Wenhui Zhou, MS4, Tufts University School of Medicine

Since the first angioplasty performed by Dr. Charles Dotter in 1964, the field of interventional radiology has evolved into a clinical discipline pioneering minimally-invasive therapies to almost every human organ and disease. The adaptation of interventional radiology procedures to target and treat cancer exemplifies a new generation of promising treatment options beyond traditional surgery, chemo- and radiation therapy. This article aims to provide an overview of interventional oncology (IO), including a brief historical perspective, and discussion of current practice and emerging technology in the interventional suite. Together these will highlight the values of IO and its potential to reshape cancer care.

 

A brief historical perspective  

Intra-arterial therapy and percutaneous ablation represent two fundamental strategies that combine advanced imaging technology and oncologic innovation for precise, minimally invasive cancer therapy. Early investigations of arterial embolization for cancer treatment was sporadically reported in the early 20th century. Doyon et al first demonstrated the application of hepatic artery embolization for treating liver tumors in the 1970s (1). Following this basic approach, later more complex embolization (e.g., lipiodol) and chemotherapeutic (e.g., doxorubicin and Y90) agents were adopted to maximize cancer cell killing (2). Similarly, non-thermal and thermal approaches to ablate tumor using imaging guidance date back to the mid-20th century. At that time, intra-tumoral injection of ethanol was at its simplest form, with early success in liver and thyroid tumors (3, 4). The advent of increasingly sophisticated technology and availability of cross-sectional imaging led to the successful adoption of many types of thermal ablation modalities (e.g., radiofrequency, cryoablation). To date, mounting clinical studies and major clinical trials (e.g., RAPTURE and PRECISION V trials) (5, 6) have demonstrated the clinical efficacy of IO treatment (examples of landmark papers is available at http://rfs.sirweb.org/service-lines/interventional-oncology-service-line). These studies have demonstrated the role of IO across a wide spectrum of disease sites (e.g., liver, lung, renal and bone) that offer cure, control, or palliative care for cancer patients.  

 

Current IO practice

 Thermal ablation  

Image-guidance for local delivery of extreme temperature are routinely utilized to destroy cancer cells. Percutaneous tumor ablation represents a well-suited alternative for patients who are poor surgical candidate. Below is a general discussion of the mechanism of action and relevant disease sites for each of the most commonly utilized thermal ablative modalities.

 Radiofrequency ablation

Radiofrequency ablation (RFA) was the first and most widely used thermal modality, utilizing high-frequency alternating current to induce frictional heating within the target tumor (a video demonstration of RFA is available at https://www.youtube.com/watch?v=OeIpYIB4qYc). This rapid heating to a temperature of 60-100ºc leads to protein denaturation, ultimately resulting in apoptosis and coagulative necrosis of tumor (7). The ideal target tumor size is less than 4 cm, with the goal to achieve 0.5 to 1.0 cm of tumor margin (8). Multiple overlapping probes may be used to create larger ablation zones to achieve complete tumor ablation. One limitation of RFA is that blood flow from adjacent vessels may lead to undesirable cooling in a phenomenon called the heat-sink effect (9, 10). As such, tumors next to large vessels may not sustain cytotoxic temperature, increasing the risk of residual disease. Nevertheless, RFA has been successfully adopted for treatment of a number of solid tumors including liver, bone and renal, representing as treatment alternative to non-surgical candidates or patients with significant comorbidities (5, 11-13). In particular, the recent prospective, multicenter RAPTURE trial featured favorable oncological and survival outcome of RFA for NSCLC non-small cell lung cancer and colorectal metastasis to the lung (5).

Cryoablation

In contrast to heat-based RFA, Cryoablation (CA) was developed to deliver extreme cold temperature to freeze the target tumors (a video demonstration of RFA is available at https://www.youtube.com/watch?v=aQteCWSpfjo). Mechanistically, argon gas expansion rapidly cools, while helium gas subsequently thaws the target tissue (14). Repetition of this freeze-thaw cycle reaches target temperatures of -20c to -40c, causing lysis and death of tumor cells (8). The ideal target tumor size is less than 4 cm; similar to RFA, multiple overlapping probes may be used to treat larger size tumor. One major advantage of CA is that real-time assessment of target tumor destruction, known as the “iceball”, can be readily visualized on imaging (15). However, CA often requires multiple probe placements which theoretically increases bleeding and other complications. In addition, multiple freeze-thaw cycle treatments inherently prolong the overall treatment time. Similar to RFA, several clinical studies have demonstrated the safety and efficacy of CA in lung, liver bone and renal malignancies (16-20). CA is considered an acceptable treatment option for in patients who are unsuitable for surgery or have significant comorbidities. 

 Microwave

Microwave ablation (MWA) represents a newer generation of ablative modality that has gained popularity over the last decade. Similar to RFA, MWA relies on high temperature to “burn” the target tumor (a video demonstration is available at https://www.youtube.com/watch?v=FxuKO2NdyC4). By contrast, MWA produces heat by rotation of water molecules by alternating electric fields from super high-speed microwaves (900 MHz to 2.45 GHz) (21). The optimal tumor size is <3 cm. Compared to RFA, MWA has the ability to deliver higher temperatures (>100c), which may be useful for tissues with higher impedance such as bone lesions (22, 23). Furthermore, MWA has other distinct advantages such as faster ablation time, better thermal conduction, and less heat-sink effect compared to RFA (8, 24, 25). Early experience has shown that MWA can achieve treatment outcomes similar to RFA and CA (21, 25-32). Given its many benefits, MWA could increasingly adopted for tumor ablation in the interventional suite. 

Intra-arterial therapy

Intra-arterial delivery of lethal chemicals or irradiating particles selective to the tumor bed has emerged as an effective loco-regional therapy, and now has become the standard-of-care for hepatocellular carcinoma (HCC) (33).  This approach relies on the dual arterial supply to the liver; the hepatic artery preferentially supplies liver lesions, while the portal vein supplies the normal liver parenchyma. As such, intra-arterial therapy delivered through branches of the hepatic artery mainly treats liver lesions in the corresponding segment, with less side-effects and normal blood flow maintained in normal liver parenchyma via the portal vein.  Below is a general discussion of the two dominant intra-arterial therapies.

 Chemoembolization

Transarterial chemoembolization (TACE) delivers embolic agent and high-dose chemotherapy into the tumor bed (a video demonstration is available at https://www.youtube.com/watch?v=2Ny4vvD81XM).In essence, the combination of embolization-induced ischemia and cytotoxic drug induced cell death aims to maximize tumor regression (34). Traditionally, conventional or bland TACE consists of a mixture of an embolic agent (e.g., gelfoam), a chemotherapy drug (e.g., doxorubicin) and a contrast agent (e.g., lipidol). Newer development of drug-eluting bead TACE (DEB-TACE) uses microsphere/bead particles coated with chemotherapy.  There is little evidence to suggest the superiority of DEB-TACE compared to conventional TACE in terms of patient survival. However, DEB-TACE has the theoretical advantages of slower, more sustained release of chemotherapy, better embolic effect, and less overall side effects (35-37). Randomized control trials have demonstrated its survival benefit for HCC, and consequently, TACE has now been widely incorporated into most clinical guidelines (33, 38, 39) . TACE is indicated as a bridge to liver transplant in early stage HCC and to downstage HCC so criteria can be met for liver transplant (40-44).

Radioembolization

Transarterial radioembolization (TARE) is a form of intra-arterial brachytherapy [also known as selective internal radiation therapy (SIRT)] by which radioactive particles (yttrium 90) are delivered to the artery branches that supply the tumor (45) (a video demonstration is available at https://www.youtube.com/watch?v=YndyQkSZl5I&list=PL3kxw2oiIxSRuiCTzHRrjBFFnU7EYxcfT). In contrast to traditional external beam radiation, TARE offers more selective radiation deposition to the tumor, sparing the normal liver parenchyma. Because of high-dose radiation particles, TARE requires pre-treatment planning for detailed mapping of the arterial anatomy and evaluation of hepatopulmonary shunting (46) (a phenomenon in which the arteriovenous shunts within the tumor may allow yttrium 90 particles to enter the systemic venous circulation via the hepatic vein). Two types of radioactive particles are available: 1) Therasphere-glass spheres and 2) SIR-sphere-resin spheres. Therasphere-glass spheres allow higher radiation dose per sphere but less embolic burden (47). It is approved by the FDA for unresectable HCC or bridge to liver transplant. SIR-sphere-resin spheres allow lower radiation dose per sphere but more embolic burden (48). It is FDA-approved for metastatic colorectal cancer to the liver. Several large studies demonstrate the survival benefits of TARE (49-60); however, there is currently lack of clear evidence to support the superiority of TARE over TACE.  

 

Emerging technology and future direction

The discussion above showcased the most common treatment modalities that offer minimally invasive and targeted locoregional therapy for cancer patients. Rapidly evolving research developments have introduced a newer generation of treatment devices, reagent and image-guidance system to expand the armamentarium of interventional oncology. For instance, irreversible electroporation (IRE) is a non-thermal modality that uses microsecond pulses of direct current to induce cell membrane damage resulting in cancer cell death by apoptosis (61). IRE has the advantage over a traditional thermal based modality because it is highly selective and minimizes collateral damage to surrounding vessels with no heat-sink effect. Early studies have shown promising results of IRE in treating pancreatic and HCC tumors near local vasculature that would otherwise preclude thermal ablation (62). Another emerging technology is high intensity focused ultrasound (HIFU) which harnesses acoustic energy to target tumor lesions without percutaneous access (63). Similarly, laser ablation and HIFU both have the potential for total non-invasiveness in which energy ablation may be safely performed transdermally. Importantly, interventional oncology offers exciting multidisciplinary collaboration as combination therapy of TACE, TARE or ablative therapies may synergize with immunotherapy, conventional chemo- or radiotherapy, and surgery (64-66). In parallel, ongoing clinical trials are investigating the benefits of interventional oncology procedures in other types of cancer, with the potential to broaden its clinical indications (67). With the evolution of new technology, interventional oncology is poised to follow an exciting path to radically reshape our ability to combat cancer.

 

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