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Selective Internal Radiation Therapy—Tackling the Tumor, Sparing the Organ
US Oncological Review, 2008;4(1):68-71
Primary liver cancer is the fifth most common cause of cancer in the world, with hepatocellular cancer (HCC) accounting for a large majority of cases. HCC has the highest incidence in East Asia and sub-Saharan Africa and is the fastest-growing cause of cancer-related death in the US.1 The liver is also a common site for metastases from other primary cancers, especially colorectal cancer because of portal venous drainage of the bowel. Approximately 20% of colon cancer patients are found to have stage IV disease at the time of initial diagnosis.2 In 40% of these cases metastases are confined to the liver, and most of these patients have no extra-hepatic metastases, even at the time of death.3
The only curative therapy for liver cancer is surgical removal of the tumor.4,5 Surgery may prolong survival in well-selected patients with liver metastases from colon cancer,3 although only 10–20% of patients with liver metastases are reasonable surgical candidates.4 If surgery is not possible, local ablative therapies such as radiofrequency ablation are possible for some patients with a limited number of small tumors.6 For those with liver tumors who cannot be treated surgically or with ablative therapy, the prognosis is generally poor. Systemic chemotherapy can downsize some metastases to the point of resectability,3 but primary liver tumors do not generally respond to this treatment.1 External-beam radiation is limited by the relatively poor tolerance of the normal liver to standard radiation techniques.7
The vascular supply of liver tumors offers a unique opportunity to selectively deliver therapeutic agents to liver tumors while sparing the rest of the organ. Liver tumors receive >80% of their blood supply via the hepatic artery, whereas the portal vein provides about 75% of the blood supply to the normal liver parenchyma.8 In addition, the microvascular density of liver tumors is three to 200 times greater than the surrounding liver parenchyma.9 These differences have been exploited in the development of treatments that are delivered via the hepatic artery, including transarterial chemotherapy, embolization to induce tumor ischemia, and embolization using drug-eluting microspheres or radiation-emitting microspheres.8
Two types of selective internal radiation therapy (SIRT) radiolabeled microspheres are available, one of which is made of glass (TheraSphere®, MDS Norton Inc., Canada) and the second of which is made of resin (SIRSpheres ®, Sirtex Medical Inc., Australia). Both carry 90yttrium (Y), a beta emitter with a half-life of 64.1 hours and an average energy of 0.94 megaelectron volts (MeV), which corresponds to a maximum range of 1.1cm within tissue with a mean path of 2.5mm. The two formulations differ considerably in terms of particle size and average dose of radioactivity delivered.10 In 2002, the US Food and Drug Administration (FDA) gave pre-market approval of SIR-Spheres as a brachytherapy device for the treatment of metastases from colorectal cancer. TheraSphere is approved as a humanitarian device for use in patients with unresectable HCC.8
Treatment with Sir-Spheres is considered to be the third-line option for patients with colorectal metastatic disease that is confined to the liver or with minimal extra-hepatic involvement. A few reports have suggested better long-term survival in patients with colorectal cancer when SIRT was used in conjunction with other chemotherapy.11 In most cases, patients have exhausted other treatment options and no longer respond to chemotherapy, cannot tolerate or refuse chemotherapy, or choose to receive both SIRT and chemotherapy.12
- El-Serag HB, Rudolph KL, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis, Gastroenterology, 2007;132(7): 2557–76.
- Jemal A, Siegel R,Ward E, et al., Cancer statistics, 2007, CA Cancer J Clin, 2007;57(1):43–66.
- Chong G, Cunningham D, Improving long-term outcomes for patients with liver metastases from colorectal cancer, J Clin Oncol, 2005;23(36):9063–6.
- Sasson AR, Sigurdson ER, Surgical treatment of liver metastases, Semin Oncol, 2002;29(2):107–18.
- Okuda K, Ohtsuki T, Obata H, et al., Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients, Cancer, 1985;56(4):918–28.
- Tanabe KK, Curley SA, Dodd GD, et al., Radiofrequency ablation: the experts weigh in, Cancer, 2004;100(3):641–50.
- Welsh JS, Kennedy AS, Thomadsen B, Selective Internal Radiation Therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma, Int J Radiat Oncol Biol Phys, 2006;66(Suppl. 2): S62–73.
- Kalva SP, Thabet A, Wicky S, Recent advances in transarterial therapy of primary and secondary liver malignancies, Radiographics, 2008;28(1):101–17.
- Lien WM, Ackerman NB, The blood supply of experimental liver metastases. II. A microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber, Surgery, 1970;68(2):334–40.
- Sangro B, Radioembolization – A new treatment for primary and secondary liver tumors, European Oncological Disease, 2006:36–8.
- Gray B, Van Hazel G, Hope M, et al., Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer, Ann Oncol, 2001;12(12):1711–20.
- Kennedy A, Nag S, Salem R, et al., Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium, Int J Radiat Oncol Biol Phys, 2007;68(1):13–23.
- Kennedy AS, Coldwell D, Nutting C, et al., Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience, Int J Radiat Oncol Biol Phys, 2006;65(2):412–25.
- Stubbs RS, O'Brien I, Correia MM, Selective internal radiation therapy with 90Y microspheres for colorectal liver metastases, ANZ J Surg, 2006;76(8):696–703.
- Jakobs TF, Hoffmann RT, Poepperl G, et al., Mid-term results in otherwise treatment refractory primary or secondary liver confined tumours treated with selective internal radiation therapy (SIRT) using 90Yttrium resin-microspheres, Eur Radiol, 2007;17(5): 1320–30.
- Lim L, Gibbs P, Yip D, et al., A prospective evaluation of treatment with Selective Internal Radiation Therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy, BMC Cancer, 2005;5:132.
- Murthy R, Xiong H, Nunez R, et al., Yttrium 90 resin microspheres for the treatment of unresectable colorectal hepatic metastases after failure of multiple chemotherapy regimens: preliminary results, J Vasc Interv Radiol, 2005;16(7):937–45.
- Sangro B, Bilbao JI, Boan J, et al., Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma, Int J Radiat Oncol Biol Phys, 2006;66(3):792–800.
- Szyszko T, Al-Nahhas A, Canelo R, et al., Assessment of response to treatment of unresectable liver tumours with 90Y microspheres: value of FDG PET versus computed tomography, Nucl Med Commun, 2007;28(1):15–20.
- Deng J, Miller FH, Rhee TK, et al., Diffusion-weighted MR imaging for determination of hepatocellular carcinoma response to 90Y radioembolization, J Vasc Interv Radiol, 2006;17(7):1195–1200.
- Kamel IR, Reyes DK, Liapi E, et al., Functional MR imaging assessment of tumor response after 90Y microsphere treatment in patients with unresectable hepatocellular carcinoma, J Vasc Interv Radiol, 2007;18(1 Pt 1):49–56.
- Van Hazel G, Blackwell A, Anderson J, et al., Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer, J Surg Oncol, 2004;88(2):78–85.
- Jiao LR, Szyszko T, Al-Nahhas A, et al., Clinical and imaging experience with yttrium-90 microspheres in the management of unresectable liver tumours, Eur J Surg Oncol, 2007;33(5):597–602.
- Sharma RA, Van Hazel GA, Morgan B, et al., Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy, J Clin Oncol, 2007;25(9):1099–1106.
- Rowe BP,Weiner R, Foster J, Dowsett R, 90Yttrium microspheres for nonresectable liver cancer: the University of Connecticut Health Center experience, Conn Med, 2007;71(9):523–8.