Targeted Radionuclide Therapy
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Targeted radionuclide therapy Targeted radionuclide therapy has the potential to selectively deliver radiation to diseased cells with minimal toxicity to surrounding tissues. M Sathekge, MB ChB, MMed (Nuclear Medicine), PhD Department of Nuclear Medicine, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa Corresponding author: M Sathekge ([email protected]) e goal of targeted radionuclide therapy is to selectively deliver radiation of the pathology and theranostic targets is beyond the scope of this to cancer cells and/or diseased tissue with minimal toxicity to surrounding article, and the reader is referred to reviews in related subjects. normal tissues. e basis for successful radionuclide therapy is a theranostic approach that integrates diagnostic testing for the presence of a molecular target for which a specic treatment/drug is intended (Fig. 1). eranostics Theranostics is a revolutionary is a revolutionary approach that promises improved therapy selection on the basis of specic molecular features of disease, greater predictive approach that promises improved power for adverse eects due to improved patient-specic absorbed dose therapy selection on the basis of estimates, and new ways to objectively monitor therapy response.[1,2] specic molecular features of disease, Currently, radionuclide therapy remains an important treatment option because ionising radiation from radionuclides can kill cells and inhibit greater predictive power for adverse growth in the benign and cancerous lesions that result from proliferative eects due to improved patient- diseases. Radiation kills cells by damaging the DNA in the cell nucleus, specic absorbed dose estimates, thereby inhibiting cellular reproduction. Rapidly developing studies also demonstrate the benecial eect of combining radionuclide therapy with and new ways to objectively monitor chemotherapy.[1] therapy response. e objective of this article is to introduce the reader to the benets of targeted radiotherapy, also known as molecular theranostics, to Targeting mechanism/radiopharmaceuticals improve patient management. e article highlights evidence-based e process of tailoring therapy for a patient is based on selecting radionuclide therapy, which is available in South Africa for thyroid appropriate radiopharmaceuticals and mechanisms. e commonly cancer, neuro-endocrine tumours, liver tumours (primary and employed radiopharmaceuticals and mechanisms are summarised in secondary), non-Hodgkin’s lymphoma, and bone metastases, and Table 1. Common examples of patient selection criteria for targeted for treating other non-cancerous diseases. A comprehensive review radionuclide therapy are shown in Table 2.[3] Table 1. Available radionuclide therapy in oncology Physical half-life Maximum Targeting Radionuclide (days) Emission range (mm) Radiopharmaceutical mechanism Indications I-131 8.04 Beta, gamma 4 I-131 as iodide yroid hormone Dierentiated thyroid synthesis cancer Lu-177 6.7 Beta, gamma 1 Lu-177 DOTATATE Somatostatin- Neuro-endocrine receptor binding tumours Y-90 2.7 Beta 12 Y-90 DOTATATE Somatostatin- Neuro-endocrine receptor binding tumours Y-90 2.7 Beta 12 Y-90 microspheres, Intravascular Liver metastases SIR-Spheres or trapping Hepatocellular eraSpheres carcinoma Y-90 2.7 Beta 12 Y-90 ibritumomab CD20 antigen Non-Hodgkin’s tiuxetan (Zevalin) binding lymphoma I-131 8.04 Beta, gamma 4 I-131 tositumomab CD20 antigen Non-Hodgkin’s (Bexxar) binding lymphoma I-131 8.04 Beta, gamma 4 I-131 MIBG Active transport and intracellular storage Sm-153 1.95 Beta, gamma 3.1 Sm-153 EDTMP Chemo-adsorption Bone pain palliation Sr-89 50.5 Beta 8 Sr-89 chloride Calcium analogue Bone pain palliation MIBG = meta-iodobenzylguanidine; EDTMP = ethylene-diamine-tetramethylene-phosphonic acid. 289 CME August 2013 Vol. 31 No. 8 Targeted radionuclide therapy Table 2. Common examples of patient selection criteria for targeted radionuclide therapy Minimum haematological and Indications biochemical criteria Contraindications Inoperable/failed conventional therapy Hb >10 g/l Pregnancy/lactation Good performance status: self-caring WCC >3x109/l Inability to comply with Con rmed histology Platelets >100x109/l radiation protection instructions Positive uptake on a diagnostic scintiscan Urea <10 mmol/l Short life expectancy Stop/suspend interfering treatment/drugs Creatinine <160 µmol/l Renal failure GFR >40 ml/min Liver failure Biochemical tumour marker Radioactive iodine therapy: Thyroid To achieve these bene ts, theranostics of better, with positron emisssion tomography/ cancer thyroid cancer is performed using I-123 or computed tomography (PET/CT) using Ga- e therapeutic use of iodine-131 (I-131) is a I-131 for diagnostics, with single photon 68-DOTATATE, is an important tool for well-established procedure that supplements emission computed tomography/computed predicting the e cacy of PRRNT, and also surgery in differentiated thyroid cancer tomography (SPECT/CT) (Fig. 2), and I-131 for the assessment of the response to PRRNT (follicular and papillary).[4] e bene ts of for personalised radionuclide therapy.[5,6] (Fig. 1). PRRNT is not useful for the treatment I-131 therapy include: Long-term follow-up con rms that patients of G3 (poorly di erentiated) tumours. ese • facilitating the interpretation of subsequent with I-131-avid metastases have signi cantly tumours have high expression of Ki67 and are serum thyroglobulin levels better 5- and 10-year survival rates than those uorodeoxyglucose (FDG)-PET/CT positive, • increasing the sensitivity of detection of whose metastases do not take up I-131 and but negative for a Ga-68-DOTATATE PET/ locoregional and/or metastatic disease cannot be treated this way. CT. [7] on subsequent follow-up whole-body radioactive iodine scans Accumulated evidence from clinical • maximising the therapeutic effect of The process of experience indicates that partial and complete subsequent treatments responses may be achieved in almost 50% of • allowing a post-ablation scan to help tailoring therapy for patients, and that the duration of the therapy identify additional sites of disease that a patient is based on response is more than 40 months.[8] The were not identi ed pre-ablation selecting appropriate patients’ self-assessed quality of life also • decreasing recurrence and disease- improves signi cantly a er treatment with speci c mortality for both known and radiopharmaceuticals Lu-177-DOTATATE. Lastly, compared with unknown microscopic and metastatic and mechanisms. historical controls, patients treated with Lu- disease. 177-DOTATATE show an increase in overall survival of several years from the time Peptide receptor radionuclide of diagnosis.[8] Side-e ects of PRRNT are therapy: Neuro-endocrine cancer typically seen in the kidneys. ese, however, Peptide receptor radionuclide therapy are usually few and mild provided adequate (PRRNT) is the treatment of choice in adult protective measures such as amino acid patients with neuro-endocrine cancer who infusion are undertaken.[3] are inoperable, who have residual disease following surgery or other ablative therapy, Selective internal radiation or who have metastases. PRRNT is based therapy: Liver cancer (primary and on the fact that about 70% of these tumours secondary) express somatostatin receptors (especially Selective internal radiation therapy (SIRT) subtype 2) on the cell surface, which or trans-arterial radio-embolisation using constitutes an excellent therapeutic target.[7] In Y-90-labelled microspheres is a treatment PRRNT, a receptor ligand (i.e. a somatostatin option for patients with unresectable analogue) is bound to a radioactive isotope primary and secondary liver malignancies.[9] (normally Lu-177 or Y-90). Commonly is technique involves the intra-arterial used radiopharmaceuticals are Lu-177- injection of commercially available Y-90- DOTATATE and Y-90-DOTATATE. The labelled microspheres (SIR-Spheres and radionuclide is thereby bound to the tumour eraSpheres) via the hepatic artery or one cells by these somatostatin analogues, which of its side branches. Liver metastases are decay, with the resulting radiation damaging primarily fed via the hepatic artery, whereas the surrounding cells.[7,8] normal liver tissue is fed primarily via the portal vein. Up to 3 times more hepatic Positive somatostatin receptor scintigraphy arterial vessels surround liver tumours with In-111 or Tc-99m-octreotide or, even than normal liver tissue.[10] erefore, a 290 CME August 2013 Vol. 31 No. 8 Targeted radionuclide therapy on perfusional ow characteristics of the targeted vascular territory, identify anatomical variants, and isolate the hepatic circulation by occluding extrahepatic vessels. A pre-treatment hepatic artery Tc- 99m macroaggregate of albumin (MAA) scan is performed to detect any extrahepatic shunting to the lung or gastrointestinal tract. Excessive shunting to the lungs that would result in a >30 Gy lung dose on a single administration excludes the patient from SIRT.[9] Given the possibility of non-target deposition of microspheres, prophylactic embolisation of all extrahepatic vessels at the time of MAA assessment is performed to avoid extrahepatic deposition of microspheres. Since these vessels/organs can revascularise quickly, SIRT is performed within 2 weeks of the initial angiographic evaluation and prophylactic embolisation. Increasing evidence confirms that early response assessment to SIRT using F-18-FDG PET/CT is superior to morphological imaging, demonstrating a correlation