Abstract
Hepatocellular carcinoma (HCC) is a global killer with preponderance in Asian and African countries. It poses a challenge for successful management in less affluent or develo** nations like India, with large populations and limited infrastructures. This review aims to assess the available options and future directions for management of HCC applicable to such countries. While summarizing current and emerging clinical strategies for detection, staging and therapy of the disease, it highlights radioisotope- and radioactivity-based strategies as part of an overall program. Using the widely accepted Barcelona Clinic Liver Cancer (BCLC) staging system as a base, it evaluates the applicability of different therapeutic approaches and their synergistic combination(s) in the context of a patient-specific dynamic results-based strategy. It distills the conclusions of multiple HCC management-focused consensus recommendations to provide a picture of clinical strategies, especially radiation-related approaches. Additionally, it discusses the logistical and economic feasibility of these approaches in the context of the limitations of the burdened public health infrastructure in India (and like nations) and highlights possible strategies both at the clinical level and in terms of an administrative health policy on HCC to provide the maximum possible benefit to the widest swathe of the affected population.
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Hepatocellular carcinoma (HCC) is a global killer with preponderance in Asian and African regions. It poses a challenge for successful management in less affluent develo** countries like India, with large populations and limited infrastructures. |
This review aims to assess the available options and future directions for management of HCC. It describes current and emerging strategies for detection, staging and therapy of the disease emphasizing measures involving clinical use of radiation. |
Using the widely accepted Barcelona Clinic Liver Cancer (BCLC) staging system as a base, it discusses different therapeutic approaches and their synergistic combinations in the context of a patient-specific dynamic results-based strategy, considering multiple HCC management consensus recommendations. |
The review has a special focus on radiant therapies that can help downstage intermediate/advanced disease or extend patient lifespan while awaiting other therapies. Such therapies can be made more widely available through development of indigenous formulations and facility installations. |
It also discusses the logistical and economic feasibility of these approaches in the context of the limitations of the burdened public health infrastructure in nations like India. |
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Introduction
Most major organ functions can at least hypothetically be substituted or supplemented by artificial means, but the liver is such a multi-functional powerhouse—purifying the blood, providing compartmentalized metabolism and directed transport of a vast array of substances, secreting metabolic regulators as well as vital proteins and hormones—that it is as yet impossible for a being to survive any meaningful span without a functioning liver [1]. This supposition is borne out by the fact that liver disease accounts for approximately 2 million deaths per year globally, of which half is attributed to viral hepatitis and hepatocellular carcinoma [2]. This review attempts to provide an overview on the current global status of liver cancer. It also discusses the modalities available for its detection, staging and clinical management, and the feasibility of their application in vulnerable countries like India. A special emphasis is made on radiation-based modalities that can be made locally available to serve the greatest fraction of the affected population.
Hepatocellular Carcinoma—A Cause for Serious Concern
Liver cancer is the fifth most common cancer globally and the third most frequent cause of cancer-related death overall (second for men, sixth for women) [3, 5, 6]. In regions of greater prevalence (Asia, sub-Saharan Africa), HCC is present in > 50% of cases associated with endemic hepatitis B virus (HBV) infection. China, with ~ 84 million infected with HBV, accounts for roughly half of the primary liver cancer incidence in the world [7]. India has ~ 43–45 million chronic HBV sufferers [8], and the reported HCC incidence ranges from 0.7 to 7.5 in men and 0.2 to 2.2 in women for every 100,000 persons per year [9]. Considering India’s population of ~ 1.4 billion, the actual numbers would be on the order of tens of thousands of new cases annually. What confounds this situation is the high ratio of mortality to incidence (0.95) and a reported median survival period of only 2–3 months, even with the best supportive care [10]. The reasons for this situation are several:
Patient Demographics and Causative Factors
There is a wide range for median age of liver cancer presentation, 40–70 years [9]. Apart from chronic HBV infection, several risk factors have been associated with HCC development, including HCV infection, alcoholism and exposure to fungal aflatoxin. Classically, 70–90% of HCC incidences have been seen with underlying liver cirrhosis, but the contribution of non-alcoholic fatty liver disease (NAFLD) independent of cirrhosis to HCC development is rising steeply. Increasingly prevalent chronic lifestyle conditions like obesity and diabetes mellitus, linked to NAFLD, are thus suspected to play a role in the malignant transformation of hepatocytes [11].
Symptomatology and Screening
HCC develops initially as slow growing nodules (with estimated doubling time of 1–19 months), which may be asymptomatic for years. Diagnosis based on external symptoms is challenging—gross symptoms such as pain, abdominal discomfort, weight loss, fatigue, decompensatory jaundice or ascites often manifest only when the disease is in an advanced stage with multiple hepatic nodules and occasionally extra-hepatic lesions [12]. For such patients many potentially curative treatments are not applicable, unless the disease is successfully downstaged.
Multiple scientific reports have urged a regular HCC screening program for high-risk groups to help in early identification and improved disease prognosis [13,14,15]. They have recommended screening at least for cirrhotic patients with HBV/HCV infections, but also admitted the difficulty of lack of consensus on non-cirrhotic patients at risk. Even in the target group, screening logistics are complicated given patient numbers, clarity of diagnosis and awareness of screening programs among patients and physicians. For less affluent countries like India, with significant portions of the population in rural/semi-urban areas, a screening program with adequate penetration and follow-up is a major endeavor for already burdened public healthcare systems. Kumar et al. have proposed a three-fold program for curbing HCC in India, consisting of (1) reducing exposure to carcinogenic hepatotoxins, (2) treating the chronic necro-inflammatory state of liver produced by hepatotoxins and (3) preventing recurrence after initial curative treatment [9]. This calls for a major commitment from the public health infrastructure with adequate consideration of logistics and economics.
Metastasis and Disease Recurrence
Due to delayed detection, HCC is curable in only a fraction of cases. HCC is mostly detected as a multi-focal phenomenon: Intra-hepatic metastases are common because of the spread of the primary lesions into the portal vein branches and the main portal vein; rarely, extra-hepatic metastases are observed in the lung or bone as well as porta-hepatic lymphadenopathy. Certain tumor foci may be missed, being undetectable by existing imaging techniques or a product of metastases that occurred prior to surgical intervention [90].
Unlike TACE, which requires release of the drug from the embolic matrix, SIRT radionuclides can exert cytotoxic action by beta-emission at the pre-capillary level bound within the matrix. Therefore, TARE agents can afford to be designed for greater stability with minimal leaching of radioactivity from the formulation. There are two categories of SIRT agents based on the type of embolic matrix: (1) radionuclide-tagged formulations of lipiodol and (2) radiolabeled microparticles.
Radionuclide-tagged Formulations of Lipiodol
In clinical trials nearly 3 decades ago, lipiodol was assessed for TARE after substitution labeling with iodine-131 (131I) [half-life 8 days, beta-energy (max) 0.6 meV, tissue penetration 0.6–2 mm], exhibiting good patient tolerance [91]. Long-term reports have shown up to 39 ± 8.3% OS at 3 years [92]. When applied in random selection trials as post-resection adjuvant therapy, it improved OS for up to 7 years (66.7% vs. 31.8% for control) [93]. Studies with [131I]lipiodol TARE found lower adverse effects than with TACE [94]. In India, [131I]lipiodol for TARE has been demonstrated capable of cost-effective indigenous preparation—using a semi-automated synthesis module and locally available reactor-produced radioisotope—of standard patient doses of 2.22 GBq 131I activity (as per European Association of Nuclear Medicine guidelines, corresponding to a mean liver dose of ~ 50 Gy) [95, 96]. This can be replicated in any radiopharmacy with the suitable setup and is an economical SIRT solution. [131I]lipiodol has certain disadvantages because of the radioisotope. Preparation must be done in a suitable ventilated cabinet to prevent accidental 131I aerosol release to ambient atmosphere. The 364-keV penetrative gamma emissions with the long 8 day half-life call for additional precautions in patient management. For example, it must be ensured that no individual in public receives > 5 mSv external dose from the patient. Hence, the patient may be discharged only after the dose at 1 m away reduces to 0.07 mSv/h [97], and necessary precautions must be followed in handling/disposal of their body waste [98]. Thyroid uptake of free 131I is also reported, though there is no consensus on the need for measures to protect against this [96]. Thus, while [131I]lipiodol has the advantage of being a well-known economical mode of TARE, it may not remain the first choice if other options become more widely available.
Lipiodol has also been prepared as a rhenium-188 (188Re) labeled formulation. Here, the transition metal forms stable lipophilic complexes with suitable ligands, such as AHDD (acetylated 4-hexadecyl-4,7-diaza-1,10-decanedithiol), DEDC (diethyl dithiocarbamate) and SSS [(S3CPh)2(S2CPh)], which can then be extracted into lipiodol. Unlike with 131I, no covalent bond exists between 188Re and lipiodol. With greater therapeutic energy and penetration (beta-energy max 2.1 meV, penetration range 2–10 mm), safer imaging-friendly gamma emission (155 keV) and a shorter half-life (16.9 h), 188Re is more suitable for TARE than 131I. Additionally, the ligands mentioned can form rhenium-188 complexes in much higher yield than the substitution labeling process for 131I and be extracted into lipiodol phase with moderate to high efficiency. Its availability through a versatile application “Good Manufacturing Practice” (GMP)-certified tungsten-188/rhenium-188 (188 W/188Re) radionuclide generator makes it convenient to elute rhenium-188 and prepare the radiopharmaceutical on demand in a radiopharmacy [99, 100]. Reports of 188Re-HDD in phase I and II trials indicate that escalation of administered radioactivity from 1.8–9.8 GBq showed good tolerance with minimal side effects, rapid renal clearance of blood radioactivity and regression/stabilization of the disease in an appreciable proportion of patients [101]. A multi-centric study by nuclear medicine departments in India and Vietnam found complete/partial disappearance of tumor or stable disease in > 68% of patients and survival rates of 58% at 24 months and 30% at 36 months, with a median survival of 980 days [99]. A more recent study showed the utility of 188Re-HDD/lipiodol for therapy in patients with solitary HCC not amenable to resection [102]. Moreover, post-administration SPECT imaging could be used to assess absorbed doses in target and normal tissue [103]. 188Re-HDD/lipiodol carries caveats of limited extraction (~ 60–70%) into lipiodol and adhesion to vial/syringe surfaces, making less therapeutic activity available for injection (50–60%) [103], but formulations like 188Re-DEDC/lipiodol and 188Re-SSS/lipiodol, capable of 80–90% extraction into lipiodol and lower surface adhesion tendencies, rectify this limitation. Phase I clinical studies with 188Re-labeled DEDC and SSS indicate good hepatic retention with minimal uptake in other tissues [104]. Automated synthesis modules for preparation of clinical scale doses of 188Re-lipiodol via DEDC and SSS have already been reported [105, 106]. In India, kits for formulating 188Re-lipiodol using DEDC have been indigenously developed, and preliminary clinical assessment at regional nuclear medicine centers has ascertained a favorable profile of the radiopharmaceutical [107]. The sole stumbling block to greater adoption of 188Re-lipiodol in India is the sparse local availability of 188W/188Re generators, still imported at a significant cost and subject to international market vagaries. An earlier report by Bal and Kumar strongly advocated the need for affordable 188Re generator technology [108], and the know-how for making various types of 188W/188Re generators in India using 188W raw material already exists [109, 110], but it would be a significant advantage for any future planned reactors to possess the requisite characteristics for indigenous 188W production for use in clinical-grade generators in India.
Radiolabeled Microparticles
Microparticles labeled with beta-emitters such as yttrium-90 (90Y) are the most widely employed form of SIRT for HCC. Made of degradation-resistant material with sufficiently large particle diameter (> 20 micron), they embolize in the terminal arterioles of tumor-feeding vasculature permanently, or at least long enough for the radiation dose to be deposited almost entirely [111]. 90Y is the most common radioisotope to address primary and secondary liver malignancies. Its 2.28-meV (maximum energy) pure beta emission, 11-mm maximum penetration range and 64.2-h half-life can provide an effective therapeutic dose to large and/or multi-nodal lesions [94]. Despite being tested for liver cancer therapy as early as 1982 [112], there are only few commercially available 90Y-labeled microparticle therapies for HCC: (1) 90Y-impregnated glass microspheres—Therasphere® (BTG, Canada); (2) 90Y-labeled resin microspheres—SIR-sphere® (Sirtex Medical, USA) [113]. The major differences between them are outlined in Table 1.
Due to the greater radioactive concentration and higher specific gravity compared to SIR-Spheres® (3.2 g/cc vs. 1.6 g/cc), Therasphere® is less amenable to dose fractionation, which may be practiced for logistics in large-scale public healthcare facilities. The multi-fold higher particle count in SIR-spheres® also means higher embolism for a given radiation dose [114]. These aspects are expected to factor in when determining the specific eligibility criteria under which these agents may be prescribed.
As previously mentioned for imaging-based diagnosis, the administration of 90Y-labeled therapeutic microparticles is preceded 1–2 weeks by a safety scan using ~ 148-185 MBq of 99mTc-labeled MAA to simulate deposition of therapeutic microparticles in the vascular bed. This is primarily to determine the lung shunt fraction (LSF), the potential extent of shunting of these microparticles to the lung because of arteriovenous anastomoses in the tumor vasculature. This helps minimize the risk of radiation pneumonitis as an adverse effect. Existing literature recommends maximum lung exposure of 30 Gy in a single session and 50 Gy across multiple sessions, beyond which dose reduction is made or TARE is contraindicated [111, 114]. It may however be noted that some reports have raised doubts over the accuracy of LSF calculated from 99mTc-MAA scans [129]. SBRT and TARE/TACE have also helped to downstage multi-focal intermediate stage cancers to where they become eligible for resection/ablation or sustained patients during the waiting period for transplantation. The advantage of TARE over TACE in patients with concomitant PVT should be duly considered when preparing the treatment strategy in these cases. TARE and EBRT may be indicated in specific situations of post-resection adjuvant therapy where ablation is contraindicated. Multi-dose SBRT may prove useful in patients with single lesions where the location is not amenable to surgery and ablative measures might prove inadequate. A combination of TARE/TACE/SBRT with systemic chemotherapy can help patients with extra-hepatic metastases to downstage the disease to where it can be addressed with other tools. A critical potential application of radiotherapy is when HCC metastases infiltrate critical tissues like the brain [130]; most other modalities are of limited application here because of permeability/systemic toxicity issues and the potential danger of any invasive protocols. TARE (or any other approach) to treat the hepatic lesions may be paired with a targeted SBRT modality to specifically address the cranial metastases. Ready availability of specific techniques in terms of equipment and trained personnel at clinical centers is an important factor. In countries that have a significant HCC-afflicted population with limited public healthcare options, resective surgery, ablation, EBRT and selected embolic therapies (TARE/TACE) represent the major strategies available to patients. Since only a small proportion of HCC patients is at least initially eligible for resection, and ablative therapies are less useful for a significant proportion of diagnosed cases, there is a strong case to enhance clinical utilization of SBRT or TARE/TACE to manage or downstage the disease till other therapy options become viable. SBRT in combination with measures like chemotherapy would be useful in countries like China, which have many beam therapy centers for the population, and has also generated many clinical data on newer drugs and drug combinations effective against HCC. India with its limited access to HCC therapy-capable beam therapy centers may have to lean more on internalized radionuclide therapies. One obstacle toward this is the currently high cost of SIRT formulations that are imported. To address this, there should be greater clinical adoption of indigenously developed solutions that can provide similar benefits with easier availability and lower cost, some of which are discussed in the relevant sections of this report. Simultaneously, the infrastructure related to their production and on-site delivery should be enhanced to keep up with the perceived demand and eventually have the capability to export to other countries at more cost-effective rates as a worldwide public health initiative. For advanced multi-focal HCC cases, China’s advances in economically more favorable systemic chemotherapy can be adapted and followed by other nations with a large public healthcare burden. Similarly, depending on the proportion of patients with such needs, the technological means to deliver a targeted dose of EBRT for HCC or metastases in critical areas should also be made more widely available. Awareness in the clinical community regarding availability of these options for HCC is also essential in ensuring that appropriate patients receive the most optimal treatment/combination of treatments.
Conclusion
When viewed from a holistic perspective, the various approaches to treatment of liver cancer are revealed to complement each other when applied after judicious tailoring on the strength of an effective screening/diagnosis program to the individual patient’s requirements and careful monitoring of their impact to ensure optimal therapeutic benefit with minimal collateral damage. Radiation and radioisotope-based approaches are seen to be a necessary component of any holistic management protocol for HCC. What is required is strategic planning at both the level of the clinical institution and the level of national health policy to identify, promote and enhance availability of the specific approaches that can provide the best possible therapeutic benefit to the greatest proportion of patients that require it.
References
Greiser J, Weigand W, Freesmeyer M. Metal-based complexes as pharmaceuticals for molecular imaging of the liver. Pharmaceuticals [Internet]. 2019;12:137. https://www.mdpi.com/1424-8247/12/3/137
Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol [Internet]. 2019;70:151–71. https://linkinghub.elsevier.com/retrieve/pii/S0168827818323882
Mak L-Y, Cruz-Ramón V, Chinchilla-López P, Torres HA, LoConte NK, Rice JP, et al. Global Epidemiology, Prevention, and Management of Hepatocellular Carcinoma. Am Soc Clin Oncol Educ B [Internet]. 2018;262–79. https://ascopubs.org/doi/https://doi.org/10.1200/EDBK_200939
Wu L, Shen F, **a Y, Yang Y-F. Evolving Role of Radiopharmaceuticals in Hepatocellular Carcinoma Treatment. Anticancer Agents Med Chem [Internet]. 2016;16:1155–65. http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1871-5206&volume=16&issue=9&spage=1155
Massarweh NN, El-Serag HB. Epidemiology of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Cancer Control. 2017;24.
Maucort-Boulch D, de Martel C, Franceschi S, Plummer M. Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide. Int J Cancer [Internet]. 2018;142:2471–7. http://doi.wiley.com/https://doi.org/10.1002/ijc.31280
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol [Internet]. 2019;16:589–604. http://www.nature.com/articles/s41575-019-0186-y
Grewal US, Walia G, Bakshi R, Chopra S. Hepatitis B and C viruses, their coinfection and correlations in chronic liver disease patients: a tertiary care hospital study. Int J Appl basic Med Res. 2018;8:204–9.
Kumar A, Acharya SK, Singh SP, Saraswat VA, Arora A, Duseja A, et al. The Indian National Association for Study of the Liver (INASL) Consensus on Prevention, Diagnosis and Management of Hepatocellular Carcinoma in India: The Puri Recommendations. J Clin Exp Hepatol [Internet]. 2014;4:S3–26. https://linkinghub.elsevier.com/retrieve/pii/S0973688314002710
Lokesh KN, Chaudhuri T, Lakshmaiah KC, Govind Babu K, Dasappa L, Jacob LA, et al. Advanced hepatocellular carcinoma: A regional cancer center experience of 48 cases. Indian J Cancer [Internet]. 2017;54:526–9. http://www.indianjcancer.com/text.asp?2017/54/3/526/233153
Saran U, Humar B, Kolly P, Dufour JF. Hepatocellular carcinoma and lifestyles. J Hepatol [Internet]. 2016;64:203–14. https://linkinghub.elsevier.com/retrieve/pii/S0168827815006005
Chedid MF, Kruel CRP, Pinto MA, Grezzana-Filho TJM, Leipnitz I, Kruel CDP, et al. Hepatocellular carcinoma: diagnosis and operative management. Arq Bras Cir Dig [Internet]. 2017;30:272–8. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-67202017000400272&lng=en&tlng=en
Frenette CT, Isaacson AJ, Bargellini I, Saab S, Singal AG. A Practical Guideline for Hepatocellular Carcinoma Screening in Patients at Risk. Mayo Clin Proc Innov Qual Outcomes [Internet]. 2019;3:302–10. https://linkinghub.elsevier.com/retrieve/pii/S2542454819300487
Xu K, Watanabe-Galloway S, Rochling FA, Zhang J, Farazi PA, Peng H, et al. Practice, Knowledge, and Barriers for Screening of Hepatocellular Carcinoma Among High-Risk Chinese Patients. Ann Glob Heal [Internet]. 2017;83:281–92. https://annalsofglobalhealth.org/articles/https://doi.org/10.1016/j.aogh.2017.02.002
Zhao C, Nguyen MH. Hepatocellular carcinoma screening and surveillance practice guidelines and real-life practice. J Clin Gastroenterol [Internet]. 2016;50:120–33. https://journals.lww.com/00004836-201602000-00008
El-Serag HB. Hepatocellular Carcinoma. N Engl J Med [Internet]. 2011;365:1118–27. http://www.nejm.org/doi/https://doi.org/10.1056/NEJMra1001683
GODT. International Report on Organ Donation and Transplantation Activities: Executive Summary 2017. [Internet]. 2017. http://www.transplant-observatory.org/download/2017-activity-data-report/
Costentin C. Le dépistage du carcinome hépatocellulaire. Press Medicale [Internet]. 2017;46:381–5. https://linkinghub.elsevier.com/retrieve/pii/S0755498216303578
Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MAM, et al. Meta-analysis: Surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther [Internet]. 2009;30:37–47. http://doi.wiley.com/https://doi.org/10.1111/j.1365-2036.2009.04014.x
Jiang HY, Chen J, **a CC, Cao LK, Duan T, Song B. Noninvasive imaging of hepatocellular carcinoma: From diagnosis to prognosis. World J Gastroenterol. 2018;24:2348–62.
Jia H, Yan D, **ao Q, Zhang G. Correlations of ultrasonic features with severity of liver cancer and p16 expression in patients with liver cancer. Neoplasma [Internet]. 2019;66:149–54. http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=5883&category_id=147&option=com_virtuemart
Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology [Internet]. 2018;154:1706–1718.e1. https://linkinghub.elsevier.com/retrieve/pii/S0016508518301550
Schwarze V, Marschner C, Völckers W, De Figueiredo GN, Rübenthaler J, Clevert DA. The diagnostic performance of contrast-enhanced ultrasound (CEUS) for evaluating hepatocellular carcinoma (HCC) juxtaposed to MRI findings; A retrospective single-center analysis of 292 patients. Hiebl B, Krüger-Genge A, Jung F, editors. Clin Hemorheol Microcirc [Internet]. 2020;76:155–60. https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=https://doi.org/10.3233/CH-209213
Chen D ‐S, Sung J ‐L. Serum alphafetoprotein in hepatocellular carcinoma. Cancer [Internet]. 1977;40:779–83. http://www.ncbi.nlm.nih.gov/pubmed/70268
Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int [Internet]. 2017;11:317–70. http://springer.longhoe.net/https://doi.org/10.1007/s12072-017-9799-9
Sharma Y, Weaver MJ, Ludwig DR, Fowler K, Vachharajani N, Chapman WC, et al. Serum alpha-fetoprotein level per total tumor volume as a predictor of recurrence of hepatocellular carcinoma after resection. Surg (United States) [Internet]. 2018;163:1002–7. https://linkinghub.elsevier.com/retrieve/pii/S0039606017308048
Chan SL, Chan AWH, Yu SCH. Alpha-Fetoprotein as a Biomarker in Hepatocellular Carcinoma: Focus on Its Role in Composition of Tumor Staging Systems and Monitoring of Treatment Response. 2017. p. 623–35. http://springer.longhoe.net/https://doi.org/10.1007/978-94-007-7675-3_41
**e D-Y, Ren Z-G, Zhou J, Fan J, Gao Q. 2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: updates and insights. Hepatobiliary Surg Nutr [Internet]. 2020;9:452–63. http://www.ncbi.nlm.nih.gov/pubmed/32832496
Carr BI, Akkiz H, Üsküdar O, Yalçın K, Guerra V, Kuran S, et al. HCC with low- and normal-serum alpha-fetoprotein levels. Clin Pract (Lond). 2018;15:453–64.
Ko YS, Bae JH, Sinn DH, Gwak GY, Kang W, Paik YH, et al. The Clinical Significance of Serum Alpha-fetoprotein in Diagnosing Hepatocellular Carcinoma in a Health Screening Population. Korean J Gastroenterol [Internet]. 2017;69:232–8. https://synapse.koreamed.org/DOIx.php?id=https://doi.org/10.4166/kjg.2017.69.4.232
Tateishi R, Yoshida H, Matsuyama Y, Mine N, Kondo Y, Omata M. Diagnostic accuracy of tumor markers for hepatocellular carcinoma: A systematic review. Hepatol Int [Internet]. 2008;2:17–30. http://springer.longhoe.net/https://doi.org/10.1007/s12072-007-9038-x
Horvat N, Monti S, Oliveira BC, Rocha CCT, Giancipoli RG, Mannelli L. State of the art in magnetic resonance imaging of hepatocellular carcinoma. Radiol Oncol. 2018;52:353–64.
Jiang L, Tan H, Panje CM, Yu H, **u Y, Shi H. Role of 18F-FDG PET/CT imaging in intrahepatic cholangiocarcinoma. Clin Nucl Med [Internet]. 2016;41:1–7. http://www.ncbi.nlm.nih.gov/pubmed/26402131
Haug AR. Imaging of primary liver tumors with positron-emission tomography. Q J Nucl Med Mol Imaging [Internet]. 2017;61:292–300. http://www.ncbi.nlm.nih.gov/pubmed/28686007
Kesler M, Levine C, Hershkovitz D, Mishani E, Menachem Y, Lerman H, et al. 68 Ga-labeled prostate-specific membrane antigen is a novel PET/CT tracer for imaging of hepatocellular carcinoma: a prospective pilot study. J Nucl Med [Internet]. 2019;60:185–91. http://www.ncbi.nlm.nih.gov/pubmed/30002112
Van de Wiele C, Sathekge M, de Spiegeleer B, de Jonghe PJ, Beels L, Maes A. PSMA-targeting positron emission agents for imaging solid tumors other than non-prostate carcinoma: A systematic review. Int J Mol Sci [Internet]. 2019;20:4886. Available from: https://www.mdpi.com/1422-0067/20/19/4886
Tolkach Y, Goltz D, Kremer A, Ahmadzadehfar H, Bergheim D, Essler M, et al. Prostate-specific membrane antigen expression in hepatocellular carcinoma: Potential use for prognosis and diagnostic imaging. Oncotarget [Internet]. 2019;10:4149–60. https://www.oncotarget.com/lookup/doi/https://doi.org/10.18632/oncotarget.27024
Jiao D, Li Y, Yang F, Han D, Wu J, Shi S, et al. Expression of prostate-specific membrane antigen in tumor-associated vasculature predicts poor prognosis in hepatocellular carcinoma. Clin Transl Gastroenterol [Internet]. 2019;10:e00041. https://journals.lww.com/01720094-201905000-00006
Labeur TA, Cieslak KP, Van Gulik TM, Takkenberg RB, Van Der Velden S, Lam MGEH, et al. The utility of 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT/CT for selective internal radiation therapy in hepatocellular carcinoma. Nucl Med Commun [Internet]. 2020;41:740–9. https://journals.lww.com/https://doi.org/10.1097/MNM.0000000000001224
Price RG, Apisarnthanarax S, Schaub SK, Nyflot MJ, Chapman TR, Matesan M, et al. Regional Radiation Dose-Response Modeling of Functional Liver in Hepatocellular Carcinoma Patients With Longitudinal Sulfur Colloid SPECT/CT: A Proof of Concept. Int J Radiat Oncol Biol Phys [Internet]. 2018;102:1349–56. https://linkinghub.elsevier.com/retrieve/pii/S0360301618310083
Lagana SM, Salomao M, Bao F, Moreira RK, Lefkowitch JH, Remotti HE. Utility of an immunohistochemical panel consisting of glypican-3, heat-shock protein-70, and glutamine synthetase in the distinction of low-grade hepatocellular carcinoma from hepatocellular adenoma. Appl Immunohistochem Mol Morphol [Internet]. 2013;21:170–6. https://journals.lww.com/00129039-201303000-00011
Yan BC, Gong C, Song J, Krausz T, Tretiakova M, Hyjek E, et al. Arginase-1: A new immunohistochemical marker of hepatocytes and hepatocellular neoplasms. Am J Surg Pathol [Internet]. 2010;34:1147–54. http://www.ncbi.nlm.nih.gov/pubmed/20661013
Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, et al. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol [Internet]. 2018;69:182–236. https://linkinghub.elsevier.com/retrieve/pii/S0168827818302150
Di Tommaso L, Spadaccini M, Donadon M, Personeni N, Elamin A, Aghemo A, et al. Role of liver biopsy in hepatocellular carcinoma. World J Gastroenterol [Internet]. 2019;25:6041–52. https://www.wjgnet.com/1007-9327/full/v25/i40/6041.htm
Omagari K, Ohba K, Kadokawa Y, Hazama H, Masuda JI, Kinoshita H, et al. Comparison of the grade evaluated by “Liver damage” of Liver Cancer Study Group of Japan and Child-Pugh classification in patients with hepatocellular carcinoma. Hepatol Res [Internet]. 2006;34:266–72. https://linkinghub.elsevier.com/retrieve/pii/S1386634606000052
Levy I, Sherman M, The Liver Cancer Study Group of the University of Toronto. Staging of hepatocellular carcinoma: Assessment of the CLIP, Okuda, and Child-Pugh staging systems in a cohort of 257 patients in Toronto. Gut [Internet]. 2002;50:881–5. https://gut.bmj.com/lookup/doi/https://doi.org/10.1136/gut.50.6.881
Pons F, Varela M, Llovet JM. Staging systems in hepatocellular carcinoma. Hpb [Internet]. 2005;7:35–41. https://linkinghub.elsevier.com/retrieve/pii/S1365182X15308418
Soldera J, Balbinot SS, Balbinot RA, Cavalcanti AG. Diagnostic and Therapeutic Approaches to Hepatocellular Carcinoma: Understanding the Barcelona Clínic Liver Cancer Protocol. Clin Med Insights Gastroenterol [Internet]. 2016;9:CGast.S30190. http://journals.sagepub.com/doi/https://doi.org/10.4137/CGast.S30190
Yau T, Tang VYF, Yao T-J, Fan S-T, Lo C-M, Poon RTP. Development of Hong Kong Liver Cancer Staging System With Treatment Stratification for Patients With Hepatocellular Carcinoma. Gastroenterology [Internet]. 2014;146:1691–1700.e3. https://linkinghub.elsevier.com/retrieve/pii/S0016508514002431
Kokudo N, Hasegawa K, Akahane M, Igaki H, Izumi N, Ichida T, et al. Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines). Hepatol Res [Internet]. 2015;45:n/a-n/a. http://doi.wiley.com/https://doi.org/10.1111/hepr.12464
Landman MP, Feurer ID, Pinson CW, Moore DE. Which is more cost‐effective under the MELD system: primary liver transplantation, or salvage transplantation after hepatic resection or after loco‐regional therapy for hepatocellular carcinoma within Milan criteria? HPB [Internet]. 2011;13:783–91. https://linkinghub.elsevier.com/retrieve/pii/S1365182X15303816
Oh JH, Sinn DH, Choi G-S, Kim JM, Joh J-W, Kang TW, et al. Comparison of outcome between liver resection, radiofrequency ablation, and transarterial therapy for multiple small hepatocellular carcinoma within the Milan criteria. Ann Surg Treat Res [Internet]. 2020;99:238. https://astr.or.kr/DOIx.php?id=https://doi.org/10.4174/astr.2020.99.4.238
Volk ML, Vijan S, Marrero JA. A Novel Model Measuring the Harm of Transplanting Hepatocellular Carcinoma Exceeding Milan Criteria. Am J Transplant [Internet]. 2008;8:839–46. http://doi.wiley.com/https://doi.org/10.1111/j.1600-6143.2007.02138.x
Shiina S, Tateishi R, Imamura M, Teratani T, Koike Y, Sato S, et al. Percutaneous ethanol injection for hepatocellular carcinoma: 20‐year outcome and prognostic factors. Liver Int [Internet]. 2012;32:1434–42. https://onlinelibrary.wiley.com/doi/https://doi.org/10.1111/j.1478-3231.2012.02838.x
Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, et al. Radiofrequency Ablation for Hepatocellular Carcinoma: 10-Year Outcome and Prognostic Factors. Am J Gastroenterol [Internet]. 2012;107:569–77. https://journals.lww.com/00000434-201204000-00016
Cheung TT-T, Kwok PC-H, Chan S, Cheung C-C, Lee A-S, Lee V, et al. Hong Kong Consensus Statements for the Management of Unresectable Hepatocellular Carcinoma. Liver Cancer [Internet]. 2018;7:40–54. https://www.karger.com/Article/FullText/485984
Donadon M, Solbiati L, Dawson L, Barry A, Sapisochin G, Greig PD, et al. Hepatocellular Carcinoma: The Role of Interventional Oncology. Liver Cancer [Internet]. 2017;6:34–43. https://www.karger.com/Article/FullText/449346
Szyszko T, Brooks A, Tait P, Rubello D, AL-Nahhas A. Therapy options for treatment of hepatic malignancy. Eur J Nucl Med Mol Imaging [Internet]. 2008;35:1824–6. Available from: http://springer.longhoe.net/https://doi.org/10.1007/s00259-008-0798-x
Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol [Internet]. 2009;10:25–34. http://www.ncbi.nlm.nih.gov/pubmed/19095497
Reiss KA, Yu S, Mamtani R, Mehta R, D’Addeo K, Wileyto EP, et al. Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study. J Clin Oncol [Internet]. 2017;35:3575–81. https://ascopubs.org/doi/https://doi.org/10.1200/JCO.2017.73.8245
Qin S, Kruger E, Tan SC, Cheng S, Wang N, Liang J. Cost-effectiveness analysis of FOLFOX4 and sorafenib for the treatment of advanced hepatocellular carcinoma in China. Cost Eff Resour Alloc [Internet]. 2018;16:29. https://resource-allocation.biomedcentral.com/articles/https://doi.org/10.1186/s12962-018-0112-0
Nishida N, Nishimura T, Kaido T, Minaga K, Yamao K, Kamata K, et al. Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy. Cancers (Basel) [Internet]. 2018;10:367. http://www.mdpi.com/2072-6694/10/10/367
Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet [Internet]. 2018;391:1163–73. https://linkinghub.elsevier.com/retrieve/pii/S0140673618302071
Zhu AX, Kang Y-K, Yen C-J, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol [Internet]. 2019;20:282–96. https://linkinghub.elsevier.com/retrieve/pii/S1470204518309379
Zhang L, Ding J, Li H-Y, Wang Z-H, Wu J. Immunotherapy for advanced hepatocellular carcinoma, where are we? Biochim Biophys Acta - Rev Cancer [Internet]. 2020;1874:188441. https://linkinghub.elsevier.com/retrieve/pii/S0304419X20301608
El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and Treatment of Hepatocellular Carcinoma. Gastroenterology [Internet]. 2008;134:1752–63. https://linkinghub.elsevier.com/retrieve/pii/S0016508508004265
Nabavizadeh N, Jahangiri Y, Rahmani R, Tomozawa Y, Geeratikun Y, Chen Y, et al. Thermal Ablation Versus Stereotactic Body Radiotherapy Following Transarterial Chemoembolization for Inoperable Hepatocellular Carcinoma: A Propensity Score Weighted Analysis. Am J Roentgenol [Internet]. 2020;AJR.20.24117. https://www.ajronline.org/doi/https://doi.org/10.2214/AJR.20.24117
Ibrahim S-M, Lewandowski R-J, Sato K-T, Gates V-L, Kulik L, Mulcahy M-F, et al. Radioembolization for the treatment of unresectable hepatocellular carcinoma: a clinical review. World J Gastroenterol [Internet]. 2008;14:1664–9. http://www.ncbi.nlm.nih.gov/pubmed/18350597
Xu M, Feng M. Radiation Therapy in HCC: What Data Exist and What Data Do We Need to Incorporate into Guidelines? Semin Liver Dis [Internet]. 2019;39:043–52. http://www.thieme-connect.de/DOI/DOI?https://doi.org/10.1055/s-0038-1676098
Zhang S-Y, Zhu G-Y, Li G, Zhang Y-B, Geng J-H. Application of stereotactic body radiation therapy to cancer liver metastasis. Cancer Lett [Internet]. 2016;379:225–9. https://linkinghub.elsevier.com/retrieve/pii/S0304383515006606
Bujold A, Massey CA, Kim JJ, Brierley J, Cho C, Wong RKS, et al. Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma. J Clin Oncol [Internet]. 2013;31:1631–9. http://ascopubs.org/doi/https://doi.org/10.1200/JCO.2012.44.1659
Sanuki N, Takeda A, Oku Y, Mizuno T, Aoki Y, Eriguchi T, et al. Stereotactic body radiotherapy for small hepatocellular carcinoma: A retrospective outcome analysis in 185 patients. Acta Oncol (Madr) [Internet]. 2014;53:399–404. http://www.tandfonline.com/doi/full/https://doi.org/10.3109/0284186X.2013.820342
Mathew AS, Atenafu EG, Owen D, Maurino C, Brade A, Brierley J, et al. Long term outcomes of stereotactic body radiation therapy for hepatocellular carcinoma without macrovascular invasion. Eur J Cancer [Internet]. 2020;134:41–51. https://linkinghub.elsevier.com/retrieve/pii/S0959804920302276
(NCCN) NCCN. NCCN Guidelines for patients [Internet]. Natl. Compr. Cancer Netw. Found. 2014. p. 1–96. http://www.nccn.org/patients/guidelines/stage_i_ii_breast/index.html#4/z
2018 Korean liver cancer association–national cancer center korea practice guidelines for the management of hepatocellular carcinoma. Korean J Radiol [Internet]. 2019;20:1042–113. https://www.kjronline.org/DOIx.php?id=https://doi.org/10.3348/kjr.2019.0140
Yoganathan S, Maria Das K, Agarwal A, Kumar S. Magnitude, impact, and management of respiration-induced target motion in radiotherapy treatment: A comprehensive review. J Med Phys [Internet]. 2017;42:101. http://www.jmp.org.in/text.asp?2017/42/3/101/214491
Chen CP. Role of radiotherapy in the treatment of hepatocellular carcinoma. J Clin Transl Hepatol [Internet]. 2019;7:183–90. http://www.xiahepublishing.com/2310-8819/ArticleFullText.aspx?sid=2&id=10.14218%2FJCTH.2018.00060
Chen CP. Role of External Beam Radiotherapy in Hepatocellular Carcinoma. Clin Liver Dis [Internet]. 2020;24:701–17. https://linkinghub.elsevier.com/retrieve/pii/S108932612030057X
Jung I-H, Yoon SM, Kwak J, Park J-H, Song SY, Lee S-W, et al. High-dose radiotherapy is associated with better local control of bone metastasis from hepatocellular carcinoma. Oncotarget [Internet]. 2017;8:15182–92. https://www.oncotarget.com/lookup/doi/https://doi.org/10.18632/oncotarget.14858
Yoo GS, Yu J Il, Park HC. Proton therapy for hepatocellular carcinoma: Current knowledges and future perspectives. World J Gastroenterol [Internet]. 2018;24:3090–100. http://www.wjgnet.com/1007-9327/full/v24/i28/3090.htm
Kim TH, Park J-W, Kim BH, Kim H, Moon SH, Kim SS, et al. Does Risk-Adapted Proton Beam Therapy Have a Role as a Complementary or Alternative Therapeutic Option for Hepatocellular Carcinoma? Cancers (Basel) [Internet]. 2019;11. http://www.ncbi.nlm.nih.gov/pubmed/30781391
Hong TS, Wo JY, Yeap BY, Ben-Josef E, McDonnell EI, Blaszkowsky LS, et al. Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Clin Oncol [Internet]. 2016;34:460–8. https://ascopubs.org/doi/https://doi.org/10.1200/JCO.2015.64.2710
Mizumoto M, Oshiro Y, Okumura T, Fukumitsu N, Numajiri H, Ohnishi K, et al. Proton beam therapy for hepatocellular carcinoma: a review of the university of tsukuba experience. Int J Part Ther. 2016;2:570–8.
Yeung RH, Chapman TR, Bowen SR, Apisarnthanarax S. Proton beam therapy for hepatocellular carcinoma. Expert Rev Anticancer Ther [Internet]. 2017;17:911–24. https://www.tandfonline.com/doi/full/https://doi.org/10.1080/14737140.2017.1368392
Wang L, Lu JJ, Yin W, Lang J. Perspectives on Patient Access to Radiation Oncology Facilities and Services in Mainland China. Semin Radiat Oncol [Internet]. 2017;27:164–8. https://linkinghub.elsevier.com/retrieve/pii/S1053429616300674
Munshi A, Ganesh T, Mohanti B. Radiotherapy in India: History, current scenario and proposed solutions. Indian J Cancer [Internet]. 2019;56:359. http://www.indianjcancer.com/text.asp?2019/56/4/359/268964
Kumar A, Acharya SK, Singh SP, Arora A, Dhiman RK, Aggarwal R, et al. 2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations. J Clin Exp Hepatol [Internet]. 2020;10:43–80. https://linkinghub.elsevier.com/retrieve/pii/S0973688319302403
Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology [Internet]. 2018;67:358–80. http://doi.wiley.com/https://doi.org/10.1002/hep.29086
Facciorusso A, Serviddio G, Muscatiello N. Transarterial radioembolization vs chemoembolization for hepatocarcinoma patients: A systematic review and meta-analysis. World J Hepatol [Internet]. 2016;8:770. http://www.wjgnet.com/1948-5182/full/v8/i18/770.htm
Titano J, Noor A, Kim E. Transarterial Chemoembolization and Radioembolization across Barcelona Clinic Liver Cancer Stages. Semin Intervent Radiol [Internet]. 2017;34:109–15. http://www.thieme-connect.de/DOI/DOI?https://doi.org/10.1055/s-0037-1602709
Raoul JI, Bretagne JF, Caucanas JP, Pariente EA, Boyer J, Paris JC, et al. Internal radiation therapy for hepatocellular carcinoma. Results of a french multicenter phase II trial of transarterial injection of iodine 131-labeled lipiodol. Cancer [Internet]. 1992;69:346–52. https://onlinelibrary.wiley.com/doi/https://doi.org/10.1002/1097-0142(19920115)69:2%3C346::AID-CNCR2820690212%3E3.0.CO;2-E
Boucher E, Garin E, Guylligomarc’h A, Olivié D, Boudjema K, Raoul J-L. Intra-arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma. Radiother Oncol [Internet]. 2007;82:76–82. https://linkinghub.elsevier.com/retrieve/pii/S0167814006005925
Lau WY, Lai ECH, Leung TWT, Yu SCH. Adjuvant Intra-arterial Iodine-131-labeled Lipiodol for Resectable Hepatocellular Carcinoma. Ann Surg [Internet]. 2008;247:43–8. https://journals.lww.com/00000658-200801000-00009
Memon K, Lewandowski RJ, Kulik L, Riaz A, Mulcahy MF, Salem R. Radioembolization for Primary and Metastatic Liver Cancer. Semin Radiat Oncol [Internet]. 2011;21:294–302. https://linkinghub.elsevier.com/retrieve/pii/S1053429611000464
Mukherjee A, Subramanian S, Ambade R, Avhad B, Dash A, Korde A. Development of semiautomated module for preparation of 131I labeled lipiodol for liver cancer therapy. Cancer Biother Radiopharm. 2017;32:33–7.
Giammarile F, Bodei L, Chiesa C, Flux G, Forrer F, Kraeber-Bodere F, et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. Eur J Nucl Med Mol Imaging [Internet]. 2011;38:1393–406. http://springer.longhoe.net/https://doi.org/10.1007/s00259-011-1812-2
Silberstein EB, Alavi A, Balon HR, Clarke SEM, Divgi C, Gelfand MJ, et al. The SNMMI Practice Guideline for Therapy of Thyroid Disease with 131I 3.0. J Nucl Med [Internet]. 2012;53:1633–51. http://jnm.snmjournals.org/cgi/doi/https://doi.org/10.2967/jnumed.112.105148
Ravichandran R, Binukumar J, Sreeram R, Arunkumar L. An overview of radioactive waste disposal procedures of a nuclear medicine department. J Med Phys [Internet]. 2011;36:95. http://www.jmp.org.in/text.asp?2011/36/2/95/79692
Kumar A, Srivastava DN, Chau TTM, Long HD, Bal C, Chandra P, et al. Inoperable Hepatocellular Carcinoma: Transarterial 188 Re HDD–Labeled Iodized Oil for Treatment—Prospective Multicenter Clinical Trial. Radiology [Internet]. 2007;243:509–19. http://pubs.rsna.org/doi/https://doi.org/10.1148/radiol.2432051246
Padhy AK, Dondi M. A Report on the Implementation Aspects of the International Atomic Energy Agency’s First Doctoral Coordinated Research Project, “Management of Liver Cancer Using Radionuclide Methods With Special Emphasis on Trans-Arterial Radio-Conjugate Therapy and Inte. Semin Nucl Med [Internet]. 2008;38:S5–12. https://linkinghub.elsevier.com/retrieve/pii/S0001299807001183
Lambert B, Bacher K, Defreyne L, Gemmel F, Van Vlierberghe H, Jeong JM, et al. 188Re-HDD/lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial. J Nucl Med [Internet]. 2005;46:60–6. http://www.ncbi.nlm.nih.gov/pubmed/15632035
Shinto AS, Karuppusamy KK, Kurup RER, Pandiyan A, Jayaraj A V. Empirical 188Re-HDD/lipiodol intra-arterial therapy based on tumor volume, in patients with solitary inoperable hepatocellular carcinoma. Nucl Med Commun [Internet]. 2020;Publish Ah. https://journals.lww.com/https://doi.org/10.1097/MNM.0000000000001296
Esquinas PL, Shinto A, Kamaleshwaran KK, Joseph J, Celler A. Biodistribution, pharmacokinetics, and organ-level dosimetry for 188Re-AHDD-Lipiodol radioembolization based on quantitative post-treatment SPECT/CT scans. EJNMMI Phys [Internet]. 2018;5:30. https://ejnmmiphys.springeropen.com/articles/https://doi.org/10.1186/s40658-018-0227-6
Delaunay K, Edeline J, Rolland Y, Lepareur N, Laffont S, Palard X, et al. Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization. Eur J Nucl Med Mol Imaging [Internet]. 2019;46:1506–17. http://springer.longhoe.net/https://doi.org/10.1007/s00259-019-04277-9
Uccelli L, Pasquali M, Boschi A, Giganti M, Duatti A. Automated preparation of Re-188 lipiodol for the treatment of hepatocellular carcinoma. Nucl Med Biol [Internet]. 2011;38:207–13. https://linkinghub.elsevier.com/retrieve/pii/S096980511000418X
Lepareur N, Ardisson V, Noiret N, Boucher E, Raoul J-L, Clément B, et al. Automation of labelling of Lipiodol with high-activity generator-produced 188Re. Appl Radiat Isot [Internet]. 2011;69:426–30. https://linkinghub.elsevier.com/retrieve/pii/S096980431000429X
Mallia MB, Chirayil V, Dash A. Improved freeze-dried kit for the preparation of 188 ReN-DEDC/lipiodol for the therapy of unresectable hepatocellular carcinoma. Appl Radiat Isot [Internet]. 2018;137:147–53. https://linkinghub.elsevier.com/retrieve/pii/S0969804317312290
Bal CS, Kumar A. Radionuclide therapy for hepatocellular carcinoma: indication, cost and efficacy. Trop Gastroenterol [Internet]. 2008;29:62–70. http://www.ncbi.nlm.nih.gov/pubmed/18972764
Chakravarty R, Dash A, Kothari K, Pillai MRA, Venkatesh M. A novel 188W/188Re electrochemical generator with potential for medical applications. Radiochim Acta [Internet]. 2009;97. https://www.degruyter.com/document/doi/https://doi.org/10.1524/ract.2009.1612/html
Chakravarty R, Dash A. Nano Structured Metal Oxides as Potential Sorbents for 188 W/188 Re Generator: A Comparative Study. Sep Sci Technol [Internet]. 2013;48:607–16. http://www.tandfonline.com/doi/abs/https://doi.org/10.1080/01496395.2012.713433
Lee EW, Alanis L, Cho S-K, Saab S. Yttrium-90 Selective Internal Radiation Therapy with Glass Microspheres for Hepatocellular Carcinoma: Current and Updated Literature Review. Korean J Radiol [Internet]. 2016;17:472. https://www.kjronline.org/DOIx.php?id=https://doi.org/10.3348/kjr.2016.17.4.472
Mantravadi R V, Spigos DG, Tan WS, Felix EL. Intraarterial yttrium 90 in the treatment of hepatic malignancy. Radiology [Internet]. 1982;142:783–6. http://pubs.rsna.org/doi/https://doi.org/10.1148/radiology.142.3.7063703
Kallini JR, Gabr A, Salem R, Lewandowski RJ. Transarterial Radioembolization with Yttrium-90 for the Treatment of Hepatocellular Carcinoma. Adv Ther [Internet]. 2016;33:699–714. http://springer.longhoe.net/https://doi.org/10.1007/s12325-016-0324-7
Hsieh T-C, Wu Y-C, Sun S-S, Yen K-Y, Kao C-H. Treating hepatocellular carcinoma with 90Y-bearing microspheres: a review. BioMedicine [Internet]. 2016;6:19. http://www.globalsciencejournals.com/article/https://doi.org/10.7603/s40681-016-0019-z
Elsayed M, Cheng B, **ng M, Sethi I, Brandon D, Schuster DM, et al. Comparison of Tc-99m MAA Planar Versus SPECT/CT Imaging for Lung Shunt Fraction Evaluation Prior to Y-90 Radioembolization: Are We Overestimating Lung Shunt Fraction? Cardiovasc Intervent Radiol [Internet]. 2021;44:254–60. http://springer.longhoe.net/https://doi.org/10.1007/s00270-020-02638-8
Lewandowski R, Salem R. Yttrium-90 Radioembolization of Hepatocellular Carcinoma and Metastatic Disease to the Liver. Semin Intervent Radiol [Internet]. 2006;23:064–72. http://www.thieme-connect.de/DOI/DOI?https://doi.org/10.1055/s-2006-939842
Lau WY, Ho S, Leung TWT, Chan M, Ho R, Johnson PJ, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol [Internet]. 1998;40:583–92. https://linkinghub.elsevier.com/retrieve/pii/S0360301697008183
Jia Z, Jiang G, Tian F, Zhu C, Qin X. A systematic review on the safety and effectiveness of yttrium-90 radioembolization for hepatocellular carcinoma with portal vein tumor thrombosis. Saudi J Gastroenterol [Internet]. 2016;22:353. http://www.saudijgastro.com/text.asp?2016/22/5/353/191139
Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux G-P, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol [Internet]. 2017;18:1624–36. https://linkinghub.elsevier.com/retrieve/pii/S1470204517306836
Sangro B, Salem R. Transarterial Chemoembolization and Radioembolization. Semin Liver Dis [Internet]. 2014;34:435–43. http://www.thieme-connect.de/DOI/DOI?https://doi.org/10.1055/s-0034-1394142
Oladeru OT, Miccio JA, Yang J, Xue Y, Ryu S, Stessin AM. Conformal external beam radiation or selective internal radiation therapy—a comparison of treatment outcomes for hepatocellular carcinoma. J Gastrointest Oncol [Internet]. 2016;7:433–40. http://jgo.amegroups.com/article/view/5670/6594
Manas D, Bell JK, Mealing S, Davies H, Baker H, Holmes H, et al. The cost-effectiveness of TheraSphere in patients with hepatocellular carcinoma who are eligible for transarterial embolization. Eur J Surg Oncol [Internet]. 2021;47:401–8. https://linkinghub.elsevier.com/retrieve/pii/S0748798320307198
Hirsch RD, Mills C, Sawhney R, Sood S, Bird V, Mishra G, et al. SIRT Compared with DEB-TACE for Hepatocellular Carcinoma: a Real-world Study (the SITAR Study). J Gastrointest Cancer [Internet]. 2020. http://springer.longhoe.net/https://doi.org/10.1007/s12029-020-00502-z
Subramanian S, Pandey U, Chaudhari P, Tyagi M, Gupta S, Singh G, et al. Preliminary evaluation of indigenous 90Y-labelled microspheres for therapy of hepatocellular carcinoma. Indian J Med Res Suppl. 2016;143.
Reinders MTM, Smits MLJ, van Roekel C, Braat AJAT. Holmium-166 Microsphere Radioembolization of Hepatic Malignancies. Semin Nucl Med [Internet]. 2019;49:237–43. https://linkinghub.elsevier.com/retrieve/pii/S0001299819300157
Kim JK, Han K-H, Lee JT, Paik YH, Ahn SH, Lee JD, et al. Long-term Clinical Outcome of Phase IIb Clinical Trial of Percutaneous Injection with Holmium-166/Chitosan Complex (Milican) for the Treatment of Small Hepatocellular Carcinoma. Clin Cancer Res [Internet]. 2006;12:543–8. http://clincancerres.aacrjournals.org/lookup/doi/https://doi.org/10.1158/1078-0432.CCR-05-1730
Sohn JH, Choi HJ, Lee JT, Lee JD, Kim JH, Moon YM, et al. Phase II Study of Transarterial Holmium-166-Chitosan Complex Treatment in Patients with a Single, Large Hepatocellular Carcinoma. Oncology [Internet]. 2009;76:1–9. https://www.karger.com/Article/FullText/173735
Lohar S, Jadhav S, Chakravarty R, Chakraborty S, Sarma HD, Dash A. A kit based methodology for convenient formulation of 166Ho-Chitosan complex for treatment of liver cancer. Appl Radiat Isot [Internet]. 2020;161:109161. https://linkinghub.elsevier.com/retrieve/pii/S0969804320302906
Yoon SM, Ryoo B-Y, Lee SJ, Kim JH, Shin JH, An JH, et al. Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion. JAMA Oncol [Internet]. 2018;4:661. http://oncology.jamanetwork.com/article.aspx?doi=https://doi.org/10.1001/jamaoncol.2017.5847
Wang S, Wang A, Lin J, **e Y, Wu L, Huang H, et al. Brain metastases from hepatocellular carcinoma: recent advances and future avenues. Oncotarget [Internet]. 2017;8:25814–29. https://www.oncotarget.com/lookup/doi/https://doi.org/10.18632/oncotarget.15730
Acknowledgements
The authors express their gratitude to P.K. Pujari, Director, Radiochemistry and Isotope Group, and Head Radiopharmaceuticals Division, Bhabha Atomic Research Centre, for providing the necessary encouragement towards the execution of this manuscript.
Funding
No specific funding or sponsorship was received for the writing or publication of this manuscript.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
Suresh Subramanian: basic concept and structure of the manuscript, literature survey and contributions for multiple sections including the introduction and modalities of screening, staging and therapy of HCC, manuscript writing and proofing. Madhava B. Mallia: structure of the manuscript, literature survey and contributions for section on SIRT therapies of HCC, manuscript writing and proofing. Ajit S. Shinto: Contributions for section on SIRT therapies of HCC and related clinical recommendations and proofing. Ashwathy S. Mathew: Contribution to the section on external beam radiation therapy and related clinical recommendations, manuscript writing and proofing.
Compliance with Ethics Guidelines
This article is a review based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Disclosures
Suresh Subramanian, Madhava B. Mallia, Ajit S. Shinto and Ashwathy S. Mathew declare that they have no personal, financial, commercial or academic conflicts of interest related to the submitted manuscript.
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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Subramanian, S., Mallia, M.B., Shinto, A.S. et al. Clinical Management of Liver Cancer in India and Other Develo** Nations: A Focus on Radiation Based Strategies. Oncol Ther 9, 273–295 (2021). https://doi.org/10.1007/s40487-021-00154-4
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DOI: https://doi.org/10.1007/s40487-021-00154-4