Handbook of Radioembolization

Physics, Biology, Nuclear Medicine, and Imaging

Alexander S. Pasciak, PhD., Yong Bradley, MD., J. Mark McKinney, MD., Alexander S. Pasciak, PhD., Yong Bradley, MD., J. Mark McKinney, MD.

• Publisher: CRC Press
• Year: 2016
• eBook ISBN:
  9781315352169
• Topic: Medicine
• Subtopic: Diagnostics Imaging

Radioembolization is a widely used treatment for non-resectable primary and secondary liver cancer. This handbook addresses the radiation biology, physics, nuclear medicine, and imaging for radioembolization using Yttrium-90 (90Y) microspheres, in addition to discussing aspects related to interventional radiology. The contents reflect on and off-label treatment indications, dose-response relationships, treatment-planning, therapy optimization, radiation safety, imaging follow-up and many other facets of this therapy necessary for both novice and advanced users alike.

PART 1

Introduction

1 Introduction to hepatic radioembolization

Andor F. Van Den Hoven, Daniel Y. Sze, and Marnix G.E.H. Lam

1

Introduction to hepatic radioembolization

ANDOR F. VAN DEN HOVEN, DANIEL Y. SZE, AND MARNIX G.E.H. LAM

1.1 General introduction

1.1.1 What is radioembolization?

1.1.2 A brief history of radioembolization

1.1.3 Indications for radioembolization

1.1.4 Comparison of radioembolization and external beam radiation therapy principles

1.2 Types of microspheres and radionuclides used

1.2.1 Yttrium-90 microspheres

1.2.2 Holmium-166 microspheres

1.3 Pretreatment workup

1.3.1 Laboratory and clinical investigations

1.3.2 Pretreatment imaging: liver CT/MRI and ¹⁸F-FDG-PET

1.3.3 Assessing the individual hepatic arterial anatomy

1.3.4 Preparatory angiography and intraprocedural imaging

1.3.5 Imaging of the scout dose distribution

1.3.6 Pretreatment activity calculations

1.4 Treatment

1.4.1 Medication and periprocedural care

1.4.2 Treatment technique

1.4.3 Catheter types and particle-fluid dynamics

1.4.4 Imaging of the therapeutic microsphere distribution

1.4.5 Dose–response relationship

1.5 Treatment-related laboratory and clinical toxicity

1.5.1 Complaints during treatment

1.5.2 Laboratory toxicity

1.6 Tumor response assessment

1.6.1 Anatomical tumor response assessment

1.6.2 Functional tumor response assessment

1.7 Conclusion

References

1.1 GENERAL INTRODUCTION

1.1.1 WHAT IS RADIOEMBOLIZATION?

Radioembolization is a therapy during which radioactive microspheres are administered through a microcatheter placed in the hepatic arterial vasculature to irradiate liver tumors from within. This therapy is based on the principle that liver tumors are almost exclusively vascularized by the hepatic artery, whereas the healthy liver tissue receives the majority of its blood supply from the portal vein. Therefore, following the administration in the hepatic artery, microspheres will be carried preferentially toward the distal arterioles in and around tumors. Clusters of microspheres are formed inside and in the periphery of tumors, where they emit high-energy β-radiation to induce cell death, while relatively sparing the healthy liver tissue (Braat et al., 2015). Radioembolization is a minimally invasive, image-guided, locoregional alternative, or adjunct to more conventional therapies such as surgery, systemic chemotherapy, and external beam radiation therapy for patients with liver-dominant malignancy. The advantages of this treatment are the targeted delivery of a very high radiation-absorbed dose to tumors, with limited systemic side effects and hepatotoxicity (Kennedy, 2014).

The efficacy and safety of radioembolization have been proven in patients with primary liver tumors such as hepatocellular carcinoma (HCC) (Hilgard et al., 2010) and intrahepatic cholangiocarcinoma (ICC) (Mouli et al., 2013), as well as in metastatic liver tumors from various primary tumors, with colorectal cancer (CRC) (Kennedy et al., 2015), breast cancer (BrC), neuroendocrine tumors (NET) (Devcic et al., 2014), and uveal melanoma (Xing et al., 2014) being the most common. Typically, radioembolization is performed as a stand-alone treatment in salvage patients with liver-dominant disease, but several clinical trials are currently evaluating its role in earlier lines of treatment and in combination with systemic therapy or other locoregional treatments such as radiofrequency ablation.

“Radioembolization” is used as an umbrella term for the treatment of liver tumors with varying disease extents ranging from a single focal subsegmental liver tumor to extensive disseminated or infiltrative disease, which can be hypo- to hypervascular in nature, situated in livers that are relatively healthy, cirrhotic, partially resected, transplanted, or heavily pretreated with systemic or intra-arterial chemotherapy. These situations pose various challenges and require other approaches with regard to safety precautions, treatment planning and dose calculation, microsphere type usage, and catheter positioning during administration. Furthermore, treatment techniques and strategies are dependent on operator experience and preferences and may differ considerably among practices.

Research continues to provide new insights into how to optimize radioembolization treatment, and new indications continue to arise. Among the latest introductions are radiation segmentectomy as a potentially curative technique to eradicate focal solitary liver tumors (Riaz et al., 2011), down-staging of unresectable disease to enable potentially curative surgical resection or transplantation (Braat et al., 2014), and radiation lobectomy to induce contralateral hypertrophy as an alternative to portal vein embolization in surgical candidates (Gaba et al., 2009; Vouche et al., 2013). Additional information on these techniques is presented in Chapter 6. Applying radioembolization principles to the treatment of solid tumors in organs other than the liver has also been provisionally explored, but falls outside the scope of this book.

1.1.2 A BRIEF HISTORY OF RADIOEMBOLIZATION

Several earlier studies and discoveries have set the backdrop for the clinical development of radioembolization as a technique to treat liver tumors. These investigations showed that large quantities of glass microspheres could be safely administered intra-arterially in animal experiments (Prinzmetal and Ornitz, 1948), that radioactive gold-covered charcoal particles administered intravenously or yttrium oxide particles administered via a pulmonary artery catheter could be used to treat lung cancer patients successfully (Muller and Rossier, 1951), and that liver tumors, even ones that reached the liver via the portal circulation, were preferentially vascularized by the hepatic artery when they exceeded about 50 μm in diameter (Bierman et al., 1951). The first report on radioembolization was published in 1960 by the American surgeon Edgar D. Grady and his colleagues, affiliated with Piedmont Hospital and Georgia Institute of Technology in Atlanta, GA, USA (Grady et al., 1960). Subsequent preclinical and clinical investigations by Kim et al. (1962), Caldarola et al. (1964), Blanchard et al. (1965a), and Ariel (1965) followed shortly thereafter. However, technical aspects such as the method to access the hepatic vasculature, the site of administration, safety precautions, size and material of the particles, and the radioactive isotope and the amount of activity to be infused still needed to be refined in the years to follow.

Experiments with New Zealand rabbits demonstrated that injection of radioactive microspheres via the hepatic artery established preferential tumor targeting, whereas injection via the portal vein did not (Blanchard et al., 1965a), which echoed early clinical results in humans (Grady, 1979). However, it proved challenging to catheterize the hepatic artery in both animals and humans. Access methods included antegrade catheterization of the celiac artery via brachial artery access, retrograde catheterization through femoral arteriotomy with the use of a balloon below the level of the celiac artery, and catheterization of the hepatic artery by accessing the gastroepiploic artery during laparotomy.

After trial and error it was learned that additional safety precautions were required, since extrahepatic deposition of radioactive microspheres (in the gastrointestinal tract or lungs) as well as too much radiation exposure of the healthy liver tissue could result in life-threatening complications (Blanchard et al., 1965b). Therefore, routine “skeletonization” (a surgical term used to describe isolation of the main vascular trunk by ligating all side branches) of the hepatic artery, as well as injection and imaging of radiolabelled albumin particles before treatment to simulate the therapeutic microsphere distribution, was advocated and eventually became standard of practice (Grady, 1979; Ariel and Padula, 1982).

Initially, glass microspheres of 50–100 µm diameter were used. Soon, however, it was recognized that smaller resin microspheres (15–30 µm) were easier to keep in suspension and would still not pass through the capillaries. After several years of experimentation with other isotopes such as Phosphorus-32 (³²P) (Caldarola et al., 1964; Grady et al., 1975), Yttrium-90 (⁹⁰Y) established its dominance. Reported benefits of ⁹⁰Y included a pure high-energy yield of tumoricidal β-radiation (max energy of 2.28 MeV), a short soft-tissue penetration (max 11 mm), and a 64-h half-life, which limited potential safety hazards for persons in close proximity to a treated patient. Early reports did, however, acknowledge the importance of imaging the posttreatment microsphere distribution and the limited possibilities inherent to the use of ⁹⁰Y (Grady et al., 1963; Ariel, 1965). The secondary bremsstrahlung γ-ray produced by β-activity could be detected with a Geiger–Muller survey meter or a scintillation crystal probe. Ariel even added Ytterbium-169 (¹⁶⁹Yb; γ-ray 52–310 keV; T_1/2 32 days) to the microspheres as a radiation source for imaging with a γ-camera (Ariel, 1965).

Determining the optimal treatment activity (pretreatment dosimetry) has been a challenge from the start (Blanchard et al., 1965b). It was already recognized that the intrahepatic microsphere distribution is highly heterogeneous after treatment, but imaging methods available at that time precluded the assessment of the tissue mass exposed to radiation. Therefore, treatment activity could not be adapted to effective tumor-absorbed dose and safe healthy liver-absorbed dose values. Instead, the required treatment activity was calculated based on a target whole liver-absorbed dose of 5000 rad (50 Gy), which had been demonstrated as a safe dose in animal experiments. Doses were prescribed based on the formula that per gram of liver tissue 1 mCi (37 MBq) would be required to deliver an absorbed dose of 182 rad (1.82 Gy) (Grady, 1979).

The first efficacy reports were case series reporting posttreatment survival and the clinical condition of patients with primary or metastatic liver cancer. These results were generally promising, and some cases showed unprecedented disease control, but these reports were written prior to the availability of computed tomography, magnetic resonance imaging, and quantitative ultrasonography. Patients with inoperable disease had no good alternatives at that time, since the effectiveness of systemic chemotherapy and external beam radiation therapy remained disappointing. In 1989, Gray et al. published the first prospective trial results on radioembolization demonstrating an objective treatment response, defined as a decline of carcinoembryonic antigen (CEA) levels after treatment in 9/10 treated patients with colorectal cancer liver metastases (Gray et al., 1989). In the next two decades, only a few prospective studies followed patients with primary liver cancer and colorectal liver metastases (Lau et al., 1994; Rosler et al., 1994; Gray et al., 2001). Among these studies was the first randomized controlled trial, which demonstrated that the addition of radioembolization to regional hepatic arterial chemotherapy (floxuridine) in salvage patients with colorectal cancer liver metastases resulted in significantly improved tumor response.

Eventually, ⁹⁰Y-microspheres received Conformité Européenne (CE) mark in the European Union and U....

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Series preface
• Preface
• Editors
• Contributors
• PART 1 INTRODUCTION
• PART 2 PATIENT SELECTION AND TREATMENT PLANNING
• PART 3 TREATING PATIENTS WITH RADIOEMBOLIZATION
• PART 4 FOLLOWING PATIENTS TREATED WITH RADIOEMBOLIZATION
• PART 5 NEW HORIZONS
• Index