Author(s):
Sherayar Orakzai
Medical College of Georgia ’21

Ivan Dimov
University of Montreal School of Medicine ’23

Devin DeLuna
University of Nebraska Medical Center ’22

Editor(s):
Yang (John) Qiao, M.D.
PGY-2 Integrated Interventional and Diagnostic Radiology
University of Texas Health Science Center at Houston / M.D. Anderson Cancer Center

Introduction
As cross-sectional imaging became widely available in the 1970s, so did the ability to precisely-target visceral tumors in a percutaneous approach with ablative therapies.  Percutaneous ablation is a modern-day technique in oncological care which utilizes thermal or cryogenic modalities for in situ destruction of solid tumors via induction of cellular injury, ultimately leading to tumor apoptosis, necrosis, and death.  Although historically utilized when disease stage, tumor location, and/or poor patient fitness status preclude the option of surgical resection or whole organ transplantation, the choice of percutaneous ablation over surgical resection is continuously gaining ground as an equal stereotactic method when a number of factors are taken into account including tumor type, size, organ, number of tumors, and the technology available to the operator.  Today, evidence-based treatment algorithms support its use by Interventional Radiologists for a wide-array of tumor etiologies including hepatocellular carcinoma, liver metastasis, non-small cell lung cancer, and renal cell carcinoma.  In general, tumors are ablated using 3 temperature-based techniques: radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation. These modalities use percutaneous probes inserted within the tumor that heat up to temperatures above 55 C in case of RFA and MWA, or freeze below -20 to -35 C in cryoablation, which results in cell death.  This article will focus on the historical developments of these three predominant ablation modalities; address the technical aspects, challenges, and limitations of percutaneous ablation modalities in a variety of organ- and tissue-specific cancers; and provide future outlook on percutaneous ablation therapies, as well as an introduction to combination ablation therapies, and the investigational next-generation modality of percutaneous electroporation therapy.

The Development of Percutaneous Ablation Therapies- How it Happened
Although the first clinically-documented RFA for percutaneous cancer treatment was performed in 1988 within the liver, the basic technique of utilizing radiofrequency currents as a general thermogenic clinical treatment modality was first investigated over a century ago by the French Physician Jacques-Arsène d’Arsonval using high frequency electrical currents (10,000 cycles per second) in animal models.1 This technique became known as “darsonvalization” and was mostly used to remove cutaneous and mucous membrane growths.  Later on in the 1930s, American Physician Edwin Beer pioneered the ability of applying direct targeted radiofrequency waves via cystoscopy for removing urologic papillary tumors. As advanced research led to better understanding of differential organ-specific conductivities and the relationship between wavelength and heat generation, the precision of RFA therapy became further calibrated for percutaneous ablation of organ-specific malignancies.  Recent advancements, including internal electrode cooling and multi-electrode application are constantly fine-tuning its clinical efficacy.

The more recently developed percutaneous thermal ablation modality of microwave ablation (MWA) was initially studied in Japan and China in the early 2000s.2 MWA utilizes a process of dielectric hysteresis (rotating dipoles) for generating heat within an aqueous environment. The rotation of dipoles within an applied electromagnetic field generates kinetic energy, which is transferred to adjacent local tissue in the form of ablation-grade heat energy. Despite its recent emergence as an accepted percutaneous cancer ablation modality, MWA has undergone rapid advancements, notably in active antenna cooling and high-power generation technologies.

Unlike thermal ablation, cryoablation utilizes the application of subzero temperatures to facilitate local tumor destruction. Observational damage of frost-bite was first empirically-tested as a therapeutic agent in the 1800s by English Physician James Arnott.3 Using a mixed salt and ice solution, Arnott designed an apparatus for applying frost as a localized therapeutic agent for treating cancers of the breast and female cervix, demonstrating pain palliation and a decrease in overall tumor size.  Subsequently, the term “cryogen” was coined.  Shortly after in 1889, cryogens made from various liquified gasses (including oxygen, nitrogen, and hydrogen) and applied via spray or brass roller devices became used for the treatment of various skin lesions, including epitheliomas.  In 1960, modern percutaneous solid organ cryoablation became feasible with advances in trocar-based cryogenic delivery systems.4 With the initiation of cryogenic therapy using nitrogen-cooled probes for neurovascular cryosurgery of the basal ganglia in Parkinson Disease patients, cryosurgery began rapidly evolving into an inclusive modality for the treatment of various localized cancers in breast, brain, prostate, kidney, and bone lesions.3 Recent advancements include argon-based cryogen generation technologies, and the role of intraoperative ultrasound in monitoring real-time tissue cryogenesis.

Organ-Specific Applications- Choosing the Appropriate Percutaneous Ablation Modality
Tumor ablation in the liver is typically performed for hepatocellular carcinoma (HCC) and metastatic disease, but can also be used to treat benign tumors such as hemangiomas and adenomas.5 HCC is staged using the Barcelona Clinic Liver Cancer (BCLC) scale, with ablation offered in early stage disease (stage 0 or A), with curative intent equal to tumor resection or transplantation.6 In these tumors, heat-based ablation is typically preferred as it avoids the complications related to cryotherapy, including the risk for hemorrhage and cryo-shock (a term used to describe a reaction similar to disseminated intravascular coagulation caused by the release of cellular debris following cryoablation).7 Another difficulty with cryoablation is predicting coverage of tumor margins, since tissues can remain viable at the margins of the iceball where temperatures are not below -20 to -35 C. In general, RFA is used for HCC 2-3 cm in diameter, and MWA is preferred for larger tumors, multiple tumors, and for tumors located within liver parenchyma near neighboring larger vessels.5 since MWA is less susceptible to the heat-sink effect (a phenomenon in which blood flow from neighboring vessels draws out heat from the adjacent ablation zone and thereby decreases the ablative efficacy).2 However, cryoablation can sometimes be considered when treatment of lesions near important hilar structures requires close monitoring of the ablation zone, as cryogenesis allows for a more graduated control of ablation margins.

Although the current preferred treatment modality for renal cell carcinoma is partial nephrectomy, patients who are poor surgical candidates (such as those with compromised kidney function and poor fitness status) can benefit from percutaneous ablative therapy.8 Due to the kidneys’ relatively small size and proximity to other important retroperitoneal and abdominal organs, ablation in this region requires careful targeting with cross sectional imaging and the use of hydrodissection (a technique in which saline is injected adjacent to the kidney, separating it from adjacent organs such as bowel to prevent iatrogenic injury during ablation). To protect against iatrogenic collecting system damage, warm saline is sometimes preoperatively infused retrograde through the ureters, via a technique called pyeloperfusion.8 Apart from renal cell carcinoma, benign tumors such as angiomyolipoma and oncocytoma have been treated with all three modalities. Due to its greater precision and slower action of onset, cryoablation is advantageous for the treatment of larger tumors and of tumors closer to the renal pelvis. In fact, recent retrospective studies have demonstrated favorable oncologic outcomes and decreased perioperative complications of cryoablation for treating stage T1a renal cell carcinoma compared with partial nephrectomy.9 RFA is also utilized, although it is empirically less effective for targeting angioliposarcomas, where adipose tissue increases electrical impedance. MWA is preferred for exophytic tumors surrounded by a safety margin of capsular fat.

Ablation of primary and metastatic tumors in the lung presents technical challenges for all three modalities. Since RFA has produced mixed results due to the inherent impedance of air in lung tissue (which hampers the effective formation of an ablation zone), MWA is therefore the ablation-of-choice for most lung lesions due to its rapid and efficient heat production.2  For lesions closer to the chest wall or mediastinum, cryoablation is used as it is less painful and better tolerated by nerve fibers in the adjacent chest wall.

Soft tissue and bone tumors can also be effectively treated with percutaneous ablation. As an alternative to radiation therapy, both thermal and cryogenic techniques are used to treat metastatic tumors within bone, which causes prolonged and treatment-resistant pain for many patients with advanced malignancy. Cryoablation is empirically the preferred modality for effective pain management and relief for bone metastases.8 Additionally, percutaneous ablation is now also the preferred treatment for osteoid osteoma, a benign but painful tumor most often found in the long bones of children and young adults.  Here, RFA delivers an excellent cure rate with minimal treatment related morbidity, as opposed to conventional surgical curettage.

The Future of Percutaneous Ablation Therapies – Where it’s Going
The outlook for the future growth and development of percutaneous tumor ablation is positive. Recent market research estimates the global market for tumor ablation will expand from 646.4 million USD in 2020, to 2.4 billion USD in 2028. This projection is attributed to the increasing incidence of cancer from an aging population, and the benefits of minimally invasive procedures such as shorter hospital stays and greater patient comfort.10 Although conventional techniques of tumor ablation have their limitations, these same limitations will reciprocally spur innovation for further development of more effective ablation modalities.

Progress is quickly being advanced in the realm of combination ablation therapies, in which concurrent application of local therapies augment the effect of tumor ablation.  Transarterial chemoembolization in combination with radiofrequency or microwave ablation is a well-established example of combination ablation therapy.  Of particular interest is the combination of ablation with immunotherapy. Tumor ablation, and in particular cryoablation, has demonstrated an ability to generate a systemic postablative anti-tumor response against exposed tumor poly-antigens following in situ ablation, which is largely not seen following surgical resection.  A study performed utilizing murine models of mammary adenocarcinoma demonstrated resistance to growth against re-implanted mammary cancer cells in 84% of mice that underwent cryoablation of the initial in situ tumor, providing empirical evidence of long-term potentiation and the generation of an adaptive tumor-specific immune response from cryoablation. Comparatively, only 14% of mice that underwent surgical resection resisted tumor growth following re-implantation of the mammary adenocarcinoma cell line. A wide variety of immunologic targets are now under investigation for their post-ablative tumor response-enhancing potential, including CpG-oligodeoxynucleotides (Toll-Like receptor [TLR] 9 agonist), imiquimod (TLR7 agonist), anti-CD25 antibodies, and anti-PD-1 antibodies.  Each of these therapies have so far demonstrated promising effects on survival following tumor ablation, and champion the importance of continued research into the synergistic effects and identification of future combination ablation therapies.11

New ablation modalities are also on the horizon for the interventional oncologist. Although thermal energy is currently most widely used for oncologic tissue ablation, limitations from the heat sink effect for targeting lesions near large vessels have driven innovation towards forms of non-thermal ablation, such as the relatively novel irreversible electroporation (IRE).  Although the technology behind electroporation has been utilized since the 1980s for genetics and chemotherapy applications, it wasn’t until the early 2000s that IRE was studied for tissue ablation. IRE is a non-thermal ablation modality that utilizes electrical pulses to disrupt the cellular membrane integrity by puncturing hydrophilic holes within the lipid bilayer of tumor cells, which disrupts voltage-gated protein channels, and ultimately leads to a loss cellular homeostasis resulting in cell death.12  Although IRE has been shown to create some thermal energy sufficient to induce thermal coagulation in specific settings, the primary mechanism-of-action for inducing cellular apoptosis via IRE is still non-thermal.13  Freedom from the thermal heat sink effect positions IRE as a potential modality-of-choice for treating tumors in close proximity to larger vessels (such as HCC located near large hepatic or portal veins) without losing ablative efficacy.14  Additionally, cellular proteins and surrounding microvasculature within the electrolytic ablation zone is spared with IRE, which preserves tumor damage-associated molecular pattern molecules for enhancing immunogenic anti-tumor T-cell responses in the post-ablative tumor bed.15  Overall, these features of IRE could potentially expand the indications for percutaneous tumor ablation. The future of IR will likely involve integration of IRE as this modality is further studied and refined.

Lastly, future advances in new imaging and guidance technology will be crucial in facilitating and expanding the scope of tumor ablation for the Interventional Radiologist. Percutaneous tumor ablation can be hindered by the need for frequent adjustments in needle positioning within tumors situated in difficult anatomy.16 One of the most recent and significant advances in interventional radiology comes from the introduction of cone beam CT, an imaging modality which allows for intraoperative evaluation of a target-of-interest with reconstructive 3D volumetric imaging. Cone beam CT has vastly improved targeting of tumors intraoperatively, which previously depended on 2D digital subtraction angiography for localization.17 Further development of fusion imaging such as real-time US/CT-MR imaging is also enhancing visualization of tumors that would have otherwise been inconspicuous using conventional B-mode US.18 Looking further into the future, augmented-reality (AR) technology may be the next imaging modality that becomes incorporated into the IR suite. Although this technology is still being refined, it is easy to imagine how AR could provide pragmatic assistance in the IR suite from displaying 3D needle trajectories to visualizing tumor ablation margins.19 Clinical trials are currently underway for investigating the feasibility of AR for peri-operative planning and assistance in percutaneous liver ablation.20

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