutics, 2017, 14 (2), 448−458. DOI: 10.1021/acs.molpharmaceut.6b00886 Mol. Pharmaceutics, 2017, 14. DOI: 10.1021/acs.molpharmaceut.7b00840 Lilienberg et al. concluded that “The poor stability of LIPDOX and the high systemic exposure (AUC and Cmax) to DOX released from this drug delivery system (DDS) compared to DEBDOX are pharmaceutical drawbacks” and “DEBDOX has a release and distribution of DOX that is more controlled than LIPDOX”.1 It is our contention that the experimental data presented in this article do not fully support these conclusions for a variety of reasons. Lilienberg et al. 1 intended to apply an interesting pharmacokinetics approach based on measurement of local and systemic plasma concentrations of both doxorubicin and its major metabolite doxorubicinol. We believe that the study includes a number of technical and methodological issues that make translation of this study into clinical practice fairly hazardous. This open, prospective, nonrandomized and multicenter (two Swedish centers) study was designed to evaluate the in vivo delivery profile of doxorubicin from either Lipiodol-based emulsion (called LIPDOX in the article) or DC Beads in HCC patients. Urinary doxorubicin and doxorubicinol excretion, short-term safety (7 days), and radiologically measured tumor response at early time points (4−6 weeks after administration) were also evaluated. Limitations Associated with LIPDOX Administration. First, it should be noted that Lipiodol is not an excipient, but a drug approved in numerous countries worldwide for interventional radiology applications. Second, it must be stressed that so-called “LIPDOX” administration, performed without any additional embolic agent, should not be confused with the so-called c-TACE procedure. This technique includes the administration of an additional embolic agent (such as gelatin sponge, trisacryl gelatin microspheres, degradable starch microspheres, or poly(vinyl alcohol) particles) after cytotoxic drug/Lipiodol emulsion delivery to induce complete blood flow stasis up to the catheter tip.8 LIPDOX administration without any additional embolic agent is classically called “TOCE” (transarterial oily chemoembolization) and is distinct from c-TACE.9 We assume that
KEYWORDS: conventional transarterial chemoembolization (c-TACE), Lipiodol, drug-eluting beads, hepatocellular carcinoma, liver cancer, doxorubicin, doxorubicinol, local therapy, interventional radiology
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INTRODUCTION
In a recent article published in Molecular Pharmaceutics, Lilienberg et al. reported the results of a clinical study comparing the pharmacokinetics and doxorubicin delivery properties of two commercial products, Lipiodol (Guerbet, Villepinte, France), and DC Beads (BTG/Biocompatibles, Surrey, U.K.) in patients with hepatocellular carcinoma (HCC).1 While these results may be relevant to a better understanding of the mechanism of action of the drug delivery systems classically used in transarterial chemoembolization (TACE) procedures, and undoubtedly are of great interest to interventional radiologists managing patients with unresectable HCC, we believe that several shortcomings and limitations in the methods and analysis of the results may somewhat preclude or limit the conclusions of the study and deserve discussion. According to the EASL-EORTC guidelines,2 chemoembolization (TACE) has been established as the standard of care for patients who meet the criteria for the intermediate stage of the BCLC staging system, i.e., those with multinodular HCC, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread.2−4 This technique is also used to treat intrahepatic cholangiocarcinoma and liver metastases of various tumors (colorectal cancer, neuroendocrine tumors, melanoma, and breast cancer). The rationale for transarterial treatments is based on the preferential blood supply of a variety of tumors growing in the liver, thereby allowing local chemotherapy and embolization of tumors by selective injection into the tumor feeding artery.5,6 Recently, beads loaded with cytotoxic agents have been proposed for the palliative treatment of primary or secondary liver tumors. A discussion of the clinical evidence supporting the use of conventional Lipiodol-based TACE (c-TACE) and drug-eluting beads (DEBs)-TACE (referred to as DEBDOX in the article by Lilienberg et al.) was recently published.7 © XXXX American Chemical Society
Received: February 23, 2017 Revised: July 28, 2017 Accepted: August 2, 2017
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DOI: 10.1021/acs.molpharmaceut.7b00138 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Communication
Molecular Pharmaceutics
neously administered intra-arterially in this group. Conversely, the dose administered in the DEBDOX group was much more heterogeneous (range: 22.5−150 mg). The authors indicated that complete embolization was achieved either without administration of an additional embolic agent, suggesting that the maximum dose of 150 mg of doxorubicin was not systematically achieved, or with administration of additional embolic agent, indicating that maximum dose of 150 mg of doxorubicin was probably administered. As the individual dose of DEBDOX administration was monitored, the authors would have integrated and computed these data in the pharmacokinetic analysis. Fourth, the lack of standardization of bead size in the DEBDOX group may prevent reliable estimation of doxorubicin loading and release properties. In 2006, Lewis et al.15 demonstrated that doxorubicin loading has a differential effect on the diameter of loaded beads as loading of 45 mg/mL of doxorubicin (similar to the conditions of the present study) significantly decreased the average diameter of 500 and 700 μm sized beads, thus potentially modifying the delivery properties of the beads. Moreover, previous in vitro studies15,16 have reported incomplete doxorubicin release from DC Beads, as only 20−30% of loaded doxorubicin was released after 5 h, with no additional doxorubicin release over the following 4 days, whereas 100% doxorubicin release was measured from Lipiodol-based emulsion.15 Assuming that either complete embolization or intended maximum dose represented the endpoint of the procedure, it may be speculated that some heterogeneity occurred inside the same group and between the two groups, thus potentially resulting in variability between patients. Lastly, several additional differences between the LIPDOX and DEBDOX groups should be stressed: Additional Embolic Agent. Ideally, the authors should have detailed the embolization conditions for each patient, including catheter placement of selective administration. Previous studies17,18 have clearly shown that the selectivity of intraarterial drug delivery, especially in the case of HCC patients, is critical to achieve optimal efficacy and safety. Conventional TACE performed at the most distal level of the subsegmental hepatic artery is classically called “ultra-selective c-TACE” and is widely used, especially in Asian countries.19,20 In a multicenter study involving 815 patients with 5 or fewer HCC lesions with maximum diameter of 7 cm, the prognosis of patients who underwent selective/superselective c-TACE was significantly better than that of patients who underwent nonselective (lobar) c-TACE.18 In the present study, treatment with LIPDOX was performed by lobar hepatic artery administration, whereas DEBDOX administration was superselective, an approach which would substantially decrease doxorubicin release in the surrounding liver parenchyma and drug release into plasma in the DEBDOX group. Superselective catheterization of the hepatic artery branch feeding the tumor, when clinically feasible, is recommended.21 Tumor Size. Because of the significant difference in tumor size between the two groups (LIPDOX, 62 [30−130] mm; DEBDOX, 36 [6−65 mm]; p < 0.05), we believe that no clear conclusions can be drawn from this study, not only in terms of plasma pharmacokinetics but also in terms of the clinical efficacy/safety profiles of TOCE/LIPDOX and DEBDOX. Clinical Study Methodology. Patients admitted to Uppsala University Hospital were assigned to LIPDOX administration, and HCC patients admitted to Karolinska University Hospital
the clinical team involved did not modify its standard operating technique for this study. Of course, this approach is perfectly understandable and legitimate and we do not suggest that Lilienberg et al. considered TOCE/LIPDOX to be equivalent to c-TACE. However, from a clinical perspective, the results could be misinterpreted if readers fail to make the distinction between TOCE/LIPDOX and c-TACE. The TOCE/LIPDOX treatment tested in the published study therefore does not constitute the reference treatment recommended by international guidelines. Basically, the purpose of embolization during transarterial treatment of HCC is 2-fold: (a) to prevent washout of the cytotoxic drug and therefore its systemic toxicity, and (b) to induce ischemic necrosis.10 With respect to the first purpose, a clinical study compared the biodistribution of doxorubicin in HCC patients treated with (a) selective administration of 50 mg of doxorubicin alone into the hepatic artery, (b) doxorubicin emulsified with 10 mL of Lipiodol and 2.5 mL of a water-soluble iodinated contrast medium, or (c) doxorubicin emulsified with Lipiodol and a water-soluble iodinated contrast medium followed by the administration of gelatin sponge particles.11 It was found that emulsification of doxorubicin substantially reduced the peak plasma concentration of doxorubicin and increased its intratumoral concentration and its half-life (measured by scintigraphy after administration of 131I-doxorubicin). Furthermore, these effects were further improved by the addition of gelatin sponge embolization.11 With respect to the second purpose, there is clinical evidence that c-TACE improves overall survival compared to TOCE (26.1% vs 18.1% at 5 years, P = 0.0017 in a prospective, randomized trial involving 322 patients).12 Embolization using gelatin sponge administered after administration of the Lipiodol and doxorubicin emulsion significantly increased complete necrosis of both main and daughter tumors in another clinical trial.13 In a swine model, additional embolization after intraarterial delivery of cytotoxic-loaded Lipiodol-based emulsion caused a significant delay of drug outflow, as well as more intense liver necrosis compared to intra-arterial delivery without additional embolization.14 Therefore, delivery of an embolic agent immediately after LIPDOX could reduce washout, systemic cytotoxic drug exposure, and Cmax. Limitations Associated with DEBDOX Administration. First, in Lilienberg et al.,1 the choice of bead size was adapted to the size of tumor vessels during the DEBDOX procedure and unloaded beads were added in the case of incomplete tumor stasis/embolization with DEBDOX. The addition of unloaded beads strongly suggests that, depending on their size, DC Beads could not fully embolize the tumor-feeding vessels although the target dose was met before stasis, which would not be totally consistent with the assertion “DEBDOX causes complete embolization by itself”.1 To clarify the procedure conditions, the authors should have described in detail the individual DEBDOX procedure conditions (dose, bead size, quantity, and volume injected). Second, the heterogeneous conditions associated with the DEBDOX treatmentincluding different bead size with or without subsequent administration of unloaded beads, and variable administered doxorubicin dosemay affect the pharmacokinetics profile of doxorubicin and doxorubicinol. Third, the TOCE/LIPDOX group was treated with 50 mg of doxorubicin. The entire dose of doxorubicin was homogeB
DOI: 10.1021/acs.molpharmaceut.7b00138 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Communication
Molecular Pharmaceutics
the Barcelona-2000 EASL Conference. European Association for the Study of the Liver. J. Hepatol. 2001, 35, 421−430. (4) Yau, T.; Tang, V. Y.; Yao, T.; Fan, S. T.; Lo, C. M.; Poon, R. T. Development of Hong Kong Liver Cancer Staging System with Treatment Stratification for Patients with hepatocellular carcinoma. Gastroenterology 2014, 146, 1691−1700.e3. (5) Breedis, C.; Young, G. The Blood Supply of Neoplasms in the Liver. Am. J. Pathol. 1954, 30, 969−977. (6) Lautt, W. W.; Greenway, C. V. Conceptual Review of the Hepatic Vascular Bed. Hepatology 1987, 7, 952−963. (7) Wang, Y. X. J.; De Baere, T.; Idée, J. M.; Ballet, S. Transcatheter Embolization Therapy in Liver Cancer: An Update of Clinical Evidences. Chin. J. Cancer Res. 2015, 27 (2), 96−101. (8) De Baere, T.; Arai, Y.; Lencioni, R.; Geschwind, J. F.; Rilling, W.; Salem, R.; Matsui, O.; Soulen, M. C. Treatment of Liver Tumors with Lipiodol TACE: Technical. Recommendations from Experts Opinion. Cardiovasc. Intervent. Radiol. 2016, 39 (3), 334−343. (9) Idée, J. M.; Guiu, B. Use of Lipiodol as a Drug-delivery System for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma: a Review. Crit. Rev. Oncol. Hematol. 2013, 88, 530−549. (10) Liapi, E.; Geschwind, J. F. Transcatheter Arterial Chemoembolization for Liver Cancer: is it Time to Distinguish Conventional From Drug-Eluting Chemoembolization? Cardiovasc. Intervent. Radiol. 2011, 34 (1), 37−49. (11) Raoul, J. L.; Heresbach, D.; Bretagne, J. F.; Bentue Ferrer, D.; Duvauferrier, R.; Bourguet, P.; Messner, M.; Gosselin, M. Chemoembolization of Hepatocellular Carcinomas. A Study of the Biodistribution and Pharmacokinetics of Doxorubicin. Cancer 1992, 70 (3), 585−590. (12) Hatanaka, Y.; Yamashita, Y.; Takahashi, M.; Koga, Y.; Saito, R.; Nakashima, K.; Urata, J.; Miyao, M. Unresectable Hepatocellular Carcinoma: Analysis of Prognostic Factors in Transcatheter Management. Radiology 1995, 195 (3), 747−752. (13) Takayasu, K.; Shima, Y.; Muramatsu, Y.; Moriyama, N.; Yamada, T.; Makuuchi, M.; Hasegawa, H.; Hirohashi, S. Hepatocellular Carcinoma: Treatment with Intraarterial Iodized oil With and Without Chemotherapeutic Agents. Radiology 1987, 163 (2), 345−351. (14) Ikoma, A.; Kawai, N.; Sato, M.; Minamiguchi, H.; Nakai, M.; Nakata, K.; Tanaka, T.; Sonomura, T. Comparison of Blood Dynamics of Anticancer Drugs (Cisplatin, Mitomycin C, Epirubicin) in Treatment Groups of Hepatic Arterial Infusion, Hepatic Arterial Infusion with Lipiodol and Transcatheter Arterial Chemoembolization With Lipiodol plus Gelatin Sponge Particles in a Swine Model. Hepatol. Res. 2012, 42 (12), 1227−1235. (15) Lewis, A. L.; Gonzalez, M. V.; Lloyd, A. W.; Hall, B.; Tang, Y.; Willis, S. L.; Leppard, S. W.; Wolfenden, L. C.; Palmer, R. R.; Stratford, P. W. DC Bead: In Vitro Characterization of a Drug-Delivery Device for Transarterial Chemoembolization. J. Vasc. Interv. Radiol. 2006, 17 (2 Part 1), 335−342. (16) Jordan, O.; Denys, A.; De Baere, T.; Boulens, N.; Doelker, E. Comparative Study of Chemoembolization Loadable Beads: In Vitro Drug Release and Physical Properties of DC Bead and Hepasphere Loaded with Doxorubicin and Irinotecan. J. Vasc. Interv. Radiol. 2010, 21 (7), 1084−1090. (17) Golfieri, R.; Cappelli, A.; Cucchetti, A.; Piscaglia, F.; Carpenzano, M.; Peri, E.; Ravaioli, M.; D’Errico-Grigioni, A.; Pinna, A. D.; Bolondi, L. Efficacy of Selective Transarterial Chemoembolization in Inducing Tumor Necrosis in Small (
