Selective internal radiation therapy

Radiation therapy 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 accelerators (see radiation oncology); however, when irradiating using external beam radiotherapy, the beam will always need to travel through healthy tissue, and the normal liver tissue is very sensitive to radiation.[1] The radiation sensitivity of the liver parenchyma limits the radiation dose that can be delivered via external beam radiotherapy. SIRT, on the other hand, results in a local and targeted deposition of radioactive dose, and 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 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.[2]

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 lobes 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, is a technique in which a high dose of radiation is delivered in one or two Couinaud liver segments 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 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 placement. The more distally the catheter is placed, the more localized the technique.[3]

Patients who are candidates for radioembolization include those with:

1) Unresectable liver cancer of primary or secondary origin, such as hepatocellular carcinoma[4] and liver-metastases from a different origin (e.g. colorectal cancer,[5] breast cancer,[6] neuroendocrine cancer,[7] or cholangiocarcinoma[8])

2) No response or intolerance to regional or systemic chemotherapy

3) No eligibility for potentially curative options such as radiofrequency ablation.[9]

SIRT is currently considered as a salvage therapy. It has been shown to be safe and effective in patients whom surgery is not possible, and chemotherapy was not effective.[4][5][10][7][8] Subsequently, several large phase III trials have been initiated 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 suffering from metastases of colorectal cancer, was evaluated in the SIRFLOX,[11] FOXFIRE[12] and FOXFIRE Global[13] studies. For primary liver cancer (HCC), two large trials comparing SIRT with standard of care chemotherapy, Sorafenib, have been completed, namely the SARAH[14] and SIRveNIB[15] trials.

Recently, the results were published, reporting no superiority of SIRT over chemotherapy in terms of overall survival (SARAH,[16] SIRveNIB,[17] FOXFIRE[18]). In the SIRFLOX study, better progression-free survival was also not observed.[19] These trials did not result in 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.[20]

More studies and cohort analyses are underway to evaluate subgroups of patients that benefit from SIRT as a first-line or later treatment option, or to evaluate the effect of SIRT in combination with chemotherapy (EPOCH,[21] SIR-STEP,[22] SORAMIC,[23] STOP HCC[24]).

For HCC patients who are currently ineligible for liver transplant, SIRT can in some cases be used to decreases tumor size allowing patients to be candidates for curative treatment. This is sometimes called bridging therapy.[25]

When comparing SIRT with transarterial chemoembolization (TACE), several studies have shown favorable results for SIRT, such as longer time to progression,[26] higher complete response rates and longer progression-free survival.[27]

There are currently three types of commercially available microspheres for SIRT. Two of these use the radionuclide yttrium-90 and are made of either glass (TheraSphere) or resin (SIR-Spheres). The third type of microsphere is based on the radionuclide holmium-166 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 radiation. All three types of microspheres are permanent implants and will remain in the tissue even after radioactivity has decayed.

The half-life of yttrium-90, a pure beta emitter, is 2.6 days, or 64.1 hours. In contrast, holmium-166 is a combined beta and gamma emitter, with a half-life of 26.8 hours. Both yttrium-90 and holmium-166 have a mean tissue penetration of a few millimeters. Yttrium-90 can be imaged using bremsstrahlung SPECT and Positron Emission Tomography (PET). Bremsstrahlung SPECT makes use of the approximately 23000 Bremsstrahlung photons per MBq that are produced by interaction of the beta particle with tissue. The required positrons for PET imaging come from a small branch of the decay produces positrons, with a branching ratio of 32×10−6.[28] The low bremsstrahlung photon and positron yield of yttrium-90 make it difficult to perform quantitative imaging.[29]

The additional gamma emission (81 KeV, 6.7%) from holmium-166 makes the holmium-166 microspheres quantifiable using a gamma-camera. In addition, the metal holmium is paramagnetic, which enables visibility and quantifiability in MRI even after the radioactivity has decayed.[30]

Glass microspheres are FDA approved under a humanitarian device exemption for hepatocellular carcinoma (HCC). Resin microspheres are FDA approved under premarket approval for colorectal metastases in combination with chemotherapy.[31] PLLA holmium-166 microspheres received CE-mark in April 2015 and are currently only available for the European market.[32]

Y-90 microsphere treatment requires patient-individualized planning with cross-sectional imaging and arteriograms.[33] Contrast computed tomography and/or contrast-enhanced magnetic resonance imaging of the liver is required to assess tumor and normal liver volumes, portal vein 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.[34] The use of iodinated contrast should be avoided or minimized in patients with chronic kidney disease. 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. A lung dose of >30 Gy indicates an increased likelihood of the adverse side effect of radiation pneumonitis.[35]

The initial angiographic evaluation can include an abdominal aortogram, Superior mesenteric and Celiac arteriograms, and selective right and left hepatic arteriograms. These studies allow for documentation of the gastrointestinal vascular anatomy and flow characteristics. Extrahepatic vessels found on angiographic evaluation can be embolized in order to prevent nontarget deposition of microspheres, that can lead to gastrointestinal ulceration. Alternatively, the catheter tip can be moved more distally, past the extrahepatic vessels.[36] Once the branch of the hepatic artery supplying the tumor is identified and the tip of the catheter is selectively placed within the artery, the yttrium-90 or holmium-166 microspheres are infused. If preferred, the particle infusion can be alternated with contrast infusion, to check for stasis or backflow. The radiation dose absorbed is dependent 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 yttrium-90[37] or 8.7mm for holmium-166.[38]

After treatment, for yttrium-90 based microspheres, bremsstrahlung SPECT or PET scanning may be performed within 24 hours after radioembolization to evaluate the distribution. For holmium-166 based microspheres, quantitative SPECT or MRI imaging can be performed. Weeks after treatment, computed tomography or MRI can performed to evaluate anatomic changes. Holmium-166 microspheres will still be visible on MRI after radioactivity has decayed due to its paramagnetic properties. Positron emission tomography may also be performed to evaluate changes in metabolic activity.

Complications include postradioembolization syndrome (PRS), hepatic complications, biliary complications, portal hypertension and lymphopenia. Complications resulting from extrahepatic deposition include radiation pneumonitis, gastrointestinal ulcers and vascular injury.[39]

Postradioembolization syndrome (PRS) includes fatigue, nausea, vomiting, abdominal discomfort or pain, and cachexia, occurring in 20-70% of patients. Steroids and anti-emetic agents may decrease the incidence of PRS.[40]

Hepatic complications include hepatic fibrosis leading to portal hypertension, radioembolization-induced liver disease (REILD), transient elevations in liver enzymes, and fulminant liver failure.[40]

Biliary complications include cholecystitis and biliary strictures.

REILD is characterized by jaundice, ascites, hyperbilirubinemia and hypoalbuminemia developing at least 2 weeks-4 months after SIRT, in the absence of tumor progression or biliary obstruction. It can range in severity from minor to fatal and is related to (over)exposure of healthy liver tissue to radiation.[40][41]

Investigations using yttrium-90 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 the initial use of resin particles of yttrium-90 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 demonstrated safety and efficacy of yttrium-90 therapy for the treatment of both primary and metastatic liver malignancies.[31][42]

Development of holmium-166 microspheres started in the 1990s. The intention was to develop a microsphere that would have a similar therapeutic radiation dose to yttrium-90, but would have better imaging properties, so that the distribution of microspheres in the liver could be assessed more precisely. In the 2000s, development progressed to animal studies. Holmium-166 microspheres for SIRT were first used in humans in 2009, which was first published in 2012.[43] Since then, several trials have been performed showing safety and efficacy of 166-holmium SIRT,[44] and more studies are ongoing.[45]

• Targeted alpha-particle therapy
• Transcatheter arterial chemoembolization

• Phase III clinical trials of SIR-spheres
• Phase III clinical trials of Therasphere