**Minimally Invasive Therapies for Hepatocellular Carcinoma: Mechanisms of Local Control and Systemic Immunologic Response Minimally Invasive Therapies for Hepatocellular Carcinoma: Mechanisms of Local Control and Systemic Immunologic Response**

DOI: 10.5772/intechopen.72275

Andrew W. Ritchey, Joshua D. Kuban and Rahul A. Sheth Andrew W. Ritchey, Joshua D. Kuban and Rahul A. Sheth Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72275

#### **Abstract**

Minimally invasive treatments for hepatocellular carcinoma (HCC) are a cornerstone in the management of this challenging disease. For many years, percutaneously guided ablative techniques, such as radiofrequency ablation (RFA), cryoablation, and microwave ablation (MWA), have successfully treated many different solid malignancies including HCC. Since the initial implementation of these ablative techniques, there have been many advances in the design, technique, and patient selection as well as investigation into the body's response to treatment. The mechanisms of thermal-based ablative techniques, advantages and disadvantages of each technique, subsequent immunologic response following ablation, and advances in care that utilize combination therapy to potentiate the immunologic response creating a robust and long-term immunity to HCC are outlined in this chapter.

**Keywords:** hepatocellular carcinoma (HCC), immunotherapy, immunologic, response, immune, cancer, carcinoma, oncology, radiofrequency, microwave, ablation, cryoablation

### **1. Introduction**

Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States due to viral hepatitis and various forms of liver cirrhosis. HCC is resistant to traditional chemotherapy and often is not amenable to surgical resection due to factors involving the primary tumor or patient comorbidities [1, 2]. Thus, minimally invasive therapies for the treatment of malignant liver tumors have become a cornerstone of treatment. These minimally invasive techniques, including radiofrequency ablation (RFA), microwave ablation (MWA),

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and cryoablation (cryo), have been shown to have distinct advantages over traditional treatment methods. These methods are not only able to locally control the malignancy through cellular necrosis and apoptosis but also potentially trigger systemic immune responses [3–6]. Additionally, these minimally invasive techniques offer other advantages such as lower morbidity, preservation of healthy tissues, lower cost, and decreased hospitalization time relative to surgical resection [5]. In this chapter, the mechanisms, advantages, disadvantages, synergism, and immunologic responses to the techniques outlined above are discussed.

to changes in fluid permeability through destruction of the membrane actin filaments. These

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Cells in the transitional zone are heated through conductive heat transfer from tissues in the central zone. This conductive heat transfer produces a sharp temperature gradient with average lower temperatures ranging from 40 to 45°C [5]. Cells within the transitional zone experience thermal injury, but since temperatures of 50°C are not reached, these cells do not undergo immediate cellular death [9]. Rather, the cells' metabolic processes and DNA repair mechanisms are impaired, which trigger specific changes that eventually lead to apoptosis or eventual cellular recovery. Other proposed mechanisms of cellular death include ischemia from vascular damage, reperfusion injury, and cytokine release and subsequent immunologic response to the damaged cells. Due to these changes, a complete response to ablation in this region will take several days to fully develop. This region also undergoes reactive hyperemia in response to the damage. The combination of hyperemia and increased cellular susceptibility creates a favorable environment to use liposomal chemotherapeutics. Liposomal chemotherapeutics will accumulate in the region due to the hyperemia and have increased activity on the already susceptible tumor cells. Since very few of the cells in this region are completely denatured, the transitional zone plays a critical role in the immunologic response, which will

Surrounding parenchyma is not left totally unaffected by RFA. While the cells within this zone will not undergo cellular changes, necrosis, or apoptosis, there are several processes that will occur. There is an upregulation of various factors, presentation of antigens to antigenpresenting cells (APCs), and stimulation of the immune system, which will be discussed more in depth in later sections. Additionally, hyperemia occurs which can result in reperfusion

All of the above processes are dependent on a multitude of different factors such as the tumor composition, the surrounding parenchyma, the rate at which the energy is applied, and surrounding anatomic structures. The majority of the data on the effects of hyperthermia have been generated from literature on low-temperature hyperthermia that was applied uniformly

Traditionally, hepatic resection (HR) has been regarded as the first-line treatment for HCC, and RFA was typically reserved for patients with non-resectable disease. However, RFA has become a first-line treatment for early-stage HCC in patients with non-resectable disease, metastatic disease, recurrent HCC after HR, and for patients who are unable or are unwilling to undergo surgery [10]. RFA is best used in patients who have a solitary nodule <5 cm measured in the greatest dimension or less than three nodules all measuring <3 cm in the greatest dimension. RFA is most effective when treating HCC lesions that are ≤2 cm measured from the largest dimension. The reason it is more effective in these smaller lesions is that ablation margins of >4–5 mm can be easily obtained [1, 10]. Histologic and prospective studies have shown that the sensitivity of CT for detecting remnant neoplasm is anywhere between 36 and

membrane changes result in an intracellular fluid shift and subsequent cytolysis [5, 8].

be discussed in more detail [5, 6, 8].

injury [5, 6].

over longer periods.

**2.2. Patient selection**
