Selective internal radiation therapy (SIRT), also known as transarterial radioembolization (TARE), radioembolization or intra-arterial micro

brachytherapy Brachytherapy is a form of radiation therapy where a sealed radiation, radiation source is placed inside or next to the area requiring treatment. The word "brachytherapy" comes from the Ancient Greek, Greek word , meaning "short-distance" or "s ...

is a form of radionuclide therapy used in

interventional radiology Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as Fluoroscopy, x-ray fluoroscopy, CT scan, computed tomography, magnetic resonance imaging, or ultraso ...

to treat

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. It is generally for selected patients with surgically unresectable cancers, especially

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

to the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. The treatment involves injecting tiny microspheres of

radioactive Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is conside ...

material into the

arteries An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

that supply the

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

, where the spheres lodge in the small vessels of the tumor. Because this treatment combines

radiotherapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle ...

with

embolization Embolization refers to the passage and lodging of an embolus within the bloodstream. It may be of natural origin ( pathological), in which sense it is also called embolism, for example a pulmonary embolism; or it may be artificially induced ...

, it is also called radioembolization. The chemotherapeutic analogue (combining

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

with embolization) is called chemoembolization, of which transcatheter arterial chemoembolization (TACE) is the usual form.

Principles

Radiation therapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a therapy, treatment using ionizing radiation, generally provided as part of treatment of cancer, cancer therapy to either kill or control the growth of malignancy, malignant cell (biology), ...

is used to kill cancer cells; however, normal cells are also damaged in the process. Currently, therapeutic doses of radiation can be targeted to tumors with great accuracy using

linear accelerator A linear particle accelerator (often shortened to linac) is a type of particle accelerator that accelerates charged subatomic particles or ions to a high speed by subjecting them to a series of oscillating electric potentials along a linear ...

s in

radiation oncology Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle a ...

; however, when irradiating using

external beam radiotherapy External beam radiation therapy (EBRT) is a form of radiotherapy that utilizes a high-energy collimated beam of ionizing radiation, from a source outside the body, to target and kill cancer cells. The radiotherapy beam is composed of particl ...

, the beam will always need to travel through healthy tissue, and the normal liver tissue is very sensitive to radiation. The radiation sensitivity of the liver parenchyma limits the radiation dose that can be delivered via external beam radiotherapy. SIRT, on the other hand, involves the direct insertion of radioactive microspheres to a region, resulting in a local and targeted deposition of radioactive dose. It is therefore well-suited for treatment of liver tumors. Due to the local deposition, SIRT is regarded as a type of locoregional therapy (LRT). The liver has a dual blood supply system; it receives blood from both the hepatic artery and the

portal vein The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approxima ...

. The healthy liver tissue is mainly perfused by the portal vein, while most liver malignancies derive their blood supply from the hepatic artery. Therefore, locoregional therapies such as transarterial chemoembolization or radioembolization, can selectively be administered in the arteries that are supplying the tumors and will preferentially lead to deposition of the particles in the tumor, while sparing the healthy liver tissue from harmful side effects. In addition, malignancies (including primary and many metastatic liver cancers) are often hypervascular; tumor blood supplies are increased compared to those of normal tissue, further leading to preferential deposition of particles in the tumors. SIRT can be performed using several techniques, including whole liver treatment, lobar or segmental approaches. Whole liver SIRT targets the entire liver in one treatment and can be used when the disease is spread throughout the liver. Radiation lobectomy targets one of the two

liver lobe The liver is a major metabolic organ exclusively found in vertebrates, which performs many essential biological functions such as detoxification of the organism, and the synthesis of various proteins and various other biochemicals necessary f ...

s and can be a good treatment option when only a single lobe is involved or when treating the whole liver in two separate treatments, one lobe at the time. The segmental approach, also called radiation

segmentectomy Segmental resection, or segmentectomy, is a surgical procedure to remove part of an organ or gland as a sub-type of resection, which might involve removing the whole body part. It may also be used to remove a tumor and the normal tissue around it ...

, is a technique where a high dose of radiation is delivered in one or two Couinaud

liver segment A liver segment is one of eight segments of the liver as described in the widely used Couinaud classification (named after Claude Couinaud) in the anatomy of the liver. This system divides the lobes of the liver into eight segments based on a ...

s only. The high dose results in eradication of the tumor while damage to healthy liver tissue is contained to the targeted segments only. This approach results in effective

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

of the targeted segments. Segmentectomy is only feasible when the tumor(s) are contained in one or two segments. Which technique is applied is determined by

catheter In medicine, a catheter ( ) is a thin tubing (material), tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. ...

placement. The more

distal Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position provi ...

ly the catheter is placed, the more localized the technique.

Therapeutic applications

Candidates for radioembolization include patients with: # Unresectable

liver cancer Liver cancer, also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy, is cancer that starts in the liver. Liver cancer can be primary in which the cancer starts in the liver, or it can be liver metastasis, or secondar ...

of primary or secondary origin, such as hepatocellular carcinoma and liver-metastases from a different origin (e.g. colorectal cancer, breast cancer, neuroendocrine cancer, cholangiocarcinoma or soft tissue sarcomas) # No response or intolerance to regional or systemic chemotherapy # No eligibility for potentially curative options such as

radiofrequency ablation Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor, sensory nerves or a dysfunctional tissue is ablated using the heat generated from medium fre ...

. SIRT is currently considered as a salvage therapy. It has been shown to be safe and effective in patients for whom surgery is not possible, and chemotherapy was not effective. Subsequently, several large

phase III trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phase ...

have been started to evaluate the efficacy of SIRT when used earlier in the treatment scheme or in combination treatments with systemic therapy. SIRT, when added to first line therapy for patients with metastases of colorectal cancer, was evaluated in the SIRFLOX, FOXFIRE and FOXFIRE Global studies. For primary liver cancer (HCC), two large trials comparing SIRT with standard of care chemotherapy, Sorafenib, have been completed, namely the SARAH and SIRveNIB trials. Results of these studies, published in 2017 and 2018, reported no superiority of SIRT over chemotherapy in terms of overall survival (SARAH, SIRveNIB, FOXFIRE). In the SIRFLOX study, better progression-free survival was also not observed. These trials did not give direct evidence supporting SIRT as a first-line treatment regime for liver cancer. However, these studies did show that SIRT is generally better tolerated than systemic therapy, with less severe adverse events. Simultaneously, for HCC, data derived from a large retrospective analysis showed promising results for SIRT as an earlier stage treatment, particularly with high dose radiation segmentectomy and lobectomy. More studies and cohort analyses are underway to evaluate subgroups of patients who benefit from SIRT as a first-line or later treatment, or to evaluate the effect of SIRT in combination with chemotherapy (EPOCH, SIR-STEP, SORAMIC, STOP HCC). For HCC patients currently ineligible for liver transplant, SIRT can sometimes be used to decreases tumor size allowing patients to be candidates for curative treatment. This is sometimes called bridging therapy. When comparing SIRT with transarterial chemoembolization (TACE), several studies have shown favorable results for SIRT, such as longer time to progression, higher complete response rates and longer progression-free survival.

Radionuclides and microspheres

There are currently three types of commercially available microsphere for SIRT. Two of these use the radionuclide

yttrium-90 Yttrium-90 () is a radioactive isotope of yttrium. Yttrium-90 has found a wide range of uses in radiation therapy to treat some forms of cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the ...

(⁹⁰Y) and are made of either

glass Glass is an amorphous (non-crystalline solid, non-crystalline) solid. Because it is often transparency and translucency, transparent and chemically inert, glass has found widespread practical, technological, and decorative use in window pane ...

( TheraSphere) or

resin A resin is a solid or highly viscous liquid that can be converted into a polymer. Resins may be biological or synthetic in origin, but are typically harvested from plants. Resins are mixtures of organic compounds, predominantly terpenes. Commo ...

( SIR-Spheres). The third type uses

holmium Holmium is a chemical element; it has symbol Ho and atomic number 67. It is a rare-earth element and the eleventh member of the lanthanide series. It is a relatively soft, silvery, fairly corrosion-resistant and malleable metal. Like many other ...

-166 (¹⁶⁶Ho) and is made of poly(l-lactic acid), PLLA, (QuiremSpheres). The therapeutic effect of all three types is based on local deposition of radiation dose by high-energy

beta particle A beta particle, also called beta ray or beta radiation (symbol β), is a high-energy, high-speed electron or positron emitted by the radioactive decay of an atomic nucleus, known as beta decay. There are two forms of beta decay, β− decay and � ...

s. All three types of microsphere are permanent implants and stay in the tissue even after radioactivity has decayed. ⁹⁰Y, a pure beta emitter, has half-life 2.6 days, or 64.1 hours. ¹⁶⁶Ho emits both beta and

gamma ray A gamma ray, also known as gamma radiation (symbol ), is a penetrating form of electromagnetic radiation arising from high energy interactions like the radioactive decay of atomic nuclei or astronomical events like solar flares. It consists o ...

s emitter, with half-life 26.8 hours. Both ⁹⁰Y and ¹⁶⁶Ho have mean tissue penetration of a few millimeters. ⁹⁰Y can be imaged using bremsstrahlung

SPECT Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...

and

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

(PET). Bremsstrahlung SPECT uses of the approximately 23000 Bremsstrahlung photons per

megabecquerel The becquerel (; symbol: Bq) is the unit of radioactivity in the International System of Units (SI). One becquerel is defined as an activity of one per second, on average, for aperiodic activity events referred to a radionuclide. For applicatio ...

that are produced by interaction of beta particles with tissue. The positrons needed for PET imaging come from a small branch of the

decay chain In nuclear science a decay chain refers to the predictable series of radioactive disintegrations undergone by the nuclei of certain unstable chemical elements. Radioactive isotopes do not usually decay directly to stable isotopes, but rather ...

( branching ratio ) that gives positrons. ⁹⁰Y's low bremsstrahlung photon and positron yield make it difficult to perform quantitative imaging. ¹⁶⁶Ho's additional gamma emission (81 KeV, 6.7%) makes ¹⁶⁶Ho microspheres quantifiable using a

gamma camera A gamma camera (γ-camera), also called a scintillation camera or Anger camera, is a device used to image gamma radiation emitting radioisotopes, a technique known as scintigraphy. The applications of scintigraphy include early drug development ...

. Holmium is also

paramagnetic Paramagnetism is a form of magnetism whereby some materials are weakly attracted by an externally applied magnetic field, and form internal, induced magnetic fields in the direction of the applied magnetic field. In contrast with this behavior, ...

, enabling visibility and quantifiability in

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

even after the radioactivity has decayed.

Regulatory approval

United States

Theraspheres (glass ⁹⁰Y microspheres) are FDA approved under a humanitarian device exemption for hepatocellular carcinoma (HCC). SIR-spheres (resin ⁹⁰Y microspheres) are FDA approved under premarket approval for colorectal metastases in combination with chemotherapy.

Europe

SIR-Spheres were CE-marked as a

medical device A medical device is any device intended to be used for medical purposes. Significant potential for hazards are inherent when using a device for medical purposes and thus medical devices must be proved safe and effective with reasonable assura ...

in 2002, for treating advanced inoperable liver tumors, and Theraspheres in 2014, for treating hepatic neoplasia. QuiremSpheres (PLLA ¹⁶⁶Ho microspheres) received their CE mark in April 2015 for treating unresectable liver tumors and are currently only available for the European market.

Procedure

⁹⁰Y microsphere treatment requires patient-individualized planning with cross-sectional imaging and arteriograms. Contrast

computed tomography A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...

and/or contrast-enhanced

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...

of the liver is required to assess tumor and normal liver volumes,

status, and extrahepatic tumor burden. Liver and kidney function tests should be performed; patients with irreversibly elevated serum bilirubin, AST and ALT are excluded, as these are markers of poor liver function. Use of

iodinated contrast Iodinated contrast is a form of water-soluble, intravenous radiocontrast agent containing iodine, which enhances the visibility of vascular structures and organs during radiography, radiographic procedures. Some pathologies, such as cancer, have p ...

should be avoided or minimized in patients with

chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

. Tumor marker levels are also evaluated. Hepatic artery technetium (99mTc) macro aggregated albumin (MAA) scan is performed to evaluate hepatopulmonary shunting (resulting from hepatopulmonary syndrome). Therapeutic radioactive particles travelling through such a shunt can result in a high absorbed radiation dose to the lungs, possibly resulting in radiation pneumonitis. Lung dose >30 gray means increased risk of such pneumonitis. Initial angiographic evaluation can include an abdominal aortogram, Superior mesenteric and Celiac arteriograms, and selective right and left liver arteriograms. These tests can show gastrointestinal vascular anatomy and flow characteristics. Extrahepatic vessels found on angiographic evaluation can be embolized, to prevent nontarget deposition of microspheres, that can lead to gastrointestinal

ulcer An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughin ...

s. Or the catheter tip can be moved more distally, past the extrahepatic vessels. Once the branch of the hepatic artery supplying the tumor is identified and the tip of the

is selectively placed within the artery, the ⁹⁰Y or ¹⁶⁶Ho microspheres are infused. If preferred, particle infusion can be alternated with contrast infusion, to check for stasis or backflow. Radiation dose absorbed, depends on microsphere distribution within the tumor vascularization. Equal distribution is necessary to ensure tumor cells are not spared due to ≈2.5mm mean tissue penetration, with maximum penetration up to 11mm for ⁹⁰Y or 8.7mm for ¹⁶⁶Ho. After treatment, for ⁹⁰Y microspheres, bremsstrahlung SPECT or PET scanning may be done within 24 hours after radioembolization to evaluate the distribution. For ¹⁶⁶Ho microspheres, quantitative SPECT or MRI can be done. Weeks after treatment,

or MRI can be done to evaluate anatomic changes. ¹⁶⁶Ho microspheres are still visible on MRI after radioactivity has decayed, because holmium is paramagnetic. FDG positron emission tomography may also be done to evaluate changes in metabolic activity.

Adverse effects

Complications include postradioembolization syndrome (PRS), hepatic complications, biliary complications, portal hypertension and

lymphopenia Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which r ...

. Complications due to extrahepatic deposition include radiation pneumonitis, gastrointestinal

ulcers An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing ...

and vascular injury. Postradioembolization syndrome (PRS) includes fatigue, nausea, vomiting, abdominal discomfort or pain, and

cachexia Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...

, occurring in 20-70% of patients. Steroids and

antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...

agents may decrease the incidence of PRS. Liver complications include

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

leading to portal hypertension, radioembolization-induced liver disease (REILD), transient elevations in liver enzymes, and fulminant liver failure. REILD is characterized by

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...

, ascites, hyperbilirubinemia and

hypoalbuminemia Hypoalbuminemia (or hypoalbuminaemia) is a medical sign in which the concentration, level of human serum albumin, albumin in the blood is low. This can be due to decreased production in the liver, increased loss in the gastrointestinal tract or ki ...

developing at least 2 weeks-4 months after SIRT, absent tumor progression or biliary obstruction. It can range from minor to fatal and is related to (over)exposure of healthy liver tissue to radiation. Biliary complications include

cholecystitis Cholecystitis is inflammation of the gallbladder. Symptoms include Right upper quadrant (abdomen), right upper abdominal pain, pain in the right shoulder, nausea, vomiting, and occasionally fever. Often gallbladder attacks (biliary colic) precede ...

and biliary strictures.

History

Investigation of

and other radioisotopes for cancer treatment began in the 1960s. Many key concepts, such as preferential blood supply and tumor vascularity, were discovered during this time. Reports of initial use of resin particles of ⁹⁰Y in humans were published in the late 1970s. In the 1980s, the safety and feasibility of resin and glass yttrium-90 microsphere therapy for liver cancer were validated in a canine model. Clinical trials of yttrium-90 applied to the liver continued throughout the late 1980s to the 1990s, establishing the safety of the therapy. More recently, larger trials and RCTs have shown safety and efficacy of ⁹⁰Y therapy for the treatment of both primary and metastatic liver malignancies. Development of holmium-166 microspheres started in the 1990s. The intention was to develop a microsphere with therapeutic radiation dose similar to ⁹⁰Y, but with better imaging properties, so that distribution of microspheres in the liver could be assessed more precisely. In the 2000s, development progressed to animal studies. ¹⁶⁶Ho microspheres for SIRT were first used in humans in 2009, which was first published in 2012. Since then, several trials have been performed showing safety and efficacy of ¹⁶⁶Ho SIRT, and more studies are ongoing.

References

External links

Phase III clinical trials of SIR-spheres

Phase III clinical trials of Therasphere
{{Radiation oncology Nuclear medicine procedures Radiation therapy procedures Interventional radiology