Comment on 'In Vivo Drug Delivery Performance of

Communication Cite This: Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Reply to “Comment on ‘In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma’” Ilse R. Dubbelboer,† Elsa Lilienberg,† Amar Karalli,‡,§ Rimma Axelsson,‡,§ Torkel B. Brismar,‡,§ Charlotte Ebeling Barbier,∥ Agneta Norén,⊥ Frans Duraj,⊥ Mikael Hedeland,# Ulf Bondesson,# Erik Sjögren,† Per Stål,∇,○ Rickard Nyman,∥ and Hans Lennernas̈ *,† †

Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden Department of Radiology, Karolinska University Hospital in Huddinge, Stockholm, Sweden § Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden ∥ Department of Radiology, Uppsala University Hospital, Uppsala University, 751 85 Uppsala, Sweden ⊥ Department of Surgical Sciences, Uppsala University Hospital, Uppsala University, 751 85 Uppsala, Sweden # Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute (SVA), 751 89 Uppsala, Sweden ∇ Unit of Gastroenterology, Department of Internal Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden ○ Department of Digestive Diseases, Karolinska University Hospital in Huddinge, Stockholm, Sweden ‡

Mol. Pharmaceutics, 2017, 14 (2), 448−458. DOI: 10.1021/acs.molpharmaceut.6b00886 Mol. Pharmaceutics, 2017, 14. DOI: 10.1021/acs.molpharmaceut.7b00138 tion. Gaba et al. considered these terms the most acceptable descriptors for the methods. They further clarified that “Chemoembolization may be performed by using conventional or drug-eluting embolic approaches”, “conventional chemoembolization is defined as the infusion of single or multiple chemotherapeutic agents with or without ethiodized oil and with or without concurrent (as a component of the chemoembolic emulsion) or tandem embolization with particles such as gelatin sponge, polyvinylalcohol, or calibrated microspheres”, and “drug-eluting embolic chemoembolization is defined as the administration of microspheres onto which chemotherapeutic medication is loaded or adsorbed with the intention of sustained in vivo drug release”. Abbreviations like TOCE (transarterial oily chemoembolization), TAE (transarterial embolization), TAI (transarterial infusion chemotherapy), and TAC (transarterial chemotherapy) were discouraged, as they considered that these terms did not improve the description of the clinical procedure.6 However, TACE (transarterial chemoembolization) was considered acceptable because it has been widely recognized and acknowledged. Conventional chemoembolization is commonly abbreviated to cTACE, and drug-eluting embolic chemoembolization to DEETACE. However, instead of using abbreviations, it was strongly recommended that study reports use a list of requirements and recommendations for describing the treatment methods. We strongly support harmonization of the terminology, and use of the list provided by Gaba et al. when writing study reports on this research subject. From a pharmaceutical perspective at least, there are often gaps in published treatment

KEYWORDS: doxorubicin, Lipiodol, drug-eluting beads, transarterial chemoembolization (TACE), hepatocelluar carcinoma, liver cancer, local therapy, interventional radiology, image-guided transarterial tumor therapy

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e would like to thank González and co-workers at Guerbet, France, for their comprehensive commentary1 on our clinical study2 on the in vivo drug-delivery performance of two drug-delivery systems frequently used in the treatment of intermediate hepatocellular carcinoma (HCC). González et al. acknowledged that the study is a useful contribution to the ongoing discussion on the various interventional techniques associated with intra-arterial embolization in the treatment of HCC. In addition they raised a number of important issues and have provided an opportunity for an interesting debate about the use and terminology of image-guided transarterial tumor therapy in the clinic.

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TERMINOLOGY The terminology used in the field of image-guided transarterial tumor therapy has been and remains unclear, although suggestions for harmonization have been made.3−9 For example, Gaba et al. (2016)6 have defined image-guided transarterial tumor therapy as “the intravascular delivery of therapeutic agents via selective catheter placement with imaging guidance for the treatment of malignancy”, in line with other published articles.3−5 Image-guided transarterial tumor therapy involves the catheterization of the common, proper, lobar, segmental, and/or subsegmental (direct tumor-feeding) hepatic arteries combined with one of the following treatment methods: embolization, chemoembolization, or radioemboliza© XXXX American Chemical Society

Received: Revised: Accepted: Published: A

September 25, 2017 November 29, 2017 November 29, 2017 November 29, 2017 DOI: 10.1021/acs.molpharmaceut.7b00840 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Communication

Molecular Pharmaceutics

stopped when stasis is observed, to avoid reflux of beads, even if the intended dose has not been administered. Karolinska University Hospital administers additional unloaded beads when stasis has not occurred after the intended dose has been administered, to obtain a near-stasis end point. There are differences between the standard procedures at Uppsala University Hospital and Karolinska University Hospital; for example, in the pharmaceutical formulations, catheter placements, and embolization grades. These differences make it difficult to pinpoint the origin of the differences between the pharmacokinetic (PK) parameters obtained with the LIPDOX and DEBDOX treatments. However, we deemed it important to publish the results, which are as clinically relevant as possible. This means that we wished to design the study in such a way that the study protocol reflected reality in Swedish clinics.

descriptions, for example in details of clinical usage, dosage, and formulation. Specifics of the formulation (emulsion ratio, composition, suspension media, etc.) and injection techniques (site of administration, infusion times, injected volumes, etc.), in particular, have often been omitted.10 We followed the recommendations and requirements set out by Gaba et al.6 closely in the treatment description in our report.2 For example, for Lipiodol treatment, we described the chemotherapy regimen, drug dosage, use of ethiodized oil, mixing method, and embolization end point (no embolization was used). Similarly, for treatment with drug-eluting beads, we described the particle type and size, number of microsphere vials (by reporting loading per vial and total intended dose), chemotherapy regimen, drug dosage, injection technique (suspension media and infusion time), and embolization end point (until stasis occurred). The names of the investigated pharmaceutical formulations in our study were, however, abbreviated to LIPDOX and DEBDOX. We defined LIPDOX as an emulsion composed of an aqueous doxorubicin (DOX) solution mixed with Lipiodol. DEBDOX was defined as DOXloaded DC bead. It should be noted that these two terms (LIPDOX and DEBDOX) in no way described the treatment procedure (e.g., catheter placement or additional embolization materials) given to the patient; they merely described the pharmaceutical formulations used in the treatment. To avoid any confusion about the treatment procedure, the abbreviation TACE (transarterial chemoembolization) was mentioned only to describe this common delivery technique and the associated exclusion criteria. To emphasize which type of treatment procedure was followed, we stated three times that LIPDOX was administered without additional embolization. Although we appreciate the efforts of González et al. to clarify the therapy we used further, we consider it to be clearly described in the report.

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STUDY DESIGN (PROCEDURE) González et al. comment that differences in the pharmacokinetics and safety and efficacy profiles between LIPDOX and DEBDOX could be ascribed to the lack of randomization of the patients to the study groups. We wish to refute their statement. Patients in Sweden are allocated to a hospital based upon their registered home address. This, in itself, can be said to be a randomization, as we had no control over which patients received which treatment. However, eventual differences between the municipalities in inhabitant origin and eventual differences in who are accepted for interventional treatment could not be avoided. Once admitted, as explained in our article, the patients received standard treatment according to the hospital they were in. Treatments were not randomized per clinic for several reasons, as described below. First, each clinic has already chosen its preferred procedure, including drug formulation and intrahepatic catheter placement. Changing the procedure for the sake of the study could have resulted in larger differences in the treatment of the patients, as the physicians would have had to learn to apply the new treatment and its procedures. If the treating physician had a strong preference for the previously used treatment, it could have introduced bias if an alternative treatment was used. Second, it would have been difficult to blind this study to the physician. LIPDOX and DEBDOX are different products, and the handling of the formulations differs both prior to and during administration. For example, the physician needs to manually emulsify the Lipiodol phase with the aqueous DOX phase in LIPDOX just prior to administration, while DEBDOX needs to be shaken carefully before administration to disperse the beads in the fluid. Third, the treatment procedure is different in each clinic. Clinicians at the Department of Radiology, Uppsala University Hospital, administer LIPDOX lobularly to treat any satellite tumors that are too small to observe by imaging. Clinicians at the Karolinska Institute administer DEBDOX superselectively, as is the custom with TACE combined with drug-eluting beads. Using the same administration site could potentially harm the patient. For example, if the administration site was subsegmental, patients with undiscovered tumors would receive worse LIPDOX treatment than patients treated lobularly at the same clinic. Fourthly, there is substantial variability among patients with liver pathophysiology, such as in the location of the tumor, tumor size, and vascularity and architecture of the vessels. It

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TREATMENT RATIONALE The standard treatment procedure used for image-guided transarterial tumor therapy at the Department of Radiology, Uppsala University Hospital, comprises repeated administration of LIPDOX every 6 weeks on up to six occasions. The composition and preparation of LIPDOX was described in the article.2 Blockage of the artery with an embolic agent was avoided so as to enable iteration of injections. Two randomized studies found no difference in tumor response11 or survival11,12 when Lipiodol emulsion was administered with or without the addition of an embolic agent. Because the areas surrounding the tumor might contain micrometastases, Lipiodol emulsion has been administered lobarly or segmentally to ensure treatment of these as well as the visible tumor/tumors. There are no published studies comparing the results of superselective and lobar/segmental administration of Lipiodol emulsions, but both methods are used worldwide and seem to provide good antitumoral effects.13,14 The standard treatment procedure used by Karolinska University Hospital is administration of DEBDOX, formulated by loading DC Bead with DOX according to the manufacturer’s instructions. The standard treatment procedure follows the guidelines published by Lencioni et al.15 That is, the smallest possible beads are chosen to fit the pathophysiology and vasculature of the tumor. Smaller beads are always administered prior to larger beads, in order to reach the inside of the tumor. Each vial of DC Bead is loaded with 75 mg of DOX and diluted prior to administration. The administration catheter is placed subsegmentally (superselectively). Infusion of DEBDOX is B

DOI: 10.1021/acs.molpharmaceut.7b00840 Mol. Pharmaceutics XXXX, XXX, XXX−XXX


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SAFETY AND EFFICACY The primary objective of the study was a PK comparison of the clinical use of LIPDOX and DEBDOX treatments. Secondary objectives were “to examine urinary excretion of DOX and DOXol and to relate the PK to short-term toxicity and antitumor effects.” It is our understanding that, in a clinical study, the primary objectives are used to estimate the number of patients required to have statistical power to (dis)prove the primary objective. Secondary objectives are meant to study a different variable, such as efficacy or safety, but will likely only give a trend as the study is not designed to have the statistical power to (dis)prove secondary objectives. The tumor response data we published indicated the effect of the treatment procedure after one treatment cycle. It is important to remember that LIPDOX treatment is meant to be repeated every 6 weeks, on up to six occasions, before the outcome is evaluated. Even with DEBDOX, repeated treatments are sometimes given. To draw a conclusion about treatment effect based on the published report would be premature. In order to compare the treatment effect of these two procedures, the number of included patients would have had to be increased and the tumor response would need to have been monitored until the last treatment was performed. González et al. speculated that tumor size or bead size might affect the treatment response. Again, the number of patients in this study was too small to allow any definite conclusions to be drawn. We evaluated whether tumor size and treatment response (mRECIST class) were associated but found no trend. Nor was a correlation between administered dose and treatment response (mRECIST class) observed. It should be noted that the study was not designed to observe any such differences, and in order to be certain of these results, further studies should be performed. An association between bead size and treatment response (mRECIST class) could not be performed because of the small sample size. It should be noted that the bead size was varied to adapt to changes in the vasculature in and around the tumor for each patient, although the end point was the complete embolization of the tumorfeeding artery. Furthermore, in vivo release is affected not only by bead size and drug loading, which are factors known to have an effect on the in vitro release rate. For example, in vivo release is also affected by clustering of the beads in the arteries, with a decrease in the percentage of DOX released as the number of beads in a cluster increases.19 The handling of the drug formulation before administration could also affect drug release, as mixing with ion-containing solutions (such as saline) could start the release of DOX from DEBDOX prior to administration.

would therefore be very difficult to define more specific terms than “subsegmental” or “lobular”. Simply put, based on long-term clinical experience, the product properties, and patient pathophysiology, given these treatment options, it would be strongly ill-advised to treat each patient exactly the same. Changing standard treatments just for this study would be likely to increase the variability of the PK parameters, and we aimed to compare these parameters in our study.

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PHARMACOKINETICS In several places, González et al. comment that the variations in dosage might have affected the PK analysis. However, as stated in the published report,2 the plasma concentration−time curves were normalized to the dose. This was done because the pharmacokinetics of DOX are linear in the investigated dose range.16 Dose-normalization eliminates the dose as a source of interpatient variability. The results of the dose-corrections are presented in Figures 2C and 2D and in Table 3 in the published report.2 To elaborate on the PK analysis, all plasma data, both original and dose-normalized, were analyzed individually. That is, noncompartmental analysis (NCA) was performed on the plasma concentration−time curves for each patient. For the dose-normalized curves, individual concentrations were first normalized for the given dose and then analyzed with NCA. Thereafter, means and standard deviations were calculated for each PK parameter. The statistical comparison between LIPDOX and DEBDOX PK parameters was carried out using the dose-normalized data. The differences in intrahepatic placement of the catheter, the use of embolization, and the bead size used for each patient would almost certainly have added to the variability of the plasma PK parameters within each treatment group (LIPDOX or DEBDOX). However, statistical differences in the maximum concentrations (Cmax) and area under the concentration−time curves (AUC0−6/24/120h) were still observed between LIPDOX and DEBDOX. It should be noted that variability in PK parameters is high even when DOX is administered as an aqueous solution through intravenous infusion.16,17 High variability (CV%) in PK parameters between patients was also observed by Varela et al.: DOX Cmax and AUC varied 73% and 19% for cTACE, respectively, and 49% and 63% for DEETACE, respectively.18 Varela et al. administered a LIPDOX formulation to their patients and followed this with embolization. Interestingly, their reported Cmax of 895 ng/mL is 1.8-fold higher than our original Cmax of 480 ng/mL. Their mean administered dose was 70 mg, and ours was 50 mg, which is a 1.4-fold difference and thus cannot account for the difference in Cmax. Our Cmax was lower, even though Varela et al. administered embolizing particles. This suggests that embolization does not necessarily decrease peak plasma concentrations. It is interesting that González et al. suggest that the size of the tumor before treatment could affect the pharmacokinetics. We performed a linear regression analysis between tumor size (mm) before treatment and Cmax (ng/mL) or AUC (h·ng/mL, 0−6/24/120/168 h) for systemic and local DOX plasma concentrations. Neither a correlation nor a trend for correlation were found (all P > 0.1234). However, the study sample was small. To be certain of a potential effect of tumor size on the pharmacokinetics, a study with more individuals would be required.

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CONCLUDING REMARKS From a pharmaceutical perspective, ideally a formulation should be well-defined, its properties well characterized, and its use standardized. DEBDOX is a product with carefully characterized properties; it is a poly(vinyl alcohol) hydrogel with sulfonate groups onto which the positively charged DOX can be loaded. The use of DEBDOX is also standardized, although bead size and loading and the embolization end point are not completely standardized. Currently there is less standardization of Lipiodol emulsions than of DEBDOX and its use in the clinic.10,20 These emulsions can consist of one or multiple cytostatic agents, the ratios between the aqueous solution and Lipiodol can differ, and the compositions of the aqueous phase C


Communication


Beads in Patients with Hepatocellular Carcinoma”. Mol. Pharmaceutics 2017, DOI: 10.1021/acs.molpharmaceut.7b00138. (2) Lilienberg, E.; Dubbelboer, I. R.; Karalli, A.; Axelsson, R.; Brismar, T. B.; Ebeling Barbier, C.; Noren, A.; Duraj, F.; Hedeland, M.; Bondesson, U.; Sjogren, E.; Stal, P.; Nyman, R.; Lennernas, H. In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or DrugEluting Beads in Patients with Hepatocellular Carcinoma. Mol. Pharmaceutics 2017, 14 (2), 448−458. (3) Brown, D. B.; Nikolic, B.; Covey, A. M.; Nutting, C. W.; Saad, W. E.; Salem, R.; Sofocleous, C. T.; Sze, D. Y. Society of Interventional Radiology Standards of Practice, C. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. Journal of vascular and interventional radiology: JVIR 2012, 23 (3), 287−94. (4) Brown, D. B.; Cardella, J. F.; Sacks, D.; Goldberg, S. N.; Gervais, D. A.; Rajan, D. K.; Vedantham, S.; Miller, D. L.; Brountzos, E. N.; Grassi, C. J.; Towbin, R. B.; SIR Standards of Practice Committee; Angle, J. F.; Balter, S.; Clark, T. W.; Cole, P. E.; Drescher, P.; Freeman, N. J.; Georgia, J. D.; Haskal, Z.; Hovsepian, D. M.; Kilnani, N. M.; Kundu, S.; Malloy, P. C.; Martin, L. G.; McGraw, J. K.; Meranze, S. G.; Meyers, P. M.; Millward, S. F.; Murphy, K.; Neithamer, C. D., Jr.; Omary, R. A.; Patel, N. H.; Roberts, A. C.; Schwartzberg, M. S.; Siskin, G. P.; Smouse, H. R.; Swan, T. L.; Thorpe, P. E.; Vesely, T. M.; Wagner, L. K.; Wiechmann, B. N.; Bakal, C. W.; Lewis, C. A.; Nemcek, A. A., Jr.; Rholl, K. S. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J. Vasc. Interv. Radiol. 2009, 20 (7, Suppl.), S219−S226 and S226 e1−10. (5) Brown, D. B.; Cardella, J. F.; Sacks, D.; Goldberg, S. N.; Gervais, D. A.; Rajan, D.; Vedantham, S.; Miller, D. L.; Brountzos, E. N.; Grassi, C. J.; Towbin, R. B. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J. Vasc. Interv. Radiol. 2006, 17 (2, Part1), 225−32. (6) Gaba, R. C.; Lewandowski, R. J.; Hickey, R.; Baerlocher, M. O.; Cohen, E. I.; Dariushnia, S. R.; d’Othée, B. J.; Padia, S. A.; Salem, R.; Wang, D. S.; Nikolic, B.; Brown, D. B.; Society of Interventional Radiology Technology Assessment Committee. Transcatheter Therapy for Hepatic Malignancy: Standardization of Terminology and Reporting Criteria. J. Vasc. Interv. Radiol. 2016, 27 (4), 457−73. (7) 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 Hemat 2013, 88 (3), 530−549. (8) Marelli, L.; Stigliano, R.; Triantos, C.; Senzolo, M.; Cholongitas, E.; Davies, N.; Tibballs, J.; Meyer, T.; Patch, D. W.; Burroughs, A. K. Transarterial therapy for hepatocellular carcinoma: Which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Inter Rad 2007, 30 (1), 6−25. (9) Lewandowski, R. J.; Geschwind, J. F.; Liapi, E.; Salem, R. Transcatheter Intraarterial Therapies: Rationale and Overview. Radiology 2011, 259 (3), 641−657. (10) Dubbelboer, I. R.; Lilienberg, E.; Ahnfelt, E.; Sjogren, E.; Axen, N.; Lennernas, H. Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems. Ther. Delivery 2014, 5 (4), 447−66. (11) Okusaka, T.; Kasugai, H.; Shioyama, Y.; Tanaka, K.; Kudo, M.; Saisho, H.; Osaki, Y.; Sata, M.; Fujiyama, S.; Kumada, T.; Sato, K.; Yamamoto, S.; Hinotsu, S.; Sato, T. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J. Hepatol. 2009, 51 (6), 1030−6. (12) Kirchhoff, T. D.; Rudolph, K. L.; Layer, G.; Chavan, A.; Greten, T. F.; Rosenthal, H.; Kubicka, S.; Galanski, M.; Manns, M. P.; Schild, H.; Gallkowski, U. Chemoocclusion vs chemoperfusion for treatment of advanced hepatocellular carcinoma: a randomised trial. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2006, 32 (2), 201−7. (13) Lammer, J.; Malagari, K.; Vogl, T.; Pilleul, F.; Denys, A.; Watkinson, A.; Pitton, M.; Sergent, G.; Pfammatter, T.; Terraz, S.;

can be different. For example, the composition and therefore the emulsion type differ throughout the world. The in vitro release of DOX is more sustained and the in vivo drug delivery capacity is better from water-in-oil LIPDOX emulsions than from oil-in-water emulsions.7 In vitro data suggest that a waterin-oil emulsion forms when the water:Lipiodol ratio is 1:2−4. When reported at all, the clinical water:Lipiodol ratio ranges from 4:1 to 1:3.33, but is mostly 1:1.10 At the Department of Radiology, Uppsala University Hospital, a ratio of 1:3.33 is used, since this ensures the preferable W/O emulsion type. Our results showed that this emulsion type did not result in the sustained release of DOX from LIPDOX, as the cumulative amount released at the local sampling site reached a plateau after the end of administration (results not shown). The release of DOX from DEBDOX was sustained, however, as the cumulative release had not reached a plateau at the local sampling site 6 h after the end of the administration. Thus, pharmaceutically, the uncontrolled release of DOX from LIPDOX and the wide variety of LIPDOX compositions used in the clinic are drawbacks for this product. It should, however, be noted that, despite the lack of standardization in cTACE treatment, both cTACE and TACE with drug-eluting beads are equally effective at treating unresectable HCC.21,22 Our report covered the release of DOX from two clinically relevant formulations used in image-guided transarterial tumor therapies, namely, LIPDOX and DEBDOX, and the effects of these formulations on the pharmacokinetics of DOX. The results are clinically relevant, as the study treatment procedures followed standard treatment procedures at the clinics participating in the study. Translation of the published report into clinical practice is thus unnecessary, as the results stem from clinical practice. However, as González et al. point out, interventional studies cannot be compared to each other without taking differences between the studies into account. Precisely because of the lack of standardization in image-guided transarterial tumor therapies, the formulation and treatment protocols between studies can differ. We recommend taking into account the differences in treatment protocol between studies when comparing the data.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +46-18 471 4317. Fax: +46-18 471 4223. E-mail: hans. [email protected]. ORCID

Ilse R. Dubbelboer: 0000-0002-7806-0447 Elsa Lilienberg: 0000-0003-0271-4536 Erik Sjögren: 0000-0003-4318-6039 Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED AUC, area under the concentration−time curve; Cmax, maximum concentration; DEBDOX, drug-eluting beads loaded with doxorubicin; DOX, doxorubicin; HCC, hepatocellular carcinoma; LIPDOX, Lipiodol−doxorubicin emulsion; NCA, noncompartmental analysis; PK, pharmacokinetic; TACE, transarterial chemoembolization

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REFERENCES

(1) González, W.; Idée, J. M.; Ballet, S. Comment on “In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting D


Communication

Molecular Pharmaceutics Benhamou, Y.; Avajon, Y.; Gruenberger, T.; Pomoni, M.; Langenberger, H.; Schuchmann, M.; Dumortier, J.; Mueller, C.; Chevallier, P.; Lencioni, R.; PRECISION V Investigators. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc. Interv. Radiol. 2010, 33 (1), 41−52. (14) Lo, C. M.; Ngan, H.; Tso, W. K.; Liu, C. L.; Lam, C. M.; Poon, R. T.; Fan, S. T.; Wong, J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002, 35 (5), 1164−71. (15) Lencioni, R.; de Baere, T.; Burrel, M.; Caridi, J. G.; Lammer, J.; Malagari, K.; Martin, R. C.; O’Grady, E.; Real, M. I.; Vogl, T. J.; Watkinson, A.; Geschwind, J. F. Transcatheter treatment of hepatocellular carcinoma with Doxorubicin-loaded DC Bead (DEBDOX): technical recommendations. Cardiovasc Intervent Radiol 2012, 35 (5), 980−5. (16) Eksborg, S.; Strandler, H. S.; Edsmyr, F.; Naslund, I.; Tahvanainen, P. Pharmacokinetic study of i.v. infusions of adriamycin. Eur. J. Clin. Pharmacol. 1985, 28 (2), 205−12. (17) Jacquet, J. M.; Bressolle, F.; Galtier, M.; Bourrier, M.; Donadio, D.; Jourdan, J.; Rossi, J. F. Doxorubicin and doxorubicinol: intra- and inter-individual variations of pharmacokinetic parameters. Cancer Chemother. Pharmacol. 1990, 27 (3), 219−25. (18) Varela, M.; Real, M. I.; Burrel, M.; Forner, A.; Sala, M.; Brunet, M.; Ayuso, C.; Castells, L.; Montana, X.; Llovet, J. M.; Bruix, J. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J. Hepatol. 2007, 46 (3), 474−81. (19) D’Inca, H.; Piot, O.; Diebold, M. D.; Piardi, T.; Marcus, C.; Burde, F.; Sommacale, D.; Manfait, M.; Thiefin, G. Doxorubicin DrugEluting Embolic Chemoembolization of Hepatocellular Carcinoma: Study of Midterm Doxorubicin Delivery in Resected Liver Specimens. Journal of vascular and interventional radiology: JVIR 2017, 28 (6), 804−810. (20) Lencioni, R.; de Baere, T.; Soulen, M. C.; Rilling, W. S.; Geschwind, J. F. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data. Hepatology 2016, 64 (1), 106−16. (21) Gao, S.; Yang, Z.; Zheng, Z.; Yao, J.; Deng, M.; Xie, H.; Zheng, S.; Zhou, L. Doxorubicin-eluting bead versus conventional TACE for unresectable hepatocellular carcinoma: a meta-analysis. Hepato-Gastroenterology 2013, 60 (124), 813−20. (22) Facciorusso, A.; Di Maso, M.; Muscatiello, N. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis. Dig. Liver Dis. 2016, 48 (6), 571−7.

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