Does Microparticle Size Affect Bland Embolization Outcomes of Local Treatment for Liver Malignancies?
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Introduction
Treatment options for primary liver tumors (i.e., hepatocellular carcinoma or HCC) and metastatic liver neoplasms have increased in the past decade in response to the incidence of these tumors; HCC is the most common primary liver cancer, while liver tumors are the sixth most common cancer and the third most common cause of cancer-related death globally.1,2 The incidence of liver cancer in the United States and Western Europe is increasing.3,4 Liver metastases from colorectal cancer (CRC) develop in 50% of patients.5
While liver resection remains the gold standard in curative local treatment, several promising local treatments have been developed in the past three decades (e.g., intra-arterial treatments, percutaneous thermal ablation, stereotactic radiotherapy, and high intensity-focused ultrasound).
There is no consensus on the best local therapy. However, intra-arterial therapies offer great promise based upon the premise that hepatic tumors are fed mainly, if not exclusively, by arteries. Using this theoretical approach, investigators have tested multiple local treatments for liver tumors, such as chemoembolization (TACE), bland embolization (TAE), intra-arterial chemotherapy (HIAC), and selective internal radiation therapy (SIRT). TACE and TAE are the most common endovascular approaches for the local treatment of liver tumors, and several embolic agents have developed for that purpose.
Two early embolic agents have proven to be less successful. Gelfoam sponge powder was one of the first embolic agents used, but the efficacy was reported to be low because it stayed only temporarily within the tumor vascular mesh. Polyvinyl-alcoholic foam (PVA) is reported to be too heterogeneous in shape and size to be effective.6,7 PVA performance of this material can be unpredictable, primarily because the particles clump and aggregate within the vessel lumen, thereby causing occlusion of larger peripheral vessels. This may allow for the development of new feeding arteries distal to the target lesion, leading to poor clinical outcomes.
In the past two decades, several spherical embolic agents have been developed, including trisacryl gelatin microspheres,8 collagen-coated microspheres,9 dextran microspheres,10 and PVA microspheres.11 The development and refinement of spherical embolic particles has dramatically increased the treatment armamentarium for liver tumors, especially HCC or “hypervascular” liver lesions.12 Spherical embolics help to reduce or avoid particle clusters within peripheral vessels and allow for a deeper penetration in the neoplasm vasculature, with permanent and effective staining. More recently, several different embolic agents were developed, some of them with promising new features such as drug elution.13,14
The question remains: What feature of spherical embolics can increase clinical outcomes? According to the literature,15 optimal microsphere calibration should allow the clinician to match the most appropriately sized microsphere to the size of the vessels to be occluded for better targeting. Moreover, the use of well-calibrated microspheres should permit better control of the extent of occlusion, which depends on the number of injected particles and the penetration of the embolic agent within the tissue.
Until now, there has been no evidence to determine the most important feature an embolic agent should have for effective local treatment. The dimension and shape of embolic particles, however, seem to be the most important characteristics for this aim.
Background
By means of injection experiments, it was shown that malignant neoplasms growing in the liver tend to acquire an exclusively arterial blood supply.16
This is mainly true for HCC in which an aberrant inner arterial network is present, defined by a surrounding capsule, and generally fed by arteries coming directly from the main branches. In patients affected by HCC who are not candidates for liver surgery or ablation, TACE and TAE are the most common approaches, with a proven improvement of survival in selected patients with well-preserved liver function.17
However, liver metastases show different vascularization compared with primary liver tumors, as well demonstrated by Breedis and Young in 1954. During an investigation of the hepatic circulation in animals, they noted ink stains within liver metastases when it was only injected via the hepatic arterial branches, compared to when it was injected via the portal vein.18 The authors observed in microscopic sections that both the portal vein and the hepatic vein, even if connected to the tumor, were invaded and/or occluded by tumor cells, preventing ink perfusion through those vessels. From the same authors, microscopic studies in humans on 13 metastatic livers16 revealed occlusion of portal branches due to the invasion by growing tumor cells, similar to what is seen in the experimental tumors. Occlusion of arterial branches by tumor invasion was never observed in experimental or human studies. They concluded that liver tumors are mainly, if not exclusively, supplied by arterial blood flow and that the occlusion of main proximal liver arteries does not result in tumor reduction, due to the presence of many peripheral connections. Much, if not all, of the failure of portal blood to supply tumors growing in the liver is due to progressive invasion and occlusion of portal branches by tumor cells. Based upon many other similar published studies, the hepatic artery has long been considered the predominant source of blood supply for colorectal liver metastases.19–22 However, targeted therapies based on arterial blood supply to the tumor have been usually disappointing. Local tumor control is rare, and the impact on survival is minimal.23,24
Discussion
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